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Sample records for multikinase inhibitor sorafenib

  1. The multikinase inhibitor Sorafenib enhances glycolysis and synergizes with glycolysis blockade for cancer cell killing

    NARCIS (Netherlands)

    Tesori, V.; Piscaglia, A.C.; Samengo, D.; Barba, M.; Bernardini, C.; Scatena, R.; Pontoglio, A.; Castellini, L.; Spelbrink, H.; Maulucci, G.; Puglisi, M.A.; Pani, G.; Gasbarrini, A.

    2015-01-01

    Although the only effective drug against primary hepatocarcinoma, the multikinase inhibitor Sorafenib (SFB) usually fails to eradicate liver cancer. Since SFB targets mitochondria, cell metabolic reprogramming may underlie intrinsic tumor resistance. To characterize cancer cell metabolic response to

  2. The multikinase inhibitor Sorafenib displays significant antiproliferative effects and induces apoptosis via caspase 3, 7 and PARP in B- and T-lymphoblastic cells

    International Nuclear Information System (INIS)

    Schult, Catrin; Boldt, Sonja; Wolkenhauer, Olaf; Neri, Luca Maria; Freund, Mathias; Junghanss, Christian; Dahlhaus, Meike; Ruck, Sabine; Sawitzky, Mandy; Amoroso, Francesca; Lange, Sandra; Etro, Daniela; Glass, Aenne; Fuellen, Georg

    2010-01-01

    Targeted therapy approaches have been successfully introduced into the treatment of several cancers. The multikinase inhibitor Sorafenib has antitumor activity in solid tumors and its effects on acute lymphoblastic leukemia (ALL) cells are still unclear. ALL cell lines (SEM, RS4;11 and Jurkat) were treated with Sorafenib alone or in combination with cytarabine, doxorubicin or RAD001. Cell count, apoptosis and necrosis rates, cell cycle distribution, protein phosphorylation and metabolic activity were determined. Sorafenib inhibited the proliferation of ALL cells by cell cycle arrest accompanied by down-regulation of CyclinD3 and CDK4. Furthermore, Sorafenib initiated apoptosis by cleavage of caspases 3, 7 and PARP. Apoptosis and necrosis rates increased significantly with most pronounced effects after 96 h. Antiproliferative effects of Sorafenib were associated with a decreased phosphorylation of Akt (Ser473 and Thr308), FoxO3A (Thr32) and 4EBP-1 (Ser65 and Thr70) as early as 0.5 h after treatment. Synergistic effects were seen when Sorafenib was combined with other cytotoxic drugs or a mTOR inhibitor emphasizing the Sorafenib effect. Sorafenib displays significant antileukemic activity in vitro by inducing cell cycle arrest and apoptosis. Furthermore, it influences PI3K/Akt/mTOR signaling in ALL cells

  3. Design and discovery of thioether and nicotinamide containing sorafenib analogues as multikinase inhibitors targeting B-Raf, B-RafV600E and VEGFR-2.

    Science.gov (United States)

    Sun, Shaofeng; He, Zuopeng; Huang, Mindong; Wang, Ningning; He, Zongzhong; Kong, Xiangkai; Yao, Jianwen

    2018-04-03

    New sorafenib derivatives containing thioether and nicotinamide moiety were designed and synthesized as B-Raf, B-Raf V600E and VEGFR-2 multikinase inhibitors. Their in vitro enzymatic inhibitory activities against B-Raf, B-Raf V600E and VEGFR-2 and their antiproliferative activities against HCT-116 and B16BL6 cell lines were evaluated and described. Most of the compounds showed potent activities against both cell lines and specific kinases. Compounds a1, b1 and c4, which exhibited the most potent inhibitory activities against B-Raf with IC 50 of 21 nM, 27 nM and 17 nM, B-Raf V600E with IC 50 of 29 nM, 28 nM and 16 nM, VEGFR-2 with IC 50 of 84 nM, 46 nM and 63 nM, respectively, and good antiproliferative activities, also demonstrated competitive antiangiogenic activities to sorafenib in in vitro HUVEC tube formation assay. Copyright © 2018 Elsevier Ltd. All rights reserved.

  4. The role of multikinase inhibitors target therapy in radioiodine-resistant differentiated thyroid cancer

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    P O Rumyantsev

    2015-06-01

    Full Text Available About 5-15% of patients with differentiated thyroid cancer (DTC primary or within follow-up have had distant metastases or inoperable tumor mass that are resistant to radioiodine therapy as well as dramatically deteriorate survival prognosis. Other treatment modalities (radiotherapy, chemotherapy etc. also ineffective. Certain expectances are associated with target therapy with multikinase inhibitors with are selectively blocking onco-kinase molecular pathways. This review is devoted to analysis of those multikinase inhibitors which have been implemented in patients with radioiodine DTC. Comparative analysis of two most perspective multikinase inhibitors (sorafenib and lenvatinib with evaluation of efficacy and adverse effects was conducted. Both of them successfully underwent 3 rd phase of clinical trial and were recommended as treatment of choice in progressive radioiodine-resistant DTC patients.

  5. Sorafenib enhances proteasome inhibitor-mediated cytotoxicity via inhibition of unfolded protein response and keratin phosphorylation

    International Nuclear Information System (INIS)

    Honma, Yuichi; Harada, Masaru

    2013-01-01

    Hepatocellular carcinoma (HCC) is highly resistant to conventional systemic therapies and prognosis for advanced HCC patients remains poor. Recent studies of the molecular mechanisms responsible for tumor initiation and progression have identified several potential molecular targets in HCC. Sorafenib is a multi-kinase inhibitor shown to have survival benefits in advanced HCC. It acts by inhibiting the serine/threonine kinases and the receptor type tyrosine kinases. In preclinical experiments sorafenib had anti-proliferative activity in hepatoma cells and it reduced tumor angiogenesis and increased apoptosis. Here, we demonstrate for the first time that the cytotoxic mechanisms of sorafenib include its inhibitory effects on protein ubiquitination, unfolded protein response (UPR) and keratin phosphorylation in response to endoplasmic reticulum (ER) stress. Moreover, we show that combined treatment with sorafenib and proteasome inhibitors (PIs) synergistically induced a marked increase in cell death in hepatoma- and hepatocyte-derived cells. These observations may open the way to potentially interesting treatment combinations that may augment the effect of sorafenib, possibly including drugs that promote ER stress. Because sorafenib blocked the cellular defense mechanisms against hepatotoxic injury not only in hepatoma cells but also in hepatocyte-derived cells, we must be careful to avoid severe liver injury. -- Graphical abstract: Display Omitted -- Highlights: •We examined the cytotoxic mechanisms of sorafenib in hepatoma cells. •Sorafenib induces cell death via apoptotic and necrotic fashion. •Sorafenib inhibits protein ubiquitination and unfolded protein response. •Autophagy induced by sorafenib may affect its cytotoxicity. •Sorafenib inhibits keratin phosphorylation and cytoplasmic inclusion formation

  6. Sorafenib in advanced hepatocellular carcinoma

    DEFF Research Database (Denmark)

    Køstner, Anne Helene; Sørensen, M; Olesen, René Krøjgaard

    2013-01-01

    Advanced HCC is a clinical challenge with limited treatment options. The multikinase inhibitor sorafenib is the first and only agent showing a survival benefit in these patients. In this study we evaluate the efficacy and tolerability of sorafenib in an unselected patient population. Furthermore ...

  7. A rare adverse reaction of sorafenib | Wang | Libyan Journal of ...

    African Journals Online (AJOL)

    2007-10-30

    Sorafenib is a multikinase inhibitor thought to target vascular endothelial growth factor and its receptor. The European Medicines Agency (EAMA) and Food and Drug Administration (FDA) approved the use of sorafenib in late-stage hepatic cellular cancer (HCC) on October 30, 2007, and November 19, 2007, respectively.

  8. Sorafenib synergizes with metformin in NSCLC through AMPK pathway activation

    NARCIS (Netherlands)

    Groenendijk, Floris H; Mellema, Wouter W; van der Burg, Eline; Schut, Eva; Hauptmann, Michael; Horlings, Hugo M; Willems, Stefan M; van den Heuvel, Michel M; Jonkers, Jos; Smit, Egbert F; Bernards, René

    2015-01-01

    The multikinase inhibitor sorafenib is under clinical investigation for the treatment of many solid tumors, but in most cases, the molecular target responsible for the clinical effect is unknown. Furthermore, enhancing the effectiveness of sorafenib using combination strategies is a major clinical

  9. Cerebrovascular Accidents Associated with Sorafenib in Hepatocellular Carcinoma

    OpenAIRE

    Saif, Muhammad W.; Isufi, Iris; Peccerillo, Jennifer; Syrigos, Kostas N.

    2011-01-01

    Sorafenib is an oral angiogenetic multikinase inhibitor approved in the treatment of renal and hepatocellular carcinoma. Bleeding and venous thrombotic events have been described with angiogenetic agents but cerebrovascular accidents are rarely reported. We report two cases of patients with hepatocellular carcinoma who developed a cerebrovascular accident while on sorafenib. Neither patient had any risk factors for the cerebrovascular events apart from gender and age in the second patient. La...

  10. The orally available multikinase inhibitor regorafenib (BAY 73-4506) in multiple myeloma.

    Science.gov (United States)

    Breitkreutz, Iris; Podar, Klaus; Figueroa-Vazquez, Vianihuini; Wilhelm, Scott; Hayden, Patrick J; Anderson, Kenneth C; Raab, Marc S

    2018-05-01

    A promising approach to the treatment of multiple myeloma (MM) involves agents that target not only the myeloma cells directly, but also the tumor microenvironment which promotes tumor cell growth, angiogenesis, and MM bone disease. Here we investigate the orally available multikinase inhibitor, regorafenib (BAY 73-4506), for its therapeutic efficacy in MM. Regorafenib is a potent inhibitor of angiogenic (VEGFR 1-3, PDGFR-b) as well as oncogenic (c-KIT, RET, FGFR, Raf) kinases. We show that regorafenib induces apoptosis in all MM cell lines at below clinically achievable concentrations. Regorafenib overcomes the growth advantage conferred by a stroma cell MM and an endothelial cell MM, co-culture systems, and abrogates growth factor-stimulated MEK, ERK, and AKT phosphorylation at nanomolar to micromolar concentrations. Moreover, it inhibits endothelial cell growth and tubule formation, abrogates both VEGF secretion and VEGF-induced MM cell migration, inhibits osteoclastogenesis, and shows synergistic cytotoxicity with dexamethasone, the immunomodulatory drug pomalidomide, and the p110δ inhibitor idelalisib. Most importantly, regorafenib significantly delays tumor growth in a xenograft mouse model of human MM. These results provide the rationale for further clinical evaluation of regorafenib, alone and in combination, in the treatment of MM.

  11. Antitumor activity of the multikinase inhibitor regorafenib in patient-derived xenograft models of gastric cancer.

    Science.gov (United States)

    Huynh, Hung; Ong, Richard; Zopf, Dieter

    2015-10-29

    Unresectable gastric cancer is associated with poor outcomes, with few treatment options available after failure of cytotoxic chemotherapy. Clinical trials of targeted therapies have generally shown no survival benefit in gastric cancer, with the exceptions of the antibodies ramucirumab (anti-VEGFR2) and trastuzumab (anti-HER2/neu). Given the efficacy of the multikinase inhibitor regorafenib in other gastrointestinal tumors, we investigated its potential in gastric cancer. The antitumor activity of oral regorafenib was assessed in eight murine patient-derived gastric cancer xenograft models. Dose-response experiments assessed the efficacy and tolerability of oral regorafenib 5, 10, and 15 mg/kg/day in two models, with 10 mg/kg/day selected for further investigation in all eight models. Tumor weight and volume was monitored during treatment; tumor cell proliferation, angiogenesis, apoptosis, and intracellular signaling were assessed using immunohistochemistry and Western blotting of total tumor lysates at the end of treatment. Regorafenib showed dose-dependent inhibition of tumor growth and was well tolerated, with no significant decreases in bodyweight or evident toxicity. Regorafenib 10 mg/kg/day significantly inhibited tumor growth in all eight models (72 to 96 %; all p Regorafenib reduced tumor angiogenesis 3- to 11-fold versus controls in all models (all p Regorafenib was effective in patient-derived models of gastric cancer of different histological subtypes, with inhibition of tumor growth, angiogenesis, and tumor-cell proliferation observed in almost all models. These findings are consistent with the observed activity of regorafenib in preclinical models of other gastrointestinal tumors, and support further clinical investigation in gastric cancer.

  12. Efficacy of a protocol including heparin ointment for treatment of multikinase inhibitor-induced hand-foot skin reactions.

    Science.gov (United States)

    Li, Jian-ri; Yang, Chi-rei; Cheng, Chen-li; Ho, Hao-chung; Chiu, Kun-yuan; Su, Chung-Kuang; Chen, Wen-Ming; Wang, Shian-Shiang; Chen, Chuan-Shu; Yang, Cheng-Kuang; Ou, Yen-chuan

    2013-03-01

    The purpose of this study is to evaluate the efficacy of a protocol including topical heparin therapy for hand-foot skin reactions (HFSR) during multikinase (MKI) treatment. We prospectively collected 26 patients who had HFSRs during treatment with the MKIs, sunitinib, sorafenib, or axitinib. The age distribution ranged from 46 to 87 years, with a mean of 66 years. The distribution of HFSR severity was 12 patients with grade 1, 12 with grade 2, and 2 with grade 3. A heparin-containing topical ointment treatment, combined with hand-foot shock absorbers and skin moisturizers, was used at the lesion sites. Changes in the grade of HFSR, MKI dosage, and interruptions of MKI therapy were recorded. The results showed that 66.7% of grade 1 patients were cured of disease, 83.3% of grade 2 patients had improved symptoms, and both grade 3 patients (100%) had improved symptoms and were downgraded to grade 2. Four (15.4%) patients required reduction of MKI dosage, but there were no treatment interruptions or dropouts. Our protocol is beneficial in promoting resolution of HFSRs induced by MKIs. Further validation in large control studies should be investigated.

  13. Cerebrovascular accidents associated with sorafenib in hepatocellular carcinoma.

    Science.gov (United States)

    Saif, Muhammad W; Isufi, Iris; Peccerillo, Jennifer; Syrigos, Kostas N

    2011-01-01

    Sorafenib is an oral angiogenetic multikinase inhibitor approved in the treatment of renal and hepatocellular carcinoma. Bleeding and venous thrombotic events have been described with angiogenetic agents but cerebrovascular accidents are rarely reported. We report two cases of patients with hepatocellular carcinoma who developed a cerebrovascular accident while on sorafenib. Neither patient had any risk factors for the cerebrovascular events apart from gender and age in the second patient. Laboratory data were noncontributory. The head CT scan did not reveal acute abnormalities. No hemodynamically significant stenosis was visible in the carotid ultrasound, and the echocardiogram showed normal size of the heart chambers and normal systolic function of the left ventricle. Sorafenib was discontinued in both cases. Physicians should monitor patients receiving sorafenib for neurologic symptoms, and in the absence of other etiology, prompt discontinuation of this drug should be considered.

  14. Metronomic capecitabine in patients with hepatocellular carcinoma unresponsive to or ineligible for sorafenib treatment: report of two cases.

    Science.gov (United States)

    Marinelli, Sara; Granito, Alessandro; Piscaglia, Fabio; Renzulli, Matteo; Stagni, Angela; Bolondi, Luigi

    2013-01-01

    Sorafenib, an oral multikinase inhibitor, is the only systemic agent proven to be effective in patients with hepatocellular carcinoma (HCC). There are no approved second line systemic therapies in patients who have had disease progression on or are not eligible to sorafenib. We describe two cases of unresectable HCC that were treated with low, "metronomic" doses of capecitabine. In the first patient, capecitabine was used after sorafenib failure. In the second case, treatment with capecitabine was attempted since the patient was considered not eligible for sorafenib due to spontaneous hepatic bleeding of a large HCC lesion. Treatment was effective and well tolerated in both patients with long-lasting objective responses. Lacking established second-line therapy, metronomic capecitabine may be a valid alternative in the treatment of HCC patients who are judged not eligible for sorafenib or those having progression disease on sorafenib.

  15. Multiple Roles of Autophagy in the Sorafenib Resistance of Hepatocellular Carcinoma

    Directory of Open Access Journals (Sweden)

    Ting Sun

    2017-11-01

    Full Text Available Hepatocellular carcinoma (HCC is the second leading cause of cancer-related death worldwide, and prognosis remains unsatisfactory since the disease is often diagnosed at the advanced stages. Currently, the multikinase inhibitor sorafenib is the only drug approved for the treatment of advanced HCC. However, primary or acquired resistance to sorafenib develops, generating a roadblock in HCC therapy. Autophagy is an intracellular lysosomal pathway involved in protein and organelle degradation, with an astonishing number of connections to human disease and physiology. Current understanding of the role of autophagy in the progression of cancer and the response to cancer therapy remains controversial. Sorafenib is able to induce autophagy in HCC, but the effect of autophagy is indistinct. Some studies established that sorafenib-induced autophagy serves as a pro-survival response. However, other studies found that sorafenib-induced autophagy improves the lethality of sorafenib against HCC cells. The mechanisms underlying autophagy and sorafenib resistance remain elusive. The purpose of this review is to summarize the progress of research focused on autophagy and sorafenib resistance and to update current knowledge of how cellular autophagy impacts sorafenib sensitivity in HCC treatment.

  16. GSK-3 inhibition in vitro and in vivo enhances antitumor effect of sorafenib in renal cell carcinoma (RCC)

    Energy Technology Data Exchange (ETDEWEB)

    Kawazoe, Hisashi; Bilim, Vladimir N. [Laboratory of Molecular Oncology, Department of Urology, Yamagata University School of Medicine, Iida-nishi 2-2-2, Yamagata 990-9585 (Japan); Ugolkov, Andrey V., E-mail: ugolkov@northwestern.edu [Tumor Biology Core, Center for Developmental Therapeutics, Chemistry of Life Processes Institute, Silverman Hall B733, Northwestern University, Evanston, IL (United States); Yuuki, Kaori; Naito, Sei; Nagaoka, Akira; Kato, Tomoyuki [Laboratory of Molecular Oncology, Department of Urology, Yamagata University School of Medicine, Iida-nishi 2-2-2, Yamagata 990-9585 (Japan); Tomita, Yoshihiko, E-mail: ytomita@med.id.yamagata-u.ac.jp [Laboratory of Molecular Oncology, Department of Urology, Yamagata University School of Medicine, Iida-nishi 2-2-2, Yamagata 990-9585 (Japan)

    2012-07-06

    Highlights: Black-Right-Pointing-Pointer Sorafenib treatment upregulated GSK-3{beta} levels in RCC cells. Black-Right-Pointing-Pointer Pharmacologic inhibition of GSK-3 suppressed xenograft RCC tumor growth. Black-Right-Pointing-Pointer Inhibition of GSK-3 enhanced antitumor effect of sorafenib in vitro and in vivo. -- Abstract: Sorafenib is a multikinase inhibitor approved for the systemic treatment of renal cell carcinoma (RCC). However, sorafenib treatment has a limited effect due to acquired chemoresistance of RCC. Previously, we identified glycogen synthase kinase-3 (GSK-3) as a new therapeutic target in RCC. Here, we observed that sorafenib inhibits proliferation and survival of RCC cells. Significantly, we revealed that sorafenib enhances GSK-3 activity in RCC cells, which could be a potential mechanism of acquired chemoresistance. We found that pharmacological inhibition of GSK-3 potentiates sorafenib antitumor effect in vitro and in vivo. Our results suggest that combining GSK-3 inhibitor and sorafenib might be a potential new therapeutic approach for RCC treatment.

  17. Research advances in sorafenib combined with orthotopic liver transplantation, radiofrequency ablation, and transarterial chemoembolization in treatment of hepatocellular carcinoma

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    ZHANG Mingjuan

    2014-08-01

    Full Text Available Hepatocellular carcinoma (HCC is one of the most common malignant tumors worldwide, and traditional surgery and chemotherapy provide limited benefit. Sorafenib, a multikinase inhibitor, was proved effective for advanced HCC in phase III clinical trial, which was a breakthrough in the treatment of HCC. In recent years, the studies on sorafenib combined with other therapies in the treatment of HCC have been conducted around the world, and inspiring results have been seen. The research advances in sorafenib combined with orthotopic liver transplantation, radiofrequency ablation, and transarterial chemoembolization in the treatment of HCC are summarized. It is thought that sorafenib combined with other anticancer therapies is expected to become a new approach of targeted therapy of HCC.

  18. Synergistic growth inhibition by sorafenib and vitamin K2 in human hepatocellular carcinoma cells.

    Science.gov (United States)

    Zhang, Yafei; Zhang, Bicheng; Zhang, Anran; Zhao, Yong; Zhao, Jie; Liu, Jian; Gao, Jianfei; Fang, Dianchun; Rao, Zhiguo

    2012-09-01

    Sorafenib is an oral multikinase inhibitor that has been proven effective as a single-agent therapy in hepatocellular carcinoma, and there is a strong rationale for investigating its use in combination with other agents. Vitamin K2 is nearly non-toxic to humans and has been shown to inhibit the growth of hepatocellular carcinoma. In this study, we evaluated the effects of a combination of sorafenib and vitamin K2 on the growth of hepatocellular carcinoma cells. Flow cytometry, 3-(4,5-dimethyl-2-thiazolyl-2,5-diphenyl-2H-tetrazolium bromide) and nude mouse xenograft assays were used to examine the effects of sorafenib and vitamin K2 on the growth of hepatocellular carcinoma cells. Western blotting was used to elucidate the possible mechanisms underlying these effects. Assays for 3-(4,5-dimethyl-2-thiazolyl-2,5-diphenyl-2H-tetrazolium bromide) revealed a strong synergistic growth-inhibitory effect between sorafenib and vitamin K2. Flow cytometry showed an increase in cell cycle arrest and apoptosis after treatment with a combination of these two drugs at low concentrations. Sorafenib-mediated inhibition of extracellular signal-regulated kinase phosphorylation was promoted by vitamin K2, and downregulation of Mcl-1, which is required for sorafenib-induced apoptosis, was observed after combined treatment. Vitamin K2 also attenuated the downregulation of p21 expression induced by sorafenib, which may represent the mechanism by which vitamin K2 promotes the inhibitory effects of sorafenib on cell proliferation. Moreover, the combination of sorafenib and vitamin K2 significantly inhibited the growth of hepatocellular carcinoma xenografts in nude mice. Our results determined that combined treatment with sorafenib and vitamin K2 can work synergistically to inhibit the growth of hepatocellular carcinoma cells. This finding raises the possibility that this combined treatment strategy might be promising as a new therapy against hepatocellular carcinoma, especially for patients

  19. The multi-targeted kinase inhibitor sorafenib inhibits enterovirus 71 replication by regulating IRES-dependent translation of viral proteins.

    Science.gov (United States)

    Gao, Meng; Duan, Hao; Liu, Jing; Zhang, Hao; Wang, Xin; Zhu, Meng; Guo, Jitao; Zhao, Zhenlong; Meng, Lirong; Peng, Yihong

    2014-06-01

    The activation of ERK and p38 signal cascade in host cells has been demonstrated to be essential for picornavirus enterovirus 71 (EV71) replication and up-regulation of virus-induced cyclooxygenase-2 (COX-2)/prostaglandins E2 (PGE2) expression. The aim of this study was to examine the effects of sorafenib, a clinically approved anti-cancer multi-targeted kinase inhibitor, on the propagation and pathogenesis of EV71, with a view to its possible mechanism and potential use in the design of therapy regimes for Hand foot and mouth disease (HFMD) patients with life threatening neurological complications. In this study, non-toxic concentrations of sorafenib were shown to inhibit the yield of infectious progeny EV71 (clinical BC08 strain) by about 90% in three different cell types. A similar inhibitory effect of sorafenib was observed on the synthesis of both viral genomic RNA and the VP1 protein. Interestingly, sorafenib exerted obvious inhibition of the EV71 internal ribosomal entry site (IRES)-mediated translation, the first step in picornavirus replication, by linking it to a firefly luciferase reporter gene. Sorafenib was also able to prevent both EV71-induced CPE and the activation of ERK and p38, which contributes to up-regulation COX-2/PGE2 expression induced by the virus. Overall, this study shows that sorafenib strongly inhibits EV71 replication at least in part by regulating viral IRES-dependent translation of viral proteins, indicating a novel potential strategy for the treatment of HFMD patients with severe neurological complications. To our knowledge, this is the first report that investigates the mechanism by which sorafenib inhibits EV71 replication. Copyright © 2014 Elsevier B.V. All rights reserved.

  20. Distinct behaviour of sorafenib in experimental cachexia-inducing tumours: the role of STAT3.

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    Míriam Toledo

    Full Text Available The presence of a tumour is very often associated with wasting in the host, affecting both skeletal muscle and adipose tissue. In the present study we used sorafenib, a multi-kinase inhibitor with anti-tumour activity, in order to investigate the effects of chemotherapy on wasting. Three different experimental mouse tumour models were included: C26 colon carcinoma, B16 melanoma and Lewis lung carcinoma (LLC. The results obtained clearly show that sorafenib was effective in reducing tumour growth in LLC and B16 models, while it had no effect on C26. Interestingly, sorafenib treatment reduced the signs of muscle wasting and improved the physical activity in the LLC model and also in the C26, despite the absence of antineoplastic action in the latter. Our results discard a role for IL-6 in the action of sorafenib since the drug did not affect the levels of this cytokine. Conversely, sorafenib seems to act by influencing both STAT3 and ERK activity at muscle level, leading to reduced accumulation of Pax7 and atrogin-1. Sorafenib may interfere with muscle wasting by decreasing the activation of these signal transduction pathways.

  1. Sorafenib targets the mitochondrial electron transport chain complexes and ATP synthase to activate the PINK1-Parkin pathway and modulate cellular drug response.

    Science.gov (United States)

    Zhang, Conggang; Liu, Zeyu; Bunker, Eric; Ramirez, Adrian; Lee, Schuyler; Peng, Yinghua; Tan, Aik-Choon; Eckhardt, S Gail; Chapnick, Douglas A; Liu, Xuedong

    2017-09-08

    Sorafenib (Nexavar) is a broad-spectrum multikinase inhibitor that proves effective in treating advanced renal-cell carcinoma and liver cancer. Despite its well-characterized mechanism of action on several established cancer-related protein kinases, sorafenib causes variable responses among human tumors, although the cause for this variation is unknown. In an unbiased screening of an oncology drug library, we found that sorafenib activates recruitment of the ubiquitin E3 ligase Parkin to damaged mitochondria. We show that sorafenib inhibits the activity of both complex II/III of the electron transport chain and ATP synthase. Dual inhibition of these complexes, but not inhibition of each individual complex, stabilizes the serine-threonine protein kinase PINK1 on the mitochondrial outer membrane and activates Parkin. Unlike the protonophore carbonyl cyanide m -chlorophenylhydrazone, which activates the mitophagy response, sorafenib treatment triggers PINK1/Parkin-dependent cellular apoptosis, which is attenuated upon Bcl-2 overexpression. In summary, our results reveal a new mechanism of action for sorafenib as a mitocan and suggest that high Parkin activity levels could make tumor cells more sensitive to sorafenib's actions, providing one possible explanation why Parkin may be a tumor suppressor gene. These insights could be useful in developing new rationally designed combination therapies with sorafenib. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  2. GSK-3beta inhibition enhances sorafenib-induced apoptosis in melanoma cell lines.

    Science.gov (United States)

    Panka, David J; Cho, Daniel C; Atkins, Michael B; Mier, James W

    2008-01-11

    Glycogen synthase kinase-3beta (GSK-3beta) can participate in the induction of apoptosis or, alternatively, provide a survival signal that minimizes cellular injury. We previously demonstrated that the multikinase inhibitor sorafenib induces apoptosis in melanoma cell lines. In this report, we show that sorafenib activates GSK-3beta in multiple subcellular compartments and that this activation undermines the lethality of the drug. Pharmacologic inhibition and/or down-modulation of the kinase enhances sorafenib-induced apoptosis as determined by propidium iodide staining and by assessing the mitochondrial release of apoptosis-inducing factor and Smac/DIABLO. Conversely, the forced expression of a constitutively active form of the enzyme (GSK-3beta(S9A)) protects the cells from the apoptotic effects of the drug. This protective effect is associated with a marked increase in basal levels of Bcl-2, Bcl-x(L), and survivin and a diminution in the degree to which these anti-apoptotic proteins are down-modulated by sorafenib exposure. Sorafenib down-modulates the pro-apoptotic Bcl-2 family member Noxa in cells with high constitutive GSK-3beta activity. Pharmacologic inhibition of GSK-3beta prevents the disappearance of Noxa induced by sorafenib and enhances the down-modulation of Mcl-1. Down-modulation of Noxa largely eliminates the enhancing effect of GSK-3 inhibition on sorafenib-induced apoptosis. These data provide a strong rationale for the use of GSK-3beta inhibitors as adjuncts to sorafenib treatment and suggest that preservation of Noxa may contribute to their efficacy.

  3. State of the art of the therapeutic perspective of sorafenib against hematological malignancies.

    Science.gov (United States)

    Zauli, G; Voltan, R; Tisato, V; Secchiero, P

    2012-01-01

    The bi-aryl urea multi-kinase inhibitor Sorafenib (BAY 43-9006, Nexavar) was initially approved for the treatment of unresectable hepatocellular carcinoma and advanced renal cell carcinoma. Eleven years after its first description in PubMed, the therapeutic potential of Sorafenib has been evaluated in an increasing number of studies, mainly focused on solid tumors. More recently, the potential usefullness of Sorafenib has started to emerge also against hematological malignancies. At the molecular level, besides the RAF kinase pathway, which represents the first therapeutic target of Sorafenib, additional kinases, in particular the vascular endothelial growth factor receptor, have been identified as important targets of Sorafenib. A great interest for the potential use of Sorafenib against acute myeloid leukemia (AML) arose when it was demonstrated that a specific mutation of a kinase gene, called FMS-like tyrosin-kinase-3- internal tandem duplication (FLT-3-ITD) and occurring in more than 30% of AML, represents a molecular target of Sorafenib. However, recent phase I and II clinical studies showed that, in spite of its ability to suppress the activity of this mutated kinase, resistence to Sorafenib rapidly occurs in AML, suggesting that Sorafenib will be more effective in combined therapy than used as single drug. Another critical molecular target of Sorafenib is the anti-apoptotic protein Mcl-1. The ability of Sorafenib to rapidly shut-off Mcl-1 in virtually all the hematological malignancies investigated, including the B-chronic lymphocytic leukemia, represents a key element for its antileukemic activity as well as for therapeutic combinations based on Sorafenib. In this respect, it is of particular interest that many chemotherapeutic drugs or innovative anti-neoplastic compounds, such as recombinant TRAIL or inibitors of MDM2 protein, are either unable to down-regulate Mcl-1 or in some instances promote a paradoxical induction of Mcl-1. In this review, the

  4. Dose study of the multikinase inhibitor, LY2457546, in patients with relapsed acute myeloid leukemia to assess safety, pharmacokinetics, and pharmacodynamics

    Directory of Open Access Journals (Sweden)

    Wacheck V

    2011-05-01

    Full Text Available Volker Wacheck1, Michael Lahn2, Gemma Dickinson3, Wolfgang Füreder4, Renata Meyer4, Susanne Herndlhofer4, Thorsten Füreder1, Georg Dorfner5, Sada Pillay2, Valérie André6, Timothy P Burkholder7, Jacqueline K Akunda8, Leann Flye-Blakemore9, Dirk Van Bockstaele9, Richard F Schlenk10, Wolfgang R Sperr4, Peter Valent4,111Department of Clinical Pharmacology, Medical University of Vienna, Währinger Gürtel, Vienna, Austria; 2Early Oncology Clinical Investigation, Eli Lilly and Company, Indianapolis, IN, USA; 3Department of Pharmacokinetics, Eli Lilly and Company, Erl Wood Research Centre, Windlesham, Surrey, UK; 4Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Währinger Gürtel, Vienna, Austria; 5Eli Lilly GesmbH, Medical Department, Vienna, Austria; 6Department of Statistics, Eli Lilly and Company, Erl Wood Research Centre, Surrey, UK; 7Discovery Chemistry Research and Technology, Eli Lilly and Company, Indianapolis, IN, USA; 8Nonclinical Toxicology, Eli Lilly and Company, Indianapolis, IN, USA; 9Flow Cytometry and Cell Analysis, Esoterix Clinical Trials Services, Mechelen, Belgium; 10Universitätsklinikum Ulm, Klinik für Innere Medizin III, Ulm, Germany; 11Ludwig Boltzmann Cluster Oncology, Vienna, AustriaBackground: Acute myeloid leukemia (AML is a life-threatening malignancy with limited treatment options in chemotherapy-refractory patients. A first-in-human dose study was designed to investigate a safe and biologically effective dose range for LY2457546, a novel multikinase inhibitor, in patients with relapsed AML.Methods: In this nonrandomized, open-label, dose escalation Phase I study, LY2457546 was administered orally once a day. Safety, pharmacokinetics, changes in phosphorylation of target kinases in AML blasts, and risk of drug–drug interactions (DDI were assessed.Results: Five patients were treated at the starting and predicted minimal biologically effective dose of 50 mg

  5. Dose study of the multikinase inhibitor, LY2457546, in patients with relapsed acute myeloid leukemia to assess safety, pharmacokinetics, and pharmacodynamics

    International Nuclear Information System (INIS)

    Wacheck, Volker; Lahn, Michael; Dickinson, Gemma; Füreder, Wolfgang; Meyer, Renata; Herndlhofer, Susanne; Füreder, Thorsten; Dorfner, Georg; Pillay, Sada; André, Valérie; Burkholder, Timothy P; Akunda, Jacqueline K; Flye-Blakemore, Leann; Van Bockstaele, Dirk; Schlenk, Richard F; Sperr, Wolfgang R; Valent, Peter

    2011-01-01

    Acute myeloid leukemia (AML) is a life-threatening malignancy with limited treatment options in chemotherapy-refractory patients. A first-in-human dose study was designed to investigate a safe and biologically effective dose range for LY2457546, a novel multikinase inhibitor, in patients with relapsed AML. In this nonrandomized, open-label, dose escalation Phase I study, LY2457546 was administered orally once a day. Safety, pharmacokinetics, changes in phosphorylation of target kinases in AML blasts, and risk of drug–drug interactions (DDI) were assessed. Five patients were treated at the starting and predicted minimal biologically effective dose of 50 mg/day. The most commonly observed adverse events were febrile neutropenia, epistaxis, petechiae, and headache. The majority of adverse events (81%) were Grade 1 or 2. One patient had generalized muscle weakness (Grade 3), which was deemed to be a dose-limiting toxicity. Notably, the pharmacokinetic profile of LY2457546 showed virtually no elimination of LY2457546 within 24 hours, and thus prevented further dose escalation. No significant DDI were observed. Ex vivo flow cytometry studies showed downregulation of the phosphoproteins, pcKIT, pFLT3, and pS6, in AML blasts after LY2457546 administration. No medically relevant responses were observed in the five treated patients. No biologically effective dose could be established for LY2457546 in chemotherapy-resistant AML patients. Lack of drug clearance prevented safe dose escalation, and the study was terminated early. Future efforts should be made to develop derivatives with a more favorable pharmacokinetic profile

  6. Prevention of pulmonary vascular and myocardial remodeling by the combined tyrosine and serine-/threonine kinase inhibitor, sorafenib, in pulmonary hypertension and right heart failure

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    M. Klein

    2008-06-01

    Full Text Available Inhibition of tyrosine kinases can reverse pulmonary hypertension but little is known about the role of serine-/threonine kinases in vascular and myocardial remodeling. We investigated the effects of sorafenib, an inhibitor of the tyrosine kinases VEGFR, PDGFR and c-kit as well as the serine-/threonine kinase Raf-1, in pulmonary hypertension and right ventricular (RV pressure overload. In monocrotaline treated rats, sorafenib (10 mg·kg–1·d–1 p.o. reduced pulmonary arterial pressure, pulmonary artery muscularization and RV hypertrophy, and improved systemic hemodynamics (table 1. Sorafenib prevented phosphorylation of Raf-1 and suppressed activation of downstream signaling pathways (Erk 1/2. After pulmonary banding, sorafenib, but not the PDGFR/c-KIT/ABL-inhibitor imatinib reduced RV mass and RV filling pressure significantly. Congruent with these results, sorafenib only prevented ERK phosphorylation and vasopressin induced hypertrophy of the cardiomyocyte cell line H9c2 dose dependently (IC50 = 300 nM. Combined inhibition of tyrosine and serine-/threonine kinases by sorafenib prevents vascular and cardiac remodeling in pulmonary hypertension, which is partly mediated via inhibition of the Raf kinase pathway.

  7. Lack of Contribution of Multidrug Resistance-associated Protein and Organic Anion-transporting Polypeptide to Pharmacokinetics of Regorafenib, a Novel Multi-Kinase Inhibitor, in Rats.

    Science.gov (United States)

    Hotta, Kazuo; Ueyama, Jun; Tatsumi, Yasuaki; Tsukiyama, Ikuto; Sugiura, Yuka; Saito, Hiroko; Matsuura, Katsuhiko; Hasegawa, Takaaki

    2015-09-01

    We investigated whether hepatic multidrug resistance-associated protein 2 (ABCC2) is involved in the hepatobiliary excretion of regorafenib, a novel multi-kinase inhibitor, using Sprague-Dawley (SD) rats and Eisai hyperbilirubinemic rats (EHBR) lacking the efflux transporter ABCC2. The involvement of organic anion-transporting polypeptide 1 (OATP1; OATP in humans) and OATP2 in the hepatic uptake of regorafenib and their protein levels in the liver were also investigated in the two rat groups. When regorafenib (5 mg/kg) was administered intravenously, the plasma concentrations of regorafenib were higher in EHBR than those in SD rats. However, the slope of the plasma concentration-time curves was the same for the two groups. Although the apparent biliary clearance of regorafenib in EHBR was lower than that of SD rats, no significant difference in the biliary excretion rate was observed between them, suggesting that regorafenib is not a substrate for ABCC2 and is not excreted into bile by ABCC2. It was also found that the contribution of biliary excretion to the systemic elimination of regorafenib is small. The protein-binding profiles of regorafenib were found to be linear in both rat groups. The binding potency, which was very high in both rat groups (>99.5%), was significantly higher in EHBR than that in SD rats. No significant differences in the plasma concentrations of unbound regorafenib were observed between the two rat groups, suggesting that the differences observed in the pharmacokinetic behaviors of regorafenib between the two rat groups were due to differences in protein-binding. When the protein levels of hepatic OATP1 and OATP2 were measured by immunoblot analysis, the expression of both transporters in EHBR was less than 40% of that in SD rats. The present results suggest that regorafenib is not a substrate for OATP1 and OATP2. These findings suggest the possibility that ABCC2-mediated hepatobiliary excretion and OATP1/OATP2-mediated hepatic uptake do

  8. Sorafenib in Advanced Hepatocellular Carcinoma: A Nationwide Retrospective Study of Efficacy and Tolerability

    Directory of Open Access Journals (Sweden)

    Anne Helene Køstner

    2013-01-01

    Full Text Available Background. Advanced HCC is a clinical challenge with limited treatment options. The multikinase inhibitor sorafenib is the first and only agent showing a survival benefit in these patients. In this study we evaluate the efficacy and tolerability of sorafenib in an unselected patient population. Furthermore we explore the role of alpha-fetoprotein (αFP as a potential biomarker for treatment efficacy and correlation to survival. Methods. Seventy-six patients with advanced HCC, not eligible for locoregional therapy, treated with sorafenib between 2007 and 2009 were included. Followup was until 2011. Results. Patients in PS 0-1 had a median overall survival (mOS of 6.2 months, compared to 1.8 months in patients with poorer PS (P=0.005. Child-Pugh A patients had a mOS of 6.6 months versus 3.6 months among patients in Child-Pugh B or C (P=0.0001. Serum αFP ≥ 200 at baseline was prognostic for a shorter survival. All patients with radiologically verified tumor response and baseline αFP ≥ 200 experienced a significant decline in αFP within the first four weeks of treatment. Conclusion. The survival of patients with advanced HCC treated with sorafenib is dependent on performance status and liver function. Treatment of patients with compromised liver function and poor performance status cannot be recommended. The correlation between αFP and objective tumor response warrants further investigation.

  9. Allosteric MEK1/2 Inhibitor Refametinib (BAY 86-9766 in Combination with Sorafenib Exhibits Antitumor Activity in Preclinical Murine and Rat Models of Hepatocellular Carcinoma

    Directory of Open Access Journals (Sweden)

    Roberta Schmieder

    2013-10-01

    Full Text Available OBJECTIVE: The objectives of the study were to evaluate the allosteric mitogen-activated protein kinase kinase (MEK inhibitor BAY 86-9766 in monotherapy and in combination with sorafenib in orthotopic and subcutaneous hepatocellular carcinoma (HCC models with different underlying etiologies in two species. DESIGN: Antiproliferative potential of BAY 86-9766 and synergistic effects with sorafenib were studied in several HCC cell lines. Relevant pathway signaling was studied in MH3924a cells. For in vivo testing, the HCC cells were implanted subcutaneously or orthotopically. Survival and mode of action (MoA were analyzed. RESULTS: BAY 86-9766 exhibited potent antiproliferative activity in HCC cell lines with half-maximal inhibitory concentration values ranging from 33 to 762 nM. BAY 86-9766 was strongly synergistic with sorafenib in suppressing tumor cell proliferation and inhibiting phosphorylation of the extracellular signal-regulated kinase (ERK. BAY 86-9766 prolonged survival in Hep3B xenografts, murine Hepa129 allografts, and MH3924A rat allografts. Additionally, tumor growth, ascites formation, and serum alpha-fetoprotein levels were reduced. Synergistic effects in combination with sorafenib were shown in Huh-7, Hep3B xenografts, and MH3924A allografts. On the signaling pathway level, the combination of BAY 86-9766 and sorafenib led to inhibition of the upregulatory feedback loop toward MEK phosphorylation observed after BAY 86-9766 monotreatment. With regard to the underlying MoA, inhibition of ERK phosphorylation, tumor cell proliferation, and microvessel density was observed in vivo. CONCLUSION: BAY 86-9766 shows potent single-agent antitumor activity and acts synergistically in combination with sorafenib in preclinical HCC models. These results support the ongoing clinical development of BAY 86-9766 and sorafenib in advanced HCC.

  10. A mesenchymal-like phenotype and expression of CD44 predict lack of apoptotic response to sorafenib in liver tumor cells.

    Science.gov (United States)

    Fernando, Joan; Malfettone, Andrea; Cepeda, Edgar B; Vilarrasa-Blasi, Roser; Bertran, Esther; Raimondi, Giulia; Fabra, Àngels; Alvarez-Barrientos, Alberto; Fernández-Salguero, Pedro; Fernández-Rodríguez, Conrado M; Giannelli, Gianluigi; Sancho, Patricia; Fabregat, Isabel

    2015-02-15

    The multikinase inhibitor sorafenib is the only effective drug in advanced cases of hepatocellular carcinoma (HCC). However, response differs among patients and effectiveness only implies a delay. We have recently described that sorafenib sensitizes HCC cells to apoptosis. In this work, we have explored the response to this drug of six different liver tumor cell lines to define a phenotypic signature that may predict lack of response in HCC patients. Results have indicated that liver tumor cells that show a mesenchymal-like phenotype, resistance to the suppressor effects of transforming growth factor beta (TGF-β) and high expression of the stem cell marker CD44 were refractory to sorafenib-induced cell death in in vitro studies, which correlated with lack of response to sorafenib in nude mice xenograft models of human HCC. In contrast, epithelial-like cells expressing the stem-related proteins EpCAM or CD133 were sensitive to sorafenib-induced apoptosis both in vitro and in vivo. A cross-talk between the TGF-β pathway and the acquisition of a mesenchymal-like phenotype with up-regulation of CD44 expression was found in the HCC cell lines. Targeted CD44 knock-down in the mesenchymal-like cells indicated that CD44 plays an active role in protecting HCC cells from sorafenib-induced apoptosis. However, CD44 effect requires a TGF-β-induced mesenchymal background, since the only overexpression of CD44 in epithelial-like HCC cells is not sufficient to impair sorafenib-induced cell death. In conclusion, a mesenchymal profile and expression of CD44, linked to activation of the TGF-β pathway, may predict lack of response to sorafenib in HCC patients. © 2014 UICC.

  11. Synergistic effect of fisetin combined with sorafenib in human cervical cancer HeLa cells through activation of death receptor-5 mediated caspase-8/caspase-3 and the mitochondria-dependent apoptotic pathway.

    Science.gov (United States)

    Lin, Ming-Te; Lin, Chia-Liang; Lin, Tzu-Yu; Cheng, Chun-Wen; Yang, Shun-Fa; Lin, Chu-Liang; Wu, Chih-Chien; Hsieh, Yi-Hsien; Tsai, Jen-Pi

    2016-05-01

    Combining antitumor agents with bioactive compounds is a potential strategy for improving the effect of chemotherapy on cancer cells. The goal of this study was to elucidate the antitumor effect of the flavonoid, fisetin, combined with the multikinase inhibitor, sorafenib, against human cervical cancer cells in vitro and in vivo. The combination of fisetin and sorafenib synergistically induced apoptosis in HeLa cells, which is accompanied by a marked increase in loss of mitochondrial membrane potential. Apoptosis induction was achieved by caspase-3 and caspase-8 activation which increased the ratio of Bax/Bcl-2 and caused the subsequent cleavage of PARP level while disrupting the mitochondrial membrane potential in HeLa cells. Decreased Bax/Bcl-2 ratio level and mitochondrial membrane potential were also observed in siDR5-treated HeLa cells. In addition, in vivo studies revealed that the combined fisetin and sorafenib treatment was clearly superior to sorafenib treatment alone using a HeLa xenograft model. Our study showed that the combination of fisetin and sorafenib exerted better synergistic effects in vitro and in vivo than either agent used alone against human cervical cancer, and this synergism was based on apoptotic potential through a mitochondrial- and DR5-dependent caspase-8/caspase-3 signaling pathway. This combined fisetin and sorafenib treatment represents a novel therapeutic strategy for further clinical developments in advanced cervical cancer.

  12. Radiation recall dermatitis induced by sorafenib. A case study and review of the literature

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    Stieb, Sonja [University Hospital Zurich, Department of Radiation Oncology, Zurich (Switzerland); Paul Scherrer Institute, Villigen PSI, Center for Proton Therapy, Villigen (Switzerland); Riesterer, Oliver; Bruessow, Cornelia; Guckenberger, Matthias [University Hospital Zurich, Department of Radiation Oncology, Zurich (Switzerland); Pestalozzi, Bernhard [University Hospital Zurich, Department of Oncology, Zurich (Switzerland); Weiler, Stefan [University Hospital and University of Zurich, Department of Clinical Pharmacology and Toxicology, Zurich (Switzerland)

    2016-05-15

    Radiation recall dermatitis (RRD) is an acute inflammatory reaction confined to previously irradiated skin, mainly subsequent to the administration of certain chemotherapeutics. Here we present a rare case of RRD induced by the oral multikinase inhibitor sorafenib. A 77-year-old male with hepatocellular carcinoma was irradiated at ten different sites for bone metastases with 20-36 Gray in 5-12 fractions from January to March 2015. Sorafenib 400 mg was administered twice daily from mid-March. One week later the patient presented with fever and erythematous lesions on the right upper arm, mandible, and trunk. All skin symptoms were confined to previously irradiated areas. After RRD was diagnosed by exclusion of other causes and skin biopsy, sorafenib was paused. With the administration of topical corticosteroids and oral antihistamines, the skin reaction subsided within several days. Sorafenib was readministered after 3 weeks, which did not lead to recurrence of RRD but did cause fluctuating fever. Only four other such cases have been reported in the literature and WHO pharmacovigilance database on individual case safety reports. The current report is the first to show a potential relationship between the severity of sorafenib-induced RRD and radiation dose, histopathological features, and simultaneous acute radiation dermatitis and mucositis. RRD induced by sorafenib is a rare phenomenon, but should be considered in patients showing erythematous skin lesions 1-2 weeks after initiation of the drug, predominantly in areas where skin has been irradiated with an equivalent dose ≥ 30 Gy. Discontinuation of sorafenib with possible readministration should be evaluated with respect to the clinical situation and severity of reaction. (orig.) [German] Recall-Strahlendermatitis (RRD) ist eine akute Entzuendungsreaktion der Haut in zuvor bestrahlten Arealen, welche meist nach Einnahme bestimmter Chemotherapeutika auftritt. Nachfolgend praesentieren wir einen seltenen Fall von

  13. Effects of low concentrations of Regorafenib and Sorafenib on human HCC cell AFP, migration, invasion and growth in vitro

    Science.gov (United States)

    Carr, Brian Irving; D’Alessandro, Rosalba; Refolo, Maria Grazia; Iacovazzi, Palma Aurelia; Lippolis, Catia; Messa, Caterina; Cavallini, Aldo; Correale, Mario; Di Carlo, Antonio

    2012-01-01

    Sorafenib was shown in clinical trial to enhance survival in hepatocellular carcinoma (HCC) patients, but with minimal tumor shrinkage. To correlate several indices of HCC growth at various drug concentrations, HCC cells were grown in various low concentrations of two multi-kinase inhibitors, Regorafenib (Stivarga) and Sorafenib (Nexavar) and their effects were examined on alpha-fetoprotein (AFP), cell growth, migration and invasion. In two AFP positive human HCC cell lines, AFP was inhibited at 0.1–1µM drug concentrations. Cell migration and invasion were also inhibited at similar low drug concentrations. However, 10-fold higher drug concentrations were required to inhibit cell growth in both AFP positive and negative cells. To investigate this concentration discrepancy of effects, cells were then grown for prolonged times and sub-cultured in low drug concentrations and then their growth was re-tested. The growth in these drug-exposed cells was found to be slower than cells without prior drug exposure and they were also more sensitive to subsequent drug challenge. Evidence was also found for changes in cell signaling pathways in these slow-growth cells. Low multi-kinase inhibitor concentrations thus modulate several aspects of HCC cell biology. PMID:23169148

  14. Radiosensitization effects of sorafenib on colon cancer cells

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    Kim, Eun Ho; Kim, Mi-Sook; Jung, Won-Gyun; Jeong, Youn Kyoung [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)

    2014-11-15

    Radiotherapy is a standard therapy in the adjuvant treatment of resected colon and rectum cancers, and its combination with chemotherapy has been shown to reduce local failure and distant metastasis still further, thereby improving the outcome of treatment. One potential chemotherapeutic agent for this, sorafenib (Nexavar, BAY43-9006), is an oral multikinase inhibitor that blocks tumor cell proliferation and angiogenesis, and induces tumor cell apoptosis by inhibiting serine/threonine kinases (c-RAF and mutant and wild-type BRAF) as well as the receptor tyrosine kinases vascular endothelial growth factor receptor 2 and 3 (VEGFR2 and VEGFR3), platelet- derived growth factor receptor , FLT3, and c-KIT. Sorafenib is currently used in clinics to treat patients with advanced renal cell carcinoma, hepatocellular carcinoma, and thyroid cancer. These findings provide a molecular evidence base for the use of chemoradiation to treat colon cancer, and in vivo modeling should be used to further assess its suitability for clinical applications.

  15. Clinical experience and critical evaluation of the role of sorafenib in renal cell carcinoma

    Directory of Open Access Journals (Sweden)

    Zustovich F

    2011-05-01

    Full Text Available Fable Zustovich1, Giuseppe Lombardi1, Davide Pastorelli1, Patrizia Farina1, Massimo Dal Bianco2, Luca De Zorzi2, Maurizia Dalla Palma1, Ornella Nicoletto1, Vittorina Zagonel11Oncologia Medica 1, Istituto Oncologico Veneto-IRCCS, Padova, Italy; 2UO Urologia, Ospedale Sant'Antonio, ULSS 16, Padova, ItalyAbstract: Renal cell carcinoma (RCC is a common malignancy worldwide with approximately 95,000 new cases per year and ranks as the sixth cause of cancer deaths. Until recently, the slightly active and very toxic cytokines were available for patients with advanced RCC. Advances have been made in understanding the molecular biology of renal cancer. The introduction of targeted agents has led to promising possibilities for treating these highly vascularized tumors. Angiogenesis inhibition is likely to represent the main potential therapeutic target. Sorafenib is an oral multikinase inhibitor with activity against tyrosine kinase receptors that are responsible for blood vessel development and has shown to be active in treating advanced RCC. In this review, we summarize the pharmacology, mode of action, pharmacokinetics, and safety of sorafenib use in therapy for advanced RCC.Keywords: sorafenib, pharmacokinetics, angiogenesis 

  16. Drug-induced lung injury associated with sorafenib: analysis of all-patient post-marketing surveillance in Japan.

    Science.gov (United States)

    Horiuchi-Yamamoto, Yuka; Gemma, Akihiko; Taniguchi, Hiroyuki; Inoue, Yoshikazu; Sakai, Fumikazu; Johkoh, Takeshi; Fujimoto, Kiminori; Kudoh, Shoji

    2013-08-01

    Sorafenib is a multi-kinase inhibitor currently approved in Japan for unresectable and/or metastatic renal cell carcinoma and unresectable hepatocellular carcinoma. Although drug-induced lung injury has recently been the focus of interest in Japanese patients treated with molecular targeting agents, the clinical features of patients receiving sorafenib remain to be completely investigated. All-patient post-marketing surveillance data was obtained within the frame of Special Drug Use Investigation; between April 2008 and March 2011, we summarized the clinical information of 62 cases with drug-induced lung injury among approximately 13,600 sorafenib-treated patients in Japan. In addition, we summarized the results of evaluation by a safety board of Japanese experts in 34 patients in whom pulmonary images were available. For the calculation of reporting frequency, interim results of Special Drug Use Investigation were used. In the sets of completed reports (2,407 in renal cell carcinoma and 647 in hepatocellular carcinoma), the reporting frequency was 0.33 % (8 patients; fatal, 4/8) and 0.62 % (4 patients; fatal, 2/4), respectively. Major clinical symptoms included dyspnea, cough, and fever. Evaluation of the images showed that 18 cases out of 34 patients had a pattern of diffuse alveolar damage. The patients with hepatocellular carcinoma showed a greater incidence and earlier onset of lung injury than those with renal cell carcinoma. Although the overall reporting frequency of sorafenib-induced lung injury is not considered high, the radiological diffuse alveolar damage pattern led to a fatal outcome. Therefore, early recognition of sorafenib-induced lung injury is crucial for physicians and patients.

  17. {sup 18}F-fluorodeoxyglucose uptake of hepatocellular carcinoma as a prognostic predictor in patients with sorafenib treatment

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    Sung, Pil Soo; Yang, Keungmo; Hwang, Seawon; Song, Myeong Jun; Jang, Jeong Won; Choi, Jong Young; Yoon, Seung Kew; Bae, Si Hyun [The Catholic University of Korea, Division of Hepatology, Department of Internal Medicine, The Catholic University Liver Research Center, College of Medicine, Seoul (Korea, Republic of); Park, Hye Lim; Yoo, Ie Ryung [The Catholic University of Korea, Division of Nuclear Medicine, Department of Radiology, College of Medicine, Seoul (Korea, Republic of)

    2018-03-15

    Sorafenib, an oral multikinase inhibitor, is a recommended treatment option available for patients with Barcelona Clinic Liver Cancer (BCLC)-C stage hepatocellular carcinoma (HCC). This study aimed to evaluate the performance of {sup 18}F-fluorodeoxyglucose positron emission tomography ({sup 18}F-FDG PET) for predicting tumour progression during sorafenib treatment. We formed a retrospective cohort comprising patients treated with sorafenib for at least 30 days and undergoing {sup 18}F-FDG PET/CT within 1 month before treatment. For statistical analyses, the tumour-to-liver standardised uptake value (SUV) ratio (TLR) of the most hypermetabolic lesion was measured. Among a total of 35 patients, two obtained partial remission, and 11 showed stable disease after the first response evaluation. Patients with a TLR ≥ 2.9 (n = 17) had a median overall survival (OS) of 3.7 months after sorafenib treatment, whereas patients with a TLR < 2.9 (n = 18) had median OS of 12.2 months (P < 0.001), although the disease control rate was not significantly different between the two groups. Pretreatment TLR ≥ 2.9 (hazard ratio [HR] = 6.318, P = 0.002) and Child-Pugh class B (HR = 4.316, P = 0.044) were poor prognostic factors for OS, and a TLR ≥ 2.9 (HR = 2.911, P = 0.024) was the only poor prognostic factor for progression-free survival in a multivariate analysis. Pretreatment tumour metabolic activity assessed by {sup 18}F-FDG PET is an independent prognostic factor for survival in patients with BCLC-C stage HCC receiving sorafenib monotherapy, although it may not predict tumour response to the treatment. (orig.)

  18. Sorafenib and locoregional deep electro-hyperthermia in advanced hepatocellular carcinoma: A phase II study

    Science.gov (United States)

    GADALETA-CALDAROLA, GENNARO; INFUSINO, STEFANIA; GALISE, IDA; RANIERI, GIROLAMO; VINCIARELLI, GIANLUCA; FAZIO, VITO; DIVELLA, ROSA; DANIELE, ANTONELLA; FILIPPELLI, GIANFRANCO; GADALETA, COSMO DAMIANO

    2014-01-01

    The standard treatment for advanced hepatocellular carcinoma (HCC) is sorafenib, a multikinase inhibitor of tumor cell proliferation and angiogenesis. Hyperthermia inhibits angiogenesis and promotes apoptosis. Potential synergic antiangiogenic and proapoptotic effects represent the rationale for combining sorafenib with electro-hyperthermia (EHY) in HCC. A total of 21 patients (median age, 64 years; range, 55–73 years) with advanced HCC were enrolled in the current study between February 2009 and September 2010. EHY was achieved by arranging capacitive electrodes with a deep hypothermia radiofrequency field of 13.56 Mhz at 80 W for 60 min, three times per week for six weeks, followed by two weeks without treatment, in combination with sorafenib at a dose of 800 mg every other day. According to the modified Response Evaluation Criteria in Solid Tumors criteria, 50% achieved stable disease, 5% achieved partial response and 45% achieved progressive disease. No complete response was observed. The progression-free survival (PFS) rate at six months was 38%, while the median PFS and overall survival times were 5.2 [95% confidence interval (CI), 4.2–6.2) and 10.4 (95% CI, 10–11) months, respectively. The overall incidence of treatment-related adverse events was 80%, predominantly of grade 1 or 2. Grade 3 toxicity included fatigue, diarrhea, hand-foot skin reaction and hypertension. In the present study, the sorafenib plus EHY combination was feasible and well tolerated, and no major complications were observed. The initial findings indicated that this combination offers a promising option for advanced HCC. PMID:25202410

  19. Sorafenib blocks tumour growth, angiogenesis and metastatic potential in preclinical models of osteosarcoma through a mechanism potentially involving the inhibition of ERK1/2, MCL-1 and ezrin pathways

    Directory of Open Access Journals (Sweden)

    Ferrari Stefano

    2009-12-01

    Full Text Available Abstract Background Osteosarcoma (OS is the most common primary bone tumour in children and young adults. Despite improved prognosis, metastatic or relapsed OS remains largely incurable and no significant improvement has been observed in the last 20 years. Therefore, the search for alternative agents in OS is mandatory. Results We investigated phospho-ERK 1/2, MCL-1, and phospho-Ezrin/Radixin/Moesin (P-ERM as potential therapeutic targets in OS. Activation of these pathways was shown by immunohistochemistry in about 70% of cases and in all OS cell lines analyzed. Mutational analysis revealed no activating mutations in KRAS whereas BRAF gene was found to be mutated in 4/30 OS samples from patients. Based on these results we tested the multi-kinase inhibitor sorafenib (BAY 43-9006 in preclinical models of OS. Sorafenib inhibited OS cell line proliferation, induced apoptosis and downregulated P-ERK1/2, MCL-1, and P-ERM in a dose-dependent manner. The dephosphorylation of ERM was not due to ERK inhibition. The downregulation of MCL-1 led to an increase in apoptosis in OS cell lines. In chick embryo chorioallantoic membranes, OS supernatants induced angiogenesis, which was blocked by sorafenib and it was also shown that sorafenib reduced VEGF and MMP2 production. In addition, sorafenib treatment dramatically reduced tumour volume of OS xenografts and lung metastasis in SCID mice. Conclusion In conclusion, ERK1/2, MCL-1 and ERM pathways are shown to be active in OS. Sorafenib is able to inhibit their signal transduction, both in vitro and in vivo, displaying anti-tumoural activity, anti-angiogenic effects, and reducing metastatic colony formation in lungs. These data support the testing of sorafenib as a potential therapeutic option in metastatic or relapsed OS patients unresponsive to standard treatments.

  20. Effects of Sorafenib on C-Terminally Truncated Androgen Receptor Variants in Human Prostate Cancer Cells

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    Mark Schrader

    2012-09-01

    Full Text Available Recent evidence suggests that the development of castration resistant prostate cancer (CRPCa is commonly associated with an aberrant, ligand-independent activation of the androgen receptor (AR. A putative mechanism allowing prostate cancer (PCa cells to grow under low levels of androgens, is the expression of constitutively active, C-terminally truncated AR lacking the AR-ligand binding domain (LBD. Due to the absence of a LBD, these receptors, termed ARΔLBD, are unable to respond to any form of anti-hormonal therapies. In this study we demonstrate that the multikinase inhibitor sorafenib inhibits AR as well as ARΔLBD-signalling in CRPCa cells. This inhibition was paralleled by proteasomal degradation of the AR- and ARΔLBD-molecules. In line with these observations, maximal antiproliferative effects of sorafenib were achieved in AR and ARΔLBD-positive PCa cells. The present findings warrant further investigations on sorafenib as an option for the treatment of advanced AR-positive PCa.

  1. Fluoro-sorafenib (Regorafenib) effects on hepatoma cells: growth inhibition, quiescence and recovery

    Science.gov (United States)

    Carr, Brian I.; Cavallini, Aldo; Lippolis, Catia; D’Alessandro, Rosalba; Messa, Caterina; Refolo, Maria Grazia; Tafaro, Angela

    2015-01-01

    To evaluate the growth-inhibitory properties of the potent multi-kinase antagonist Regorafenib (Fluoro-Sorafenib), which was synthesized as a more potent Sorafenib, a Raf inhibitor and to determine whether similar mechanisms were involved, human hepatoma cell lines were grown in the presence or absence of Regorafanib and examined for growth inhibition. Western blots were performed for Raf targets, for apoptosis and autophagy. Regorafenib inhibited growth of human Hep3B, PLC/PRF/5 and HepG2 cells in a concentration- and time-dependent manner. Multiple signaling pathways were altered, including MAP kinases phospho-ERK and phospho-JNK and its target phospho-c-Jun. There was evidence for apoptosis by FACS, cleavage of caspases and increased Bax levels; as well as induction of autophagy, as judged by increased Beclin-1 and LC3 (II) levels. Prolonged drug exposure resulted in cell quiescence. Full growth recovery occurred after drug removal, unlike with doxorubicin chemotherapy. Regorafenib is a potent inhibitor of cell growth. Cells surviving Regorafenib treatment remain viable, but quiescent and capable of regrowth following drug removal. The reversibility of tumor cell growth suppression after drug removal may have clinical implications. PMID:22777740

  2. The combination of sorafenib and everolimus shows antitumor activity in preclinical models of malignant pleural mesothelioma

    International Nuclear Information System (INIS)

    Pignochino, Ymera; Dell’Aglio, Carmine; Inghilleri, Simona; Zorzetto, Michele; Basiricò, Marco; Capozzi, Federica; Canta, Marta; Piloni, Davide; Cemmi, Francesca; Sangiolo, Dario; Gammaitoni, Loretta; Soster, Marco; Marchiò, Serena; Pozzi, Ernesto; Morbini, Patrizia; Luisetti, Maurizio; Aglietta, Massimo; Grignani, Giovanni; Stella, Giulia M

    2015-01-01

    Malignant Pleural Mesothelioma (MPM) is an aggressive tumor arising from mesothelial cells lining the pleural cavities characterized by resistance to standard therapies. Most of the molecular steps responsible for pleural transformation remain unclear; however, several growth factor signaling cascades are known to be altered during MPM onset and progression. Transducers of these pathways, such as PIK3CA-mTOR-AKT, MAPK, and ezrin/radixin/moesin (ERM) could therefore be exploited as possible targets for pharmacological intervention. This study aimed to identify ‘druggable’ pathways in MPM and to formulate a targeted approach based on the use of commercially available molecules, such as the multikinase inhibitor sorafenib and the mTOR inhibitor everolimus. We planned a triple approach based on: i) analysis of immunophenotypes and mutational profiles in a cohort of thoracoscopic MPM samples, ii) in vitro pharmacological assays, ii) in vivo therapeutic approaches on MPM xenografts. No mutations were found in ‘hot spot’ regions of the mTOR upstream genes (e.g. EGFR, KRAS and PIK3CA). Phosphorylated mTOR and ERM were specifically overexpressed in the analyzed MPM samples. Sorafenib and everolimus combination was effective in mTOR and ERM blockade; exerted synergistic effects on the inhibition of MPM cell proliferation; triggered ROS production and consequent AMPK-p38 mediated-apoptosis. The antitumor activity was displayed when orally administered to MPM-bearing NOD/SCID mice. ERM and mTOR pathways are activated in MPM and ‘druggable’ by a combination of sorafenib and everolimus. Combination therapy is a promising therapeutic strategy against MPM. The online version of this article (doi:10.1186/s12885-015-1363-1) contains supplementary material, which is available to authorized users

  3. Targeted Approaches Applied to Uncommon Diseases: A Case of Salivary Duct Carcinoma Metastatic to the Brain Treated with the Multikinase Inhibitor Neratinib

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    Karl R. Sorenson

    2017-08-01

    Full Text Available Salivary duct carcinoma is a rare malignancy associated with hormone receptor and human epidermal growth factor receptor 2 (HER2 overexpression. Local surgical control is the cornerstone of therapy, but a subset of patients develops metastatic disease portending a poor prognosis and limited management options. Intracranial metastases are an uncommon manifestation and present a therapeutic challenge. We report the case of a 31-year-old male who presented with facial pain and swelling subsequently diagnosed with salivary duct carcinoma. Our patient underwent extensive locoregional resection and analysis of the tumor tissue demonstrated evidence of androgen receptor expression and HER2 overexpression. His course was complicated by metastatic extra- and intracranial recurrence despite combined modality treatment with radiation and chemotherapy followed by anti-HER2 monoclonal antibody therapy and androgen deprivation therapy. After exhausting standard treatment options, he received experimental therapy with a new small-molecule tyrosine kinase inhibitor, neratinib, with evidence of a transient clinical response and no significant adverse effects. This case exemplifies the potential and limitations of targeted therapy, particularly when applied to patients with rare diseases and presentations.

  4. Targeted Approaches Applied to Uncommon Diseases: A Case of Salivary Duct Carcinoma Metastatic to the Brain Treated with the Multikinase Inhibitor Neratinib.

    Science.gov (United States)

    Sorenson, Karl R; Piovezani Ramos, Guilherme; Villasboas Bisneto, Jose Caetano; Price, Katharine

    2017-01-01

    Salivary duct carcinoma is a rare malignancy associated with hormone receptor and human epidermal growth factor receptor 2 (HER2) overexpression. Local surgical control is the cornerstone of therapy, but a subset of patients develops metastatic disease portending a poor prognosis and limited management options. Intracranial metastases are an uncommon manifestation and present a therapeutic challenge. We report the case of a 31-year-old male who presented with facial pain and swelling subsequently diagnosed with salivary duct carcinoma. Our patient underwent extensive locoregional resection and analysis of the tumor tissue demonstrated evidence of androgen receptor expression and HER2 overexpression. His course was complicated by metastatic extra- and intracranial recurrence despite combined modality treatment with radiation and chemotherapy followed by anti-HER2 monoclonal antibody therapy and androgen deprivation therapy. After exhausting standard treatment options, he received experimental therapy with a new small-molecule tyrosine kinase inhibitor, neratinib, with evidence of a transient clinical response and no significant adverse effects. This case exemplifies the potential and limitations of targeted therapy, particularly when applied to patients with rare diseases and presentations.

  5. Intrinsic fluorescence of the clinically approved multikinase inhibitor nintedanib reveals lysosomal sequestration as resistance mechanism in FGFR-driven lung cancer.

    Science.gov (United States)

    Englinger, Bernhard; Kallus, Sebastian; Senkiv, Julia; Heilos, Daniela; Gabler, Lisa; van Schoonhoven, Sushilla; Terenzi, Alessio; Moser, Patrick; Pirker, Christine; Timelthaler, Gerald; Jäger, Walter; Kowol, Christian R; Heffeter, Petra; Grusch, Michael; Berger, Walter

    2017-09-07

    Studying the intracellular distribution of pharmacological agents, including anticancer compounds, is of central importance in biomedical research. It constitutes a prerequisite for a better understanding of the molecular mechanisms underlying drug action and resistance development. Hyperactivated fibroblast growth factor receptors (FGFRs) constitute a promising therapy target in several types of malignancies including lung cancer. The clinically approved small-molecule FGFR inhibitor nintedanib exerts strong cytotoxicity in FGFR-driven lung cancer cells. However, subcellular pharmacokinetics of this compound and its impact on therapeutic efficacy remain obscure. 3-dimensional fluorescence spectroscopy was conducted to asses cell-free nintedanib fluorescence properties. MTT assay was used to determine the impact of the lysosome-targeting agents bafilomycin A1 and chloroquine combined with nintedanib on lung cancer cell viability. Flow cytometry and live cell as well as confocal microscopy were performed to analyze uptake kinetics as well as subcellular distribution of nintedanib. Western blot was conducted to investigate protein expression. Cryosections of subcutaneous tumor allografts were generated to detect intratumoral nintedanib in mice after oral drug administration. Here, we report for the first time drug-intrinsic fluorescence properties of nintedanib in living and fixed cancer cells as well as in cryosections derived from allograft tumors of orally treated mice. Using this feature in conjunction with flow cytometry and confocal microscopy allowed to determine cellular drug accumulation levels, impact of the ABCB1 efflux pump and to uncover nintedanib trapping into lysosomes. Lysosomal sequestration - resulting in an organelle-specific and pH-dependent nintedanib fluorescence - was identified as an intrinsic resistance mechanism in FGFR-driven lung cancer cells. Accordingly, combination of nintedanib with agents compromising lysosomal acidification

  6. Differential modulatory effects of GSK-3β and HDM2 on sorafenib-induced AIF nuclear translocation (programmed necrosis in melanoma

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    Mier James W

    2011-09-01

    Full Text Available Abstract Background GSK-3β phosphorylates numerous substrates that govern cell survival. It phosphorylates p53, for example, and induces its nuclear export, HDM2-dependent ubiquitination, and proteasomal degradation. GSK-3β can either enhance or inhibit programmed cell death, depending on the nature of the pro-apoptotic stimulus. We previously showed that the multikinase inhibitor sorafenib activated GSK-3β and that this activation attenuated the cytotoxic effects of the drug in various BRAF-mutant melanoma cell lines. In this report, we describe the results of studies exploring the effects of GSK-3β on the cytotoxicity and antitumor activity of sorafenib combined with the HDM2 antagonist MI-319. Results MI-319 alone increased p53 levels and p53-dependent gene expression in melanoma cells but did not induce programmed cell death. Its cytotoxicity, however, was augmented in some melanoma cell lines by the addition of sorafenib. In responsive cell lines, the MI-319/sorafenib combination induced the disappearance of p53 from the nucleus, the down modulation of Bcl-2 and Bcl-xL, the translocation of p53 to the mitochondria and that of AIF to the nuclei. These events were all GSK-3β-dependent in that they were blocked with a GSK-3β shRNA and facilitated in otherwise unresponsive melanoma cell lines by the introduction of a constitutively active form of the kinase (GSK-3β-S9A. These modulatory effects of GSK-3β on the activities of the sorafenib/MI-319 combination were the exact reverse of its effects on the activities of sorafenib alone, which induced the down modulation of Bcl-2 and Bcl-xL and the nuclear translocation of AIF only in cells in which GSK-3β activity was either down modulated or constitutively low. In A375 xenografts, the antitumor effects of sorafenib and MI-319 were additive and associated with the down modulation of Bcl-2 and Bcl-xL, the nuclear translocation of AIF, and increased suppression of tumor angiogenesis

  7. Pro-angiogenic TIE-2-expressing monocytes/TEMs as a biomarker of the effect of sorafenib in patients with advanced hepatocellular carcinoma.

    Science.gov (United States)

    Shoji, Hirotaka; Yoshio, Sachiyo; Mano, Yohei; Doi, Hiroyoshi; Sugiyama, Masaya; Osawa, Yosuke; Kimura, Kiminori; Arai, Taeang; Itokawa, Norio; Atsukawa, Masanori; Aoki, Yoshihiko; Fukai, Moto; Taketomi, Akinobu; Mizokami, Masashi; Kanto, Tatsuya

    2017-09-01

    Sorafenib, a multi-kinase inhibitor, inhibits tumor angiogenesis and is the first-line systemic therapy for patients with advanced hepatocellular carcinoma (HCC). However, due to its limited effects and frequent occurrence of side effects, biomarkers are needed to predict the effects of sorafenib. We considered the possibility of using TIE-2-expressing monocytes (TEMs) to predict the response in sorafenib-treated patients with advanced HCC. TEMs serve as a diagnostic marker of HCC and are related to angiogenesis. We analyzed 25 advanced HCC patients and prospectively evaluated TEMs before (Pre TEMs) and at 1 month after initial therapy (T1m TEMs). The radiologic response was evaluated by modified Response Evaluation Criteria in Solid Tumors (mRECIST). Median survival time (MST) was significantly longer in the partial response/stable disease (PR/SD) group (21.8 months) than in the PD group (8.7 months). ΔTEMs (changes of T1m TEMs compared to Pre TEMs) were significantly lower in the PR/SD group than in the PD group. MST of the ΔTEMs low group (14.2 months) was significantly longer than that of the high group (8.7 months). Univariate and multivariate Cox regression analyses showed that ΔTEMs [hazard ratio (HR) = 8.53, 95% confidence interval (CI) = 1.51-48.16, p = 0.015] and Child-Pugh class (HR = 5.59, 95% CI = 1.06-29.63, p = 0.043) were independently associated with overall survival. Our results suggest that ΔTEMs could serve as a biomarker for predicting radiologic response and overall survival in sorafenib-treated patients with advanced HCC. © 2017 UICC.

  8. Rationale and design of decision: a double-blind, randomized, placebo-controlled phase III trial evaluating the efficacy and safety of sorafenib in patients with locally advanced or metastatic radioactive iodine (RAI)-refractory, differentiated thyroid cancer

    International Nuclear Information System (INIS)

    Brose, Marcia S; Schlumberger, Martin; Nutting, Christopher M; Sherman, Steven I; Shong, Young Kee; Smit, Johannes WA; Reike, Gerhard; Chung, John; Kalmus, Joachim; Kappeler, Christian

    2011-01-01

    The incidence of thyroid cancer and the number of patients who die from this disease are increasing globally. Differentiated thyroid cancer (DTC) is the histologic subtype present in most patients and is primarily responsible for the increased overall incidence of thyroid cancer. Sorafenib is a multikinase inhibitor that targets several molecular signals believed to be involved in the pathogenesis of thyroid cancer, including those implicated in DTC. In phase II studies of patients with DTC, sorafenib treatment has yielded a median progression-free survival (PFS) of 58 to 84 weeks and disease control rates of 59% to 100%. The DECISION trial was designed to assess the ability of sorafenib to improve PFS in patients with locally advanced or metastatic, radioactive iodine (RAI)-refractory DTC. DECISION is a multicenter, double-blind, randomized, placebo-controlled phase III study in patients with locally advanced/metastatic RAI-refractory DTC. Study treatment will continue until radiographically documented disease progression, unacceptable toxicity, noncompliance, or withdrawal of consent. Efficacy will be evaluated every 56 days (2 cycles), whereas safety will be evaluated every 28 days (1 cycle) for the first 8 months and every 56 days thereafter. Following disease progression, patients may continue or start sorafenib, depending on whether they were randomized to receive sorafenib or placebo, at investigator discretion. Patients originally randomized to receive sorafenib will be followed up every 3 months for overall survival (OS); patients originally randomized to receive placebo will be followed up every month for 8 months after cross-over to sorafenib. The duration of the trial is expected to be 30 months from the time the first patient is randomized until the planned number of PFS events is attained. The primary endpoint is PFS; secondary endpoints include OS, time to disease progression, disease control rate, response rate, duration of response, safety, and

  9. Antagonism of Sorafenib and Regorafenib actions by platelet factors in hepatocellular carcinoma cell lines

    International Nuclear Information System (INIS)

    D’Alessandro, Rosalba; Refolo, Maria G; Lippolis, Catia; Giannuzzi, Grazia; Carella, Nicola; Messa, Caterina; Cavallini, Aldo; Carr, Brian I

    2014-01-01

    Platelets are frequently altered in hepatocellular carcinoma (HCC) patients. Platelet lysates (hPL) can enhance HCC cell growth and decrease apoptosis. The aims were to evaluate whether hPL can modulate the actions of Sorafenib or Regorafenib, two clinical HCC multikinase antagonists. Several human HCC cell lines were grown in the presence and absence of Sorafenib or Regorafenib, with or without hPL. Growth was measured by MTT assay, apoptosis was assessed by Annexin V and by western blot, and autophagy and MAPK growth signaling were also measured by western blot, and migration and invasion were measured by standard in vitro assays. Both Sorafenib and Regorafenib-mediated inhibition of cell growth, migration and invasion were all antagonized by hPL. Drug-mediated apoptosis and decrease in phospho-ERK levels were both blocked by hPL, which also increased anti-apoptotic phospho-STAT, Bax and Bcl-xL levels. Preliminary data, obtained with epidermal growth factor (EGF) and insulin-like growth factor-I (IGF-I), included in hPL, revealed that these factors were able to antagonized Sorafenib in a proliferation assay, in particular when used in combination. Platelet factors can antagonize Sorafenib or Regorafenib-mediated growth inhibition and apoptosis in HCC cells. The modulation of platelet activity or numbers has the potential to enhance multikinase drug actions

  10. Inhibition of retinopathy of prematurity in rat by intravitreal injection of sorafenib

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    Li-Li Tian

    2014-04-01

    Full Text Available AIM:To investigate the effect of intravitreal injection administered sorafenib, a multikinase inhibitor, in a rat model of oxygen-induced retinopathy (OIR.METHODS:Seven-day-old Sprague-Dawley rats (n=144 were randomly assigned to six groups. Group A received normal partial oxygen pressure and groups B, C, D, E and F were exposed to hyperoxia (75±2% from postnatal 7d (P7 to P12 to induce retinopathy of prematurity. The rats in groups C, D, E and F were received intravitreal injections of either vehicle (DMSO or sorafenib at P12 (5, 20 and 80 μg, respectively. Then they returned to normoxia after P12. The retinas were whole-mounted and imaged with a confocal microscopy. The vascular branching points were counted to quantify neovascularization at P17. Cross-sections of the retina were stained with hematoxylin and eosin (HE. The nuclei of new vessels breaking the internal limiting membrane were counted to quantify the proliferative neovascular response.RESULTS:The retinal vessel in groups B and C turned into tortuosity and a great deal of neovascularization were observed. Sorafenib-treated rats had significantly less neovascularization as compared with vehicle-treated and control rats in a dose dependent manner (P<0.05. The number of vascular branching points in A, B, C, D, E and F were 16.50±3.90, 37.44±6.47, 37.08±5.10, 30.80±6.85, 26.08±5.08 and 19.83±3.51, respectively. The number of the nuclei of retinal new vessel in A, B, C, D, E and F were 0.22±0.42, 35.66±4.70, 35.30±4.54, 27.30±4.28, 21.41±3.53, and 7.41±2.87, respectively. There were significant difference between each group (P<0.05 except groups B and C.CONCLUSION: In the rat OIR model, sorafenib could inhibit retinal neovascularization in a dose dependent manner.

  11. Overexpression of c-Jun contributes to sorafenib resistance in human hepatoma cell lines.

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    Yuki Haga

    Full Text Available Despite recent advances in treatment strategies, it is still difficult to cure patients with hepatocellular carcinoma (HCC. Sorafenib is the only approved multiple kinase inhibitor for systemic chemotherapy in patients with advanced HCC. The majority of advanced HCC patients are resistant to sorafenib. The mechanisms of sorafenib resistance are still unknown.The expression of molecules involved in the mitogen-activated protein kinase (MAPK signaling pathway in human hepatoma cell lines was examined in the presence or absence of sorafenib. Apoptosis of human hepatoma cells treated with sorafenib was investigated, and the expression of Jun proto-oncogene (c-Jun was measured.The expression and phosphorylation of c-Jun were enhanced in human hepatoma cell lines after treatment with sorafenib. Inhibiting c-Jun enhanced sorafenib-induced apoptosis. The overexpression of c-Jun impaired sorafenib-induced apoptosis. The expression of osteopontin, one of the established AP-1 target genes, was enhanced after treatment with sorafenib in human hepatoma cell lines.The protein c-Jun plays a role in sorafenib resistance in human hepatoma cell lines. The modulation and phosphorylation of c-Jun could be a new therapeutic option for enhancing responsiveness to sorafenib. Modulating c-Jun may be useful for certain HCC patients with sorafenib resistance.

  12. Efficacy of sorafenib, a multi-tyrosine kinase inhibitor, in an adenoid cystic carcinoma metastatic to the lung: case report and review of literature

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    Santos Edgardo S

    2011-09-01

    Full Text Available Abstract Introduction Treatment for squamous cell carcinoma of the head and neck has significantly improved with the addition of cetuximab, a monoclonal antibody against the epidermal growth factor receptor, to conventional cytotoxic agents. The most significant aspect of this treatment approach is the proof that head and neck cancers are suitable for targeted therapies as has been shown in other malignancies. Unfortunately, there are other rare histologic types of head and neck cancer such as adenocarcinoma and adenoid cystic carcinoma. The latter has traditionally been considered to be chemotherapy resistant and surgical resection with or without adjuvant radiation therapy has been the rule as far as treatment is concerned. The course of adenoid cystic carcinoma ranges from indolent to aggressive; however, most patients succumb to the disease as a result of distant metastases. This clinical scenario poses a challenge to oncologists. Several conventional chemotherapy regimens and novel targeted agents have been tried in this rare histologic subtype without success. Case presentation In this case report, we present a 59-year-old Caucasian female with refractory adenoid cystic carcinoma of the maxilla metastatic to the lung that responded to sorafenib, a novel multi-tyrosine kinase inhibitor, which targets angiogenesis, Raf kinase pathway, platelet-derived growth factor Ret, and c-Kit. Conclusion This case illustrates the possibility that this chemoresistant tumor may need the inhibition or blocking of several oncogenic pathways. Certainly, it is imperative that more studies are done in this special population trying to identify tumorigenesis mechanisms that may be upregulated in this malignancy and could be potential targets for therapeutic development.

  13. Dynamic PET evaluation of elevated FLT level after sorafenib treatment in mice bearing human renal cell carcinoma xenograft.

    Science.gov (United States)

    Ukon, Naoyuki; Zhao, Songji; Yu, Wenwen; Shimizu, Yoichi; Nishijima, Ken-Ichi; Kubo, Naoki; Kitagawa, Yoshimasa; Tamaki, Nagara; Higashikawa, Kei; Yasui, Hironobu; Kuge, Yuji

    2016-12-01

    Sorafenib, an oral multikinase inhibitor, has anti-proliferative and anti-angiogenic activities and is therapeutically effective against renal cell carcinoma (RCC). Recently, we have evaluated the tumor responses to sorafenib treatment in a RCC xenograft using [Methyl- 3 H(N)]-3'-fluoro-3'-deoxythythymidine ([ 3 H]FLT). Contrary to our expectation, the FLT level in the tumor significantly increased after the treatment. In this study, to clarify the reason for the elevated FLT level, dynamic 3'-[ 18 F]fluoro-3'-deoxythymidine ([ 18 F]FLT) positron emission tomography (PET) and kinetic studies were performed in mice bearing a RCC xenograft (A498). The A498 xenograft was established in nude mice, and the mice were assigned to the control (n = 5) and treatment (n = 5) groups. The mice in the treatment group were orally given sorafenib (20 mg/kg/day p.o.) once daily for 3 days. Twenty-four hours after the treatment, dynamic [ 18 F]FLT PET was performed by small-animal PET. Three-dimensional regions of interest (ROIs) were manually defined for the tumors. A three-compartment model fitting was carried out to estimate four rate constants using the time activity curve (TAC) in the tumor and the blood clearance rate of [ 18 F]FLT. The dynamic pattern of [ 18 F]FLT levels in the tumor significantly changed after the treatment. The rate constant of [ 18 F]FLT phosphorylation (k 3 ) was significantly higher in the treatment group (0.111 ± 0.027 [1/min]) than in the control group (0.082 ± 0.009 [1/min]). No significant changes were observed in the distribution volume, the ratio of [ 18 F]FLT forward transport (K 1 ) to reverse transport (k 2 ), between the two groups (0.556 ± 0.073 and 0.641 ± 0.052 [mL/g] in the control group). Our dynamic PET studies indicated that the increase in FLT level may be caused by the phosphorylation of FLT in the tumor after the sorafenib treatment in the mice bearing a RCC xenograft. Dynamic PET studies with kinetic

  14. Prognostic significance of adverse events in patients with hepatocellular carcinoma treated with sorafenib.

    Science.gov (United States)

    Granito, Alessandro; Marinelli, Sara; Negrini, Giulia; Menetti, Saverio; Benevento, Francesca; Bolondi, Luigi

    2016-03-01

    Sorafenib is the standard treatment for patients with hepatocellular carcinoma (HCC) with advanced stage disease. Although its effectiveness has been demonstrated by randomized clinical trials and confirmed by field practice studies, reliable markers predicting therapeutic response have not yet been identified. Like other tyrosine kinase inhibitors, treatment with sorafenib is burdened by the development of adverse effects, the most frequent being cutaneous toxicity, diarrhoea, arterial hypertension and fatigue. In recent years, several studies have analysed the correlation between off-target effects and sorafenib efficacy in patients with HCC. In this review, an overview of the studies assessing the prognostic significance of sorafenib-related adverse events is provided.

  15. Herb-Drug Interaction between the Traditional Hepatoprotective Formulation and Sorafenib on Hepatotoxicity, Histopathology and Pharmacokinetics in Rats

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    Chin-Tsung Ting

    2017-06-01

    Full Text Available Sorafenib has been used as a standard therapy for advanced hepatocellular carcinoma (HCC. In Asia, patients with HCC are potentially treated with the combination of sorafenib and Chinese herbal medicines to improve the efficiency and reduce the side effects of sorafenib. However, limited information about the herb-drug interactions is available. We hypothesize that the Chinese herbal medicine may exert hepatoprotective effects on the sorafenib-treated group. The aim of this study is to investigate the pharmacokinetic mechanism of drug-drug interactions of sorafenib including interacting with hepatoprotective formulation, Long-Dan-Xie-Gan-Tang formulation (LDXGT and with two cytochrome P450 3A4 (CYP3A4 inhibitors, grapefruit juice and ketoconazole. Liver enzyme levels and histopathology of liver slices were used to evaluate sorafenib-induced hepatotoxicity and the potential hepatoprotective effects of the LDXGT formulation on subjects treated with the combination of sorafenib and the herbal medicine. In this study, a validated HPLC-photodiode array analytical system was developed for the pharmacokinetic study of sorafenib in rats. As the result of the pharmacokinetic data, pretreatment with the LDXGT formulation did not significantly interact with sorafenib compared with sorafenib oral administration alone. Furthermore, grapefruit juice and ketoconazole did not significantly affect sorafenib metabolism. Furthermore, pretreatment with variable, single or repeat doses of the LDXGT formulation did not suppress or exacerbate the sorafenib-induced hepatotoxicity and histopathological alterations. According to these results, the LDXGT formulation is safe, but has no beneficial effects on sorafenib-induced hepatotoxicity. A detailed clinical trial should be performed to further evaluate the efficacy or adverse effects of the LDXGT formulation in combination with sorafenib in humans.

  16. Sorafenib-triggered radiation recall dermatitis with a disseminated exanthematous reaction

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    Oh, Dong Ryul; Park, Hee Chul; Lim, Ho Yeong; Yoo, Byung Chul [Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of)

    2013-09-15

    Sorafenib is a multi-targeted kinase inhibitor, which is the current standard treatment for advanced hepatocellular carcinoma (HCC). Only one case of radiation recall dermatitis (RRD) associated with sorafenib has been reported so far. Our patient with recurrent HCC was treated with palliative radiotherapy (RT) for the chest wall mass. Sorafenib at 400 mg twice daily was begun on the day following RT. On the 14th day post-RT, an erythematous patch was observed on right chest wall which matched area previously irradiated. It was consistent with RRD. Ten days later, a disseminated exanthematous rash and severe pruritus occurred. Sorafenib was stopped and an oral antihistamine was prescribed to relieve symptoms. At the 1-week follow-up after the cessation of sorafenib, all symptoms were resolved. Physicians should be alert to this recall phenomenon as it can occur both in the skin and elsewhere and the occurrence of RRD may be unpredictable.

  17. Research advances in sorafenib-induced apoptotic signaling pathways in liver cancer cells

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    ZHANG Chaoya

    2016-04-01

    Full Text Available Currently, sorafenib is the multi-target inhibitor for the treatment of advanced primary liver cancer, and can effectively prolong the progression-free survival and overall survival in patients with advanced primary liver cancer. The application of sorafenib in the targeted therapy for liver cancer has become a hot topic. Major targets or signaling pathways include Raf/Mek/Erk, Jak/Stat, PI3K/Akt/mTOR, VEGFR and PDGFR, STAT, microRNA, Wnt/β-catenin, autolysosome, and tumor-related proteins, and sorafenib can regulate the proliferation, differentiation, metastasis, and apoptosis of liver cancer cells through these targets. This article reviews the current research on the action of sorafenib on these targets or signaling pathways to provide useful references for further clinical research on sorafenib.

  18. Localized palmar-plantar epidermal hyperplasia: a previously undefined dermatologic toxicity to sorafenib.

    Science.gov (United States)

    Beldner, Matthew; Jacobson, Michael; Burges, Gene E; Dewaay, Deborah; Maize, John C; Chaudhary, Uzair B

    2007-10-01

    The development of multitargeted tyrosine kinase inhibitors has provided significant advances in the treatment of renal cell carcinoma. This case describes initial therapy for managing renal cell cancer with the administration of sorafenib, a multitargeted tyrosine kinase inhibitor. We report the development of localized palmar-plantar epidermal hyperplasia, a rare but significant cutaneous adverse event from sorafenib therapy. Mild-to-moderate dermatologic toxicity from sorafenib has been well described in the literature. We also review the current knowledge and the proposed hypothesis for the development of cutaneous events related to tyrosine kinase inhibitors. This particular case represents a unique form of dermatologic toxicity to sorafenib that has not previously been described in the literature.

  19. Nucleoside-Lipid-Based Nanocarriers for Sorafenib Delivery

    Science.gov (United States)

    Benizri, Sebastien; Ferey, Ludivine; Alies, Bruno; Mebarek, Naila; Vacher, Gaelle; Appavoo, Ananda; Staedel, Cathy; Gaudin, Karen; Barthélémy, Philippe

    2018-01-01

    Although the application of sorafenib, a small inhibitor of tyrosine protein kinases, to cancer treatments remains a worldwide option in chemotherapy, novel strategies are needed to address the low water solubility (drug. In this context, the use of nanocarriers is currently investigated in order to overcome these drawbacks. In this contribution, we report a new type of sorafenib-based nanoparticles stabilized by hybrid nucleoside-lipids. The solid lipid nanoparticles (SLNs) showed negative or positive zeta potential values depending on the nucleoside-lipid charge. Transmission electron microscopy of sorafenib-loaded SLNs revealed parallelepiped nanoparticles of about 200 nm. Biological studies achieved on four different cell lines, including liver and breast cancers, revealed enhanced anticancer activities of Sorafenib-based SLNs compared to the free drug. Importantly, contrast phase microscopy images recorded after incubation of cancer cells in the presence of SLNs at high concentration in sorafenib (> 80 μM) revealed a total cancer cell death in all cases. These results highlight the potential of nucleoside-lipid-based SLNs as drug delivery systems.

  20. Sorafenib-induced defective autophagy promotes cell death by necroptosis.

    Science.gov (United States)

    Kharaziha, Pedram; Chioureas, Dimitris; Baltatzis, George; Fonseca, Pedro; Rodriguez, Patricia; Gogvadze, Vladimir; Lennartsson, Lena; Björklund, Ann-Charlotte; Zhivotovsky, Boris; Grandér, Dan; Egevad, Lars; Nilsson, Sten; Panaretakis, Theocharis

    2015-11-10

    Autophagy is one of the main cytoprotective mechanisms that cancer cells deploy to withstand the cytotoxic stress and survive the lethal damage induced by anti-cancer drugs. However, under specific conditions, autophagy may, directly or indirectly, induce cell death. In our study, treatment of the Atg5-deficient DU145 prostate cancer cells, with the multi-tyrosine kinase inhibitor, sorafenib, induces mitochondrial damage, autophagy and cell death. Molecular inhibition of autophagy by silencing ULK1 and Beclin1 rescues DU145 cells from cell death indicating that, in this setting, autophagy promotes cell death. Re-expression of Atg5 restores the lipidation of LC3 and rescues DU145 and MEF atg5-/- cells from sorafenib-induced cell death. Despite the lack of Atg5 expression and LC3 lipidation, DU145 cells form autophagosomes as demonstrated by transmission and immuno-electron microscopy, and the formation of LC3 positive foci. However, the lack of cellular content in the autophagosomes, the accumulation of long-lived proteins, the presence of GFP-RFP-LC3 positive foci and the accumulated p62 protein levels indicate that these autophagosomes may not be fully functional. DU145 cells treated with sorafenib undergo a caspase-independent cell death that is inhibited by the RIPK1 inhibitor, necrostatin-1. Furthermore, treatment with sorafenib induces the interaction of RIPK1 with p62, as demonstrated by immunoprecipitation and a proximity ligation assay. Silencing of p62 decreases the RIPK1 protein levels and renders necrostatin-1 ineffective in blocking sorafenib-induced cell death. In summary, the formation of Atg5-deficient autophagosomes in response to sorafenib promotes the interaction of p62 with RIPK leading to cell death by necroptosis.

  1. Sorafenib for Metastatic Thyroid Cancer

    Science.gov (United States)

    A summary of results from an international phase III trial that compared sorafenib (Nexavar®) and a placebo for the treatment of locally advanced or metastatic differentiated thyroid cancer that is no longer responding to treatment with radioactive iodine

  2. Case report of severe Cushing's syndrome in medullary thyroid cancer complicated by functional diabetes insipidus, aortic dissection, jejunal intussusception, and paraneoplastic dysautonomia: remission with sorafenib without reduction in cortisol concentration.

    Science.gov (United States)

    Hammami, Muhammad M; Duaiji, Najla; Mutairi, Ghazi; Aklabi, Sabah; Qattan, Nasser; Abouzied, Mohei El-Din M; Sous, Mohamed W

    2015-09-09

    Normalization of cortisol concentration by multikinase inhibitors have been reported in three patients with medullary thyroid cancer-related Cushing's syndrome. Aortic dissection has been reported in three patients with Cushing's syndrome. Diabetes insipidus without intrasellar metastasis, intestinal intussusception, and paraneoplastic dysautonomia have not been reported in medullary thyroid cancer. An adult male with metastatic medullary thyroid cancer presented with hyperglycemia, hypernatremia, hypokalemia, hypertension, acne-like rash, and diabetes insipidus (urine volume >8 L/d, osmolality 190 mOsm/kg). Serum cortisol, adrenocorticoitropic hormone, dehydroepiandrostenedione sulfate, and urinary free cortisol were elevated 8, 20, 4.4, and 340 folds, respectively. Pituitary imaging was normal. Computed tomography scan revealed jejunal intussusception and incidental abdominal aortic dissection. Sorafenib treatment was associated with Cushing's syndrome remission, elevated progesterone (>10 fold), normalization of dehydroepiandrostenedione sulfate, but persistently elevated cortisol concentration. Newly-developed proximal lower limb weakness and decreased salivation were associated with elevated ganglionic neuronal acetylcholine receptor (alpha-3) and borderline P/Q type calcium channel antibodies. Extreme cortisol concentration may have contributed to aortic dissection and suppressed antidiuretic hormone secretion; which combined with hypokalemia due cortisol activation of mineralocorticoid receptors, manifested as diabetes insipidus. This is the first report of paraneoplastic dysautonomia and jejunal intussusception in medullary thyroid cancer, they may be related to medullary thyroid cancer's neuroendocrine origin and metastasis, respectively. Remission of Cushing's syndrome without measurable reduction in cortisol concentration suggests a novel cortisol-independent mechanism of action or assay cross-reactivity. Normalization of dehydroepiandrostenedione

  3. Sorafenib-induced defective autophagy promotes cell death by necroptosis

    OpenAIRE

    Kharaziha, Pedram; Chioureas, Dimitris; Baltatzis, George; Fonseca, Pedro; Rodriguez, Patricia; Gogvadze, Vladimir; Lennartsson, Lena; Bj?rklund, Ann-Charlotte; Zhivotovsky, Boris; Grand?r, Dan; Egevad, Lars; Nilsson, Sten; Panaretakis, Theocharis

    2015-01-01

    Autophagy is one of the main cytoprotective mechanisms that cancer cells deploy to withstand the cytotoxic stress and survive the lethal damage induced by anti-cancer drugs. However, under specific conditions, autophagy may, directly or indirectly, induce cell death. In our study, treatment of the Atg5-deficient DU145 prostate cancer cells, with the multi-tyrosine kinase inhibitor, sorafenib, induces mitochondrial damage, autophagy and cell death. Molecular inhibition of autophagy by silencin...

  4. Hepatic Stellate Cell Coculture Enables Sorafenib Resistance in Huh7 Cells through HGF/c-Met/Akt and Jak2/Stat3 Pathways

    Directory of Open Access Journals (Sweden)

    Weibo Chen

    2014-01-01

    Full Text Available Purpose. Tumor microenvironment confers drug resistance to kinase inhibitors by increasing RKT ligand levels that result in the activation of cell-survival signaling including PI3K and MAPK signals. We assessed whether HSC-LX2 coculture conferred sorafenib resistance in Huh7 and revealed the mechanism underlying the drug resistance. Experimental Design. The effect of LX2 on sorafenib resistance was determined by coculture system with Huh7 cells. The rescue function of LX2 supernatants was assessed by MTT assay and fluorescence microscopy. The underlying mechanism was tested by administration of pathway inhibitors and manifested by Western blotting. Results. LX2 coculture significantly induced sorafenib resistance in Huh7 by activating p-Akt that led to reactivation of p-ERK. LX2 secreted HGF into the culture medium that triggered drug resistance, and exogenous HGF could also induce sorafenib resistance. The inhibition of p-Akt blocked sorafenib resistance caused by LX2 coculture. Increased phosphorylation of Jak2 and Stat3 was also detected in LX2 cocultured Huh7 cells. The Jak inhibitor tofacitinib reversed sorafenib resistance by blocking Jak2 and Stat3 activation. The combined administration of sorafenib and p-Stat3 inhibitor S3I-201 augmented induced apoptosis even in the presence of sorafenib resistance. Conclusions. HSC-LX2 coculture induced sorafenib resistance in Huh7 through multiple pathways: HGF/c-Met/Akt pathway and Jak2/Stat3 pathway. A combined administration of sorafenib and S3I-201 was able to augment sorafenib-induced apoptosis even in the presence of LX2 coculture.

  5. Successful treatment of paraganglioma with sorafenib: a case report and brief review of the literature

    Directory of Open Access Journals (Sweden)

    Lin Y

    2013-11-01

    Full Text Available Yun Lin,1,* Qun Li,1,* Wei Huang,1 Xinyan Jia,1 Hong Jiang,1 Yong Gao,1 Qi Li1,21Department of Oncology, Shanghai East Hospital, 2Department of Oncology, Shanghai First People's Hospital, Shanghai, People's Republic of China*These authors contributed equally to this work, and are joint first authorsIntroduction: To date, no effective systemic therapies have been made available for paraganglioma. However, multiple mutations in susceptibility genes have been identified that are potential targets for sorafenib, an oral multitargeted tyrosine-kinase inhibitor.Case presentation: We report the case of a 69-year-old Chinese man with mediastinal paraganglioma that had metastasized to the bone. The paraganglioma responded to sorafenib, a novel multi-tyrosine kinase inhibitor that targets angiogenesis, the Raf-kinase pathway, the platelet-derived growth factor Ret, and c-Kit. The patient was diagnosed as having paraganglioma after biopsy of the mediastinal mass. We first treated the patient with radiotherapy. Then he tolerated an etoposide-and-cisplatin chemotherapy regimen. Subsequently, he received 6 months of maintenance treatment with sorafenib (400 mg twice daily. A dramatic reduction in tumor volume was observed. At present, the patient has achieved a partial response, and his clinical status remains unchanged.Conclusion: We suggest that sorafenib should be further investigated in the management of patients with paraganglioma.Keywords: sorafenib, paraganglioma, molecular-targeted drug

  6. Cancer patients treated with sunitinib or sorafenib have sufficient antibody and cellular immune responses to warrant influenza vaccination.

    Science.gov (United States)

    Mulder, Sasja F; Jacobs, Joannes F M; Olde Nordkamp, Michel A M; Galama, Joep M D; Desar, Ingrid M E; Torensma, Ruurd; Teerenstra, Steven; Mulders, Peter F A; Vissers, Kris C P; Punt, Cornelis J A; de Vries, I Jolanda M; van Herpen, Carla M L

    2011-07-01

    The tyrosine kinase inhibitors sorafenib and sunitinib have efficacy in several types of cancer. Recent studies indicate that these agents affect the immune system. The way it affects the immune response to influenza vaccination is unknown. The aim of this study was to elucidate the specific immune response to seasonal flu vaccination in cancer patients treated with sunitinib or sorafenib. Sunitinib- or sorafenib-treated cancer patients were vaccinated against seasonal influenza with an inactivated vaccine. Healthy controls and patients with metastatic renal cell cancer (mRCC) without systemic treatment (nontreated mRCC controls) were included for comparison. Antibody responses were measured at baseline, day 8, and day 22 by a standard hemagglutination inhibition assay and cellular T-cell responses at baseline and day 8 by proliferation assay and secretion of cytokines. Forty subjects were enrolled: 16 patients treated with sunitinib, 6 patients with sorafenib, 7 nontreated mRCC controls, and 11 healthy controls. All patients treated with sunitinib and sorafenib developed seroprotection rates comparable with controls. Functional T-cell reactivity was observed in all groups, except for patients treated with sorafenib who showed a decreased proliferation rate and IFN-γ/IL-2 production and increased IL-10 compared with healthy controls. We conclude that influenza vaccination should be recommended to cancer patients treated with sunitinib or sorafenib.

  7. CM363, a novel naphthoquinone derivative which acts as multikinase modulator and overcomes imatinib resistance in chronic myelogenous leukemia

    Science.gov (United States)

    Díaz-Chico, Juan Carlos; McNaughton-Smith, Grant; Jiménez-Alonso, Sandra; Hueso-Falcón, Idaira; Montero, Juan Carlos; Blanco, Raquel; León, Javier; Rodríguez-González, Germán; Estévez-Braun, Ana; Pandiella, Atanasio; Díaz-Chico, Bonifacio Nicolás; Fernández-Pérez, Leandro

    2017-01-01

    Human Chronic Myelogenous Leukemia (CML) is a hematological stem cell disorder which is associated with activation of Bcr-Abl-Stat5 oncogenic pathway. Direct Bcr-Abl inhibitors are initially successful for the treatment of CML but over time many patients develop drug resistance. In the present study, the effects of CM363, a novel naphthoquinone (NPQ) derivative, were evaluated on human CML-derived K562 cells. CM363 revealed an effective cell growth inhibition (IC50 = 0.7 ± 0.5 μM) by inducing cancer cells to undergo cell cycle arrest and apoptosis. CM363 caused a dose- and time-dependent reduction of cells in G0/G1 and G2/M phases. This cell cycle arrest was associated with increased levels of cyclin E, pChk1 and pChk2 whereas CM363 downregulated cyclin B, cyclin D3, p27, pRB, Wee1, and BUBR1. CM363 increased the double-strand DNA break marker γH2AX. CM363 caused a time-dependent increase of annexin V-positive cells, DNA fragmentation and increased number of apoptotic nuclei. CM363 triggered the mitochondrial apoptotic pathway as reflected by a release of cytochrome C from mitochondria and induction of the cleavage of caspase-3 and -9, and PARP. CM363 showed multikinase modulatory effects through an early increased JNK phosphorylation followed by inhibition of pY-Bcrl-Abl and pY-Stat5. CM363 worked synergistically with imatinib to inhibit cell viability and maintained its activity in imatinib-resistant cells. Finally, CM363 (10 mg/Kg) suppressed the growth of K562 xenograft tumors in athymic mice. In summary, CM363 is a novel multikinase modulator that offers advantages to circumvent imanitib resistance and might be therapeutically effective in Bcrl-Abl-Stat5 related malignancies. PMID:27557509

  8. Simultaneous silencing of ACSL4 and induction of GADD45B in hepatocellular carcinoma cells amplifies the synergistic therapeutic effect of aspirin and sorafenib

    Science.gov (United States)

    Xia, Hongping; Lee, Kee Wah; Chen, Jianxiang; Kong, Shik Nie; Sekar, Karthik; Deivasigamani, Amudha; Seshachalam, Veerabrahma Pratap; Goh, Brian Kim Poh; Ooi, London Lucien; Hui, Kam M

    2017-01-01

    Sorafenib is currently the only US Food and Drug Administration (FDA)-approved molecular inhibitor for the systemic therapy of advanced hepatocellular carcinoma (HCC). Aspirin has been studied extensively as an anti-inflammation, cancer preventive and therapeutic agent. However, the potential synergistic therapeutic effects of sorafenib and aspirin on advanced HCC treatment have not been well studied. Drug combination studies and their synergy quantification were performed using the combination index method of Chou-Talalay. The synergistic therapeutic effects of sorafenib and aspirin were evaluated using an orthotopic mouse model of HCC and comprehensive gene profiling analyses were conducted to identify key factors mediating the synergistic therapeutic effects of sorafenib and aspirin. Sorafenib was determined to act synergistically on HCC cells with aspirin in vitro. Using Hep3B and HuH7 HCC cells, it was demonstrated that sorafenib and aspirin acted synergistically to induce apoptosis. Mechanistic studies demonstrated that combining sorafenib and aspirin yielded significant synergistically anti-tumor effects by simultaneously silencing ACSL4 and the induction of GADD45B expression in HCC cells both in vitro and in the orthotopic HCC xenograft mouse model. Importantly, clinical evidence has independently corroborated that survival of HCC patients expressing ACSL4highGADD45Blow was significantly poorer compared to patients with ACSL4lowGADD45Bhigh, thus demonstrating the potential clinical value of combining aspirin and sorafenib for HCC patients expressing ACSL4highGADD45Blow. In conclusion, sorafenib and aspirin provide synergistic therapeutic effects on HCC cells that are achieved through simultaneous silencing of ACSL4 and induction of GADD45B expression. Targeting HCC with ACSL4highGADD45Blow expression with aspirin and sorafenib could provide potential synergistic therapeutic benefits. PMID:28900541

  9. Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells.

    Science.gov (United States)

    Mathew, Nimitha R; Baumgartner, Francis; Braun, Lukas; O'Sullivan, David; Thomas, Simone; Waterhouse, Miguel; Müller, Tony A; Hanke, Kathrin; Taromi, Sanaz; Apostolova, Petya; Illert, Anna L; Melchinger, Wolfgang; Duquesne, Sandra; Schmitt-Graeff, Annette; Osswald, Lena; Yan, Kai-Li; Weber, Arnim; Tugues, Sonia; Spath, Sabine; Pfeifer, Dietmar; Follo, Marie; Claus, Rainer; Lübbert, Michael; Rummelt, Christoph; Bertz, Hartmut; Wäsch, Ralph; Haag, Johanna; Schmidts, Andrea; Schultheiss, Michael; Bettinger, Dominik; Thimme, Robert; Ullrich, Evelyn; Tanriver, Yakup; Vuong, Giang Lam; Arnold, Renate; Hemmati, Philipp; Wolf, Dominik; Ditschkowski, Markus; Jilg, Cordula; Wilhelm, Konrad; Leiber, Christian; Gerull, Sabine; Halter, Jörg; Lengerke, Claudia; Pabst, Thomas; Schroeder, Thomas; Kobbe, Guido; Rösler, Wolf; Doostkam, Soroush; Meckel, Stephan; Stabla, Kathleen; Metzelder, Stephan K; Halbach, Sebastian; Brummer, Tilman; Hu, Zehan; Dengjel, Joern; Hackanson, Björn; Schmid, Christoph; Holtick, Udo; Scheid, Christof; Spyridonidis, Alexandros; Stölzel, Friedrich; Ordemann, Rainer; Müller, Lutz P; Sicre-de-Fontbrune, Flore; Ihorst, Gabriele; Kuball, Jürgen; Ehlert, Jan E; Feger, Daniel; Wagner, Eva-Maria; Cahn, Jean-Yves; Schnell, Jacqueline; Kuchenbauer, Florian; Bunjes, Donald; Chakraverty, Ronjon; Richardson, Simon; Gill, Saar; Kröger, Nicolaus; Ayuk, Francis; Vago, Luca; Ciceri, Fabio; Müller, Antonia M; Kondo, Takeshi; Teshima, Takanori; Klaeger, Susan; Kuster, Bernhard; Kim, Dennis Dong Hwan; Weisdorf, Daniel; van der Velden, Walter; Dörfel, Daniela; Bethge, Wolfgang; Hilgendorf, Inken; Hochhaus, Andreas; Andrieux, Geoffroy; Börries, Melanie; Busch, Hauke; Magenau, John; Reddy, Pavan; Labopin, Myriam; Antin, Joseph H; Henden, Andrea S; Hill, Geoffrey R; Kennedy, Glen A; Bar, Merav; Sarma, Anita; McLornan, Donal; Mufti, Ghulam; Oran, Betul; Rezvani, Katayoun; Shah, Omid; Negrin, Robert S; Nagler, Arnon; Prinz, Marco; Burchert, Andreas; Neubauer, Andreas; Beelen, Dietrich; Mackensen, Andreas; von Bubnoff, Nikolas; Herr, Wolfgang; Becher, Burkhard; Socié, Gerard; Caligiuri, Michael A; Ruggiero, Eliana; Bonini, Chiara; Häcker, Georg; Duyster, Justus; Finke, Jürgen; Pearce, Erika; Blazar, Bruce R; Zeiser, Robert

    2018-03-01

    Individuals with acute myeloid leukemia (AML) harboring an internal tandem duplication (ITD) in the gene encoding Fms-related tyrosine kinase 3 (FLT3) who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) have a 1-year survival rate below 20%. We observed that sorafenib, a multitargeted tyrosine kinase inhibitor, increased IL-15 production by FLT3-ITD + leukemia cells. This synergized with the allogeneic CD8 + T cell response, leading to long-term survival in six mouse models of FLT3-ITD + AML. Sorafenib-related IL-15 production caused an increase in CD8 + CD107a + IFN-γ + T cells with features of longevity (high levels of Bcl-2 and reduced PD-1 levels), which eradicated leukemia in secondary recipients. Mechanistically, sorafenib reduced expression of the transcription factor ATF4, thereby blocking negative regulation of interferon regulatory factor 7 (IRF7) activation, which enhanced IL-15 transcription. Both IRF7 knockdown and ATF4 overexpression in leukemia cells antagonized sorafenib-induced IL-15 production in vitro. Human FLT3-ITD + AML cells obtained from sorafenib responders following sorafenib therapy showed increased levels of IL-15, phosphorylated IRF7, and a transcriptionally active IRF7 chromatin state. The mitochondrial spare respiratory capacity and glycolytic capacity of CD8 + T cells increased upon sorafenib treatment in sorafenib responders but not in nonresponders. Our findings indicate that the synergism of T cells and sorafenib is mediated via reduced ATF4 expression, causing activation of the IRF7-IL-15 axis in leukemia cells and thereby leading to metabolic reprogramming of leukemia-reactive T cells in humans. Therefore, sorafenib treatment has the potential to contribute to an immune-mediated cure of FLT3-ITD-mutant AML relapse, an otherwise fatal complication after allo-HCT.

  10. Plectin deficiency in liver cancer cells promotes cell migration and sensitivity to sorafenib treatment.

    Science.gov (United States)

    Cheng, Chiung-Chi; Chao, Wei-Ting; Liao, Chen-Chun; Tseng, Yu-Hui; Lai, Yen-Chang Clark; Lai, Yih-Shyong; Hsu, Yung-Hsiang; Liu, Yi-Hsiang

    2018-01-02

    Plectin involved in activation of kinases in cell signaling pathway and plays important role in cell morphology and migration. Plectin knockdown promotes cell migration by activating focal adhesion kinase and Rac1-GTPase activity in liver cells. Sorafenib is a multi-targeting tyrosine kinase inhibitor that improves patient survival on hepatocellular carcinoma. The aim of this study is to investigate the correlation between the expression of plectin and cell migration as well as the sensitivity of hepatoma cell lines exposing to sorafenib. Hepatoma cell lines PLC/PRF/5 and HepG2 were used to examine the level of plectin expression and cell migration in comparison with Chang liver cell line. In addition, sensitivity of the 3 cell lines to sorafenib treatment was also measured. Expression of plectin was lower in PLC/PRF/5 and HepG2 hepatoma cells than that of Chang liver cells whereas HepG2 and PLC/PRF/5 cells exhibit higher rate of cell migration in trans-well migration assay. Immunohistofluorecent staining on E-cadherin revealed the highest rate of collective cell migration in HepG2 cells and the lowest was found in Chang liver cells. Likewise, HepG2 cell line was most sensitive to sorafenib treatment and Chang liver cells exhibited the least sensitivity. The drug sensitivity to sorafenib treatment showed inverse correlation with the expression of plectin. We suggest that plectin deficiency and increased E-cadherin in hepatoma cells were associated with higher rates of cell motility, collective cell migration as well as higher drug sensitivity to sorafenib treatment.

  11. Sorafenib inhibits tumor growth and vascularization of rhabdomyosarcoma cells by blocking IGF-1R-mediated signaling

    Directory of Open Access Journals (Sweden)

    Wessen Maruwge

    2008-11-01

    Full Text Available Wessen Maruwge1, Pádraig D’Arcy1, Annika Folin1,2, Slavica Brnjic1, Johan Wejde1, Anthony Davis1, Fredrik Erlandsson3, Jonas Bergh1,2, Bertha Brodin11Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden; 2Radiumhemmet, Karolinska University Hospital, Stockholm, Sweden; 3Bayer Pharmaceutical Corporation, SwedenAbstract: The growth of many soft tissue sarcomas is dependent on aberrant growth factor signaling, which promotes their proliferation and motility. With this in mind, we evaluated the effect of sorafenib, a receptor tyrosine kinase inhibitor, on cell growth and apoptosis in sarcoma cell lines of various histological subtypes. We found that sorafenib effectively inhibited cell proliferation in rhabdomyosarcoma, synovial sarcoma and Ewing’s sarcoma with IC50 values <5 µM. Sorafenib effectively induced growth arrest in rhabdomyosarcoma cells, which was concurrent with inhibition of Akt and Erk signaling. Studies of ligand-induced phosphorylation of Erk and Akt in rhabdomyosarcoma cells showed that insulin-like growth factor-1 is a potent activator, which can be blocked by treatment with sorafenib. In vivo sorafenib treatment of rhabdomyosarcoma xenografts had a significant inhibitory effect on tumor growth, which was associated with inhibited vascularization and enhanced necrosis in the adjacent tumor stroma. Our results demonstrate that in vitro and in vivo growth of rhabdomyosarcoma can be suppressed by treatment with sorafenib, and suggests the possibilities of using sorafenib as a potential adjuvant therapy for the treatment of rhabdomyosarcoma.Keywords: soft tissue sarcoma, kinase inhibitors, targeted therapy, vascularization

  12. PKI-587 and sorafenib targeting PI3K/AKT/mTOR and Ras/Raf/MAPK pathways synergistically inhibit HCC cell proliferation.

    Science.gov (United States)

    Gedaly, Roberto; Angulo, Paul; Hundley, Jonathan; Daily, Michael F; Chen, Changguo; Evers, B Mark

    2012-08-01

    Deregulated Ras/Raf/MAPK and PI3K/AKT/mTOR signaling pathways are found in hepatocellular carcinoma (HCC). This study aimed to test the inhibitory effects of PKI-587 and sorafenib as single agents or in combination on HCC (Huh7 cell line) proliferation. (3)H-thymidine incorporation and MTT assay were used to assess Huh7 cell proliferation. Phosphorylation of the key enzymes in the Ras/Raf/MAPK and PI3K/AKT/mTOR pathways was detected by Western blot. We found that PKI-587 is a more potent PI3K/mTOR inhibitor than PI-103. Combination of PKI-587 and sorafenib was a more effective inhibitor of Huh7 proliferation than the combination of PI-103 and sorafenib. Combination of PKI-587 and sorafenib synergistically inhibited epidermal growth factor (EGF)-stimulated Huh7 proliferation compared with monodrug therapy. EGF increased phosphorylation of Ras/Raf downstream signaling proteins MEK and ERK; EGF-stimulated activation was inhibited by sorafenib. However, sorafenib, as a single agent, increased AKT (Ser473) phosphorylation. EGF-stimulated AKT (ser473) activation was inhibited by PKI-587. PKI-587 is a potent inhibitor of AKT (Ser473), mTOR (Ser2448), and S6K (Thr389) phosphorylation; in contrast, rapamycin stimulated mTOR complex 2 substrate AKT(Ser473) phosphorylation although it inhibited mTOR complex 1 substrate S6K phosphorylation. PKI-587, as a single agent, stimulated MEK and ERK phosphorylation. However, when PKI-587 and sorafenib were used in combination, they inhibited all the tested kinases in the Ras/Raf /MAPK and PI3K/AKT/mTOR pathways. The combination of PKI-587 and sorafenib has the advantage over monodrug therapy on inhibition of HCC cell proliferation by blocking both PI3K/AKT/mTOR and Ras/Raf/MAPK signaling pathways. Copyright © 2012 Elsevier Inc. All rights reserved.

  13. Hypothyroidism Side Effect in Patients Treated with Sunitinib or Sorafenib: Clinical and Structural Analyses

    Science.gov (United States)

    Shu, Mao; Zai, Xiaoli; Zhang, Beina; Wang, Rui; Lin, Zhihua

    2016-01-01

    Tyrosine kinase inhibitors (TKIs) provide more effective targeted treatments for cancer, but are subject to a variety of adverse effects, such as hypothyroidism. TKI-induced hypothyroidism is a highly complicated issue, because of not only the unrealized toxicological mechanisms, but also different incidences of individual TKI drugs. While sunitinib is suspected for causing thyroid dysfunction more often than other TKIs, sorafenib is believed to be less risky. Here we integrated clinical data and in silico drug-protein interactions to examine the pharmacological distinction between sunitinib and sorafenib. Statistical analysis on the FDA Adverse Event Reporting System (FAERS) confirmed that sunitinib is more concurrent with hypothyroidism than sorafenib, which was observed in both female and male patients. Then, we used docking method and identified 3 proteins specifically binding to sunitinib but not sorafenib, i.e., retinoid X receptor alpha, retinoic acid receptors beta and gamma. As potential off-targets of sunitinib, these proteins are well known to assemble with thyroid hormone receptors, which can explain the profound impact of sunitinib on thyroid function. Taken together, we established a strategy of integrated analysis on clinical records and drug off-targets, which can be applied to explore the molecular basis of various adverse drug reactions. PMID:26784451

  14. Cancer patients treated with sunitinib or sorafenib have sufficient antibody and cellular immune responses to warrant influenza vaccination

    NARCIS (Netherlands)

    Mulder, Sasja F.; Jacobs, Joannes F. M.; Olde Nordkamp, Michel A. M.; Galama, Joep M. D.; Desar, Ingrid M. E.; Torensma, Ruurd; Teerenstra, Steven; Mulders, Peter F. A.; Vissers, Kris C. P.; Punt, Cornelis J. A.; de Vries, I. Jolanda M.; van Herpen, Carla M. L.

    2011-01-01

    The tyrosine kinase inhibitors sorafenib and sunitinib have efficacy in several types of cancer. Recent studies indicate that these agents affect the immune system. The way it affects the immune response to influenza vaccination is unknown. The aim of this study was to elucidate the specific immune

  15. Cancer patients treated with sunitinib or sorafenib have sufficient antibody and cellular immune responses to warrant influenza vaccination

    NARCIS (Netherlands)

    Mulder, S.F.; Jacobs, J.F.M.; Olde Nordkamp, M.A.M.; Galama, J.M.D.; Desar, I.M.E.; Torensma, R.; Teerenstra, S.; Mulders, P.F.; Vissers, K.C.P.; Punt, C.J.A.; Vries, I.J.M. de; Herpen, C.M.L. van

    2011-01-01

    PURPOSE: The tyrosine kinase inhibitors sorafenib and sunitinib have efficacy in several types of cancer. Recent studies indicate that these agents affect the immune system. The way it affects the immune response to influenza vaccination is unknown. The aim of this study was to elucidate the

  16. Fasting inhibits hepatic stellate cells activation and potentiates anti-cancer activity of Sorafenib in hepatocellular cancer cells.

    Science.gov (United States)

    Lo Re, Oriana; Panebianco, Concetta; Porto, Stefania; Cervi, Carlo; Rappa, Francesca; Di Biase, Stefano; Caraglia, Michele; Pazienza, Valerio; Vinciguerra, Manlio

    2018-02-01

    Hepatocellular carcinoma (HCC) has a poor outcome. Most HCCs develop in the context of liver fibrosis and cirrhosis caused by chronic inflammation. Short-term fasting approaches enhance the activity of chemotherapy in preclinical cancer models, other than HCC. Multi-tyrosine kinase inhibitor Sorafenib is the mainstay of treatment in HCC. However, its benefit is frequently short-lived. Whether fasting can alleviate liver fibrosis and whether combining fasting with Sorafenib is beneficial remains unknown. A 24 hr fasting (2% serum, 0.1% glucose)-induced changes on human hepatic stellate cells (HSC) LX-2 proliferation/viability/cell cycle were assessed by MTT and flow cytometry. Expression of lypolysaccharide (LPS)-induced activation markers (vimentin, αSMA) was evaluated by qPCR and immunoblotting. Liver fibrosis and inflammation were evaluated in a mouse model of steatohepatitis exposed to cycles of fasting, by histological and biochemical analyses. A 24 hr fasting-induced changes were also analyzed on the proliferation/viability/glucose uptake of human HCC cells exposed to Sorafenib. An expression panel of genes involved in survival, inflammation, and metabolism was examined by qPCR in HCC cells exposed to fasting and/or Sorafenib. Fasting decreased the proliferation and the activation of HSC. Repeated cycles of short term starvation were safe in mice but did not improve fibrosis. Fasting synergized with Sorafenib in hampering HCC cell growth and glucose uptake. Finally, fasting normalized the expression levels of genes which are commonly altered by Sorafenib in HCC cells. Fasting or fasting-mimicking diet diets should be evaluated in preclinical studies as a mean to potentiate the activity of Sorafenib in clinical use. © 2017 Wiley Periodicals, Inc.

  17. Sorafenib-Associated Heart Failure Complicated by Cardiogenic Shock after Treatment of Advanced Stage Hepatocellular Carcinoma: A Clinical Case Discussion

    Directory of Open Access Journals (Sweden)

    Candace Wu

    2017-01-01

    Full Text Available Background. Sorafenib, an oral tyrosine kinase inhibitor (TKI, targets multiple tyrosine kinase receptors (TKRs involved in angiogenesis and tumor growth. Studies suggest that inhibition of TKR impacts cardiomyocyte survival. Inhibition of VEGF signaling interrupts angiogenesis and is associated with the development of hypertension and compensatory hypertrophy. Compensated hypertrophy ultimately leads to heart failure. Case Description. A 76-year-old man with a past medical history of systolic heart failure due to ischemic cardiomyopathy and stage IIIC hepatocellular carcinoma (HCC presented with symptoms of decompensated heart failure. Four months prior to admission, he was started on sorafenib. Results. Our patient was treated with intravenous furosemide and guideline directed therapy. Clinical status was complicated by the development of low cardiac output and shock requiring inotropic support. Careful titration of heart failure medication led to hemodynamic improvement and discontinuation of dobutamine. Conclusion. Greater awareness of sorafenib cardiotoxicity is essential. As TKI usage grows for treatment of cancers, heart failure-related complications will increase. In our patient, routine heart failure management and cessation of sorafenib led to clinical improvement. Future studies on the treatment of sorafenib cardiotoxicity should be explored further in this unique patient population.

  18. Epigastric Distress Caused by Esophageal Candidiasis in 2 Patients Who Received Sorafenib Plus Radiotherapy for Hepatocellular Carcinoma: Case Report.

    Science.gov (United States)

    Chen, Kuo-Hsin; Weng, Meng-Tzu; Chou, Yueh-Hung; Lu, Yueh-Feng; Hsieh, Chen-Hsi

    2016-03-01

    Sorafenib followed by fractionated radiotherapy (RT) has been shown to decrease the phagocytic and candidacidal activities of antifungal agents due to radiosensitization. Moreover, sorafenib has been shown to suppress the immune system, thereby increasing the risk for candida colonization and infection. In this study, we present the 2 hepatocellular carcinoma (HCC) patients suffered from epigastric distress caused by esophageal candidiasis who received sorafenib plus RT. Two patients who had received sorafenib and RT for HCC with bone metastasis presented with hiccups, gastric ulcer, epigastric distress, anorexia, heart burn, and fatigue. Empiric antiemetic agents, antacids, and pain killers were ineffective at relieving symptoms. Panendoscopy revealed diffuse white lesions in the esophagus. Candida esophagitis was suspected. Results of periodic acid-Schiff staining were diagnostic of candidiasis. Oral fluconazole (150 mg) twice daily and proton-pump inhibitors were prescribed. At 2-weak follow-up, esophagitis had resolved and both patients were free of gastrointestinal symptoms. Physicians should be aware that sorafenib combined with RT may induce an immunosuppressive state in patients with HCC, thereby increasing their risk of developing esophagitis due to candida species.

  19. Sorafenib Increases Tumor Hypoxia in Cervical Cancer Patients Treated With Radiation Therapy: Results of a Phase 1 Clinical Study

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    Milosevic, Michael F., E-mail: mike.milosevic@rmp.uhn.ca [Radiation Medicine Program, Princess Margaret Cancer Center, University Health Network, Toronto (Canada); Department of Radiation Oncology, University of Toronto, Toronto (Canada); Townsley, Carol A. [Department of Medical Oncology, Princess Margaret Cancer Center, University Health Network, Toronto (Canada); Chaudary, Naz [Department of Advanced Molecular Oncology, Princess Margaret Cancer Center, University Health Network, Toronto (Canada); Clarke, Blaise [Department of Pathology, Princess Margaret Cancer Center, University Health Network, Toronto (Canada); Department of Laboratory Medicine and Pathology, University of Toronto, Toronto (Canada); Pintilie, Melania [Department of Clinical Study Coordination and Biostatistics, Princess Margaret Cancer Center, University Health Network, Toronto (Canada); Fan, Stacy; Glicksman, Rachel [Radiation Medicine Program, Princess Margaret Cancer Center, University Health Network, Toronto (Canada); Haider, Masoom [Department of Medical Imaging, Sunnybrook Health Sciences Centre, Toronto (Canada); Department of Medical Imaging, University of Toronto, Toronto (Canada); Kim, Sunmo [Radiation Medicine Program, Princess Margaret Cancer Center, University Health Network, Toronto (Canada); MacKay, Helen [Department of Medical Oncology, Princess Margaret Cancer Center, University Health Network, Toronto (Canada); Department of Medicine, University of Toronto, Toronto (Canada); Yeung, Ivan [Radiation Medicine Program, Princess Margaret Cancer Center, University Health Network, Toronto (Canada); Department of Radiation Oncology, University of Toronto, Toronto (Canada); Hill, Richard P. [Department of Radiation Oncology, University of Toronto, Toronto (Canada); Department of Advanced Molecular Oncology, Princess Margaret Cancer Center, University Health Network, Toronto (Canada); Department of Medical Biophysics, University of Toronto, Toronto (Canada); and others

    2016-01-01

    Purpose: Preclinical studies have shown that angiogenesis inhibition can improve response to radiation therapy (RT). The purpose of this phase 1 study was to examine the angiogenesis inhibitor sorafenib in patients with cervical cancer receiving radical RT and concurrent cisplatin (RTCT). Methods and Materials: Thirteen patients with stage IB to IIIB cervical cancer participated. Sorafenib was administered daily for 7 days before the start of standard RTCT in patients with early-stage, low-risk disease and also during RTCT in patients with high-risk disease. Biomarkers of tumor vascularity, perfusion, and hypoxia were measured at baseline and again after 7 days of sorafenib alone before the start of RTCT. The median follow-up time was 4.5 years. Results: Initial complete response was seen in 12 patients. One patient died without achieving disease control, and 4 experienced recurrent disease. One patient with an extensive, infiltrative tumor experienced pelvic fistulas during treatment. The 4-year actuarial survival was 85%. Late grade 3 gastrointestinal toxicity developed in 4 patients. Sorafenib alone produced a reduction in tumor perfusion/permeability and an increase in hypoxia, which resulted in early closure of the study. Conclusions: Sorafenib increased tumor hypoxia, raising concern that it might impair rather than improve disease control when added to RTCT.

  20. Study on Biopharmaceutics Classification and Oral Bioavailability of a Novel Multikinase Inhibitor NCE for Cancer Therapy

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    Yang Yang

    2014-04-01

    Full Text Available Specific biopharmaceutics classification investigation and study on phamacokinetic profile of a novel drug candidate (2-methylcarbamoyl-4-{4-[3- (trifluoromethyl benzamido] phenoxy} pyridinium 4-methylbenzenesulfonate monohydrate, NCE were carried out. Equilibrium solubility and intrinsic dissolution rate (IDR of NCE were estimated in different phosphate buffers. Effective intestinal permeability (Peff of NCE was determined using single-pass intestinal perfusion technique in rat duodenum, jejunum and ileum at three concentrations. Theophylline (high permeability and ranitidine (low permeability were also applied to access the permeability of NCE as reference compounds. The bioavailability after intragastrical and intravenous administration was measured in beagle dogs. The solubility of NCE in tested phosphate buffers was quite low with the maximum solubility of 81.73 μg/mL at pH 1.0. The intrinsic dissolution ratio of NCE was 1 × 10−4 mg·min−1·cm−2. The Peff value of NCE in all intestinal segments was more proximate to the high-permeability reference theophylline. Therefore, NCE was classified as class II drug according to Biopharmaceutics Classification System due to its low solubility and high intestinal permeability. In addition, concentration-dependent permeability was not observed in all the segments, indicating that there might be passive transportation for NCE. The absolute oral bioavailability of NCE in beagle dogs was 26.75%. Therefore, dissolution promotion will be crucial for oral formulation development and intravenous administration route will also be suggested for further NCE formulation development. All the data would provide a reference for biopharmaceutics classification research of other novel drug candidates.

  1. Study on biopharmaceutics classification and oral bioavailability of a novel multikinase inhibitor NCE for cancer therapy.

    Science.gov (United States)

    Yang, Yang; Fan, Chun-Mei; He, Xuan; Ren, Ke; Zhang, Jin-Kun; He, Ying-Ju; Yu, Luo-Ting; Zhao, Ying-Lan; Gong, Chang-Yang; Zheng, Yu; Song, Xiang-Rong; Zeng, Jun

    2014-04-25

    Specific biopharmaceutics classification investigation and study on phamacokinetic profile of a novel drug candidate (2-methylcarbamoyl-4-{4-[3- (trifluoromethyl) benzamido] phenoxy} pyridinium 4-methylbenzenesulfonate monohydrate, NCE) were carried out. Equilibrium solubility and intrinsic dissolution rate (IDR) of NCE were estimated in different phosphate buffers. Effective intestinal permeability (P(eff)) of NCE was determined using single-pass intestinal perfusion technique in rat duodenum, jejunum and ileum at three concentrations. Theophylline (high permeability) and ranitidine (low permeability) were also applied to access the permeability of NCE as reference compounds. The bioavailability after intragastrical and intravenous administration was measured in beagle dogs. The solubility of NCE in tested phosphate buffers was quite low with the maximum solubility of 81.73 μg/mL at pH 1.0. The intrinsic dissolution ratio of NCE was 1 × 10⁻⁴ mg·min⁻¹·cm⁻². The P(eff) value of NCE in all intestinal segments was more proximate to the high-permeability reference theophylline. Therefore, NCE was classified as class II drug according to Biopharmaceutics Classification System due to its low solubility and high intestinal permeability. In addition, concentration-dependent permeability was not observed in all the segments, indicating that there might be passive transportation for NCE. The absolute oral bioavailability of NCE in beagle dogs was 26.75%. Therefore, dissolution promotion will be crucial for oral formulation development and intravenous administration route will also be suggested for further NCE formulation development. All the data would provide a reference for biopharmaceutics classification research of other novel drug candidates.

  2. A pooled analysis of sequential therapies with sorafenib and sunitinib in metastatic renal cell carcinoma.

    Science.gov (United States)

    Stenner, Frank; Chastonay, Rahel; Liewen, Heike; Haile, Sarah R; Cathomas, Richard; Rothermundt, Christian; Siciliano, Raffaele D; Stoll, Susanna; Knuth, Alexander; Buchler, Tomas; Porta, Camillo; Renner, Christoph; Samaras, Panagiotis

    2012-01-01

    To evaluate the optimal sequence for the receptor tyrosine kinase inhibitors (rTKIs) sorafenib and sunitinib in metastatic renal cell cancer. We performed a retrospective analysis of patients who had received sequential therapy with both rTKIs and integrated these results into a pooled analysis of available data from other publications. Differences in median progression-free survival (PFS) for first- (PFS1) and second-line treatment (PFS2), and for the combined PFS (PFS1 plus PFS2) were examined using weighted linear regression. In the pooled analysis encompassing 853 patients, the median combined PFS for first-line sunitinib and 2nd-line sorafenib (SuSo) was 12.1 months compared with 15.4 months for the reverse sequence (SoSu; 95% CI for difference 1.45-5.12, p = 0.0013). Regarding first-line treatment, no significant difference in PFS1 was noted regardless of which drug was initially used (0.62 months average increase on sorafenib, 95% CI for difference -1.01 to 2.26, p = 0.43). In second-line treatment, sunitinib showed a significantly longer PFS2 than sorafenib (average increase 2.66 months, 95% CI 1.02-4.3, p = 0.003). The SoSu sequence translates into a longer combined PFS compared to the SuSo sequence. Predominantly the superiority of sunitinib regarding PFS2 contributed to the longer combined PFS in sequential use. Copyright © 2012 S. Karger AG, Basel.

  3. Optimal therapy for patients with hepatocellular carcinoma and resistance or intolerance to sorafenib: challenges and solutions

    Directory of Open Access Journals (Sweden)

    Ray EM

    2017-11-01

    Full Text Available Emily M Ray, Hanna K Sanoff Division of Hematology/Oncology, University of North Carolina, Chapel Hill, NC, USA Abstract: The only US Food and Drug Administration (FDA-approved first-line systemic therapy for hepatocellular carcinoma (HCC is sorafenib; however, resistance or intolerance to sorafenib is unfortunately common. In this review, we briefly describe systemic therapies that can be considered for patients with HCC who show resistance or intolerance to sorafenib. For all patients with HCC who need systemic therapy, we strongly advocate for participation in clinical trials. Cytotoxic chemotherapy plays a minor role in the treatment of advanced HCC, with some data supporting the use of FOLFOX (infusional fluorouracil, leucovorin, and oxaliplatin and GEMOX (gemcitabine-oxaliplatin. Multi-target kinase inhibitors such as lenvantinib and regorafenib have recently met their primary endpoints as first- and second-line therapy, respectively, with regorafenib now representing the only FDA-approved drug for second-line treatment of HCC. Other targeted therapies remain under investigation, but results so far have not significantly changed clinical practice. Immunotherapy is an interesting area of research in the treatment of HCC with preclinical and early clinical data demonstrating exciting results; thus numerous investigational studies are currently focusing on immunotherapy in the treatment of HCC. While systemic treatment options in HCC remain a challenge for providers, in this review, we summarize the current literature and highlight areas of progress with respect to the treatment of patients with HCC and resistance or intolerance to sorafenib. Keywords: liver cancer, chemotherapy, immunotherapy

  4. The cystic fibrosis transmembrane recruiter the alter ego of CFTR as a multi-kinase anchor.

    Science.gov (United States)

    Mehta, Anil

    2007-11-01

    This review focuses on a newly discovered interaction between protein kinases involved in cellular energetics, a process that may be disturbed in cystic fibrosis for unknown reasons. I propose a new model where kinase-mediated cellular transmission of energy provides mechanistic insight to a latent role of the cystic fibrosis transmembrane conductance regulator (CFTR). I suggest that CFTR acts as a multi-kinase recruiter to the apical epithelial membrane. My group finds that, in the cytosol, two protein kinases involved in cell energy homeostasis, nucleoside diphosphate kinase (NDPK) and AMP-activated kinase (AMPK), bind one another. Preliminary data suggest that both can also bind CFTR (function unclear). The disrupted role of this CFTR-kinase complex as 'membrane transmitter to the cell' is proposed as an alternative paradigm to the conventional ion transport mediated and CFTR/chloride-centric view of cystic fibrosis pathogenesis. Chloride remains important, but instead, chloride-induced control of the phosphohistidine content of one kinase component (NDPK, via a multi-kinase complex that also includes a third kinase, CK2; formerly casein kinase 2). I suggest that this complex provides the necessary near-equilibrium conditions needed for efficient transmission of phosphate energy to proteins controlling cellular energetics. Crucially, a new role for CFTR as a kinase controller is proposed with ionic concentration acting as a signal. The model posits a regulatory control relay for energy sensing involving a cascade of protein kinases bound to CFTR.

  5. Sorafenib prescribed by gastroenterologists and hepatologists for hepatocellular carcinoma

    Science.gov (United States)

    Kaplan, David E.; Mehta, Rajni; D’Addeo, Kathryn; Valderrama, Adriana; Taddei, Tamar H.

    2018-01-01

    Abstract Sorafenib is the only Food and Drug Administration (FDA)-approved first-line therapy shown to have survival benefit for patients with advanced hepatocellular carcinoma (HCC). Patients with advanced HCC are often but not exclusively transferred from non-oncologists to oncologists to initiate systemic therapy. The objective of this study was to assess whether sorafenib prescribing by non-oncologists has any impact on utilization, adverse effects, cost or outcome. This was a retrospective cohort study utilizing data from patients prescribed sorafenib for HCC within Veterans Health Administration hospitals with 100% chart abstraction to confirm HCC diagnosis, identify prescribing provider specialty (oncology versus gastroenterology/hepatology), and obtain data required for cancer staging by the Barcelona Clinic Liver Cancer (BCLC) system. The primary outcome was overall survival from the time of sorafenib prescription. A total of 4903 patients who prescribed sorafenib for HCC were identified, for whom 340 patients (6.9%) were prescribed drug by a non-oncologist (Onc). BCLC Stage, age, Child–Turcotte–Pugh score, and comorbidity indices were similar between patients prescribed sorafenib by oncologists and non-oncologists. Oncologists more often discontinued sorafenib due to progression, whereas non-oncologists were more likely to continue sorafenib until death resulting in greater pill utilization and cost. Overall survival in both unadjusted and multivariable models showed no significant impact of prescriber type on survival (222 vs 217 days, P = .96), confirmed with propensity-matched subcohorts. Similar survival outcomes were observed for patients with HCC prescribed sorafenib by non-oncologists and oncologists, suggesting that non-oncologists with expertise in the management of HCC can safely and effectively administer sorafenib. PMID:29369224

  6. Sorafenib suppresses TGF-β responses by inducing caveolae/lipid raft-mediated internalization/degradation of cell-surface type II TGF-β receptors: Implications in development of effective adjunctive therapy for hepatocellular carcinoma.

    Science.gov (United States)

    Chung, Chih-Ling; Wang, Shih-Wei; Sun, Wei-Chih; Shu, Chih-Wen; Kao, Yu-Chen; Shiao, Meng-Shin; Chen, Chun-Lin

    2018-04-18

    Sorafenib is the only FDA approved drug for the treatment of advanced hepatocellular carcinoma (HCC) and other malignancies. Studies indicate that TGF-β signalling is associated with tumour progression in HCC. Autocrine and paracrine TGF-β promotes tumour growth and malignancy by inducing epithelial-mesenchymal transition (EMT). Sorafenib is believed to antagonize tumour progression by inhibiting TGF-β-induced EMT. It improves survival of patients but HCC later develops resistance and relapses. The underlying mechanism of resistance is unknown. Understanding of the molecular mechanism of sorafenib inhibition of TGF-β-induced signalling or responses in HCC may lead to development of adjunctive effective therapy for HCC. In this study, we demonstrate that sorafenib suppresses TGF-β responsiveness in hepatoma cells, hepatocytes, and animal liver, mainly by downregulating cell-surface type II TGF-β receptors (TβRII) localized in caveolae/lipid rafts and non-lipid raft microdomains via caveolae/lipid rafts-mediated internalization and degradation. Furthermore, sorafenib-induced downregulation and degradation of cell-surface TβRII is prevented by simultaneous treatment with a caveolae disruptor or lysosomal inhibitors. On the other hand, sorafenib only downregulates cell-surface TβRII localized in caveolae/lipid rafts but not localized in non-lipid raft microdomains in hepatic stellate cells. These results suggest that sorafenib inhibits TGF-β signalling mainly by inducing caveolae/lipid raft-mediated internalization and degradation of cell-surface TβR-II in target cells. They may also imply that treatment with agents which promote formation of caveolae/lipid rafts, TGF-β receptor kinase inhibitors (e.g., LY2157299) or TGF-β peptide antagonists (by liver-targeting delivery) may be considered as effective adjunct therapy with sorafenib for HCC. Copyright © 2018 Elsevier Inc. All rights reserved.

  7. Randomize Trial of Cisplatin plus Gemcitabine with either Sorafenib or Placebo as First-line Therapy for Non-small Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Yan WANG

    2011-03-01

    Full Text Available Background and objective Platinum-based chemotherapy doublets reached an efficacy plateau in nonsmall-cell lung cancer (NSCLC. This randomized controlled study prospectively assessed the efficacy and safety of cisplatin plus gemcitabine with either Sorafenib or placebo as first-line therapy for NSCLC. Methods Thirty patients, which were confirmed advanced NSCLC histologically or cytologically, were randomly assigned to receive up to six cycles of cisplatin plus gemcitabine with sorafenib or placebo. The maintenance of sorafenib or placebo after chemotherapy will continued in patients with response or stable disease until disease progression or unacceptable adverse events. Results Overall demographics were balanced between experimental group (sorafenib+chemotherapy and controlled group (chemotherapy only. Overall response (OS rate was 55.6% and 41.7% in experimental arm and controlled arm, respectively (P=0.905. Median progressivefree survival (PFS and median overall survial were similar (5 months vs 4 months, P=0.75; 18 months vs 18 months, P=0.68. Adverse events were tolerable, though the risk of hypertension and diarrhea was increase in experimental arm. Since patients with ECOG PS 0, stage IIIb, no liver metastasis and tyrasine kinasis inhibitor treatment after study had longer survive, these factors seemed to be predictive factors favor of survival in Cox regression analyses. Conclusion No additional benefit of response rate, PFS or OS were observed from adding targeted agent-sorafenib to regular cisplatin plus gemcitabine chemotherapy. Selecting aproper patients is needed in further study.

  8. [Randomize trial of cisplatin plus gemcitabine with either sorafenib or placebo as first-line therapy for non-small cell lung cancer].

    Science.gov (United States)

    Wang, Yan; Wang, Lin; Liu, Yutao; Yu, Shufei; Zhang, Xiangru; Shi, Yuankai; Sun, Yan

    2011-03-01

    Platinum-based chemotherapy doublets reached an efficacy plateau in nonsmall-cell lung cancer (NSCLC). This randomized controlled study prospectively assessed the efficacy and safety of cisplatin plus gemcitabine with either Sorafenib or placebo as first-line therapy for NSCLC. Thirty patients, which were confirmed advanced NSCLC histologically or cytologically, were randomly assigned to receive up to six cycles of cisplatin plus gemcitabine with sorafenib or placebo. The maintenance of sorafenib or placebo after chemotherapy will continued in patients with response or stable disease until disease progression or unacceptable adverse events. Overall demographics were balanced between experimental group (sorafenib+chemotherapy) and controlled group (chemotherapy only). Overall response (OS) rate was 55.6% and 41.7% in experimental arm and controlled arm, respectively (P=0.905). Median progressive-free survival (PFS) and median overall survival were similar (5 months vs 4 months, P=0.75; 18 months vs 18 months, P=0.68). Adverse events were tolerable, though the risk of hypertension and diarrhea was increase in experimental arm. Since patients with ECOG PS 0, stage IIIb, no liver metastasis and tyrasine kinasis inhibitor treatment after study had longer survive, these factors seemed to be predictive factors favor of survival in Cox regression analyses. No additional benefit of response rate, PFS or OS were observed from adding targeted agent-sorafenib to regular cisplatin plus gemcitabine chemotherapy. Selecting aproper patients is needed in further study.

  9. Inhibitors

    Science.gov (United States)

    ... JM, and the Hemophilia Inhibitor Research Study Investigators. Validation of Nijmegen-Bethesda assay modifications to allow inhibitor ... webinars on blood disorders Language: English (US) Español (Spanish) File Formats Help: How do I view different ...

  10. A combination of sorafenib and nilotinib reduces the growth of castrate-resistant prostate cancer

    Directory of Open Access Journals (Sweden)

    Archibald M

    2016-01-01

    Full Text Available Monica Archibald,1 Tara Pritchard,1 Hayley Nehoff,1 Rhonda J Rosengren,1 Khaled Greish,1,2 Sebastien Taurin1 1Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand; 2Aljawhara Centre for Molecular Medicine, Arabian Gulf University, Manama, Kingdom of Bahrain Abstract: Castrate-resistant prostate cancer (CRPC remains incurable due to the lack of effective therapies. Several tyrosine kinases have been implicated in the development and growth of CRPC, as such targeting these kinases may offer an alternative therapeutic strategy. We established the combination of two tyrosine kinase inhibitors (TKIs, sorafenib and nilotinib, as the most cytotoxic. In addtion, to improve their bioavailability and reduce their metabolism, we encapsulated sorafenib and nilotinib into styrene-co-maleic acid micelles. The micelles’ charge, size, and release rate were characterized. We assessed the effect of the combination on the cytotoxicity, cell cycle, apoptosis, protein expression, tumor spheroid integrity, migration, and invasion. The micelles exhibited a mean diameter of 100 nm, a neutral charge, and appeared highly stable. The micellar TKIs promoted greater cytotoxicity, decreased cell proliferation, and increased apoptosis relative to the free TKIs. In addition, the combination reduced the expression and activity of several tyrosine kinases and reduced tumor spheroid integrity and metastatic potential of CRPC cell lines more efficiently than the single treatments. The combination increased the therapeutic potential and demonstrated the relevance of a targeted combination therapy for the treatment of CRPC. In addition, the efficacy of the encapsulated drugs provides the basis for an in vivo preclinical testing. Keywords: sorafenib, nilotinib, castrate-resistant prostate cancer, tyrosine kinase inhibitors, nanomedicine

  11. Inhibition of Cell Proliferation in an NRAS Mutant Melanoma Cell Line by Combining Sorafenib and α-Mangostin.

    Directory of Open Access Journals (Sweden)

    Yun Xia

    Full Text Available α-Mangostin is a natural product commonly used in Asia for cosmetic and medicinal applications including topical treatment of acne and skin cancer. Towards finding new pharmacological strategies that overcome NRAS mutant melanoma, we performed a cell proliferation-based combination screen using a collection of well-characterized small molecule kinase inhibitors and α-Mangostin. We found that α-Mangostin significantly enhances Sorafenib pharmacological efficacy against an NRAS mutant melanoma cell line. The synergistic effects of α-Mangostin and Sorafenib were associated with enhanced inhibition of activated AKT and ERK, induced ER stress, and reduced autophagy, eventually leading to apoptosis. The structure of α-Mangostin resembles several inhibitors of the Retinoid X receptor (RXR. MITF expression, which is regulated by RXR, was modulated by α-Mangostin. Molecular docking revealed that α-Mangostin can be accommodated by the ligand binding pocket of RXR and may thereby compete with RXR-mediated control of MITF expression. In summary, these data demonstrate an unanticipated synergy between α-Mangostin and sorafenib, with mechanistic actions that convert a known safe natural product to a candidate combinatorial therapeutic agent.

  12. 1082-39, an analogue of sorafenib, inhibited human cancer cell growth more potently than sorafenib.

    Science.gov (United States)

    Chu, Jia-Hui; Zhao, Cui-Rong; Song, Zhi-Yu; Wang, Rui-Qi; Qin, Yi-Zhuo; Li, Wen-Bao; Qu, Xian-Jun

    2014-04-01

    1082-39, an analogue of sorafenib, is a derivative of indazole diarylurea. We evaluated the activity of 1082-39 against human cancer cell growth. Its effects and mechanisms of action were then compared with those of sorafenib. The experiments were performed in human melanoma M21 cells. Cell viability was estimated by using the colorimetric assay. Annexin V-FITC/PI staining assay was used to recognize the apoptotic cells. Further analysis of the mitochondria membrane potential (MMP) was performed by the JC-1 fluorescence probe staining. The levels of apoptotic proteins and kinases related to cancer proliferation were determined by western blotting assay. 1082-39 possessed the activity against cancer cell proliferation with time- and dose-dependent manner. 1082-39 induced M21 cell to apoptosis, showing the increase of annexin V-FITC/PI staining cells, the MMP collapse and releasing cytochrome c from mitochondria. Western blotting analysis showed the activation of the mitochondria-mediated intrinsic pathway, showing the increase of cleaved caspase-9, cleaved caspase-3 and cleaved PARP. Statistical analysis suggested that 1082-39 possessed greater activities than sorafenib in the inhibition of M21 proliferation and induction of apoptosis. These effects of 1082-39 might arise from its activity of regulation the PI3K/Akt and Wnt/β-catenin signaling pathways. 1082-39 is a promising candidate compound which could develop as a potent anticancer agent. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  13. Prospective randomized double-blind multicentre phase II study comparing gemcitabine and cisplatin plus sorafenib chemotherapy with gemcitabine and cisplatin plus placebo in locally advanced and/or metastasized urothelial cancer: SUSE (AUO-AB 31/05).

    Science.gov (United States)

    Krege, Susanne; Rexer, Heidrun; vom Dorp, Frank; de Geeter, Patrick; Klotz, Theodor; Retz, Margitte; Heidenreich, Axel; Kühn, Michael; Kamradt, Joern; Feyerabend, Susan; Wülfing, Christian; Zastrow, Stefan; Albers, Peter; Hakenberg, Oliver; Roigas, Jan; Fenner, Martin; Heinzer, Hans; Schrader, Mark

    2014-03-01

    To evaluate the efficacy and safety of gemcitabine and cisplatin in combination with sorafenib, a tyrosine-kinase inhibitor, compared with chemotherapy alone as first-line treatment in advanced urothelial cancer. The study was a randomized phase II trial. Its primary aim was to show an improvement in progression-free survival (PFS) of 4.5 months by adding sorafenib to conventional chemotherapy. Secondary objectives were objective response rate (ORR), overall survival (OS) and toxicity. The patients included in the trial had histologically confirmed locally advanced and/or metastatic urothelial cancer of the bladder or upper urinary tract. Chemotherapy with gemcitabine (1250 mg/qm on days 1 and 8) and cisplatin (70 mg/qm on day 1) repeated every 21 days, was administered to all patients in a double-blind randomization of additional sorafenib (400 mg twice daily) vs placebo (two tablets twice daily) on days 3-21. Treatment continued until progression or unacceptable toxicity, the maximum number of cycles was limited to eight. The response assessment was repeated after every two cycles. Between October 2006 and October 2010, 98 of 132 planned patients were recruited. Nine patients were ineligible. The final analysis included 40 patients in the sorafenib and 49 patients in the placebo arm. There were no significant differences between the two arms concerning ORR (sorafenib: complete response [CR] 12.5%, partial response [PR] 40%; placebo: CR 12%, PR 35%), median PFS (sorafenib: 6.3 months, placebo: 6.1 months) or OS (sorafenib: 11.3 months, placebo: 10.6 months). Toxicity was moderately higher in the sorafenib arm. Diarrrhoea occurred significantly more often in the sorafenib arm and hand-foot syndrome occurred only in the sorafenib arm. The study was closed prematurely because of slow recruitment. Although the addition of sorafenib to standard chemotherapy showed acceptable toxicity, the trial failed to show a 4.5 months improvement in PFS. © 2013 The Authors

  14. Design and Development of a Series of Potent and Selective Type II Inhibitors of CDK8

    Science.gov (United States)

    2016-01-01

    Using Sorafenib as a starting point, a series of potent and selective inhibitors of CDK8 was developed. When cocrystallized with CDK8 and cyclin C, these compounds exhibit a Type-II (DMG-out) binding mode. PMID:27326333

  15. Synergistic activity of vorinostat combined with gefitinib but not with sorafenib in mutant KRAS human non-small cell lung cancers and hepatocarcinoma.

    Science.gov (United States)

    Jeannot, Victor; Busser, Benoit; Vanwonterghem, Laetitia; Michallet, Sophie; Ferroudj, Sana; Cokol, Murat; Coll, Jean-Luc; Ozturk, Mehmet; Hurbin, Amandine

    2016-01-01

    Development of drug resistance limits the efficacy of targeted therapies. Alternative approaches using different combinations of therapeutic agents to inhibit several pathways could be a more effective strategy for treating cancer. The effects of the approved epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (gefitinib) or a multi-targeted kinase inhibitor (sorafenib) in combination with a histone deacetylase inhibitor (vorinostat) on cell proliferation, cell cycle distribution, apoptosis, and signaling pathway activation in human lung adenocarcinoma and hepatocarcinoma cells with wild-type EGFR and mutant KRAS were investigated. The effects of the synergistic drug combinations were also studied in human lung adenocarcinoma and hepatocarcinoma cells in vivo. The combination of gefitinib and vorinostat synergistically reduced cell growth and strongly induced apoptosis through inhibition of the insulin-like growth factor-1 receptor/protein kinase B (IGF-1R/AKT)-dependent signaling pathway. Moreover, the gefitinib and vorinostat combination strongly inhibited tumor growth in mice with lung adenocarcinoma or hepatocarcinoma tumor xenografts. In contrast, the combination of sorafenib and vorinostat did not inhibit cell proliferation compared to a single treatment and induced G 2 /M cell cycle arrest without apoptosis. The sorafenib and vorinostat combination sustained the IGF-1R-, AKT-, and mitogen-activated protein kinase-dependent signaling pathways. These results showed that there was synergistic cytotoxicity when vorinostat was combined with gefitinib for both lung adenocarcinoma and hepatocarcinoma with mutant KRAS in vitro and in vivo but that the combination of vorinostat with sorafenib did not show any benefit. These findings highlight the important role of the IGF-1R/AKT pathway in the resistance to targeted therapies and support the use of histone deacetylase inhibitors in combination with EGFR-tyrosine kinase inhibitors, especially for

  16. VEGF and VEGFR genotyping in the prediction of clinical outcome for HCC patients receiving sorafenib: the ALICE-1 study.

    Science.gov (United States)

    Scartozzi, Mario; Faloppi, Luca; Svegliati Baroni, Gianluca; Loretelli, Cristian; Piscaglia, Fabio; Iavarone, Massimo; Toniutto, Pierluigi; Fava, Giammarco; De Minicis, Samuele; Mandolesi, Alessandra; Bianconi, Maristella; Giampieri, Riccardo; Granito, Alessandro; Facchetti, Floriana; Bitetto, Davide; Marinelli, Sara; Venerandi, Laura; Vavassori, Sara; Gemini, Stefano; D'Errico, Antonietta; Colombo, Massimo; Bolondi, Luigi; Bearzi, Italo; Benedetti, Antonio; Cascinu, Stefano

    2014-09-01

    Although new treatment modalities changed the global approach to hepatocellular carcinoma (HCC), this disease still represents a medical challenge. Currently, the therapeutic stronghold is sorafenib, a tyrosine kinase inhibitor (TKI) directed against the vascular endothelial growth factor (VEGF) family. Previous observations suggested that polymorphisms of VEGF and its receptor (VEGFR) genes may regulate angiogenesis and lymphangiogenesis and thus tumour growth control. The aim of our study was to evaluate the role of VEGF and VEGFR polymorphisms in determining the clinical outcome of HCC patients receiving sorafenib. From a multicentre experience 148 samples (tumour or blood samples) of HCC patients receiving sorafenib were tested for VEGF-A, VEGF-C and VEGFR-1,2,3 single nucleotide polymorphisms (SNPs). Patients' progression-free survival (PFS) and overall survival (OS) were analysed. At univariate analysis VEGF-A alleles C of rs25648, T of rs833061, C of rs699947, C of rs2010963, VEGF-C alleles T of rs4604006, G of rs664393, VEGFR-2 alleles C of rs2071559, C of rs2305948 were significant predictors of PFS and OS. At multivariate analysis rs2010963, rs4604006 and BCLC (Barcelona Clinic Liver Cancer) stage resulted to be independent factors influencing PFS and OS. Once prospectively validated, the analysis of VEGF and VEGFR SNPs may represent a clinical tool to better identify HCC patients more likely to benefit from sorafenib. On the other hand, the availability of more accurate predictive factors could help avoiding unnecessary toxicities to potentially resistant patients who may be optimal candidates for different treatments interfering with other tumour molecular pathways. © 2014 UICC.

  17. PHARMACOECONOMICAL RESEARCH OF THE USE OF SORAFENIB IN MALIGNANT TUMORS

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    M. Y. Frolov

    2016-01-01

    Full Text Available Purpose. Pharmacoeconomic rationale for the use of sorafenib in malignant tumors in comparison with drugs that are included in the list of pharmaceuticals to provide to certain categories of citizens.Method of the study. Pharmacoeconomic rationale for the use of sorafenib in this study is made by analyzing the impact on the budget. The calculated costs of treatment with sorafenib at a hypothetical group of 100 patients with metastatic renal cell carcinoma (MRCC, hepatocellular carcinoma (HCC and differentiated thyroid cancer resistant to radioactive iodine (DCT. These costs were compared with costs of treatment of a similar group of 100 patients, with treatment of MRCC applied bevacizumab (original or generic in combination with interferon α, and patients with HCC and DCT were excluded from receiving drugs from a program of providing with necessary medicines (PNM. As a result the potential economic effect of the inclusion of sorafenib in the list of PNM was calculated.Results. Treatment of MRCC is cheaper with the use of sorafenib compared to bevacizumab in combination with interferon α: savings is 592 878 rubles in the original use of bevacizumab and 274 976 rubles in the use of generic bevacizumab for one patient-year. If we use sorafenib in a group of 100 people with MRCC, HCC and DCT suitable for treatment with sorafenib, the overall expenses are more than 175 million rubles, while using the original combination of bevacizumab with interferon α – more than 204 million rubles, and in the application of the generic combination of bevacizumab with interferon α – more than 176 million rubles, while in the two last cases the treatment of patients with HCC and DCT is not carried out. The total amount of annual budget savings in the treatment of 100 patients is more than 28.5 million rubles at the account of original of bevacizumab or more than 1 million rubles in accounting of generic bevacizumab.Conclusion. The inclusion of

  18. Efficacy and Safety of Axitinib Versus Sorafenib in Metastatic Renal Cell Carcinoma: Subgroup Analysis of Japanese Patients from the Global Randomized Phase 3 AXIS Trial

    OpenAIRE

    Ueda, Takeshi; Uemura, Hirotsugu; Tomita, Yoshihiko; Tsukamoto, Taiji; Kanayama, Hiroomi; Shinohara, Nobuo; Tarazi, Jamal; Chen, Connie; Kim, Sinil; Ozono, Seiichiro; Naito, Seiji; Akaza, Hideyuki

    2013-01-01

    Objective Axitinib is a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors 1, 2 and 3. The efficacy and safety of axitinib in Japanese patients with metastatic renal cell carcinoma were evaluated. Methods A subgroup analysis was conducted in Japanese patients enrolled in the randomized Phase III trial of axitinib versus sorafenib after failure of one prior systemic therapy for metastatic renal cell carcinoma. Results Twenty-five (of 361) and 29 (o...

  19. By inhibiting PFKFB3, aspirin overcomes sorafenib resistance in hepatocellular carcinoma.

    Science.gov (United States)

    Li, Sainan; Dai, Weiqi; Mo, Wenhui; Li, Jingjing; Feng, Jiao; Wu, Liwei; Liu, Tong; Yu, Qiang; Xu, Shizan; Wang, Wenwen; Lu, Xiya; Zhang, Qinghui; Chen, Kan; Xia, Yujing; Lu, Jie; Zhou, Yingqun; Fan, Xiaoming; Xu, Ling; Guo, Chuanyong

    2017-12-15

    Hepatocellular carcinoma (HCC) is one of the few cancers with a continuous increase in incidence and mortality. Drug resistance is a major problem in the treatment of HCC. In this study, two sorafenib-resistant HCC cell lines and a nude mouse subcutaneously tumor model were used to explore the possible mechanisms leading to sorafenib resistance, and to investigate whether aspirin could increase the sensitivity of hepatoma cells to sorafenib. The combination of aspirin and sorafenib resulted in a synergistic antitumor effect against liver tumors both in vitro and in vivo. High glycolysis and PFKFB3 overexpression occupied a dominant position in sorafenib resistance, and can be targeted and overcome by aspirin. Aspirin plus sorafenib induced apoptosis in tumors without inducing weight loss, hepatotoxicity or inflammation. Our results suggest that aspirin overcomes sorafenib resistance and their combination may be an effective treatment approach for HCC. © 2017 UICC.

  20. Inositol Polyphosphate Multikinase Inhibits Angiogenesis via Inositol Pentakisphosphate-Induced HIF-1α Degradation.

    Science.gov (United States)

    Fu, Chenglai; Tyagi, Richa; Chin, Alfred C; Rojas, Tomas; Li, Ruo-Jing; Guha, Prasun; Bernstein, Isaac A; Rao, Feng; Xu, Risheng; Cha, Jiyoung Y; Xu, Jing; Snowman, Adele M; Semenza, Gregg L; Snyder, Solomon H

    2018-02-02

    Inositol polyphosphate multikinase (IPMK) and its major product inositol pentakisphosphate (IP5) regulate a variety of cellular functions, but their role in vascular biology remains unexplored. We have investigated the role of IPMK in regulating angiogenesis. Deletion of IPMK in fibroblasts induces angiogenesis in both in vitro and in vivo models. IPMK deletion elicits a substantial increase of VEGF (vascular endothelial growth factor), which mediates the regulation of angiogenesis by IPMK. The regulation of VEGF by IPMK requires its catalytic activity. IPMK is predominantly nuclear and regulates gene transcription. However, IPMK does not apparently serve as a transcription factor for VEGF. HIF (hypoxia-inducible factor)-1α is a major determinant of angiogenesis and induces VEGF transcription. IPMK deletion elicits a major enrichment of HIF-1α protein and thus VEGF. HIF-1α is constitutively ubiquitinated by pVHL (von Hippel-Lindau protein) followed by proteasomal degradation under normal conditions. However, HIF-1α is not recognized and ubiquitinated by pVHL in IPMK KO (knockout) cells. IP5 reinstates the interaction of HIF-1α and pVHL. HIF-1α prolyl hydroxylation, which is prerequisite for pVHL recognition, is interrupted in IPMK-deleted cells. IP5 promotes HIF-1α prolyl hydroxylation and thus pVHL-dependent degradation of HIF-1α. Deletion of IPMK in mouse brain increases HIF-1α/VEGF levels and vascularization. The increased VEGF in IPMK KO disrupts blood-brain barrier and enhances brain blood vessel permeability. IPMK, via its product IP5, negatively regulates angiogenesis by inhibiting VEGF expression. IP5 acts by enhancing HIF-1α hydroxylation and thus pVHL-dependent degradation of HIF-1α. © 2017 American Heart Association, Inc.

  1. A polymeric nanoparticle formulation of curcumin in combination with sorafenib synergistically inhibits tumor growth and metastasis in an orthotopic model of human hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Hu, Bo; Sun, Ding; Sun, Chao; Sun, Yun-Fan; Sun, Hai-Xiang; Zhu, Qing-Feng; Yang, Xin-Rong; Gao, Ya-Bo; Tang, Wei-Guo; Fan, Jia; Maitra, Anirban

    2015-01-01

    Curcumin, a yellow polyphenol extracted from the rhizome of turmeric root (Curcuma longa) has potent anti-cancer properties in many types of tumors with ability to reverse multidrug resistance of cancer cells. However, widespread clinical application of this agent in cancer and other diseases has been limited due to its poor aqueous solubility. The recent findings of polymeric nanoparticle formulation of curcumin (NFC) have shown the potential for circumventing the problem of poor solubility, however evidences for NFC's anti-cancer and reverse multidrug resistance properties are lacking. Here we provide models of human hepatocellular carcinoma (HCC), the most common form of primary liver cancer, in vitro and in vivo to evaluate the efficacy of NFC alone and in combination with sorafenib, a kinase inhibitor approved for treatment of HCC. Results showed that NFC not only inhibited the proliferation and invasion of HCC cell lines in vitro, but also drastically suppressed primary tumor growth and lung metastases in vivo. Moreover, in combination with sorafenib, NFC induced HCC cell apoptosis and cell cycle arrest. Mechanistically, NFC and sorafenib synergistically down-regulated the expression of MMP9 via NF-κB/p65 signaling pathway. Furthermore, the combination therapy significantly decreased the population of CD133-positive HCC cells, which have been reported as cancer initiating cells in HCC. Taken together, NanoCurcumin provides an opportunity to expand the clinical repertoire of this agent. Additional studies utilizing a combination of NanoCurcumin and sorafenib in HCC are needed for further clinical development. - Highlights: • Polymeric nanoparticle formulation of curcumin not only inhibited the proliferation and invasion of HCC cell lines in vitro, but also drastically suppressed primary tumor growth and lung metastases in vivo. • In combination with sorafenib, NanoCurcumin induced HCC cell apoptosis and cell cycle arrest. • NanoCurcumin and

  2. A polymeric nanoparticle formulation of curcumin in combination with sorafenib synergistically inhibits tumor growth and metastasis in an orthotopic model of human hepatocellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Hu, Bo [Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032 (China); Sun, Ding [Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032 (China); Department of Hepatobiliary Surgery, First Affiliated Hospital of Soochow University, Suzhou, 215004 (China); Sun, Chao; Sun, Yun-Fan; Sun, Hai-Xiang [Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032 (China); Zhu, Qing-Feng [The Johns Hopkins University School of Medicine, Division of Gastrointestinal and Liver Pathology, Baltimore, MD, 21205 (United States); Institute of Biomedical Sciences, Fudan University, Shanghai, 200032 (China); Yang, Xin-Rong [Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032 (China); Gao, Ya-Bo [Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032 (China); Tang, Wei-Guo [Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032 (China); Fan, Jia [Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032 (China); Institute of Biomedical Sciences, Fudan University, Shanghai, 200032 (China); Maitra, Anirban [The Sol Goldman Pancreatic Cancer Research Center, Departments of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205 (United States); and others

    2015-12-25

    Curcumin, a yellow polyphenol extracted from the rhizome of turmeric root (Curcuma longa) has potent anti-cancer properties in many types of tumors with ability to reverse multidrug resistance of cancer cells. However, widespread clinical application of this agent in cancer and other diseases has been limited due to its poor aqueous solubility. The recent findings of polymeric nanoparticle formulation of curcumin (NFC) have shown the potential for circumventing the problem of poor solubility, however evidences for NFC's anti-cancer and reverse multidrug resistance properties are lacking. Here we provide models of human hepatocellular carcinoma (HCC), the most common form of primary liver cancer, in vitro and in vivo to evaluate the efficacy of NFC alone and in combination with sorafenib, a kinase inhibitor approved for treatment of HCC. Results showed that NFC not only inhibited the proliferation and invasion of HCC cell lines in vitro, but also drastically suppressed primary tumor growth and lung metastases in vivo. Moreover, in combination with sorafenib, NFC induced HCC cell apoptosis and cell cycle arrest. Mechanistically, NFC and sorafenib synergistically down-regulated the expression of MMP9 via NF-κB/p65 signaling pathway. Furthermore, the combination therapy significantly decreased the population of CD133-positive HCC cells, which have been reported as cancer initiating cells in HCC. Taken together, NanoCurcumin provides an opportunity to expand the clinical repertoire of this agent. Additional studies utilizing a combination of NanoCurcumin and sorafenib in HCC are needed for further clinical development. - Highlights: • Polymeric nanoparticle formulation of curcumin not only inhibited the proliferation and invasion of HCC cell lines in vitro, but also drastically suppressed primary tumor growth and lung metastases in vivo. • In combination with sorafenib, NanoCurcumin induced HCC cell apoptosis and cell cycle arrest. • NanoCurcumin and

  3. Potential efficacy of therapies targeting intrahepatic lesions after sorafenib treatment of patients with hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Terashima, Takeshi; Yamashita, Tatsuya; Horii, Rika; Arai, Kuniaki; Kawaguchi, Kazunori; Kitamura, Kazuya; Yamashita, Taro; Sakai, Yoshio; Mizukoshi, Eishiro; Honda, Masao; Kaneko, Shuichi

    2016-01-01

    We investigated the contribution of subsequent therapy for advanced hepatocellular carcinoma refractory or intolerant to sorafenib. Further, we investigated the impact of sorafenib on overall survival using individual data. We reviewed the medical records of patients with advanced hepatocellular carcinoma treated with sorafenib. Survival after sorafenib treatment and overall survival were defined as the time when we discovered that patients were either refractory or intolerant to sorafenib and the period from the start of sorafenib treatment, respectively, until death during the study. We compared patients’ prognoses according to their subsequent treatment as follows: group A, therapies targeting intrahepatic lesions; group B, systemic therapies alone; group C, no subsequent therapy. We used linear regression analysis to determine whether there was an association with survival after sorafenib treatment and with overall survival. Of 79 patients, 63 (79.7 %) received one or more subsequent therapies (44 and 19 patients in groups A and B, respectively). The five patients who survived more than two years after sorafenib treatment was discontinued responded to therapies targeting intrahepatic lesions. The median survival times of groups A, B, and C were 11.9 months, 5.8 months, and 3.6 months, respectively. Multivariate analysis revealed that group A, Child-Pugh score, serum α-fetoprotein level, and cause of failure of sorafenib treatment were independent prognostic factors for survival after sorafenib treatment. Individual survival after sorafenib treatment correlated highly with overall survival. Targeting intrahepatic lesions may be useful for treating patients with advanced hepatocellular carcinoma patients after sorafenib treatment is discontinued. The online version of this article (doi:10.1186/s12885-016-2380-4) contains supplementary material, which is available to authorized users

  4. Questiomycin A stimulates sorafenib-induced cell death via suppression of glucose-regulated protein 78.

    Science.gov (United States)

    Machihara, Kayo; Tanaka, Hidenori; Hayashi, Yoshihiro; Murakami, Ichiro; Namba, Takushi

    2017-10-07

    Hepatocellular carcinoma (HCC) is one of the most difficult cancers to treat owing to the lack of effective chemotherapeutic methods. Sorafenib, the first-line and only available treatment for HCC, extends patient overall survival by several months, with a response rate below 10%. Thus, the identification of an agent that enhances the anticancer effect of sorafenib is critical for the development of therapeutic options for HCC. Endoplasmic reticulum (ER) stress response is one of the methods of sorafenib-induced cell death. Here we report that questiomycin A suppresses expression of GRP78, a cell-protective ER chaperone protein. Analysis of the molecular mechanisms of questiomycin A revealed that this compound stimulated GRP78 protein degradation in an ER stress response-independent manner. Cotreatment with sorafenib and questiomycin A suppressed GRP78 protein expression, which is essential for the stimulation of sorafenib-induced cell death. Moreover, our in vivo study demonstrated that the coadministration of sorafenib and questiomycin A suppressed tumor formation in HCC-induced xenograft models. These results suggest that cotreatment with sorafenib and questiomycin A is a novel therapeutic strategy for HCC by enhancing sorafenib-dependent ER stress-induced cell death, and downregulation of GRP78 is a new target for the stimulation of the therapeutic effects of sorafenib in HCC. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Clinical factors related to long-term administration of sorafenib in patients with hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Nojiri, Shunsuke; Kusakabe, Atsunori; Fujiwara, Kei; Shinkai, Noboru; Matsuura, Kentaro; Iio, Etsuko; Miyaki, Tomokatsu; Nomura, Tomoyuki; Sobue, Satoshi; Sano, Hitoshi; Hasegawa, Izumi; Ohno, Tomoyoshi; Takahashi, Yoshitsugu; Orito, Etsuro; Joh, Takashi

    2012-01-01

    Sorafenib has been approved in the indication of unresectable hepatocellular carcinoma, but there are many cases in which administration of the drug is discontinued due to severe side effects. In this study, we compared the characteristics of patients who continued and discontinued sorafenib. Ninety-six patients (75 men and 21 women) were initiated on sorafenib from July 2009 through September 2011. The patient characteristics of interest included gender, age, etiology, Child-Pugh classification, treatment history and frequency, and levels of α-fetoprotein, des- gamma-carboxy prothrombin, aspartate amino acid transferase, and alanine aminotransferase. Duration of administration of sorafenib and reasons for its discontinuation were compared. Median overall survival was 11.8 months. Discontinuation of sorafenib within 90 days was identified as an independent prognostic factor for overall survival on multivariate analysis (P < 0.0001). Transarterial chemoembolization performed six times or more (P = 0.013) was also identified as an independent factor contributing to discontinuation of sorafenib within 90 days in multivariate analysis. Patients who received sorafenib for ≥90 days had significantly longer overall survival than those who discontinued it (P < 0.0001). Prolonged treatment with sorafenib is an important factor in achieving extended overall survival. We recommend starting sorafenib before latent liver damage has occurred as a result of too many transarterial chemoembolization procedures

  6. Synthesis of thermosensitive magnetic nanocarrier for controlled sorafenib delivery

    Energy Technology Data Exchange (ETDEWEB)

    Heidarinasab, Amir [Department of Chemical Engineering, Science and Research Branch, Islamic Azad University, Tehran (Iran, Islamic Republic of); Ahmad Panahi, Homayon [Department of Chemistry, Central Tehran Branch, Islamic Azad University, Tehran (Iran, Islamic Republic of); Faramarzi, Mehdi, E-mail: faramarzi.iaug@gmail.com [Department of Chemical Engineering, Science and Research Branch, Islamic Azad University, Tehran (Iran, Islamic Republic of); Farjadian, Fatemeh [Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz (Iran, Islamic Republic of)

    2016-10-01

    Allyl glycidyl ether/N-isopropylacrylamide-grafted magnetic nanoparticles were prepared using silica-coated magnetic nanoparticles as a substrate for radical copolymerization of allyl glycidyl ether and N-isopropylacrylamide. Chitosan was coupled with the prepared nanoparticles by opening the epoxy ring of the allyl glycidyl ether. The thermosensitive magnetic nanocarrier (TSMNC) obtained can be applied as a potent drug carrier. The TSMNC structure was characterized using Fourier transform infrared spectroscopy, X-ray diffraction, thermogravimetric analysis, differential scanning calorimetry, vibrating sample magnetometer, and elemental analysis. Its morphology and size were investigated using field emission scanning electron microscopy, transmission electron microscopy and dynamic light scattering. The feasibility of employing the TSMNC for adsorption and in vitro controlled release of the chemotherapeutic agent sorafenib was tested. The effect of the adsorption parameters of pH, temperature, and loading time of sorafenib onto TSMNC was evaluated. The adsorption data was fitted to the Langmuir and Freundlich isotherms and the relevant parameters derived. The drug release profile indicated that 88% of the adsorbed drug was released within 35 h at 45 °C and drug release was Fickian diffusion-controlled. The results confirmed that the TSMNC has a high adsorption capacity at low temperature and good controlled release in a slow rate at a high temperature and could be developed for further application as a drug nanocarrier. - Graphical abstract: Magnetic nanoparticles were functionalized with chitosan and N-isopropylacrylamide. It was evaluated for sorafenib (SFB) adsorption and tested as a controlled-release system in response to changes in temperature. The TSMNC showed superparamagnetic properties with a high adsorption capacity and desirable controlled release at below and above LCST. Display Omitted - Highlights: • A TSMNC was synthesized for controlled

  7. Inositol polyphosphate multikinase is a coactivator for serum response factor-dependent induction of immediate early genes

    Science.gov (United States)

    Kim, Eunha; Tyagi, Richa; Lee, Joo-Young; Park, Jina; Kim, Young-ran; Beon, Jiyoon; Chen, Po Yu; Cha, Jiyoung Y.; Snyder, Solomon H.; Kim, Seyun

    2013-01-01

    Inositol polyphosphate multikinase (IPMK) is a notably pleiotropic protein. It displays both inositol phosphate kinase and phosphatidylinositol kinase catalytic activities. Noncatalytically, IPMK stabilizes the mammalian target of rapamycin complex 1 and acts as a transcriptional coactivator for CREB-binding protein/E1A binding protein p300 and tumor suppressor protein p53. Serum response factor (SRF) is a major transcription factor for a wide range of immediate early genes. We report that IPMK, in a noncatalytic role, is a transcriptional coactivator for SRF mediating the transcription of immediate early genes. Stimulation by serum of many immediate early genes is greatly reduced by IPMK deletion. IPMK stimulates expression of these genes, an influence also displayed by catalytically inactive IPMK. IPMK acts by binding directly to SRF and thereby enhancing interactions of SRF with the serum response element of diverse genes. PMID:24248338

  8. Discovery of potent, orally active compounds of tyrosine kinase and ...

    African Journals Online (AJOL)

    Traditional medicines have become the most productive source of leads for drugs development, particularly as anti-cancer agents. Various screening approaches are being applied. Sorafenib, a multikinase inhibitor, is used to treat primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer.

  9. Thyroid size change by CT monitoring after sorafenib or sunitinib treatment in patients with renal cell carcinoma: Comparison with thyroid function

    International Nuclear Information System (INIS)

    Kitajima, Kazuhiro; Takahashi, Satoru; Maeda, Tetsuo; Yoshikawa, Takeshi; Ohno, Yoshiharu; Fujii, Masahiko; Miyake, Hideaki; Fujisawa, Masato; Sugimura, Kazuro

    2012-01-01

    Objective: Hypothyroidism is a common complication in patients receiving tyrosine kinase inhibitors. We evaluated the relationship between thyroid size evident on CT and thyroid function in patients with advanced renal cell carcinoma (RCC) receiving tyrosine kinase inhibitors. Materials and methods: Forty-two patients with metastatic RCC receiving tyrosine kinase inhibitors (sorafenib n = 25; sunitinib n = 17) and, followed-up for ≥12 months were eligible. Patients who had ever shown an elevated thyroid-stimulating hormone (TSH) level of >10 mU/l were defined as having “hypothyroidism”. CT scans were performed before, and 3, 6, 9, and 12 months after the start of treatment. The area of the thyroid in the maximum section at each examination was measured and compared with that before treatment. Using repeated-measures ANOVA, differences in thyroid size were compared over time between patients with and without “hypothyroidism”, in relation to the type of drug employed. Results: Twenty-one patients (sorafenib 9, sunitinib 12) developed “hypothyroidism” 95 ± 88 days (range 12–315 days) after the start of treatment. In such patients, the thyroid was reduced in size to 89 ± 16% after 3 months, 81 ± 21% after 6 months, 71 ± 21% after 9 months and 68 ± 21% after 12 months, whereas the patients without “hypothyroidism” maintained a thyroid size of 90 ± 12% even after 12 months (p = 0.0030). Among the patients with “hypothyroidism”, those treated with sunitinib tended to show greater thyroid size reduction than those with sorafenib (59 ± 23% vs. 79 ± 13%, after 12 months). Conclusion: Tyrosine kinase inhibitors cause an apparent thyroid size reduction in patients with “hypothyroidism”

  10. Thyroid size change by CT monitoring after sorafenib or sunitinib treatment in patients with renal cell carcinoma: Comparison with thyroid function

    Energy Technology Data Exchange (ETDEWEB)

    Kitajima, Kazuhiro, E-mail: kitajima@med.kobe-u.ac.jp [Department of Radiology, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017 (Japan); Takahashi, Satoru; Maeda, Tetsuo; Yoshikawa, Takeshi; Ohno, Yoshiharu; Fujii, Masahiko [Department of Radiology, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017 (Japan); Miyake, Hideaki; Fujisawa, Masato [Department of Urology, Kobe University Graduate School of Medicine, Kobe (Japan); Sugimura, Kazuro [Department of Radiology, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017 (Japan)

    2012-09-15

    Objective: Hypothyroidism is a common complication in patients receiving tyrosine kinase inhibitors. We evaluated the relationship between thyroid size evident on CT and thyroid function in patients with advanced renal cell carcinoma (RCC) receiving tyrosine kinase inhibitors. Materials and methods: Forty-two patients with metastatic RCC receiving tyrosine kinase inhibitors (sorafenib n = 25; sunitinib n = 17) and, followed-up for ≥12 months were eligible. Patients who had ever shown an elevated thyroid-stimulating hormone (TSH) level of >10 mU/l were defined as having “hypothyroidism”. CT scans were performed before, and 3, 6, 9, and 12 months after the start of treatment. The area of the thyroid in the maximum section at each examination was measured and compared with that before treatment. Using repeated-measures ANOVA, differences in thyroid size were compared over time between patients with and without “hypothyroidism”, in relation to the type of drug employed. Results: Twenty-one patients (sorafenib 9, sunitinib 12) developed “hypothyroidism” 95 ± 88 days (range 12–315 days) after the start of treatment. In such patients, the thyroid was reduced in size to 89 ± 16% after 3 months, 81 ± 21% after 6 months, 71 ± 21% after 9 months and 68 ± 21% after 12 months, whereas the patients without “hypothyroidism” maintained a thyroid size of 90 ± 12% even after 12 months (p = 0.0030). Among the patients with “hypothyroidism”, those treated with sunitinib tended to show greater thyroid size reduction than those with sorafenib (59 ± 23% vs. 79 ± 13%, after 12 months). Conclusion: Tyrosine kinase inhibitors cause an apparent thyroid size reduction in patients with “hypothyroidism”.

  11. Efficacy of sorafenib in BRAF-mutated non-small-cell lung cancer (NSCLC) and no response in synchronous BRAF wild type-hepatocellular carcinoma: a case report

    International Nuclear Information System (INIS)

    Casadei Gardini, Andrea; Chiadini, Elisa; Faloppi, Luca; Marisi, Giorgia; Delmonte, Angelo; Scartozzi, Mario; Loretelli, Cristian; Lucchesi, Alessandro; Oboldi, Devil; Dubini, Alessandra; Frassineti, Giovanni Luca; Ulivi, Paola

    2016-01-01

    Sorafenib is a multi-targeted kinase inhibitor with a demonstrated activity in renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC), and it is currently used for the treatment of these pathologies. Ongoing clinical trials are studying its activity in other malignancies, such as non-small-cell lung cancer (NSCLC). However, no biological marker is known to define either the sensitivity or resistance to the drug. Here we report a case of a patient with two synchronous tumors, HCC and NSCLC, with metastases in the contralateral lung and bone. The patient was treated with gemcitabine as first line, with a resulting progressive disease after two months, and then with sorafenib at standard dosage in the second line setting. After 6 months of treatment CT scan showed a partial response in the primary lesion of the lung, complete response of the metastasis in the contralateral lung, and stability of HCC. The patient had progression in the lung, liver and bone after 13 months of therapy. A molecular characterization of NSCLC and HCC lesions was performed, revealing a BRAF exon 11 mutation (G469V) only in NSCLC. We hypothesize that the response observed in NSCLC lesions could be due to the presence of BRAF mutation, and that this alteration could be responsible in determining sorafenib sensitivity. Results observed in this case encourage further research on the activity of sorafenib in both HCC and NSCLC, based on the presence of BRAF mutation. This could lead to a selection of HCC patients to be treated with this drug, and could help identify a novel treatment strategy for BRAF-mutated NSCLC patients

  12. Synergistic activity of vorinostat combined with gefitinib but not with sorafenib in mutant KRAS human non-small cell lung cancers and hepatocarcinoma

    Directory of Open Access Journals (Sweden)

    Jeannot V

    2016-11-01

    Full Text Available Victor Jeannot,1,2 Benoit Busser,1–3 Laetitia Vanwonterghem,1,2 Sophie Michallet,1,2 Sana Ferroudj,1,2 Murat Cokol,4 Jean-Luc Coll,1,2 Mehmet Ozturk,1,2,5 Amandine Hurbin1,2 1INSERM U1209, Department Cancer Targets and Experimental Therapeutics, Grenoble, France; 2University Grenoble Alpes, Institute for Advanced Biosciences, Grenoble, France; 3Department of Biochemistry, Toxicology and Pharmacology, Grenoble University Hospital, Grenoble, France; 4Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul, Turkey; 5Faculty of Medicine, Dokuz Eyul University, Izmir Biomedicine and Genome Center, Izmir, Turkey Abstract: Development of drug resistance limits the efficacy of targeted therapies. Alternative approaches using different combinations of therapeutic agents to inhibit several pathways could be a more effective strategy for treating cancer. The effects of the approved epidermal growth factor receptor (EGFR-tyrosine kinase inhibitor (gefitinib or a multi-targeted kinase inhibitor (sorafenib in combination with a histone deacetylase inhibitor (vorinostat on cell proliferation, cell cycle distribution, apoptosis, and signaling pathway activation in human lung adenocarcinoma and hepatocarcinoma cells with wild-type EGFR and mutant KRAS were investigated. The effects of the synergistic drug combinations were also studied in human lung adenocarcinoma and hepatocarcinoma cells in vivo. The combination of gefitinib and vorinostat synergistically reduced cell growth and strongly induced apoptosis through inhibition of the insulin-like growth factor-1 receptor/protein kinase B (IGF-1R/AKT-dependent signaling pathway. Moreover, the gefitinib and vorinostat combination strongly inhibited tumor growth in mice with lung adenocarcinoma or hepatocarcinoma tumor xenografts. In contrast, the combination of sorafenib and vorinostat did not inhibit cell proliferation compared to a single treatment and induced G2/M cell cycle arrest without

  13. Radiation recall dermatitis triggered by sorafenib after radiation therapy for hepatocellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Gwi Eon; Song, Hee Sung; Kim, Young Suk [Jeju National University Hospital, Jeju National University School of Medicine, Jeju (Korea, Republic of); Ahn, Ki Jung [Dept. of Radiation Oncology, Inje University Busan Paik Hospital, Inje University of Medicine, Busan (Korea, Republic of)

    2017-09-15

    Sorafenib is widely used for unresectable and metastatic hepatocellular carcinomas. Radiation recall dermatitis (RRD) is an acute inflammatory reaction confined to previously irradiated skin that occurs after the administration of certain drugs. RRD after sorafenib treatment is rare; five cases have been reported thus far. We describe a 44-year-old man irradiated for chest wall bone metastasis from hepatocellular carcinoma. Eight days after radiotherapy completion, systemic therapy for metastatic hepatocellular carcinoma was initiated with sorafenib treatment. Eleven days after starting sorafenib, the patient complained of erythematous rash with pruritus in the chest wall, in a location consistent with the previous radiation field. Sorafenib was continued at the same dose, despite the RRD. The skin reaction subsided over the next 2 weeks without any medical intervention.

  14. Antitumor effects of regorafenib and sorafenib in preclinical models of hepatocellular carcinoma.

    Science.gov (United States)

    Kissel, Maria; Berndt, Sandra; Fiebig, Lukas; Kling, Simon; Ji, Qunsheng; Gu, Qingyang; Lang, Tina; Hafner, Frank-Thorsten; Teufel, Michael; Zopf, Dieter

    2017-12-05

    The purpose of this study was to investigate the antitumor activity of regorafenib and sorafenib in preclinical models of HCC and to assess their mechanism of action by associated changes in protein expression in a HCC-PDX mouse model. Both drugs were administered orally once daily at 10 mg/kg (regorafenib) or 30 mg/kg (sorafenib), which recapitulate the human exposure at the maximally tolerated dose in mice. In a H129 hepatoma model, survival times differed significantly between regorafenib versus vehicle (p=0.0269; median survival times 36 vs 27 days), but not between sorafenib versus vehicle (p=0.1961; 33 vs 28 days). Effects on tumor growth were assessed in 10 patient-derived HCC xenograft (HCC-PDX) models. Significant tumor growth inhibition was observed in 8/10 models with regorafenib and 7/10 with sorafenib; in four models, superior response was observed with regorafenib versus sorafenib which was deemed not to be due to lower sorafenib exposure. Bead-based multiplex western blot analysis was performed with total protein lysates from drug- and vehicle-treated HCC-PDX xenografts. Protein expression was substantially different in regorafenib- and sorafenib-treated samples compared with vehicle. The pattern of upregulated proteins was similar with both drugs and indicates an activated RAF/MEK/ERK pathway, but more proteins were downregulated with sorafenib versus regorafenib. Overall, both regorafenib and sorafenib were effective in mouse models of HCC, although several cases showed better regorafenib activity which may explain the observed efficacy of regorafenib in sorafenib-refractory patients.

  15. Synthesis and Antitumor Activity of Triazole-Containing Sorafenib Analogs

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    Wenjing Ye

    2017-10-01

    Full Text Available Using a highly effective binuclear Cu complex as the catalyst, the 1,3-dipolar cycloaddition reactions between 16 alkynes and two azides were successfully performed and resulted in the production of 25 new triazole-containing sorafenib analogs. Several compounds were evaluated as potent antitumor agents. Among them, 4-(4-(4-(3-fluorophenyl-1H-1,2,3-triazol-1-ylphenoxy-N-methylpicolinamide (8f potently suppressed the proliferation of HT-29 cancer cells by inducing apoptosis and almost completely inhibited colony formation at a low micromolar concentration.

  16. Metronomic capecitabine as second-line treatment for hepatocellular carcinoma after sorafenib discontinuation.

    Science.gov (United States)

    Trevisani, Franco; Brandi, Giovanni; Garuti, Francesca; Barbera, Maria Aurelia; Tortora, Raffaella; Casadei Gardini, Andrea; Granito, Alessandro; Tovoli, Francesco; De Lorenzo, Stefania; Inghilesi, Andrea Lorenzo; Foschi, Francesco Giuseppe; Bernardi, Mauro; Marra, Fabio; Sacco, Rodolfo; Di Costanzo, Giovan Giuseppe

    2018-02-01

    Metronomic capecitabine (MC) is a well-tolerated systemic treatment showing promising results in one retrospective study, as second-line therapy after sorafenib failure, in patients with hepatocellular carcinoma (HCC). 117 patients undergoing MC were compared to 112 patients, eligible for this treatment, but undergoing best supportive care (BSC) after sorafenib discontinuation for toxicity or HCC progression. The two groups were compared for demographic and clinical features. A multivariate regression analysis was conducted to detect independent prognostic factors. To balance confounding factors between the two groups, a propensity score model based on independent prognosticators (performance status, neoplastic thrombosis, causes of sorafenib discontinuation and pre-sorafenib treatment) was performed. Patients undergoing MC showed better performance status, lower tumor burden, lower prevalence of portal vein thrombosis, and better cancer stage. Median (95% CI) post-sorafenib survival (PSS) was longer in MC than in BSC patients [9.5 (7.5-11.6) vs 5.0 (4.2-5.7) months (p < 0.001)]. Neoplastic thrombosis, cause of sorafenib discontinuation, pre-sorafenib treatment and MC were independent prognosticators. The benefit of capecitabine was confirmed in patients after matching with propensity score [PSS: 9.9 (6.8-12.9) vs. 5.8 (4.8-6.8) months, (p = 0.001)]. MC lowered the mortality risk by about 40%. MC achieved better results in patients who stopped sorafenib for adverse events than in those who progressed during it [PSS: 17.3 (10.5-24.1) vs. 7.8 (5.2-10.1) months, (p = 0.035)]. Treatment toxicity was low and easily manageable with dose modulation. MC may be an efficient and safe second-line systemic therapy for HCC patients who discontinued sorafenib for toxicity or tumor progression.

  17. Synergistic inhibitory effect of hyperbaric oxygen combined with sorafenib on hepatoma cells.

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    Hai-Shan Peng

    Full Text Available OBJECTIVES: Hypoxia is a common phenomenon in solid tumors, associated with chemotherapy and radiotherapy resistance, recurrence and metastasis. Hyperbaric oxygen (HBO therapy can increase tissue oxygen pressure and content to prevent the resistance, recurrence and metastasis of cancer. Presently, Sorafenib is a first-line drug, targeted for hepatocellular carcinoma (HCC but effective in only a small portion of patients and can induce hypoxia. The purpose of this study is to investigate the effect of HBO in combination with sorafenib on hepatoma cells. METHODS: Hepatoma cell lines (BEL-7402 and SK-Hep1 were treated with HBO at 2 atmosphere absolute pressure for 80 min per day or combined with sorafenib or cisplatin. At different time points, cells were tested for cell growth, colony formation, apoptosis, cell cycle and migration. Finally, miRNA from the hepatoma cells was detected by microRNA array and validated by qRT-PCR. RESULTS: Although HBO, sorafenib or cisplatin alone could inhibit growth of hepatoma cells, HBO combined with sorafenib or cisplatin resulted in much greater synergistic growth inhibition (cell proliferation and colony formation in hepatoma cells. Similarly, the synergistic effect of HBO and sorafenib on induction of apoptosis was also observed in hepatoma cells. HBO induced G1 arrest in SK-Hep1 not in BEL-7402 cells, but enhanced cell cycle arrest induced by sorafenib in BEL-7402 treated cells. However, HBO had no obvious effect on the migration of hepatoma cells, and microRNA array analysis showed that hepatoma cells with HBO treatment had significantly different microRNA expression profiles from those with blank control. CONCLUSIONS: We show for the first time that HBO combined with sorafenib results in synergistic growth inhibition and apoptosis in hepatoma cells, suggesting a potential application of HBO combined with sorafenib in HCC patients. Additionally, we also show that HBO significantly altered microRNA expression

  18. Outcomes of sequential treatment with sorafenib followed by regorafenib for HCC: additional analyses from the phase 3 RESORCE trial.

    Science.gov (United States)

    Finn, Richard S; Merle, Philippe; Granito, Alessandro; Huang, Yi-Hsiang; Bodoky, György; Pracht, Marc; Yokosuka, Osamu; Rosmorduc, Olivier; Gerolami, René; Caparello, Chiara; Cabrera, Roniel; Chang, Charissa; Sun, Weijing; LeBerre, Marie-Aude; Baumhauer, Annette; Meinhardt, Gerold; Bruix, Jordi

    2018-04-25

    The RESORCE trial showed that regorafenib improves overall survival (OS) in patients with hepatocellular carcinoma progressing during sorafenib treatment (hazard ratio [HR] 0.62, 95% confidence interval [CI] 0.50, 0.78; P<.0001). This exploratory analysis describes outcomes of sequential treatment with sorafenib followed by regorafenib. In RESORCE, 573 patients were randomized 2:1 to regorafenib 160mg/day or placebo for 3 weeks on/1 week off. Efficacy and safety were evaluated by last sorafenib dose. The time from the start of sorafenib to death was assessed. Time to progression (TTP) in RESORCE was analyzed by TTP during prior sorafenib treatment. HRs (regorafenib/placebo) for OS by last sorafenib dose were similar (0.67 for 800 mg/day; 0.68 for <800 mg/day). Rates of grade 3, 4, and 5 adverse events with regorafenib by last sorafenib dose (800 mg/day versus <800 mg/day) were 52%, 11%, and 15% versus 60%, 10%, and 12%, respectively. Median times (95% CI) from the start of sorafenib to death were 26.0 months (22.6, 28.1) for regorafenib and 19.2 months (16.3, 22.8) for placebo. Median time from the start of sorafenib to progression on sorafenib was 7.2 months for the regorafenib arm and 7.1 months for the placebo arm. An analysis of TTP in RESORCE in subgroups defined by TTP during prior sorafenib in quartiles (Q) showed HRs (regorafenib/placebo; 95% CI) of 0.66 (0.45, 0.96; Q1); 0.26 (0.17, 0.40; Q2); 0.40 (0.27, 0.60; Q3); and 0.54 (0.36, 0.81; Q4). These exploratory analyses show that regorafenib conferred a clinical benefit regardless of the last sorafenib dose or TTP on prior sorafenib. Rates of adverse events were generally similar regardless of the last sorafenib dose. This analysis examined characteristics and outcomes of patients with HCC who were treated with regorafenib after they had disease progression during sorafenib treatment. Regorafenib provided clinical benefit to patients regardless of the pace of their disease progression during prior sorafenib

  19. Inhibition of human UDP-glucuronosyltransferase enzymes by lapatinib, pazopanib, regorafenib and sorafenib: Implications for hyperbilirubinemia.

    Science.gov (United States)

    Miners, John O; Chau, Nuy; Rowland, Andrew; Burns, Kushari; McKinnon, Ross A; Mackenzie, Peter I; Tucker, Geoffrey T; Knights, Kathleen M; Kichenadasse, Ganessan

    2017-04-01

    Kinase inhibitors (KIs) are a rapidly expanding class of drugs used primarily for the treatment of cancer. Data relating to the inhibition of UDP-glucuronosyltransferase (UGT) enzymes by KIs is sparse. However, lapatinib (LAP), pazopanib (PAZ), regorafenib (REG) and sorafenib (SOR) have been implicated in the development of hyperbilirubinemia in patients. This study aimed to characterise the role of UGT1A1 inhibition in hyperbilirubinemia and assess the broader potential of these drugs to perpetrate drug-drug interactions arising from UGT enzyme inhibition. Twelve recombinant human UGTs from subfamilies 1A and 2B were screened for inhibition by LAP, PAZ, REG and SOR. IC 50 values for the inhibition of all UGT1A enzymes, except UGT1A3 and UGT1A4, by the four KIs were enzyme identified to date. In vitro-in vivo extrapolation indicates that inhibition of UGT1A1 contributes significantly to the hyperbilirubinemia observed in patients treated with REG and SOR, but not with LAP and PAZ. Inhibition of other UGT1A1 substrates in vivo is likely. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Safety and tolerability of sorafenib in patients with radioiodine-refractory thyroid cancer

    NARCIS (Netherlands)

    Worden, F.; Fassnacht, M.; Shi, Y.; Hadjieva, T.; Bonichon, F.; Gao, M.; Fugazzola, L.; Ando, Y.; Hasegawa, Y.; do, J. Park; Shong, Y.K.; Smit, J.W.A.; Chung, J.; Kappeler, C.; Meinhardt, G.; Schlumberger, M.; Brose, M.S.

    2015-01-01

    Effective adverse event (AE) management is critical to maintaining patients on anticancer therapies. The DECISION trial was a multicenter, randomized, double-blind, placebo-controlled, Phase 3 trial which investigated sorafenib for treatment of progressive, advanced, or metastatic radioactive

  1. The observation and nursing for advanced hepatocellular carcinoma patients treated with Sorafenib

    International Nuclear Information System (INIS)

    Chen Yu; Xu Jing; Lin Fuqun

    2011-01-01

    Objective: To summarize the author's experience which was obtained in observing and nursing the adverse reactions of advanced hepatocellular carcinoma patients who were treated with Sorafenib. Methods: The adverse reactions and their severity observed in 34 patients with advanced hepatocellular carcinoma who were treated with Sorafenib were retrospectively analyzed. Results: Side effects or toxic reaction were observed in all the patients, which included neutropenia, foot-hand syndrome (FHS), fatigue, diarrhea, hypertention, rash, etc. Five patients had to cut down the dose of Sorafenib in order to relieve the symptom, among them one patient had grade 4 FHS, 3 patients had grade 3 FHS and one patient had grade 3 neutropenia. Conclusion: Being familiar with sorafenib's adverse reaction, closely observing the patients condition and affording appropriate nursing measures, all the above items can definitely improve the therapeutic results and patient's living quality. (authors)

  2. Selective internal radiation therapy compared with sorafenib for hepatocellular carcinoma with portal vein thrombosis

    Energy Technology Data Exchange (ETDEWEB)

    Edeline, Julien [Centre Eugene Marquis, Medical Oncology Department, Rennes (France); Inserm UMR991, Rennes (France); Crouzet, Laurence; Pracht, Marc; Boucher, Eveline [Centre Eugene Marquis, Medical Oncology Department, Rennes (France); Campillo-Gimenez, Boris [Centre Eugene Marquis, Clinical Research Department, Rennes (France); Rolland, Yan; Rohou, Tanguy [Centre Eugene Marquis, Imaging Department, Rennes (France); Guillygomarc' h, Anne [CHU Pontchaillou, Hepatology Department, Rennes (France); Boudjema, Karim [CHU Pontchaillou, Hepatobiliary Surgery, Rennes (France); Lenoir, Laurence [Centre Eugene Marquis, Nuclear Medicine Department, Rennes (France); Adhoute, Xavier [Hopital Saint-Joseph, Hepato-Gastroenterology Department, Marseille (France); Clement, Bruno [Inserm UMR991, Rennes (France); Blanc, Jean-Frederic [Hopital Saint-Andre, Hepato-Gastroenterology Department, Bordeaux (France); Garin, Etienne [Inserm UMR991, Rennes (France); Centre Eugene Marquis, Nuclear Medicine Department, Rennes (France)

    2016-04-15

    Tumoural portal vein thrombosis (PVT) is a major prognostic factor in hepatocellular carcinoma (HCC). The efficacy of sorafenib, the only treatment approved at an advanced stage, is limited. Based on previous data, selective internal radiation therapy (SIRT), or {sup 90}Y radioembolization, seems an interesting option. We aimed to compare both treatments in this population. We retrospectively compared patients treated in two centres for HCC with tumoural PVT. We compared overall survival (OS) between patients treated with SIRT and patients treated with sorafenib. Analyses were performed before and after 1:1 matching with a propensity score for controlling indication bias, using a Cox proportional hazards model. A total of 151 patients were analysed, 34 patients treated with SIRT and 117 patients treated with sorafenib only. In the whole population, SIRT was associated with a higher median OS as compared with sorafenib: 18.8 vs 6.5 months (log-rank p < 0.001). There was an imbalance of baseline characteristics between patients treated by SIRT and sorafenib, which justified patient matching with use of a propensity score: 24 patients treated with SIRT could be matched with 24 patients treated with sorafenib. OS was estimated with a median of 26.2 vs 8.7 months in patients treated with SIRT vs sorafenib, respectively (log-rank p = 0.054). Before and after patient matching, the adjusted hazard ratio related to treatment by SIRT was estimated at 0.62 [95 % confidence interval (CI) 0.39-0.97] (p = 0.037) and 0.40 (95 % CI 0.19-0.82) (p = 0.013), respectively. SIRT seems more effective than sorafenib in patients presenting with HCC and tumoural PVT. This hypothesis is being tested in prospective randomized trials. (orig.)

  3. Antitumor effects of regorafenib and sorafenib in preclinical models of hepatocellular carcinoma

    OpenAIRE

    Kissel, Maria; Berndt, Sandra; Fiebig, Lukas; Kling, Simon; Ji, Qunsheng; Gu, Qingyang; Lang, Tina; Hafner, Frank-Thorsten; Teufel, Michael; Zopf, Dieter

    2017-01-01

    The purpose of this study was to investigate the antitumor activity of regorafenib and sorafenib in preclinical models of HCC and to assess their mechanism of action by associated changes in protein expression in a HCC-PDX mouse model. Both drugs were administered orally once daily at 10 mg/kg (regorafenib) or 30 mg/kg (sorafenib), which recapitulate the human exposure at the maximally tolerated dose in mice. In a H129 hepatoma model, survival times differed significantly between regorafenib ...

  4. Selective internal radiation therapy compared with sorafenib for hepatocellular carcinoma with portal vein thrombosis

    International Nuclear Information System (INIS)

    Edeline, Julien; Crouzet, Laurence; Pracht, Marc; Boucher, Eveline; Campillo-Gimenez, Boris; Rolland, Yan; Rohou, Tanguy; Guillygomarc'h, Anne; Boudjema, Karim; Lenoir, Laurence; Adhoute, Xavier; Clement, Bruno; Blanc, Jean-Frederic; Garin, Etienne

    2016-01-01

    Tumoural portal vein thrombosis (PVT) is a major prognostic factor in hepatocellular carcinoma (HCC). The efficacy of sorafenib, the only treatment approved at an advanced stage, is limited. Based on previous data, selective internal radiation therapy (SIRT), or 90 Y radioembolization, seems an interesting option. We aimed to compare both treatments in this population. We retrospectively compared patients treated in two centres for HCC with tumoural PVT. We compared overall survival (OS) between patients treated with SIRT and patients treated with sorafenib. Analyses were performed before and after 1:1 matching with a propensity score for controlling indication bias, using a Cox proportional hazards model. A total of 151 patients were analysed, 34 patients treated with SIRT and 117 patients treated with sorafenib only. In the whole population, SIRT was associated with a higher median OS as compared with sorafenib: 18.8 vs 6.5 months (log-rank p < 0.001). There was an imbalance of baseline characteristics between patients treated by SIRT and sorafenib, which justified patient matching with use of a propensity score: 24 patients treated with SIRT could be matched with 24 patients treated with sorafenib. OS was estimated with a median of 26.2 vs 8.7 months in patients treated with SIRT vs sorafenib, respectively (log-rank p = 0.054). Before and after patient matching, the adjusted hazard ratio related to treatment by SIRT was estimated at 0.62 [95 % confidence interval (CI) 0.39-0.97] (p = 0.037) and 0.40 (95 % CI 0.19-0.82) (p = 0.013), respectively. SIRT seems more effective than sorafenib in patients presenting with HCC and tumoural PVT. This hypothesis is being tested in prospective randomized trials. (orig.)

  5. Sorafenib modulates the radio sensitivity of hepatocellular carcinoma cells in vitro in a schedule-dependent manner

    International Nuclear Information System (INIS)

    Li, Qiaoqiao; Hu, Yonghong; Xi, Mian; He, Liru; Zhao, Lei; Liu, Mengzhong

    2012-01-01

    Hepatocellular carcinoma (HCC) has a high incidence and mortality. Radiotherapy and sorafenib have proven effective for HCC. Here, we investigated whether sorafenib modulated the response of HCC cells to irradiation in vitro, effect of timing of sorafenib, and the underlying mechanisms. Cell viability of the HCC cell lines, SMMC-7721 and Bel-7402, was examined by the 3-(4,5-dimethylthiazol-2-yl)-5(3-carboxymethoxyphenyl)-2(4-sulfophenyl)-2 H-terazolium (MTT) assays. Clonogenic growth assays of SMMC-7721 and Bel-7402 were determined by colony formation assays. DNA damage was assessed by monitoring γ-HAX foci in irradiated cells with immunofluorescence microscopy, and cell cycle distribution changes were examined by flow cytometry. Effects of sorafenib (15 μM) added 30 min prior to radiation (pre-irradiation sorafenib) of SMMC-7721 and BEL-7402 or 24 h post-irradiation (post-irradiation sorafenib) on irradiated SMMC-7721 and BEL-7402 cells were compared to those of radiation alone or no treatment. The effect of sorafenib was dependent on its time of addition in relationship to irradiation of cells. Pre-irradiation sorafenib did not significantly affect the viability of SMMC-7221 and BEL-7402 cells compared with irradiation treatment alone. In contrast, post-irradiation sorafenib increased the sensitivity of irradiated SMMC-7221 and BEL-7402 cells significantly in a time-dependent manner. Pre-irradiation sorafenib significantly increased the surviving fraction of SMMC-7221 and BEL-7402 cells in clonogenic assays whereas post-irradiation sorafenib significantly reduced the surviving fractions of SMMC-7221 and BEL-7402 cells. SMMC-7721 cells treated with sorafenib 30 min before irradiation had significantly fewer cells with γ-H2AX foci (23.8 ± 2.9%) than SMMC-7721 cells receiving radiation alone (59.9 ± 2.4; P < 0.001). Similarly, BEL-7402 cells receiving sorafenib prior to irradiation had significantly fewer cells with γ-H2AX foci (46.4 ± 3.8%) than those

  6. Sorafenib paradoxically activates the RAS/RAF/ERK pathway in polyclonal human NK cells during expansion and thereby enhances effector functions in a dose- and time-dependent manner.

    Science.gov (United States)

    Lohmeyer, J; Nerreter, T; Dotterweich, J; Einsele, H; Seggewiss-Bernhardt, R

    2018-03-24

    Natural killer (NK) cells play a major role in host immunity against leukaemia and lymphoma. However, clinical trials applying NK cells have not been as efficient as hoped for. Patients treated with rapidly accelerated fibrosarcoma (RAF) inhibitors exhibit increased tumour infiltration by immune cells, suggesting that a combination of RAF inhibitors with immunotherapy might be beneficial. As mitogen-activated protein kinases (MAPKs) such as raf-1 proto-oncogene, serine/threonine kinase (CRAF) regulate NK cell functions, we performed an in-vitro investigation on the potential of clinically relevant short-acting tyrosine kinase inhibitors (TKIs) as potential adjuvants for NK cell therapy: NK cells from healthy human blood donors were thus treated with sorafenib, sunitinib or the pan-RAF inhibitor ZM336372 during ex-vivo expansion. Functional outcomes assessed after washout of the drugs included cytokine production, degranulation, cytotoxicity, apoptosis induction and signal transduction with/without target cell contact. Paradoxically, sorafenib enhanced NK cell effector functions in a time- and dose-dependent manner by raising the steady-state activation level. Of note, this did not lead to NK cell exhaustion, but enhanced activity against target cells such as K562 or Daudis mediated via the RAS/RAF/extracellular-regulated kinase (ERK) pathway, but not via protein kinase B (AKT). Our data will pave the path to develop a rationale for the considered use of RAF inhibitors such as sorafenib for pre-activation in NK cell-based adoptive immune therapy. © 2018 British Society for Immunology.

  7. Sorafenib ameliorates renal fibrosis through inhibition of TGF-β-induced epithelial-mesenchymal transition.

    Directory of Open Access Journals (Sweden)

    Lining Jia

    Full Text Available This study was to investigate whether sorafenib can inhibit the progression of renal fibrosis and to study the possible mechanisms of this effect.Eight-week-old rats were subjected to unilateral ureteral obstruction (UUO and were intragastrically administered sorafenib, while control and sham groups were administered vehicle for 14 or 21 days. NRK-52E cells were treated with TGF-β1 and sorafenib for 24 or 48 hours. HE and Masson staining were used to visualize fibrosis of the renal tissue in each group. The expression of α-SMA and E-cadherin in kidney tissue and NRK-52E cells were performed using immunohistochemistry and immunofluorescence. The apoptosis rate of NRK-52E cells was determined by flow cytometry analysis. The protein levels of Smad3 and p-Smad3 in kidney tissue and NRK-52E cells were detected by western blot analysis.HE staining demonstrated that kidney interstitial fibrosis, tubular atrophy, and inflammatory cell infiltration in the sorafenib-treated-UUO groups were significantly decreased compared with the vehicle-treated-UUO group (p<0.05. Masson staining showed that the area of fibrosis was significantly decreased in the sorafenib-treated-UUO groups compared with vehicle-treated-UUO group (p<0.01. The size of the kidney did not significantly increase; the cortex of the kidney was thicker and had a richer blood supply in the middle-dose sorafenib group compared with the vehicle-treated-UUO group (p<0.05. Compared with the vehicle-treated-UUO and TGF-β-stimulated NRK-52E groups, the expression of a-SMA and E-cadherin decreased and increased, respectively, in the UUO kidneys and NRK-52E cells of the sorafenib-treated groups (p<0.05. The apoptotic rate of NRK-52E cells treated with sorafenib decreased for 24 hours in a dose-dependent manner (p<0.05. Compared with the vehicle-treated UUO and TGF-β-stimulated NRK-52E groups, the ratio of p-Smad3 to Smad3 decreased in the sorafenib-treated groups (p<0.05.Our results suggest that

  8. Fisetin, a phytochemical, potentiates sorafenib-induced apoptosis and abrogates tumor growth in athymic nude mice implanted with BRAF-mutated melanoma cells.

    Science.gov (United States)

    Pal, Harish Chandra; Baxter, Ronald D; Hunt, Katherine M; Agarwal, Jyoti; Elmets, Craig A; Athar, Mohammad; Afaq, Farrukh

    2015-09-29

    Melanoma is the most deadly form of cutaneous malignancy, and its incidence rates are rising worldwide. In melanoma, constitutive activation of the BRAF/MEK/ERK (MAPK) and PI3K/AKT/mTOR (PI3K) signaling pathways plays a pivotal role in cell proliferation, survival and tumorigenesis. A combination of compounds that lead to an optimal blockade of these critical signaling pathways may provide an effective strategy for prevention and treatment of melanoma. The phytochemical fisetin is known to possess anti-proliferative and pro-apoptotic activities. We found that fisetin treatment inhibited PI3K signaling pathway in melanoma cells. Therefore, we investigated the effect of fisetin and sorafenib (an RAF inhibitor) alone and in combination on cell proliferation, apoptosis and tumor growth. Combination treatment (fisetin + sorafenib) more effectively reduced the growth of BRAF-mutated human melanoma cells at lower doses when compared to individual agents. In addition, combination treatment resulted in enhanced (i) apoptosis, (ii) cleavage of caspase-3 and PARP, (iii) expression of Bax and Bak, (iv) inhibition of Bcl2 and Mcl-1, and (v) inhibition of expression of PI3K, phosphorylation of MEK1/2, ERK1/2, AKT and mTOR. In athymic nude mice subcutaneously implanted with melanoma cells (A375 and SK-MEL-28), we found that combination therapy resulted in greater reduction of tumor growth when compared to individual agents. Furthermore, combination therapy was more effective than monotherapy in: (i) inhibition of proliferation and angiogenesis, (ii) induction of apoptosis, and (iii) inhibition of the MAPK and PI3K pathways in xenograft tumors. These data suggest that simultaneous inhibition of both these signaling pathways using combination of fisetin and sorafenib may serve as a therapeutic option for the management of melanoma.

  9. Sorafenib metabolism is significantly altered in the liver tumor tissue of hepatocellular carcinoma patient.

    Directory of Open Access Journals (Sweden)

    Ling Ye

    Full Text Available BACKGROUND: Sorafenib, the drug used as first line treatment for hepatocellular carcinoma (HCC, is metabolized by cytochrome P450 (CYP 3A4-mediated oxidation and uridine diphosphate glucuronosyl transferase (UGT 1A9-mediated glucuronidation. Liver diseases are associated with reduced CYP and UGT activities, which can considerably affect drug metabolism, leading to drug toxicity. Thus, understanding the metabolism of therapeutic compounds in patients with liver diseases is necessary. However, the metabolism characteristic of sorafenib has not been systematically determined in HCC patients. METHODS: Sorafenib metabolism was tested in the pooled and individual tumor hepatic microsomes (THLMs and adjacent normal hepatic microsomes (NHLMs of HCC patients (n = 18. Commercial hepatic microsomes (CHLMs were used as a control. In addition, CYP3A4 and UGT1A9 protein expression in different tissues were measured by Western blotting. RESULTS: The mean rates of oxidation and glucuronidation of sorafenib were significantly decreased in the pooled THLMs compared with those in NHLMs and CHLMs. The maximal velocity (Vmax of sorafenib oxidation and glucuronidation were approximately 25-fold and 2-fold decreased in the pooled THLMs, respectively, with unchanged Km values. The oxidation of sorafenib in individual THLMs sample was significantly decreased (ranging from 7 to 67-fold than that in corresponding NHLMs sample. The reduction of glucuronidation in THLMs was observed in 15 out of 18 patients' samples. Additionally, the level of CYP3A4 and UGT1A9 expression were both notably decreased in the pooled THLMs. CONCLUSIONS: Sorafenib metabolism was remarkably decreased in THLMs. This result was associated with the down regulation of the protein expression of CYP3A4 and UGT1A9.

  10. Triclosan treatment decreased the antitumor effect of sorafenib on hepatocellular carcinoma cells

    Directory of Open Access Journals (Sweden)

    Wu M

    2018-05-01

    Full Text Available Man Wu,1,2 Guanren Zhao,2 Xiaomei Zhuang,1 Tianhong Zhang,1 Ce Zhang,2 Wenpeng Zhang,1 Zhenqing Zhang1 1State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, China; 2Department of Pharmacy, The 309th Hospital of PLA, Beijing, China Background: Triclosan is a widely applied antimicrobial agent which affects the endocrine system and homeostasis; it may also promote the cirrhosis and hepatocellular carcinoma (HCC growth in a mice model. The exact roles of triclosan in regulating human hepatocellular carcinoma development and treatment remain unknown. Methods: MHCC97-H, a highly aggressive HCC cell line, was treated with indicated concentration of triclosan or sorafenib. The expression of drug-resistance genes was examined by qPCR. The clearance or metabolism of sorafenib was determined by liquid chromatograph-mass spectrometer/mass spectrometer (LC-MS/MS. MTT assay was used to examine the MHCC97-H cell proliferation. Nude mice were used to exam the anti-tumor effect of sorafenib on subcutaneous and intrahepatic growth of MHCC97-H cells. Results: In the present study, triclosan could induce the expression of drug-resistance genes in MHCC97-H cells (a highly aggressive HCC cell line, accelerate the clearance of sorafenib, and attenuate the anti-proliferation effect of this molecular targeted agent in MHCC97-H cells. Triclosan decreased the antitumor effect of sorafenib on subcutaneous and intrahepatic growth of MHCC97-H in nude mice. Conclusion: By discovering the fact that triclosan treatment enhances sorafenib resistance in HCC cells, this work suggests exposure of triclosan is detrimental to HCC patients during chemotherapy. Keywords: HCC, triclosan, sorafenib resistance, drug clearance 

  11. Sorafenib and everolimus for patients with unresectable high-grade osteosarcoma progressing after standard treatment: a non-randomised phase 2 clinical trial.

    Science.gov (United States)

    Grignani, Giovanni; Palmerini, Emanuela; Ferraresi, Virginia; D'Ambrosio, Lorenzo; Bertulli, Rossella; Asaftei, Sebastian Dorin; Tamburini, Angela; Pignochino, Ymera; Sangiolo, Dario; Marchesi, Emanuela; Capozzi, Federica; Biagini, Roberto; Gambarotti, Marco; Fagioli, Franca; Casali, Paolo Giovanni; Picci, Piero; Ferrari, Stefano; Aglietta, Massimo

    2015-01-01

    Results of previous study showed promising but short-lived activity of sorafenib in the treatment of patients with unresectable advanced and metastatic osteosarcoma. This treatment failure has been attributed to the mTOR pathway and might therefore be overcome with the addition of mTOR inhibitors. We aimed to investigate the activity of sorafenib in combination with everolimus in patients with inoperable high-grade osteosarcoma progressing after standard treatment. We did this non-randomised phase 2 trial in three Italian Sarcoma Group centres. We enrolled adults (≥18 years) with relapsed or unresectable osteosarcoma progressing after standard treatment (methotrexate, cisplatin, and doxorubicin, with or without ifosfamide). Patients received 800 mg sorafenib plus 5 mg everolimus once a day until disease progression or unacceptable toxic effects. The primary endpoint was 6 month progression-free survival (PFS). All analyses were intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT01804374. We enrolled 38 patients between June 16, 2011, and June 4, 2013. 17 (45%; 95% CI 28-61) of 38 patients were progression free at 6 months. Toxic effects led to dose reductions, or short interruptions, or both in 25 (66%) of 38 patients and permanent discontinuation for two (5%) patients. The most common grade 3-4 adverse events were lymphopenia and hypophosphataemia each in six (16%) patients, hand and foot syndrome in five (13%), thrombocytopenia in four (11%), and fatigue, oral mucositis, diarrhoea, and anaemia each in two (5%). One patient (3%) had a grade 3 pneumothorax that required trans-thoracic drainage, and that recurred at the time of disease progression. This was reported as a serious adverse event related to the study drugs in both instances. No other serious adverse events were reported during the trial. There were no treatment-related deaths. Although the combination of sorafenib and everolimus showed activity as a further-line treatment

  12. Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial.

    Science.gov (United States)

    Cheng, Ann-Lii; Kang, Yoon-Koo; Lin, Deng-Yn; Park, Joong-Won; Kudo, Masatoshi; Qin, Shukui; Chung, Hyun-Cheol; Song, Xiangqun; Xu, Jianming; Poggi, Guido; Omata, Masao; Pitman Lowenthal, Susan; Lanzalone, Silvana; Yang, Liqiang; Lechuga, Maria Jose; Raymond, Eric

    2013-11-10

    Open-label, phase III trial evaluating whether sunitinib was superior or equivalent to sorafenib in hepatocellular cancer. Patients were stratified and randomly assigned to receive sunitinib 37.5 mg once per day or sorafenib 400 mg twice per day. Primary end point was overall survival (OS). Early trial termination occurred for futility and safety reasons. A total of 1,074 patients were randomly assigned to the study (sunitinib arm, n = 530; sorafenib arm, n = 544). For sunitinib and sorafenib, respectively, median OS was 7.9 versus 10.2 months (hazard ratio [HR], 1.30; one-sided P = .9990; two-sided P = .0014); median progression-free survival (PFS; 3.6 v 3.0 months; HR, 1.13; one-sided P = .8785; two-sided P = .2286) and time to progression (TTP; 4.1 v 3.8 months; HR, 1.13; one-sided P = .8312; two-sided P = .3082) were comparable. Median OS was similar among Asian (7.7 v 8.8 months; HR, 1.21; one-sided P = .9829) and hepatitis B-infected patients (7.6 v 8.0 months; HR, 1.10; one-sided P = .8286), but was shorter with sunitinib in hepatitis C-infected patients (9.2 v 17.6 months; HR, 1.52; one-sided P = .9835). Sunitinib was associated with more frequent and severe adverse events (AEs) than sorafenib. Common grade 3/4 AEs were thrombocytopenia (29.7%) and neutropenia (25.7%) for sunitinib; hand-foot syndrome (21.2%) for sorafenib. Discontinuations owing to AEs were similar (sunitinib, 13.3%; sorafenib, 12.7%). OS with sunitinib was not superior or equivalent but was significantly inferior to sorafenib. OS was comparable in Asian and hepatitis B-infected patients. OS was superior in hepatitis C-infected patients who received sorafenib. Sunitinib-treated patients reported more frequent and severe toxicity.

  13. Alpha-fetoprotein is a biomarker of unfolded protein response and altered proteostasis in hepatocellular carcinoma cells exposed to sorafenib.

    Science.gov (United States)

    Houessinon, Aline; Gicquel, Albane; Bochereau, Flora; Louandre, Christophe; Nyga, Rémy; Godin, Corinne; Degonville, James; Fournier, Emma; Saidak, Zuzana; Drullion, Claire; Barbare, Jean-Claude; Chauffert, Bruno; François, Catherine; Pluquet, Olivier; Galmiche, Antoine

    2016-01-28

    Sorafenib is the treatment of reference for advanced hepatocellular carcinoma (HCC). A decrease in the serum levels of Alpha-fetoprotein (AFP) is reported to be the biological parameter that is best associated with disease control by sorafenib. In order to provide a biological rationale for the variations of AFP, we analyzed the various steps of AFP production in human HCC cell lines exposed to sorafenib. Sorafenib dramatically reduced the levels of AFP produced by HCC cells independently of its effect on cell viability. The mRNA levels of AFP decreased upon sorafenib treatment, while the AFP protein remained localized in the Golgi apparatus. Sorafenib activated the Regulated Inositol-Requiring Enzyme-1α (IRE-1α) and the PKR-like ER Kinase (PERK)-dependent arms of the Unfolded Protein Response (UPR). The inhibition of IRE-1α partially restored the mRNA levels of AFP upon treatment with sorafenib. The inhibition of both pathways partially prevented the drop in the production of AFP induced by sorafenib. The findings provide new insights on the regulation of AFP, and identify it as a biomarker suitable for the exploration of HCC cell proteostasis in the context of therapeutic targeting. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  14. Sorafenib prevents liver fibrosis in a non-alcoholic steatohepatitis (NASH) rodent model

    Energy Technology Data Exchange (ETDEWEB)

    Stefano, J.T.; Pereira, I.V.A.; Torres, M.M.; Bida, P.M. [Disciplina de Gastroenterologia Clínica (LIM-07), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Coelho, A.M.M. [Disciplina de Transplante de Órgãos do Aparelho Digestivo (LIM-37), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Xerfan, M.P. [Disciplina de Gastroenterologia Clínica (LIM-07), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Cogliati, B. [Departamento de Patologia, Faculdade de Medicina Veterinária e Zootecnia, Universidade de São Paulo, São Paulo, SP (Brazil); Barbeiro, D.F. [Disciplina de Emergências Clínicas (LIM-51), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Mazo, D.F.C. [Disciplina de Gastroenterologia Clínica (LIM-07), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Kubrusly, M.S.; D' Albuquerque, L.A.C. [Disciplina de Transplante de Órgãos do Aparelho Digestivo (LIM-37), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Souza, H.P. [Disciplina de Emergências Clínicas (LIM-51), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Carrilho, F.J.; Oliveira, C.P. [Disciplina de Gastroenterologia Clínica (LIM-07), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil)

    2015-02-24

    Liver fibrosis occurring as an outcome of non-alcoholic steatohepatitis (NASH) can precede the development of cirrhosis. We investigated the effects of sorafenib in preventing liver fibrosis in a rodent model of NASH. Adult Sprague-Dawley rats were fed a choline-deficient high-fat diet and exposed to diethylnitrosamine for 6 weeks. The NASH group (n=10) received vehicle and the sorafenib group (n=10) received 2.5 mg·kg{sup -1}·day{sup -1} by gavage. A control group (n=4) received only standard diet and vehicle. Following treatment, animals were sacrificed and liver tissue was collected for histologic examination, mRNA isolation, and analysis of mitochondrial function. Genes related to fibrosis (MMP9, TIMP1, TIMP2), oxidative stress (HSP60, HSP90, GST), and mitochondrial biogenesis (PGC1α) were evaluated by real-time quantitative polymerase chain reaction (RT-qPCR). Liver mitochondrial oxidation activity was measured by a polarographic method, and cytokines by enzyme-linked immunosorbent assay (ELISA). Sorafenib treatment restored mitochondrial function and reduced collagen deposition by nearly 63% compared to the NASH group. Sorafenib upregulated PGC1α and MMP9 and reduced TIMP1 and TIMP2 mRNA and IL-6 and IL-10 protein expression. There were no differences in HSP60, HSP90 and GST expression. Sorafenib modulated PGC1α expression, improved mitochondrial respiration and prevented collagen deposition. It may, therefore, be useful in the treatment of liver fibrosis in NASH.

  15. Sorafenib modulates the radio sensitivity of hepatocellular carcinoma cells in vitro in a schedule-dependent manner

    Directory of Open Access Journals (Sweden)

    Li Qiaoqiao

    2012-10-01

    Full Text Available Abstract Background Hepatocellular carcinoma (HCC has a high incidence and mortality. Radiotherapy and sorafenib have proven effective for HCC. Here, we investigated whether sorafenib modulated the response of HCC cells to irradiation in vitro, effect of timing of sorafenib, and the underlying mechanisms. Methods Cell viability of the HCC cell lines, SMMC-7721 and Bel-7402, was examined by the 3-(4,5-dimethylthiazol-2-yl-5(3-carboxymethoxyphenyl-2(4-sulfophenyl-2 H-terazolium (MTT assays. Clonogenic growth assays of SMMC-7721 and Bel-7402 were determined by colony formation assays. DNA damage was assessed by monitoring γ-HAX foci in irradiated cells with immunofluorescence microscopy, and cell cycle distribution changes were examined by flow cytometry. Effects of sorafenib (15 μM added 30 min prior to radiation (pre-irradiation sorafenib of SMMC-7721 and BEL-7402 or 24 h post-irradiation (post-irradiation sorafenib on irradiated SMMC-7721 and BEL-7402 cells were compared to those of radiation alone or no treatment. Results The effect of sorafenib was dependent on its time of addition in relationship to irradiation of cells. Pre-irradiation sorafenib did not significantly affect the viability of SMMC-7221 and BEL-7402 cells compared with irradiation treatment alone. In contrast, post-irradiation sorafenib increased the sensitivity of irradiated SMMC-7221 and BEL-7402 cells significantly in a time-dependent manner. Pre-irradiation sorafenib significantly increased the surviving fraction of SMMC-7221 and BEL-7402 cells in clonogenic assays whereas post-irradiation sorafenib significantly reduced the surviving fractions of SMMC-7221 and BEL-7402 cells. SMMC-7721 cells treated with sorafenib 30 min before irradiation had significantly fewer cells with γ-H2AX foci (23.8 ± 2.9% than SMMC-7721 cells receiving radiation alone (59.9 ± 2.4; P  Conclusions Sorafenib combined with irradiation exerted a schedule-dependent effect in

  16. Toxicity management of angiogenesis inhibitors: resolution of expert panel

    Directory of Open Access Journals (Sweden)

    Pavel O. Rumiantsev

    2017-12-01

    Full Text Available On 22 June 2017 in St. Petersburg the expert panel was held on the topic “Management of toxicity of angiogenesis inhibitors”, which discussed current issues of systemic therapy of advanced differentiated thyroid cancer resistant to radioactive iodine therapy, advanced kidney cancer and questions of efficacy and safety of new target drugs in the treatment of these diseases. The reports and discussions of experts raised the following questions: 1. Own experience of using lenvatinib in patients with differentiated thyroid cancer refractory to therapy with radioactive iodine and kidney cancer. 2. Profile of efficacy and safety of modern targeted therapy with multikinase inhibitors. 3. Prophylaxis and management of predictable toxicity.

  17. Can the tyrosine kinase inhibitors trigger metabolic encephalopathy in cirrhotic patients?

    Science.gov (United States)

    Brandi, Giovanni; de Rosa, Francesco; Calzà, Laura; Girolamo, Stefania Di; Tufoni, Manuel; Ricci, Carmen Serena; Cirignotta, Fabio; Caraceni, Paolo; Biasco, Guido

    2013-03-01

    Sorafenib is the standard treatment of advanced hepatocarcinoma (HCC) in cirrhotic patients with preserved liver function. It shares many adverse effects with other tyrosine-kinase (TK) inhibitors and antiangiogenic drugs. TK inhibitors could have a direct toxicity on CNS, both by interfering with TK-related pathways and by inhibiting angiogenesis. The aim of this study was to investigate whether sorafenib administration can be associated to metabolic encephalopathy in patients with cirrhosis. We retrospectively reviewed medical records of all cirrhotic patients treated with sorafenib for HCC afferent at our Department from January 2009 to December 2011. Among 62 patients, we identified 10 patients with clinically significant cognitive impairment. Seven of these were clearly diagnosed with overt hepatic encephalopathy (HE), one with brain metastases and two with drug-related toxic-metabolic encephalopathy. These last two cases were characterized by severe cognitive impairment, mood alteration and memory deficit. Clinical exam, blood tests and brain CT excluded organic causes of encephalopathy and precipitating factors of HE. Sorafenib discontinuation was associated with complete reversal of the syndrome, which recurred on drug re-administration in one case. Our study suggests that sorafenib may be a precipitating factor of metabolic encephalopathy in cirrhotic patients with advanced HCC. This neurological syndrome appears to be not responsive to the conventional treatment for HE, but it is fully reversible by drug discontinuation. It can be speculated that the potential direct neuronal action of sorafenib may represent a trigger for the onset of metabolic encephalopathy in a subset of cirrhotic patients. © 2012 John Wiley & Sons A/S.

  18. Combination of transcatheter arterial chemoembolization and interrupted dosing sorafenib improves patient survival in early–intermediate stage hepatocellular carcinoma

    Science.gov (United States)

    Lee, Teng-Yu; Lin, Chen-Chun; Chen, Chiung-Yu; Wang, Tsang-En; Lo, Gin-Ho; Chang, Chi-Sen; Chao, Yee

    2017-01-01

    Abstract Background/Objective: The survival benefit of treatment for unresectable hepatocellular carcinoma (HCC) with transcatheter arterial chemoembolization (TACE) combined with sorafenib remains uncertain. We compared the survival of patients treated with TACE and sorafenib with that of patients treated with TACE alone. Methods: This was a post hoc analysis of the Study in Asia of the Combination of TACE with Sorafenib in Patients with HCC (START) trial. All patients who received TACE and interrupted dosing of sorafenib for early or intermediate-stage HCC in Taiwan from 2009 to 2010 were recruited into the TACE and sorafenib group. They were randomly matched 1:1 by age, sex, Child–Pugh score, tumor size, tumor number, and tumor stage with patients from Taichung Veterans General Hospital in Taiwan who received TACE alone and who fulfilled the selection criteria of the START trial during the same time period (control group). Patient survival [cumulative incidence and hazard ratio (HR)] of the 2 groups were analyzed and compared. Results: The baseline characteristics of the 36 patients in each group were similar. Tumor response rates were significantly better in the TACE and sorafenib group (P < .04). Overall survival of the TACE and sorafenib group was also significantly better than that of the control (TACE alone) group over the 2 years [78%, 95% confidence interval (95% CI) 64–91 vs 49, 95% CI 32–66; P = .012]. In the multivariate regression analysis, TACE and sorafenib was found to be independently associated with a decreased risk of mortality (HR 0.33, 95% CI 0.12–0.89; P = .015). Multivariate stratified analyses verified this association in each patient subgroup (all HR < 1.0). Conclusion: With a high patient tolerance to an interrupted sorafenib dosing schedule, the combination of TACE with sorafenib was associated with improved overall survival in early–intermediate stage HCC when compared with treatment with TACE alone. PMID

  19. Cost-effectiveness of sorafenib versus SBRT for unresectable advanced hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Leung, Henry W. C.; Liu, Chung-Feng; Chan, Agnes L. F.

    2016-01-01

    Stereotactic body radiotherapy (SBRT) has been shown to improve overall survival in patients with advanced hepatocellular carcinoma. This study aimed to assess the cost-effectiveness of SBRT compared to sorafenib which is the only drug for advanced hepatocellular carcinoma. A Markov decision-analytic model was performed to compare the cost-effectiveness of SBRT and sorafenib for unresectable advanced hepatocellular carcinoma. Patients transitioned between three health states: stable disease, progression disease and death. We calculated the data on cost from the perspective of our National Health Insurance Bureau. Sensitivity analyses were conducted to determine the impact of several variables. The incremental cost effectiveness ratio (ICER) for sorafenib compared to SBRT was NT$3,788,238 per quality-adjusted life year gained (cost/QALY), which was higher than the willingness to pay threshold of Taiwan according to WHO’s guideline. One-way sensitivity analysis revealed that the utility of progression disease for the sorafenib treatment, utility of progression free survival for SBRT, utility of progression free survival for sorafenib, utility of PFS to progression disease for SBRT and transition probability of progression disease to dead for SBRT were the most sensitive parameters in all cost scenarios. The Monte-Carlo simulation demonstrated that the probability of cost-effectiveness at a willingness to pay threshold of NT$ 2,213,145 per QALY was 100 % and 0 % chance for SBRT and sorafenib. This study indicated that SBRT for advanced hepatocellular carcinoma is cost-effective at a willingness to pay threshold as defined by WHO guideline in Taiwan

  20. Sorafenib tosylate, Ribavirn and Sofosbuvir combination therapy for HCV virus infected patients with decompensated liver cancer.

    Science.gov (United States)

    Munir, Bushra; Ahmed, Bilal; Kiran, Shumaila; Jalal, Fatima; Zahoor, Muhammad Kashif; Shehzadi, Saba; Oranab, Sadaf; Kamran, Sayed Kashif; Ghaffar, Abdul

    2017-11-01

    Hepatitis C is the most common health problem worldwide and is major cause of death due to proliferation of hepatocellular carcinoma. The medicines available for HCV treatment overcome up-to 95% complications of HCV. However, liver cancer needs some additional care. Normally Sorafenib tosylate 200 mg is recommended for liver cancer. There is no such trial in which this drug could effectively be used in combination of direct acting antivirals for HCV. The study was conducted for HCV patients (n=30) with liver cancer having decompensated stage. Combination of Sorafenib tosylate, Ribavirn and Sofosbuvir were used for the pharmacokinetics of these medicines. Child pugh score less then 7 (CP A) in adults during treatment phase (received 12 weeks of Sorafenib tosylate 200 mg, Ribavirn and Sofosbuvir 400 mg once daily) have no side effect while child pugh score 7-9 (CP B) have evidence of hypertension. The main efficiency end point sustained virology response with overcoming liver cancer as well in 12 weeks after end treatment (SVR-LLC 12). Mean pharmacokinetic exposure to Sorafenib tosylate 200 mg, Ribavirn and Sofosbuvir at week 8th was 2.1, 1.5,1.2 times greater in CP B than in CP A. Adverse effects (AEs) were observed in 12 out of 30 patients but not severe as lethal for life. Treatment with Sorafenib tosylate, Ribavirn and Sofosbuvir for twelve weeks was harmless and well accepted, 100 % patients achieve (SVR LLC 12) with 10-fold cure rate more than previous ones. The combination therapy of Sorafenib tosylate, Ribavirn and Sofosbuvir was found helpful for the management of decompensated liver cancer.

  1. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer

    DEFF Research Database (Denmark)

    Brose, Marcia S; Nutting, Christopher M; Jarzab, Barbara

    2014-01-01

    cancer that had progressed within the past 14 months. Adult patients (≥18 years of age) with this type of cancer were enrolled from 77 centres in 18 countries. To be eligible for inclusion, participants had to have at least one measurable lesion by CT or MRI according to Response Evaluation Criteria...... cancer. Adverse events were consistent with the known safety profile of sorafenib. These results suggest that sorafenib is a new treatment option for patients with progressive radioactive iodine-refractory differentiated thyroid cancer. FUNDING: Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals...

  2. Discovery of amido-benzisoxazoles as potent c-Kit inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Kunz, Roxanne K.; Rumfelt, Shannon; Chen, Ning; Zhang, Dawei; Tasker, Andrew S.; Bürli, Roland; Hungate, Randall; Yu, Violeta; Nguyen, Yen; Whittington, Douglas A.; Meagher, Kristin L.; Plant, Matthew; Tudor, Yanyan; Schrag, Michael; Xu, Yang; Ng, Gordon Y.; Hu, Essa (Amgen)

    2010-01-12

    Deregulation of the receptor tyrosine kinase c-Kit is associated with an increasing number of human diseases, including certain cancers and mast cell diseases. Interference of c-Kit signaling with multi-kinase inhibitors has been shown clinically to successfully treat gastrointestinal stromal tumors and mastocytosis. Targeted therapy of c-Kit activity may provide therapeutic advantages against off-target effects for non-oncology applications. A new structural class of c-Kit inhibitors is described, including in vitro c-Kit potency, kinase selectivity, and the observed binding mode.

  3. OSU-2S/sorafenib synergistic antitumor combination against hepatocellular carcinoma: The role of PKCδ/p53

    Directory of Open Access Journals (Sweden)

    Hany A Omar

    2016-11-01

    Full Text Available Background: Sorafenib (Nexavar® is an FDA-approved systemic therapy for advanced hepatocellular carcinoma (HCC. However, the low efficacy and adverse effects at high doses limit the clinical application of sorafenib and strongly recommend its combination with other agents aiming at ameliorating its drawbacks. OSU-2S, a PKCδ activator, was selected as a potential candidate anticancer agent to be combined with sorafenib to promote the anti-cancer activity through synergistic interaction. Methods: The antitumor effects of sorafenib, OSU-2S and their combination were assessed by MTT assay, caspase activation, Western blotting, migration/invasion assays in four different HCC cell lines. The synergistic interactions were determined by Calcusyn analysis. PKCδ knockdown was used to elucidate the role of PKCδ activation as a mechanism for the synergy. The knockdown/over-expression of p53 was used to explain the differential sensitivity of HCC cell lines to sorafenib and/or OSU-2S. Results: OSU-2S synergistically enhanced the anti-proliferative effects of sorafenib in the four used HCC cell lines with combination indices < 1. This effect was accompanied by parallel increases in caspase 3/7 activity, PARP cleavage, PKCδ activation and HCC cell migration/invasion. In addition, PKCδ knockdown abolished the synergy between sorafenib and OSU-2S. Furthermore, p53 restoration in Hep3B cells through the over-expression rendered them more sensitive to both agents while p53 knockdown from HepG2 cells increased their resistance to both agents. Conclusions: OSU-2S augments the anti-proliferative effect of sorafenib in HCC cell lines, in part, through the activation of PKCδ. The p53 status in HCC cells predicts their sensitivity towards both sorafenib and OSU-2S. The proposed combination represents a therapeutically relevant approach that can lead to a new HCC therapeutic protocol.

  4. Tyrosine kinase inhibitors: Multi-targeted or single-targeted?

    Science.gov (United States)

    Broekman, Fleur; Giovannetti, Elisa; Peters, Godefridus J

    2011-02-10

    Since in most tumors multiple signaling pathways are involved, many of the inhibitors in clinical development are designed to affect a wide range of targeted kinases. The most important tyrosine kinase families in the development of tyrosine kinase inhibitors are the ABL, SCR, platelet derived growth factor, vascular endothelial growth factor receptor and epidermal growth factor receptor families. Both multi-kinase inhibitors and single-kinase inhibitors have advantages and disadvantages, which are related to potential resistance mechanisms, pharmacokinetics, selectivity and tumor environment. In different malignancies various tyrosine kinases are mutated or overexpressed and several resistance mechanisms exist. Pharmacokinetics is influenced by interindividual differences and differs for two single targeted inhibitors or between patients treated by the same tyrosine kinase inhibitor. Different tyrosine kinase inhibitors have various mechanisms to achieve selectivity, while differences in gene expression exist between tumor and stromal cells. Considering these aspects, one type of inhibitor can generally not be preferred above the other, but will depend on the specific genetic constitution of the patient and the tumor, allowing personalized therapy. The most effective way of cancer treatment by using tyrosine kinase inhibitors is to consider each patient/tumor individually and to determine the strategy that specifically targets the consequences of altered (epi)genetics of the tumor. This strategy might result in treatment by a single multi kinase inhibitor for one patient, but in treatment by a couple of single kinase inhibitors for other patients.

  5. Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial

    Science.gov (United States)

    Haas, Naomi B; Manola, Judith; Uzzo, Robert G; Flaherty, Keith T; Wood, Christopher G; Kane, Christopher; Jewett, Michael; Dutcher, Janice P; Atkins, Michael B; Pins, Michael; Wilding, George; Cella, David; Wagner, Lynne; Matin, Surena; Kuzel, Timothy M; Sexton, Wade J; Wong, Yu-Ning; Choueiri, Toni K; Pili, Roberto; Puzanov, Igor; Kohli, Manish; Stadler, Walter; Carducci, Michael; Coomes, Robert; DiPaola, Robert S

    2016-01-01

    drug was reduced and then individually titrated up to the original full doses. On Oct 16, 2014, because of low conditional power for the primary endpoint, the ECOG-ACRIN Data Safety Monitoring Committee recommended that blinded follow-up cease and the results be released. The primary analysis showed no significant differences in disease-free survival. Median disease-free survival was 5·8 years (IQR 1·6–8·2) for sunitinib (hazard ratio [HR] 1·02, 97·5% CI 0·85–1·23, p=0·8038), 6·1 years (IQR 1·7–not estimable [NE]) for sorafenib (HR 0·97, 97·5% CI 0·80–1·17, p=0·7184), and 6·6 years (IQR 1·5–NE) for placebo. The most common grade 3 or worse adverse events were hypertension (105 [17%] patients on sunitinib and 102 [16%] patients on sorafenib), hand-foot syndrome (94 [15%] patients on sunitinib and 208 [33%] patients on sorafenib), rash (15 [2%] patients on sunitinib and 95 [15%] patients on sorafenib), and fatigue (110 [17%] patients on sunitinib and 44 [7%] patients on sorafenib). There were five deaths related to treatment or occurring within 30 days of the end of treatment; one patient receiving sorafenib died from infectious colitis while on treatment and four patients receiving sunitinib died, with one death due to each of neurological sequelae, sequelae of gastric perforation, pulmonary embolus, and disease progression. Revised dosing still resulted in high toxicity. Interpretation Adjuvant treatment with the VEGF receptor tyrosine kinase inhibitors sorafenib or sunitinib showed no survival benefit relative to placebo in a definitive phase 3 study. Furthermore, substantial treatment discontinuation occurred because of excessive toxicity, despite dose reductions. These results provide a strong rationale against the use of these drugs for high-risk kidney cancer in the adjuvant setting and suggest that the biology of cancer recurrence might be independent of angiogenesis. Funding US National Cancer Institute and ECOG-ACRIN Cancer Research

  6. Lipid nanocarriers containing sorafenib inhibit colonies formation in human hepatocarcinoma cells.

    Science.gov (United States)

    Bondì, Maria Luisa; Botto, Chiara; Amore, Erika; Emma, Maria Rita; Augello, Giuseppa; Craparo, Emanuela Fabiola; Cervello, Melchiorre

    2015-09-30

    Here, the potential of two nanostructured lipid carriers (NLC) for controlled release of sorafenib was evaluated. The obtained systems showed characteristics suitable as drug delivery systems for the treatment of hepatocellular carcinoma (HCC) through parenteral administration. The use of a mixture between a solid lipid (tripalmitin) with a liquid lipid (Captex 355 EP/NF or Miglyol 812) to prepare NLC systems could give a higher drug loading capacity and a longer term stability during storage than that obtained by using only solid lipids. The obtained nanoparticles showed a nanometer size and high negative zeta potential values. Scansion electron microscopy (SEM) of the sorafenib loaded NLC revealed a spherical shape with a diameter <300 nm. In vitro biological studies demonstrated that sorafenib loaded into NLC had enhanced anti-tumor activity compared to that of free drug. This finding raises hope in terms of future drug delivery strategy of sorafenib loaded NLC, that can be useful for therapeutic application in HCC. Copyright © 2015 Elsevier B.V. All rights reserved.

  7. Initial Experience of Sorafenib Neoadjuvant Therapy Combined with Retroperitoneoscopy in Treating T2 Large Renal Carcinoma

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    Chun-hua Lin

    2015-01-01

    Full Text Available Objectives. To investigate the safety and feasibility of sorafenib neoadjuvant therapy combined with retroperitoneoscopic radical nephrectomy (RRN in treating T2 large renal cell carcinoma (RCC. Methods. Retrospectively analyzed 5 cases (2 males and 3 females, aged 52–73 years of T2 stage large RCC who receive preoperative sorafenib targeted treatment (400 mg bid for 1–3 months and RRN between March, 2013, and July, 2014. Patient information, therapeutic regimen, drug adverse effect, tumor changes before and after surgery, and perioperative parameters were recorded. Results. During the sorafenib therapy adverse effects included 2 cases of hypertension (Grade I toxicity, 1 case of hand-foot syndrome (Grade I, and 1 case of diarrhea (Grade II, which were all tolerable for patients. CT scan and histopathological tests confirmed significant reduction in the longest dimension (LD and medium density (MD of the tumor after therapy as well as tumor hemorrhage, necrosis, and cystic degeneration. All 5 patients received RRN surgery successfully around 2 weeks after drug discontinuation with only 1 case of perioperative complication. Conclusions. Sorafenib neoadjuvant therapy could significantly reduce the size and aggressiveness of T2 large renal tumors, thus reducing the operative challenge and enabling patients who were previously disqualified for operation to receive surgical treatment.

  8. Transferrin targeted core-shell nanomedicine for combinatorial delivery of doxorubicin and sorafenib against hepatocellular carcinoma.

    Science.gov (United States)

    Malarvizhi, Giridharan Loghanathan; Retnakumari, Archana Payickattu; Nair, Shantikumar; Koyakutty, Manzoor

    2014-11-01

    Combinatorial drug delivery is an attractive, but challenging requirement of next generation cancer nanomedicines. Here, we report a transferrin-targeted core-shell nanomedicine formed by encapsulating two clinically used single-agent drugs, doxorubicin and sorafenib against liver cancer. Doxorubicin was loaded in poly(vinyl alcohol) nano-core and sorafenib in albumin nano-shell, both formed by a sequential freeze-thaw/coacervation method. While sorafenib from the nano-shell inhibited aberrant oncogenic signaling involved in cell proliferation, doxorubicin from the nano-core evoked DNA intercalation thereby killing >75% of cancer cells. Upon targeting using transferrin ligands, the nanoparticles showed enhanced cellular uptake and synergistic cytotoxicity in ~92% of cells, particularly in iron-deficient microenvironment. Studies using 3D spheroids of liver tumor indicated efficient penetration of targeted core-shell nanoparticles throughout the tissue causing uniform cell killing. Thus, we show that rationally designed core-shell nanoparticles can effectively combine clinically relevant single-agent drugs for exerting synergistic activity against liver cancer. Transferrin-targeted core-shell nanomedicine encapsulating doxorubicin and sorafenib was studied as a drug delivery system against hepatocellular carcinoma, resulting in enhanced and synergistic therapeutic effects, paving the way towards potential future clinical applications of similar techniques. Copyright © 2014 Elsevier Inc. All rights reserved.

  9. New Sorafenib Derivatives: Synthesis, Antiproliferative Activity Against Tumour Cell Lines and Antimetabolic Evaluation

    Directory of Open Access Journals (Sweden)

    Branka Zorc

    2012-01-01

    Full Text Available Sorafenib is a relatively new cytostatic drug approved for the treatment of renal cell and hepatocellular carcinoma. In this report we describe the synthesis of sorafenib derivatives 4a–e which differ from sorafenib in their amide part. A 4-step synthetic pathway includes preparation of 4-chloropyridine-2-carbonyl chloride hydrochloride (1, 4-chloro-pyridine-2-carboxamides 2a–e, 4-(4-aminophenoxy-pyridine-2-carboxamides 3a–e and the target compounds 4-[4-[[4-chloro-3-(trifluoromethylphenyl]carbamoylamino]-phenoxy]-pyridine-2-carboxamides 4a–e. All compounds were fully chemically characterized and evaluated for their cytostatic activity against a panel of carcinoma, lymphoma and leukemia tumour cell lines. In addition, their antimetabolic potential was investigated as well. The most prominent antiproliferative activity was obtained for compounds 4a–e (IC50 = 1-4.3 μmol·L−1. Their potency was comparable to the potency of sorafenib, or even better. The compounds inhibited DNA, RNA and protein synthesis to a similar extent and did not discriminate between tumour cell lines and primary fibroblasts in terms of their anti-proliferative activity.

  10. Multicenter phase II study of sequential radioembolization-sorafenib therapy for inoperable hepatocellular carcinoma.

    Directory of Open Access Journals (Sweden)

    Pierce K H Chow

    Full Text Available The safety and tolerability of sequential radioembolization-sorafenib therapy is unknown. An open-label, single arm, investigator-initiated Phase II study (NCT0071279 was conducted at four Asia-Pacific centers to evaluate the safety and efficacy of sequential radioembolization-sorafenib in patients with hepatocellular carcinoma (HCC not amenable to curative therapies.Sorafenib (400 mg twice-daily was initiated 14 days post-radioembolization with yttrium-90 (90Y resin microspheres given as a single procedure. The primary endpoints were safety and tolerability and best overall response rate (ORR using RECIST v1.0.Secondary endpoints included: disease control rate (complete [CR] plus partial responses [PR] and stable disease [SD] and overall survival (OS.Twenty-nine patients with Barcelona Clinic Liver Cancer (BCLC stage B (38% or C (62% HCC received a median of 3.0 GBq (interquartile range, 1.0 90Y-microspheres followed by sorafenib (median dose/day, 600.0 mg; median duration, 4.1 months. Twenty eight patients experienced ≥1 toxicity; 15 (52% grade ≥3. Best ORR was 25%, including 2 (7% CR and 5 (18% PR, and 15 (54% SD. Disease control was 100% and 65% in BCLC stage B and C, respectively. Two patients (7% had sufficient response to enable radical therapy. Median survivals for BCLC stage B and C were 20.3 and 8.6 months, respectively.This study shows the potential efficacy and manageable toxicity of sequential radioembolization-sorafenib.ClinicalTrials.gov NCT00712790.

  11. Sorafenib neoadjuvant therapy in the treatment of high risk renal cell carcinoma.

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    Yushi Zhang

    Full Text Available To evaluate the clinical efficacy of sorafenib as preoperative neoadjuvant therapy in patients with high risk renal cell carcinoma (RCC.Clinical data of 18 patients with high risk RCC who received surgery done successfully after preoperative neoadjuvant therapy with sorafenib in Peking Union Medical College Hospital (PUMCH from April 2007 to October 2013 have been reviewed and analyzed in this study.Among the 18 patients there were 13 male and 5 female, with a median age of 54.6 years. The objective response rate (ORR of the operation on the selected patients is very high (94.4%, including 4 cases (22.2% of partial response (PR and 13 cases (72.2% of stable disease (SD. After preoperative sorafenib treatment, the average tumor size of the 18 patients decreased from 7.8 cm (ranging from 3.6 to 19.2 cm to 6.2 cm (ranging from 2.4 to 16.8 cm, and the median value of average tumor CT value decreased from 61HU to 52 HU. Among the 5 patients who had IVC tumor thrombi, the grades of tumor thrombi in 2 patients who were grade II before sorafenib treatment became grade I and grade 0 respectively, 2 patients of grade III both became grade II.Preoperative neoadjuvant therapy with sorafenib for high risk RCC patients can significantly decrease primary tumor volume as well as tumor thrombus, which could help the nephron-sparing surgery (NSS or radical nephrectomy to be done successfully.

  12. Sorafenib for Egyptian patients with advanced hepatocellular carcinoma; single center experience

    International Nuclear Information System (INIS)

    Abdel-Rahman, O.; Abdelwahab, M.; Shaker, M.; Abdelwahab, Sh.; Elbassiony, M.; Ellithy, M.

    2014-01-01

    Background: According to the results of a number of phase 3 randomized studies, sorafenib is the only approved systemic therapy for advanced HCC; however the issue of high eco- Sorafenib nomic cost remains challenging; thus we have conducted this retrospective analysis of our HCC patients treated with sorafenib. Methods: HCC Shams University Hospitals, in the period between 2010 and 2012 were reviewed. Eligible patients were those who had received sorafenib for advanced HCC not eligible for or progressed after surgery or locoregional therapy. We investigated the impact of baseline clinico pathological factors (age, gender, child status, performance score, BCLC tumor stage, cause of chronic liver disease, median baseline alpha fetoprotein level and previous treatment received for HCC) on overall survival (OS) in an adjusted Cox regression model. Results: 41 patients were included in the analysis fulfilling the inclusion criteria. At a median follow up period of 13 months, the median PFS for the whole group was 4 months; the median OS for the whole group is 6.25 months. Multivariate analysis identified three baseline characteristics that were prognostic indicators for overall survival: ECOG performance status (median OS for ECOG 1 = 7.01 months and for ECOG 2 = 3.03 months), Child-Pugh status (median OS for child A = 12.04 months and for child B = 5.23 months), and median baseline levels of alpha-fetoprotein. Conclusions: In limited resource countries like Egypt, we suggest that the use of sorafenib for the treatment of advanced HCC cases should be restricted to a highly selected subgroup of patients with good performance and child A.

  13. The evolving field of kinase inhibitors in thyroid cancer.

    Science.gov (United States)

    Marotta, V; Sciammarella, C; Vitale, M; Colao, A; Faggiano, A

    2015-01-01

    Most of the genetic events implicated in the pathogenesis of thyroid cancer (TC) involve genes with kinase activity. Thus, kinase inhibitors (KIs) are very relevant in this field. KIs are considered the most suitable treatment for patients with iodine-refractory differentiated TC; these patients comprise the subgroup with the poorer prognosis. To date, only sorafenib has been approved for this indication, but promising results have been reported with several other KIs. In particular, lenvatinib has demonstrated excellent efficacy, with both progression-free survival and objective tumour response being better than with sorafenib. Despite being considered to be well tolerated, both sorafenib and lenvatinib have shown a remarkable toxicity, which has led to dose reductions in the majority of patients and to treatment discontinuation in a significant proportion of cases. The role of KIs in differentiated TC may be revolutionised by the finding that selumetinib may restore a clinical response to radioactive iodine (RAI). Vandetanib and cabozantinib have been approved for the treatment of advanced, progressive medullary TC (MTC). Nevertheless, the toxicity of both compounds suggests their selective use in those patients with strong disease progression. Treatment with the mTOR-inhibitor everolimus, alone or in combination with somatostatin analogues, should be studied in metastatic MTC patients with slow progression of disease, these representing the vast majority of patients. KIs did not significantly impact on the clinical features of anaplastic TC (ATC). Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  14. A phase I trial of sorafenib combined with cisplatin/etoposide or carboplatin/pemetrexed in refractory solid tumor patients.

    Science.gov (United States)

    Davies, Janine M; Dhruva, Nirav S; Walko, Christine M; Socinski, Mark A; Bernard, Stephen; Hayes, D Neil; Kim, William Y; Ivanova, Anastasia; Keller, Kimberly; Hilbun, Layla R; Chiu, Michael; Dees, E Claire; Stinchcombe, Thomas E

    2011-02-01

    Sorafenib has demonstrated single agent activity in non-small cell (NSCLC) and small cell lung cancer (SCLC). Carboplatin/pemetrexed (CbP) and cisplatin/etoposide (PE) are commonly used in the treatment of these diseases. A phase I trial escalating doses of sorafenib in combination with fixed doses of PE (Arm A) or CbP (Arm B) was performed using a 3-patient cohort design to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT); DLT were assessed in the first cycle. The trial was subsequently amended with closure of Arm B and to include Arm C with a reduced dose of carboplatin. Between 9/2007 and 9/2008, 20 pts were treated on the trial; median age 62 (range 42-73), male/female ratio 12/8, PS 0/1 ratio 6/14, and median number of prior therapies 2 (range 1-4). The most common tumor types were NSCLC and SCLC. On Arm A at dose level 0 (sorafenib 200 mg BID), 2 of 4 patients experienced DLT; 2 patients were enrolled at dose level -1 (sorafenib 200 mg QD) without DLT, but this arm was closed due to slow accrual. On Arm B, 2 of 3 patients experienced DLT at dose level 0 (sorafenib 200 mg BID). On Arm C at dose level 0 (sorafenib 200 mg BID), 1 of 6 patients experienced DLT, and at dose level +1 (sorafenib 400 mg BID) 2 of 5 patients experienced a DLT. The MTD of sorafenib was 200 mg BID continuously in combination with carboplatin (AUC of 5) and pemetrexed 500 mg/m² every 3 weeks. However, only 6 patients were treated at this dose level, and the results should be interpreted cautiously. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  15. Everolimus: the first approved product for patients with advanced renal cell cancer after sunitinib and/or sorafenib

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    Chris Coppin

    2010-04-01

    Full Text Available Chris CoppinMedical Oncology, BC Cancer Agency and University of British Columbia, Vancouver, CanadaAbstract: Everolimus (RAD001, Afinitor® Novartis is the first oral inhibitor of mTOR (mammalian target of rapamycin to reach the oncology clinic. Everolimus 10 mg daily achieves complete inhibition of its target at below the maximum tolerable dose for most patients. A phase III randomized placebo-controlled trial has examined the impact of everolimus in patients with clear cell renal cancers and progressive disease on or within 6 months of the VEGFR tyrosine kinase inhibitors sunitinib and/or sorafenib. The primary endpoint of progression-free survival was increased from median 1.9 to 4.9 months (hazard ratio 0.33, P < 0.001 and 25% were still progression-free after 10 months of everolimus therapy. There was a delay in time to decline of performance status and trends to improvement in quality of life, disease-related symptoms, and overall survival despite crossover of the majority of patients assigned to placebo. In 2009, everolimus was approved in the US and Europe as the only validated option for this indication. Toxicities are usually mild to moderate and can be managed with dose reduction or interruption if necessary. Opportunistic infections and non-infectious pneumonitis are seen as a class effect. Management of common practical management issues are discussed. Clinical trials are in progress to examine additional roles for everolimus in renal cancer, alone and in combination with other agents.Keywords: everolimus, drug therapy, advanced renal cancer

  16. Targeting human liver cancer cells with lactobionic acid-G(4)-PAMAM-FITC sorafenib loaded dendrimers.

    Science.gov (United States)

    Iacobazzi, Rosa Maria; Porcelli, Letizia; Lopedota, Angela Assunta; Laquintana, Valentino; Lopalco, Antonio; Cutrignelli, Annalisa; Altamura, Emiliano; Di Fonte, Roberta; Azzariti, Amalia; Franco, Massimo; Denora, Nunzio

    2017-08-07

    Reported here is the synthesis and biological evaluation of the asialoglycoprotein receptor (ASGP-R) targeted fourth generation poliamidoamine dendrimer (G(4)-PAMAM) loaded with sorafenib. The ASGP-R targeted dendrimer was obtained by conjugation of Lactobionic acid (La) to the G(4)-PAMAM dendrimer, followed by acetylation (Ac) of the free amino groups in order to reduce the non-specific interactions with the cell membrane. Moreover, by additionally grafting fluorescein (FITC), it was easy to characterize the internalization pathway and the intracellular fate of the targeted dendrimer Ac-La-G(4)-PAMAM-FITC. In vitro experiments performed on HepG-2 and HLE cell lines, allowed to study the ability of the dendrimers to affect the cell vitality. Confocal microscopy and cytofluorimetric analysis confirmed higher binding and uptake ability of the Ac-La-G(4)-PAMAM-FITC dendrimer in well differentiated and ASGP-R expressing human liver cancer cell line HepG-2 compared non-expressing HLE cells. Ac-La-G(4)-PAMAM-FITC dendrimer loaded with sorafenib was stable and showed sustained sorafenib release. As evidenced by the cytotoxicity studies, sorafenib included in the dendrimer maintained its effectiveness, and was able to produce a longer lasting effect over the time compared to molar equivalent doses of free sorafenib. This new targeted dendrimer appears to be a suitable carrier for the delivery of sorafenib to liver cancer cells expressing ASGP-R. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Fluorescence imaging of bombesin and transferrin receptor expression is comparable to 18F-FDG PET in early detection of sorafenib-induced changes in tumor metabolism.

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    Jen-Chieh Tseng

    Full Text Available Physical measurement of tumor volume reduction is the most commonly used approach to assess tumor progression and treatment efficacy in mouse tumor models. However, it is relatively insensitive, and often requires long treatment courses to achieve gross physical tumor destruction. As alternatives, several non-invasive imaging methods such as bioluminescence imaging (BLI, fluorescence imaging (FLI and positron emission tomography (PET have been developed for more accurate measurement. As tumors have elevated glucose metabolism, 18F-fludeoxyglucose (18F-FDG has become a sensitive PET imaging tracer for cancer detection, diagnosis, and efficacy assessment by measuring alterations in glucose metabolism. In particular, the ability of 18F-FDG imaging to detect drug-induced effects on tumor metabolism at a very early phase has dramatically improved the speed of decision-making regarding treatment efficacy. Here we demonstrated an approach with FLI that offers not only comparable performance to PET imaging, but also provides additional benefits, including ease of use, imaging throughput, probe stability, and the potential for multiplex imaging. In this report, we used sorafenib, a tyrosine kinase inhibitor clinically approved for cancer therapy, for treatment of a mouse tumor xenograft model. The drug is known to block several key signaling pathways involved in tumor metabolism. We first identified an appropriate sorafenib dose, 40 mg/kg (daily on days 0-4 and 7-10, that retained ultimate therapeutic efficacy yet provided a 2-3 day window post-treatment for imaging early, subtle metabolic changes prior to gross tumor regression. We then used 18F-FDG PET as the gold standard for assessing the effects of sorafenib treatment on tumor metabolism and compared this to results obtained by measurement of tumor size, tumor BLI, and tumor FLI changes. PET imaging showed ~55-60% inhibition of tumor uptake of 18F-FDG as early as days 2 and 3 post-treatment, without

  18. Early α-fetoprotein response predicts survival in patients with advanced hepatocellular carcinoma treated with sorafenib

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    Lee SH

    2015-04-01

    Full Text Available Sangheun Lee,1,* Beom Kyung Kim,2–5,* Seung Up Kim,2–5 Jun Yong Park,2–5 Do Young Kim,2–5 Sang Hoon Ahn,2–6 Kwang-Hyub Han2–6 1Department of Internal Medicine, International St Mary’s Hospital, Catholic Kwandong University, Incheon Metropolitan City, Republic of Korea; 2Department of Internal Medicine, 3Institute of Gastroenterology, 4Liver Cancer Special Clinic, Yonsei University College of Medicine, Seoul, Republic of Korea; 5Liver Cirrhosis Clinical Research Center, Seoul, Republic of Korea; 6Brain Korea 21 Project for Medical Science, Seoul, Republic of Korea.   *These authors contributed equally to this work Background: It is not clear whether tumor marker responses can predict survival during sorafenib treatment in hepatocellular carcinoma (HCC. We investigated whether the α-fetoprotein (AFP response is associated with survival in patients with advanced HCC treated with sorafenib. Methods: We retrospectively reviewed the records of 126 patients with advanced HCC treated with sorafenib between 2007 and 2012. An AFP response was defined as >20% decrease from baseline. At 6–8 weeks after commencing sorafenib, AFP and radiological responses were assessed by modified Response Evaluation Criteria in Solid Tumors. Results: The median overall survival (OS and progression-free survival (PFS were 6.2 and 3.5 months, respectively. Of the study population, a partial response (PR was identified in 5 patients (4.0%, stable disease (SD in 65 patients (51.6%, and progressive disease (PD in 57 patients (44.4%, respectively. AFP non-response was an independent prognostic factor for poor OS (median 10.9 months for AFP response vs 5.2 months for AFP non-response, together with Child-Pugh B, tumor diameter ≥10 cm, and portal vein invasion (all P<0.05, and PFS (median 5.3 months for AFP response vs 2.9 months for AFP non-response, together with tumor diameter ≥10 cm and portal vein invasion (all P<0.05. SD or PR was more frequently found

  19. Safety and efficacy of transarterial chemoembolization plus sorafenib for hepatocellular carcinoma with portal venous tumour thrombus

    International Nuclear Information System (INIS)

    Pan, T.; Li, X.-S.; Xie, Q.-K.; Wang, J.-P.; Li, W.; Wu, P.-H.; Zhao, M.

    2014-01-01

    Aim: To evaluate the safety and efficacy of combined therapy with transarterial chemoembolization (TACE) and sorafenib for hepatocellular carcinoma (HCC) with portal venous tumour thrombus (PVTT). Materials and methods: This study was approved by the institutional review board. From May 2009 to May 2012, 170 consecutive patients were newly diagnosed with advanced-stage HCC and treated with TACE plus sorafenib. Among them, 41 patients with PVTT were retrospectively enrolled in the study. The adverse events (AEs), overall survival (OS), time to progression (TTP), and prognostic factors were analysed. Statistical analysis was performed with the Kaplan–Meier method using the log-rank test and Cox regression models. Results: The most common AEs were hand–foot skin reaction related to sorafenib and fever related to TACE. Procedure-related mortality and grade 4 AEs were not observed. Grade 3 AEs were observed in five patients. During the median follow-up period of 13.5 months (range 1.4–45 months), the 6-month and 1-year survival rates were 87.7% and 53.6%, respectively. The median OS was 13 months (range 1.4–44.8 months), and the median TTP was 7 months (range 1–18.6 months). The Child–Pugh class (p = 0.022), extrahepatic metastasis (p = 0.009), and gross morphological type (nodular type versus diffuse type; p = 0.008) were prognostic factors related to OS in the multivariate analysis. Conclusion: TACE plus sorafenib in an interrupted therapeutic scheme was well tolerated and might improve OS for HCC patients with PVTT, especially in those with Child–Pugh class A, no extrahepatic metastasis, or nodular-type HCC. - Highlights: • We introduce the safety of TACE plus sorafenib for patients with advanced HCC and PVTT. • We suggest that the combined therapy might prolong the TTP and OS than sorafenib alone. • Clinic benefit determinations with the Child-Pugh class, extrahepatic metastasis or gross type

  20. Sorafenib for hepatocellular carcinoma patients beyond Milan criteria after orthotopic liver transplantation: a case control study

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    Teng Chieh-Lin

    2012-02-01

    Full Text Available Abstract Background Orthotopic liver transplantation (OLT is one of the most effective treatments for patients with hepatocellular carcinoma (HCC within the Milan criteria. However, for patients beyond these criteria, the recurrence rate is higher and the prognosis is worse. Sorafenib is the only drug showing survival benefits in advanced HCC patients; however, its role in patients beyond the Milan criteria after OLT remains unclear and requires further investigation. Methods As a case-control study, we retrospectively analyzed 17 Chinese patients beyond Milan criteria undergoing OLT for HCC. These patients were stratified into adjuvant (n = 5, palliative (n = 6, and control groups (n = 6. Results Nine of 11 patients who received sorafenib after OLT needed dose reduction due to more than grade 2 side effects. The disease-free survival rates for patients with or without adjuvant sorafenib were 100% versus 37.5% (p = 0.034 at 6 months, 66.7% versus 9.4% (p = 0.026 at 12 months, and 66.7% versus 0.0% (p = 0.011 at 18 months, respectively. The overall survival rates for patients in palliative and control groups were 66.7% versus 40.0% (p = 0.248 at 6 months, 66.7% versus 40.0% (p = 0.248 at 12 months, and 50.0% versus 20.0% (p = 0.17 at 18 months, respectively. Patients in the adjuvant group had better overall survival rates than those in the palliative and control groups (p = 0.031 at 24-month follow-up. Conclusions Adjuvant sorafenib could possibly extend both disease-free and overall survival for HCC patients beyond Milan criteria after OLT.

  1. Sorafenib-Regorafenib Sequential Therapy in Advanced Hepatocellular Carcinoma: A Single-Institute Experience.

    Science.gov (United States)

    Ueshima, Kazuomi; Nishida, Naoshi; Kudo, Masatoshi

    2017-01-01

    Previously, no therapeutic agent has been known to improve the overall survival compared with placebo in patients with hepatocellular carcinoma (HCC), who have progressed after sorafenib. In this patient population, regorafenib was first demonstrated to confer a survival benefit in the RESORCE trial, and subsequently it was approved as a second-line treatment for patients with advanced HCC. An open-label expanded access program (EAP) of regorafenib was implemented for compassionate use. We investigated the efficacy and safety of regorafenib based on our experience of the RESORCE trial and the EAP. Data from 5 patients from the RESORCE trial and 6 from the EAP were analyzed retrospectively. All patients had tolerated prior sorafenib and were progressing during sorafenib treatment. The median progression-free survival was 9.2 months (95% CI 2.3-16.1). One patient achieved a partial response and 7 achieved stable disease. The objective response rate was 9.1%, and the disease control rate was 72.7%. No treatment-associated mortalities were observed. Grade 3 hypophosphatemia was observed in 2 patients, grade 2 anorexia was observed in 5 patients, and grade 3 neutropenia was observed in 2 patients. Grade 2 and grade 3 thrombocytopenia were observed in 2 and 3 patients, respectively. All treatment-related adverse events were improved by reduction or interruption of regorafenib. Five patients showed decreased serum albumin levels. Sorafenib and regorafenib sequential therapy presents a safe and effective treatment option for patients with advanced HCC. © 2017 S. Karger AG, Basel.

  2. Regulation of Multidrug Resistance Proteins by Genistein in a Hepatocarcinoma Cell Line: Impact on Sorafenib Cytotoxicity

    OpenAIRE

    Rigalli, Juan Pablo; Ciriaci, Nadia; Arias, Agostina; Ceballos, Mar?a Paula; Villanueva, Silvina Stella Maris; Luquita, Marcelo Gabriel; Mottino, Aldo Domingo; Ghanem, Carolina In?s; Catania, Viviana Alicia; Ruiz, Mar?a Laura

    2015-01-01

    Hepatocellular carcinoma (HCC) is the fifth most frequent cancer worldwide. Sorafenib is the only drug available that improves the overall survival of HCC patients. P-glycoprotein (P-gp), Multidrug resistance-associated proteins 2 and 3 (MRP2 and 3) and Breast cancer resistance protein (BCRP) are efflux pumps that play a key role in cancer chemoresistance. Their modulation by dietary compounds may affect the intracellular accumulation and therapeutic efficacy of drugs that are substrates of t...

  3. Correlation between LDH levels and response to sorafenib in HCC patients: an analysis of the ITA.LI.CA database.

    Science.gov (United States)

    Sacco, Rodolfo; Mismas, Valeria; Granito, Alessandro; Musettini, Gianna; Masi, Gianluca; Caparello, Chiara; Vivaldi, Caterina; Felder, Martina; Bresci, Giampaolo; Fornaro, Lorenzo

    2015-02-24

    Lactate dehydrogenase (LDH) is a predictor of clinical outcome in hepatocellular carcinoma (HCC) patients. However, its predictive role in the clinical outcomes of sorafenib treatment has been poorly documented. The correlation between LDH levels and clinical outcomes in HCC patients treated with sorafenib and included in the nationwide Italian database ITA.LI.CA was investigated here. The ITA.LI.CA database contains data for 5,136 HCC patients. All patients treated with sorafenib treatment and with available LDH values were considered. Overall survival (OS) and time to progression (TTP) were compared in patients with LDH levels above and below a defined threshold, determined through an ROC analysis. An explorative analysis investigated the relationship between the variation of LDH levels during treatment and response to sorafenib. Baseline LDH levels were available for 97 patients. The most accurate cutoff value for LDH concentration was 297 U/L. Patients with LDH values above (n=45) and below (n=52) this threshold showed equal OS (12.0 months) and TTP (4.0 months) values. Data on LDH levels during sorafenib treatment were reported for 10 patients. LDH values decreased in 3 patients (mean difference = -219 U/L) who also reported a prolonged OS and TTP versus those with unmodified/increased LDH (OS: NE (not evaluated) vs. 8.0 months, p=0.0083; TTP: 19.0 vs. 3.0 months, p=0.008). The clinical benefits of sorafenib do not seem to be influenced by baseline LDH. According to the results of an explorative analysis, however, a decreased LDH concentration during sorafenib might be associated with improved clinical outcomes.

  4. Yttrium-90 radioembolization vs sorafenib for intermediate-locally advanced hepatocellular carcinoma: a cohort study with propensity score analysis.

    Science.gov (United States)

    Gramenzi, Annagiulia; Golfieri, Rita; Mosconi, Cristina; Cappelli, Alberta; Granito, Alessandro; Cucchetti, Alessandro; Marinelli, Sara; Pettinato, Cinzia; Erroi, Virginia; Fiumana, Silvia; Bolondi, Luigi; Bernardi, Mauro; Trevisani, Franco

    2015-03-01

    Sorafenib and transarterial (90) Y-radioembolization (TARE) are possible treatments for Barcelona Clinic Liver Cancer (BCLC) intermediate-advanced stage hepatocellular carcinoma (HCC). No study directly comparing sorafenib and TARE is currently available. This single-centre retrospective study compares the outcomes achieved with sorafenib and TARE in HCC patients potentially amenable to either therapy. Seventy-four sorafenib (71 ± 10 years, male 87%, BCLC B/C 53%/47%) and 63 TARE HCC patients (66 ± 9 years, male 79%, BCLC B/C 41%/59%) were included based on the following criteria: Child-Pugh class A/B, performance status ≤1, HCC unfit for other effective therapies, no metastases and no previous systemic chemotherapy. Median overall survivals of the two groups were comparable, being 14.4 months (95% CI: 4.3-24.5) in sorafenib and 13.2 months (95% CI: 6.1-20.2) in TARE patients, with 1-, 2- and 3-year survival rates of 52.1%, 29.3% and 14.7% vs 51.8%, 27.8% and 21.6% respectively. Two TARE patients underwent liver transplantation after successful down-staging. To minimize the impact of confounding factors on survival analysis, propensity model matched 32 patients of each group for median age, tumour gross pathology and the independent prognostic factors (portal vein thrombosis, performance status, Model for End Liver Disease). Even after matching, the median survival did not differ between sorafenib (13.1 months; 95% CI: 1.2-25.9) and TARE patients (11.2 months; 95% CI: 6.7-15.7), with comparable 1-, 2- and 3-year survival rates. In cirrhotic patients with intermediate-advanced or not-otherwise-treatable HCC, sorafenib and TARE provide similar survivals. Down-staging allowing liver transplantation only occurred after TARE. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  5. HATT: a phase IV, single-arm, open-label study of sorafenib in Taiwanese patients with advanced hepatocellular carcinoma.

    Science.gov (United States)

    Lin, Shi-Ming; Lu, Sheng-Nan; Chen, Ping-Tsung; Jeng, Long-Bin; Chen, Shinn-Cherng; Hu, Chi-Tan; Yang, Sien-Sing; Le Berre, Marie-Aude; Liu, Xuan; Mitchell, David Y; Prins, Klaas; Grevel, Joachim; Peña, Carol A E; Meinhardt, Gerold

    2017-03-01

    Sorafenib significantly improves survival in patients with advanced hepatocellular carcinoma (HCC). This phase IV study assessed sorafenib efficacy/safety in Taiwanese patients with advanced HCC and Child-Pugh A status. All patients received 400 mg sorafenib BID. Safety, efficacy, sorafenib pharmacokinetics, and Child-Pugh progression were evaluated. A hand-foot skin reaction (HFSR) prevention substudy assessed HFSR incidence and grade/severity and time to HFSR in 29 and 34 patients randomized to corticosteroid and noncorticosteroid ointments, respectively, and in 88 nonrandomized patients. The 151 patients included 120 (80%) male patients and 81 (54%) with stage IV disease. Mean sorafenib dose was 626 mg/day, and median treatment duration was 4.2 months. Median overall survival (OS), progression-free survival, and time to progression (TTP) were 8.6, 2.7, and 3.8 months, respectively. Disease control and response rates (partial responses only) were 48 and 6.6%, respectively. Median TTP from Child-Pugh A to B/C was 88 days. Drug-related adverse events (AEs) occurred in 89.4% of patients; none were new or unexpected. The most frequent grade ≥3 drug-related, treatment-emergent AEs were HFSR (13.2%), diarrhea (11.9%), and hypertension (6.6%). Corticosteroid ointment tended to reduce the severity and incidence of all HFSR-associated parameters. Pharmacokinetic exposure was unaltered by Child-Pugh progression. The final pharmacokinetic model predicted 13.1 and 33.8% reductions in sorafenib exposure over 6 and 12 months, respectively. There was a trend of longer OS and TTP in Taiwanese patients with advanced HCC compared with patients with advanced HCC in the Asia-Pacific trial. Sorafenib exposure did not correlate with liver function. Reduced pharmacokinetic exposure over time was unrelated to reduced or interrupted dosing.

  6. Magnetic resonance imaging following treatment of advanced hepatocellular carcinoma with sorafenib

    Directory of Open Access Journals (Sweden)

    Joon-Il Choi

    2014-06-01

    Full Text Available Hepatocellular carcinomas are highly vascular tumors, showing progressive hypervascularity by the process of neoangiogenesis. Tumor angiogenesis is critical for tumor growth as well as metastatic spread therefore, imaging and quantification of tumor neo-angiogenesis is essential for monitoring response to targeted therapies and predicting disease progression. Sorafenib is a molecular targeting agent used for treating hypervascular tumors. This drug is now the standard of care in treatment of patients with advanced hepatocellular carcinoma. Due to its anti-angiogenic and anti-proliferative actions, imaging findings following treatment with Sorafenib are quite distinct when compared to conventional chemotherapeutic agents. Liver MRI is a widely adopted imaging modality for assessing treatment response in hepatocellular carcinoma and imaging features may reflect pathophysiological changes within the tumor. In this mini-review, we will discuss MRI findings after Sorafenib treatment in hepatocellular carcinoma and review the feasibility of MRI as an early biomarker in differentiating responders from non-responders after treatment with molecular targeting agents.

  7. PKI-587 and sorafenib alone and in combination on inhibition of liver cancer stem cell proliferation.

    Science.gov (United States)

    Gedaly, Roberto; Galuppo, Roberto; Musgrave, Yolanda; Angulo, Paul; Hundley, Jonathan; Shah, Malay; Daily, Michael F; Chen, Changguo; Cohen, Donald A; Spear, Brett T; Evers, B Mark

    2013-11-01

    Deregulated Ras/Raf/mitogen-activated protein kinase and PI3 K/AKT/mTOR signaling pathways are significant in hepatocellular carcinoma proliferation (HCC). In this study we evaluated differences in the antiproliferative effect of dual PI3 K/Akt/mTOR and Ras/Raf/mitogen-activated protein kinase inhibition of non liver cancer stem cell lines (PLC and HuH7) and liver cancer stem cell (LCSC) lines (CD133, CD44, CD24, and aldehyde dehydrogenase 1-positive cells). Flow cytometry was performed on the resulting tumors to identify the LCSC markers CD133, CD44, CD24, and aldehyde dehydrogenase 1. Methylthiazol tetrazolium assay was used to assess cellular proliferation. Finally, a Western blot assay was used to evaluate for inhibition of specific enzymes in these two signaling pathways. Using flow cytometry, we found that LCSC contain 64.4% CD133 + cells, 83.2% CD44 + cells, and 96.4% CD24 + cells. PKI-587 and sorafenib caused inhibiton of LCSC and HCC cell proliferation. PLC cells were more sensitive to PKI-587 than LCSC or Huh7 (P PKI-587 and sorafenib caused significantly more inhibition than monotherapy in HuH7, PLC, and LCSC. Using the methylthiazol tetrazolium assay, we found that the LCSC proliferation was inhibited with sorafenib monotherapy 39% at 5 μM (P PKI-587 at 0.1 μM (P = 0.002, n = 12) compared with control. The combination of PKI-587 and sorafenib, however, synergistically inhibited LCSC proliferation by 86% (P = 0.002; n = 12). LCSC (CD133+, CD44+, CD24+) were able to develop very aggressive tumors with low cell concentrations at 4 to 6 wk. Cells CD133+, CD44+, CD24+, which demonstrated at least moderate resistance to therapy in vitro. The combination of PKI-587 and sorafenib was better than either drug alone at inhibiting of LCSC and on HCC cell proliferation. Copyright © 2013 Elsevier Inc. All rights reserved.

  8. Advanced inoperable type B3 thymoma: monitoring of a novel therapeutic approach with radio-chemotherapy and sorafenib by FDG-PET and CT

    International Nuclear Information System (INIS)

    Winder, T.; Gasser, K.; Schuster, A.; Becherer, A.; Vries, A. de; Gruber-Moesenbacher, U.; Muendlein, A.; Drexel, H.; Lang, A.

    2010-01-01

    This report highlights the benefit of radio-chemotherapy followed by sorafenib in a 55 years old woman, diagnosed with an inoperable type B3 thymoma and illustrates the potential usefulness of 18 F-FDG in monitoring treatment with sorafenib. (orig.)

  9. Safety and efficacy results of the advanced renal cell carcinoma sorafenib expanded access program in North America.

    Science.gov (United States)

    Stadler, Walter M; Figlin, Robert A; McDermott, David F; Dutcher, Janice P; Knox, Jennifer J; Miller, Wilson H; Hainsworth, John D; Henderson, Charles A; George, Jeffrey R; Hajdenberg, Julio; Kindwall-Keller, Tamila L; Ernstoff, Marc S; Drabkin, Harry A; Curti, Brendan D; Chu, Luis; Ryan, Christopher W; Hotte, Sebastien J; Xia, Chenghua; Cupit, Lisa; Bukowski, Ronald M

    2010-03-01

    The Advanced Renal Cell Carcinoma Sorafenib (ARCCS) program made sorafenib available to patients with advanced renal cell carcinoma (RCC) before regulatory approval. In this nonrandomized, open-label expanded access program, 2504 patients from the United States and Canada were treated with oral sorafenib 400 mg twice daily. Safety and efficacy were explored overall and in subgroups of patients including those with no prior therapy, nonclear cell (nonclear cell) RCC, brain metastases, prior bevacizumab treatment, and elderly patients. Sorafenib was approved for RCC 6 months after study initiation, at which time patients with no prior therapy or with nonclear cell RCC could enroll in an extension protocol for continued assessment for a period of 6 months. The most common grade > or =2 drug-related adverse events were hand-foot skin reaction (18%), rash (14%), hypertension (12%), and fatigue (11%). In the 1891 patients evaluable for response, complete response was observed in 1 patient, partial response in 67 patients (4%), and stable disease for at least 8 weeks in 1511 patients (80%). Median progression-free survival in the extension population was 36 weeks (95% confidence interval [CI], 33-45 weeks; censorship rate, 56%); median overall survival in the entire population was 50 weeks (95% CI, 46-52 weeks; censorship rate, 63%). The efficacy and safety results were similar across the subgroups. Sorafenib 400 mg twice daily demonstrated activity and a clinically acceptable toxicity profile in all patient subsets enrolled in the ARCCS expanded access program (clinicaltrials.gov identifier: NCT00111020).

  10. Safety and toxicity of radioembolization plus Sorafenib in advanced hepatocellular carcinoma: analysis of the European multicentre trial SORAMIC.

    Science.gov (United States)

    Ricke, Jens; Bulla, Karsten; Kolligs, Frank; Peck-Radosavljevic, Markus; Reimer, Peter; Sangro, Bruno; Schott, Eckart; Schütte, Kerstin; Verslype, Chris; Walecki, Jerzy; Malfertheiner, Peter

    2015-02-01

    The benefits of combined systemic and liver-directed treatments in inoperable intermediate- or advanced-stage hepatocellular carcinoma (HCC) have yet to be defined. This article presents the planned safety analyses for the first 40 patients randomized to radioembolization with yttrium-90 ((90) Y) resin microspheres followed by sorafenib (n = 20) or sorafenib only (n = 20) in the SORAMIC study. Patients identified for palliative treatment who were poor candidates for transarterial (chemo)embolization (including those failing TACE) with preserved liver function (Child-Pugh ≤B7) and ECOG performance status arm. Patients were followed up for a median of 8.3 months. Median total implanted activity of (90) Y was 1.87 (range: 0.54-2.35) GBq. Patients received a similar intensity and duration of sorafenib in the combination-treatment arm (median daily dose 614 mg over 8.5 months) and control arm (557 mg over 9.6 months). The incidence of total (196 vs. 222) and grade ≥3 (43 vs. 47) adverse events was similar in combination-treatment arm and control arm respectively (P > 0.05). No significant differences in the number of total or grade 3/4 toxicities were recorded for: total bilirubin, albumin, liver enzymes, ascites, Child-Pugh, fatigue, hand-foot skin reaction, blood pressure or diarrhoea. Radioembolization followed by sorafenib appears to be as well tolerated as sorafenib alone. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  11. Measurement of sorafenib plasma concentration by high-performance liquid chromatography in patients with advanced hepatocellular carcinoma: is it useful the application in clinical practice? A pilot study.

    Science.gov (United States)

    Fucile, Carmen; Marenco, Simona; Bazzica, Marco; Zuccoli, Maria Laura; Lantieri, Francesca; Robbiano, Luigi; Marini, Valeria; Di Gion, Paola; Pieri, Giulia; Stura, Paola; Martelli, Antonietta; Savarino, Vincenzo; Mattioli, Francesca; Picciotto, Antonino

    2015-01-01

    Pharmacokinetics and dose-finding studies on sorafenib were conducted on heterogeneous groups of patients with solid tumors. Portal hypertension, gut motility impairment and altered bile enterohepatic circulation may explain different sorafenib toxicological profile in cirrhotic patients. This study evaluated sorafenib plasma concentration in a homogeneous group of cirrhotic patients with hepatocellular carcinoma (HCC). Sorafenib concentrations were determined by liquid chromatography in 12 consecutive patients. Data have been evaluated by the generalized estimating equations method (p value statistical level was set at α = 0.05). (1) There were not significant differences between sorafenib concentrations in patients who tolerate the full dose versus patients with reduced dose due to toxicity; (2) the average sorafenib concentrations measured 3 h after the morning dosing were lower than those measured 12 h after the evening dosing (p = 0.005); (3) sorafenib concentrations decrease overtime (p < 10(-4)); (4) it has been found an association between the development of severe adverse reactions and sorafenib concentrations (p < 10(-5)). The relationship between dose and concentration of sorafenib in HCC patients is poor and not clinically predictable, confirming the variability both in the maximum tolerated dose and in plasma concentrations. Several factors may influence the pharmacokinetics in patients with liver disease. This may explain the inter-patient variability of concentrations and the lack of differences in concentration at different dosages. It could be interesting to extend the series of HCC patients to enhance information on the kinetics of the drug; furthermore, to establish a threshold of plasma sorafenib concentrations to predict severe adverse reactions would be clinically useful.

  12. Flavopiridol Synergizes with Sorafenib to Induce Cytotoxicity and Potentiate Antitumorigenic Activity in EGFR/HER-2 and Mutant RAS/RAF Breast Cancer Model Systems

    Directory of Open Access Journals (Sweden)

    Teddy S Nagaria

    2013-08-01

    Full Text Available Oncogenic receptor tyrosine kinase (RTK signaling through the Ras-Raf-Mek-Erk (Ras-MAPK pathway is implicated in a wide array of carcinomas, including those of the breast. The cyclin-dependent kinases (CDKs are implicated in regulating proliferative and survival signaling downstream of this pathway. Here, we show that CDK inhibitors exhibit an order of magnitude greater cytotoxic potency than a suite of inhibitors targeting RTK and Ras-MAPK signaling in cell lines representative of clinically recognized breast cancer (BC subtypes. Drug combination studies show that the pan-CDK inhibitor, flavopiridol (FPD, synergistically potentiated cytotoxicity induced by the Raf inhibitor, sorafenib (SFN. This synergy was most pronounced at sub-EC50 SFN concentrations in MDA-MB-231 (KRAS-G13D and BRAF-G464V mutations, MDA-MB-468 [epidermal growth factor receptor (EGFR overexpression], and SKBR3 [ErbB2/EGFR2 (HER-2 overexpression] cells but not in hormone-dependent MCF-7 and T47D cells. Potentiation of SFN cytotoxicity by FPD correlated with enhanced apoptosis, suppression of retinoblastoma (Rb signaling, and reduced Mcl-1 expression. SFN and FPD were also tested in an MDA-MB-231 mammary fat pad engraftment model of tumorigenesis. Mice treated with both drugs exhibited reduced primary tumor growth rates and metastatic tumor load in the lungs compared to treatment with either drug alone, and this correlated with greater reductions in Rb signaling and Mcl-1 expression in resected tumors. These findings support the development of CDK and Raf co-targeting strategies in EGFR/HER-2-overexpressing or RAS/RAF mutant BCs.

  13. Metronomic capecitabine as second-line treatment in hepatocellular carcinoma after sorafenib failure.

    Science.gov (United States)

    Granito, Alessandro; Marinelli, Sara; Terzi, Eleonora; Piscaglia, Fabio; Renzulli, Matteo; Venerandi, Laura; Benevento, Francesca; Bolondi, Luigi

    2015-06-01

    No standard second-line treatments are available for hepatocellular carcinoma patients who fail sorafenib therapy. We assessed the safety and efficacy of metronomic capecitabine after first-line sorafenib failure. Retrospective analysis of consecutive hepatocellular carcinoma patients receiving metronomic capecitabine between January 2012 and November 2014. The primary end-point was safety, secondary end-point was efficacy, including time-to-progression and overall survival. Twenty-six patients (80% Child-Pugh A, 80% Barcelona Clinic Liver Cancer stage C) received metronomic capecitabine (500 mg/bid). Median treatment duration was 3.2 months (range 0.6-31). Fourteen (53%) patients experienced at least one adverse event. The most frequent drug-related adverse events were bilirubin elevation (23%), fatigue (15%), anaemia (11%), lymphoedema (11%), and hand-foot syndrome (7.6%). Treatment was interrupted in 19 (73%) for disease progression, in 4 (15%) for liver deterioration, and in 1 (3.8%) for adverse event. Disease control was achieved in 6 (23%) patients. Median time-to-progression was 4 months (95% confidence interval 3.2-4.7). Median overall survival was 8 months (95% confidence interval 3.7-12.3). Metronomic capecitabine was well tolerated in hepatocellular carcinoma patients who had been treated with sorafenib. Preliminary data show potential anti-tumour activity with long-lasting disease control in a subgroup of patients that warrants further evaluation in a phase III study. Copyright © 2015 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

  14. Therapeutic evaluation of sorafenib for hepatocellular carcinoma using contrast-enhanced ultrasonography: Preliminary result.

    Science.gov (United States)

    Shiozawa, Kazue; Watanabe, Manabu; Ikehara, Takashi; Kogame, Michio; Kikuchi, Yoshinori; Igarashi, Yoshinori; Sumino, Yasukiyo

    2016-07-01

    The present study aimed to determine the usefulness of contrast-enhanced ultrasonography (CEUS) with Sonazoid in evaluating the therapeutic response to sorafenib for hepatocellular carcinoma (HCC). In total, 26 patients with advanced HCC who received sorafenib and were followed up by CEUS were enrolled in the present study. CEUS was performed prior to and within 2-4 weeks of treatment, and the images of the target lesion in the post-vascular phase with a re-injection method were analyzed. The presence (+) or absence (-) of intratumoral necrosis and the intratumoral vascular architecture on micro-flow imaging (MFI) were compared prior to and subsequent to treatment. Target lesions that exhibited non-enhancement after re-injection were considered to indicate intratumoral necrosis. The intratumoral vascular architecture was classified into three groups, as follows: Vd, the intratumoral vessels visually narrowed or decreased; Vnc, the vessels remained unchanged; and Vi, the vessels were thickened or increased. Survival curves were estimated using the Kaplan-Meier method and compared using the log rank test between the intratumoral necrosis (+) and (-) groups, and among the Vd, Vnc and Vi groups. PVnc group and 5 patients in the Vi group. The MSTs in the Vd, Vnc and Vi groups were 15.6 months (95% CI, 5.0-23.3), 11.0 months (95% CI, 3.5-17.6) and 3.6 months (95% CI: 1.2-6.0), respectively. The P-value for the differences between the Vd and Vnc groups, Vd and Vi groups, and Vnc and Vi groups were 0.78, 0.016 and 0.047, respectively, which indicated that the survival time decreased significantly in the Vi group. Evaluation of intratumoral vascular architecture using MFI demonstrates promise for assessing the therapeutic response to sorafenib in patients with HCC.

  15. Phase 2 Study of Combined Sorafenib and Radiation Therapy in Patients With Advanced Hepatocellular Carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Shang-Wen, E-mail: sjfchiou@gmail.com [Department of Radiation Oncology, China Medical University Hospital, Taichung, Taiwan (China); School of Medicine, Taipei Medical University, Taipei, Taiwan (China); School of Medicine, China Medical University, Taichung, Taiwan (China); Lin, Li-Ching [Department of Radiation Oncology, Chi-Mei Hospital, Tainan, Taiwan (China); School of Medicine, Taipei Medical University, Taipei, Taiwan (China); Kuo, Yu-Cheng [Department of Radiation Oncology, China Medical University Hospital, Taichung, Taiwan (China); Department of Biomedical Imaging and Radiological Science, China Medical University, Taichung, Taiwan (China); Liang, Ji-An [Department of Radiation Oncology, China Medical University Hospital, Taichung, Taiwan (China); School of Medicine, China Medical University, Taichung, Taiwan (China); Kuo, Chia-Chun [Department of Radiation Oncology, Taipei Medical University Hospital, Taipei, Taiwan (China); Chiou, Jeng-Fong [Department of Radiation Oncology, Taipei Medical University Hospital, Taipei, Taiwan (China); School of Medicine, Taipei Medical University, Taipei, Taiwan (China)

    2014-04-01

    Purpose: This phase 2 study evaluated the efficacy of radiation therapy (RT) with concurrent and sequential sorafenib therapy in patients with unresectable hepatocellular carcinoma (HCC). Methods and Materials: Forty patients with unresectable HCC unfit for transarterial chemoembolization were treated with RT with concurrent and sequential sorafenib. Sorafenib was administered from the commencement of RT at a dose of 400 mg twice daily and continued to clinical or radiologic progression, unacceptable adverse events, or death. All patients had underlying Child-Pugh A cirrhosis. The maximal tumor diameter ranged from 3.0 cm to 15.5 cm. Coexisting portal vein thrombosis was found in 24 patients and was irradiated simultaneously. The cumulative RT dose ranged from 40 Gy to 60 Gy (median, 50 Gy). Image studies were done 1 month after RT and then every 3 months thereafter. Results: Thirty-three (83%) completed the allocated RT. During RT, the incidence of hand-foot skin reactions ≥ grade 2 and diarrhea were 37.5% and 25%, respectively, and 35% of patients had hepatic toxicities grade ≥2. Twenty-two (55.0%) patients achieved complete or partial remission at the initial assessment, and 18 (45%) had stable or progressive disease. The 2-year overall survival and infield progression-free survival (IFPS) were 32% and 39%, respectively. A Cancer of the Liver Italian Program (CLIP) score ≥2 was associated with an inferior outcome in overall survival. Six patients (15%) developed treatment-related hepatic toxicity grade ≥3 during the sequential phase, and 3 of them were fatal. Conclusions: When RT and sorafenib therapy were combined in patients with unresectable HCC, the initial complete or partial response rate was 55% with a 2-year IFPS of 39%. A CLIP score ≥2 was associated with an inferior outcome in overall survival. Hepatic toxicities are a major determinant of the safety; the combination should be used with caution and needs further investigation.

  16. Extraordinary radiation super-sensitivity accompanying with sorafenib combination therapy: what lies beneath?

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Ja Young; Lee, Ju Hye; Yoon, Han Bin; Lee, Ho Jeong; Jeon, Ho Sang; Nam, Ji Ho [Dept. of Radiation Oncology, Pusan National University Yangsan Hospital, Yangsan (Korea, Republic of)

    2017-06-15

    Primary liver tumor, especially hepatocellular carcinoma (HCC), is a common cause of cancer death worldwide. The incidence is generally higher in Asian countries than in western countries. Carcinogenesis of HCC is often associated with hepatitis viral infections. Current standard treatment of HCC is surgical resection or transplantation in patients with early stage disease. However, the patient with advanced stage disease, surgical resection is often limited. Sorafenib or other treatment modalities are not so effective as well. We report a case of unusual radiation super-sensitivity in advanced stage HCC, and review the literature.

  17. A Phase I Study of the Combination of Sorafenib With Temozolomide and Radiation Therapy for the Treatment of Primary and Recurrent High-Grade Gliomas

    International Nuclear Information System (INIS)

    Den, Robert B.; Kamrava, Mitchell; Sheng, Zhi; Werner-Wasik, Maria; Dougherty, Erin; Marinucchi, Michelle; Lawrence, Yaacov R.; Hegarty, Sarah; Hyslop, Terry; Andrews, David W.; Glass, Jon; Friedman, David P.; Green, Michael R.; Camphausen, Kevin; Dicker, Adam P.

    2013-01-01

    Purpose: Despite recent advances in the management of high-grade and recurrent gliomas, survival remains poor. Antiangiogenic therapy has been shown to be efficacious in the treatment of high-grade gliomas both in preclinical models and in clinical trials. We sought to determine the safety and maximum tolerated dose of sorafenib when combined with both radiation and temozolomide in the primary setting or radiation alone in the recurrent setting. Methods and Materials: This was a preclinical study and an open-label phase I dose escalation trial. Multiple glioma cell lines were analyzed for viability after treatment with radiation, temozolomide, or sorafenib or combinations of them. For patients with primary disease, sorafenib was given concurrently with temozolomide (75 mg/m 2 ) and 60 Gy radiation, for 30 days after completion of radiation. For patients with recurrent disease, sorafenib was combined with a hypofractionated course of radiation (35 Gy in 10 fractions). Results: Cell viability was significantly reduced with the combination of radiation, temozolomide, and sorafenib or radiation and sorafenib. Eighteen patients (11 in the primary cohort, 7 in the recurrent cohort) were enrolled onto this trial approved by the institutional review board. All patients completed the planned course of radiation therapy. The most common toxicities were hematologic, fatigue, and rash. There were 18 grade 3 or higher toxicities. The median overall survival was 18 months for the entire population. Conclusions: Sorafenib can be safely combined with radiation and temozolomide in patients with high-grade glioma and with radiation alone in patients with recurrent glioma. The recommended phase II dose of sorafenib is 200 mg twice daily when combined with temozolomide and radiation and 400 mg with radiation alone. To our knowledge, this is the first publication of concurrent sorafenib with radiation monotherapy or combined with radiation and temozolomide.

  18. Partial response to sorafenib treatment associated with transient grade 3 thrombocytopenia in a patient with locally advanced thyroid cancer

    Energy Technology Data Exchange (ETDEWEB)

    Pitoia Fabian; Abelleira, Erika; Jerkovich, Fernando; Urciuoli, Carolina; Cross, Graciela, E-mail: fpitoia@intramed.net [Division de Endocrinologia, Hospital de Clinicas, Universidad de Buenos Aires Buenos Aires (Argentina)

    2015-08-15

    Advanced radioactive refractory and progressive or symptomatic differentiated thyroid carcinoma (DTC) is a rare condition. Sorafenib was recently approved for the treatment of these patients. We present the case of a 67 year old woman diagnosed with DTC who underwent a total thyroidectomy with central, lateral-compartment neck dissection and shaving of the trachea and esophagus due to tumor infiltration. A local recurrence was detected 14 months later requiring, additionally, two tracheal rings resection. The patient received a cumulative {sup 131}I dose of 650 mCi and developed dysphagia and dyspnea 63 months after initial surgery. A {sup 18}FGD-PET/CT showed progression of the local mass associated to hypermetabolic pulmonary nodules. Sorafenib 800 mg/day was then prescribed. A dose reduction to 400 mg/day was necessary due to grade 3 thrombocytopenia that appeared four months after drug prescription. Platelet count went to normal after this dose reduction. Five months after initiation of sorafenib, a partial response of the local mass with significant intra-tumoral necrosis was observed. We conclude that sorafenib is a valid option for locally advanced DTC and that the platelet count should be evaluated regularly because it seems that thrombocytopenia might be more frequently observed in DTC than in other types of tumors. (author)

  19. Phase 1 Pharmacogenetic and Pharmacodynamic Study of Sorafenib With Concurrent Radiation Therapy and Gemcitabine in Locally Advanced Unresectable Pancreatic Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Chiorean, E. Gabriela, E-mail: gchiorea@uw.edu [Department of Medicine, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana (United States); Department of Medicine, University of Washington, Seattle, Washington (United States); Schneider, Bryan P. [Department of Medicine, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana (United States); Akisik, Fatih M. [Department of Radiology, Indiana University School of Medicine, Indianapolis, Indiana (United States); Perkins, Susan M. [Department of Biostatistics, Indiana University School of Medicine, Indianapolis, Indiana (United States); Anderson, Stephen [Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana (United States); Johnson, Cynthia S. [Department of Biostatistics, Indiana University School of Medicine, Indianapolis, Indiana (United States); DeWitt, John [Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana (United States); Helft, Paul; Clark, Romnee; Johnston, Erica L.; Spittler, A. John [Department of Medicine, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana (United States); Deluca, Jill [Department of Radiation Oncology, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana (United States); Bu, Guixue [Department of Radiology, Indiana University School of Medicine, Indianapolis, Indiana (United States); Shahda, Safi; Loehrer, Patrick J. [Department of Medicine, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana (United States); Sandrasegaran, Kumar [Department of Radiology, Indiana University School of Medicine, Indianapolis, Indiana (United States); Cardenes, Higinia R. [Department of Radiation Oncology, Indiana University School of Medicine, Indianapolis, Indiana (United States)

    2014-06-01

    Purpose: To define the safety, efficacy, and pharmacogenetic and pharmacodynamic effects of sorafenib with gemcitabine-based chemoradiotherapy (CRT) in locally advanced pancreatic cancer. Methods and Materials: Patients received gemcitabine 1000 mg/m{sup 2} intravenously weekly × 3 every 4 weeks per cycle for 1 cycle before CRT and continued for up to 4 cycles after CRT. Weekly gemcitabine 600 mg/m{sup 2} intravenously was given during concurrent intensity modulated radiation therapy of 50 Gy to gross tumor volume in 25 fractions. Sorafenib was dosed orally 400 mg twice daily until progression, except during CRT when it was escalated from 200 mg to 400 mg daily, and 400 mg twice daily. The maximum tolerated dose cohort was expanded to 15 patients. Correlative studies included dynamic contrast-enhanced MRI and angiogenesis genes polymorphisms (VEGF-A and VEGF-R2 single nucleotide polymorphisms). Results: Twenty-seven patients were enrolled. No dose-limiting toxicity occurred during induction gemcitabine/sorafenib followed by concurrent CRT. The most common grade 3/4 toxicities were fatigue, hematologic, and gastrointestinal. The maximum tolerated dose was sorafenib 400 mg twice daily. The median progression-free survival and overall survival for 25 evaluable patients were 10.6 and 12.6 months, respectively. The median overall survival for patients with VEGF-A -2578 AA, -1498 CC, and -1154 AA versus alternate genotypes was 21.6 versus 14.7 months. Dynamic contrast-enhanced MRI demonstrated higher baseline K{sup trans} in responding patients. Conclusions: Concurrent sorafenib with CRT had modest clinical activity with increased gastrointestinal toxicity in localized unresectable pancreatic cancer. Select VEGF-A/VEGF-R2 genotypes were associated with favorable survival.

  20. Phase 1 Pharmacogenetic and Pharmacodynamic Study of Sorafenib With Concurrent Radiation Therapy and Gemcitabine in Locally Advanced Unresectable Pancreatic Cancer

    International Nuclear Information System (INIS)

    Chiorean, E. Gabriela; Schneider, Bryan P.; Akisik, Fatih M.; Perkins, Susan M.; Anderson, Stephen; Johnson, Cynthia S.; DeWitt, John; Helft, Paul; Clark, Romnee; Johnston, Erica L.; Spittler, A. John; Deluca, Jill; Bu, Guixue; Shahda, Safi; Loehrer, Patrick J.; Sandrasegaran, Kumar; Cardenes, Higinia R.

    2014-01-01

    Purpose: To define the safety, efficacy, and pharmacogenetic and pharmacodynamic effects of sorafenib with gemcitabine-based chemoradiotherapy (CRT) in locally advanced pancreatic cancer. Methods and Materials: Patients received gemcitabine 1000 mg/m 2 intravenously weekly × 3 every 4 weeks per cycle for 1 cycle before CRT and continued for up to 4 cycles after CRT. Weekly gemcitabine 600 mg/m 2 intravenously was given during concurrent intensity modulated radiation therapy of 50 Gy to gross tumor volume in 25 fractions. Sorafenib was dosed orally 400 mg twice daily until progression, except during CRT when it was escalated from 200 mg to 400 mg daily, and 400 mg twice daily. The maximum tolerated dose cohort was expanded to 15 patients. Correlative studies included dynamic contrast-enhanced MRI and angiogenesis genes polymorphisms (VEGF-A and VEGF-R2 single nucleotide polymorphisms). Results: Twenty-seven patients were enrolled. No dose-limiting toxicity occurred during induction gemcitabine/sorafenib followed by concurrent CRT. The most common grade 3/4 toxicities were fatigue, hematologic, and gastrointestinal. The maximum tolerated dose was sorafenib 400 mg twice daily. The median progression-free survival and overall survival for 25 evaluable patients were 10.6 and 12.6 months, respectively. The median overall survival for patients with VEGF-A -2578 AA, -1498 CC, and -1154 AA versus alternate genotypes was 21.6 versus 14.7 months. Dynamic contrast-enhanced MRI demonstrated higher baseline K trans in responding patients. Conclusions: Concurrent sorafenib with CRT had modest clinical activity with increased gastrointestinal toxicity in localized unresectable pancreatic cancer. Select VEGF-A/VEGF-R2 genotypes were associated with favorable survival

  1. Cyclooxygenase-2 inhibitor is a robust enhancer of anticancer agents against hepatocellular carcinoma multicellular spheroids

    Directory of Open Access Journals (Sweden)

    Cui J

    2014-02-01

    Full Text Available Jie Cui,1,2 Ya-Huan Guo,3 Hong-Yi Zhang,4 Li-Li Jiang,1 Jie-Qun Ma,1 Wen-Juan Wang,1 Min-Cong Wang,1 Cheng-Cheng Yang,1 Ke-Jun Nan,1 Li-Ping Song5 1Department of Oncology, First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, 2Department of Oncology, Yan'an University Affiliated Hospital, Yan'an, 3Department of Oncology, Shaanxi Province Cancer Hospital, Xi'an, 4Department of Urology, Yan'an University Affiliated Hospital, Yan'an, 5Department of Radiotherapy, First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, People's Republic of China Purpose: Celecoxib, an inhibitor of cyclooxygenase-2 (COX2, was investigated for enhancement of chemotherapeutic efficacy in cancer clinical trials. This study aimed to determine whether celecoxib combined with 5-fluorouracil or sorafenib or gefitinib is beneficial in HepG2 multicellular spheroids (MCSs, as well as elucidate the underlying mechanisms. Methods: The human hepatocellular carcinoma cell line HepG2 MCSs were used as in vitro models to investigate the effects of celecoxib combined with 5-fluorouracil or sorafenib or gefitinib treatment on cell growth, apoptosis, and signaling pathway. Results: MCSs showed resistance to drugs compared with monolayer cells. Celecoxib combined with 5-fluorouracil or sorafenib exhibited a synergistic action. Exposure to celecoxib (21.8 µmol/L plus 5-fluorouracil (8.1 × 10-3 g/L or sorafenib (4.4 µmol/L increased apoptosis but exerted no effect on COX2, phosphorylated epidermal growth-factor receptor (p-EGFR and phosphorylated (p-AKT expression. Gefitinib (5 µmol/L, which exhibits no growth-inhibition activity as a single agent, increased the inhibitory effect of celecoxib. Gefitinib (5 µmol/L plus celecoxib (21.8 µmol/L increased apoptosis. COX2, p-EGFR, and p-AKT were inhibited. Conclusion: Celecoxib combined with 5-fluorouracil or sorafenib or gefitinib may be superior to single-agent therapy in HepG2

  2. Impact of neo-adjuvant Sorafenib treatment on liver transplantation in HCC patients - a prospective, randomized, double-blind, phase III trial

    International Nuclear Information System (INIS)

    Hoffmann, Katrin; Ganten, Tom; Gotthardtp, Daniel; Radeleff, Boris; Settmacher, Utz; Kollmar, Otto; Nadalin, Silvio; Karapanagiotou-Schenkel, Irini; Kalle, Christof von; Jäger, Dirk; Büchler, Markus W; Schemmer, Peter

    2015-01-01

    Liver Transplantation (LT) is treatment of choice for patients with hepatocellular carcinoma (HCC) within MILAN Criteria. Tumour progression and subsequent dropout from waiting list have significant impact on the survival. Transarterial chemoembolization (TACE) controls tumour growth in the treated HCC nodule, however, the risk of tumour development in the untreated liver is increased by simultaneous release of neo-angiogenic factors. Due to its anti-angiogenic effects, Sorafenib delays the progression of HCC. Aim of this study was to determine whether combination of TACE and Sorafenib improves tumour control in HCC patients on waiting list for LT. Fifty patients were randomly assigned on a 1:1 ratio in double-blinded fashion at four centers in Germany and treated with TACE plus either Sorafenib (n = 24) or placebo (n = 26). The end of treatment was development of progressive disease according to mRECIST criteria or LT. The primary endpoint of the trial was the Time-to-Progression (TTP). Other efficacy endpoints were Tumour Response, Progression-free Survival (PFS), and Time-to-LT (TTLT). The median time of treatment was 125 days with Sorafenib and 171 days with the placebo. Fourteen patients (seven from each group) developed tumour progression during the course of the study period. The Hazard Ratio of TTP was 1.106 (95% CI: 0.387, 3.162). The results of the Objective Response Rate, Disease Control Rate, PFS, and TTLT were comparable in both groups. The incidence of AEs was comparable in the placebo group (n = 23, 92%) and in the Sorafenib group (n = 23, 96%). Twelve patients (50%) on Sorafenib and four patients (16%) on placebo experienced severe treatment-related AEs. The TTP is similar after neo-adjuvant treatment with TACE and Sorafenib before LT compared to TACE and placebo. The Tumour Response, PFS, and TTLT were comparable. The safety profile of the Sorafenib group was similar to that of the placebo group

  3. Randomize Trial of Cisplatin plus Gemcitabine with either Sorafenib or Placebo as First-line Therapy for Non-small Cell Lung Cancer

    OpenAIRE

    Yan WANG; Lin WANG; Yutao LIU; Shufei YU; Xiangru ZHANG; Yuankai SHI; Yan SUN

    2011-01-01

    Background and objective Platinum-based chemotherapy doublets reached an efficacy plateau in nonsmall-cell lung cancer (NSCLC). This randomized controlled study prospectively assessed the efficacy and safety of cisplatin plus gemcitabine with either Sorafenib or placebo as first-line therapy for NSCLC. Methods Thirty patients, which were confirmed advanced NSCLC histologically or cytologically, were randomly assigned to receive up to six cycles of cisplatin plus gemcitabine with sorafenib or ...

  4. Transarterial chemoembolization combined with sorafenib for the treatment of hepatocellular carcinoma with hepatic vein tumor thrombus

    Directory of Open Access Journals (Sweden)

    Zhang YF

    2016-07-01

    Full Text Available Yong-Fa Zhang,1–3,* Wei Wei,1–3,* Jia-Hong Wang,1–3,* Li Xu,1–3 Pei-En Jian,1–3 Cheng-Zuo Xiao,4 Xiao-Ping Zhong,1–3 Ming Shi,1–3 Rong-Ping Guo1–3 1Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, 2State Key Laboratory of Oncology in South China, 3Collaborative Innovation Center for Cancer Medicine, Guangzhou, 4Department of General Surgery, Shenzhen Shajing Affiliated Hospital of Guangzhou Medical University, Shenzhen, People’s Republic of China *These authors contributed equally to this work Objective: To compare the treatment outcomes of sorafenib plus transarterial chemoembolization (TACE vs TACE alone in patients with hepatocellular carcinoma (HCC and hepatic vein tumor thrombus (HVTT.Methods: Twenty patients who were initially diagnosed with HCC and HVTT and received TACE combined with sorafenib during February 2009 to October 2013 were included in the study. To minimize selection bias, these patients were compared with 60 case-matched controls selected from a pool of 81 patients (in a 1:3 ratio who received TACE alone during the same period. The primary end point was overall survival (OS. The secondary end points were time to progression, disease control rate, and adverse events.Results: After a median follow-up period of 12.5 months (range, 1.03–44.23 months, the OS of the combined group was found to be significantly higher compared with the monotherapy group (14.9 vs 6.1 months, P=0.010. The time to progression was found to be significantly longer in the combined group (4.9 vs 2.4 months, P=0.016. Univariate and multivariate analyses revealed that the treatment allocation was an independent predictor of OS.Conclusion: Sorafenib plus TACE was well tolerated and was more effective in treating patients with advanced HCC and HVTT. Future trials with prospective larger samples are required to validate these results. Keywords: hepatocellular carcinoma, hepatic vein tumor thrombus, prognosis

  5. Orthotopic liver transplantation after the combined use of locoregional therapy and sorafenib for advanced hepatocellular carcinoma

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    Yoo EJ

    2013-06-01

    Full Text Available Eun Jin Yoo,1,* Hye Sun Shin,1,* Seung Up Kim,1,2,7 Dong Jin Joo,3,4 Jun Yong Park,1,2,7 Gi Hong Choi,3 Do Young Kim,1,2,7 Sang Hoon Ahn,1,2,7 Jinsil Seong,5 Myung Joo Koh,6 Kwang-Hyub Han,1,2,7 Chae Yoon Chon1,2,7 1Department of Internal Medicine, 2Institute of Gastroenterology, 3Department of Surgery, 4Research Institute for Transplantation, 5Department of Radiation Oncology, 6Department of Pathology, Yonsei University College of Medicine, Seoul, South Korea; 7Liver Cirrhosis Clinical Research Center, Seoul, South Korea *These authors contributed equally to this work Abstract: We herein report a patient with advanced hepatitis B virus-related hepatocellular carcinoma (HCC beyond the Milan criteria. He underwent orthotopic liver transplantation after successful HCC downstaging that satisfied the University of California, San Francisco criteria, using concurrent chemoradiation therapy with a combination of repeated hepatic arterial infusion chemotherapy (HAIC and sorafenib. A 52-year-old male was diagnosed with advanced hepatitis B virus-related HCC beyond the Milan criteria. He underwent concurrent chemoradiation therapy (50 Gy with 20 fractions over 5 weeks with HAIC using 5-fluorouracil at a dose of 500 mg/day, which was administered during the first and fifth weeks of radiation therapy as an initial treatment modality. This was followed by the combined use of HAIC using 5-fluorouracil (500 mg/m2 for 5 hours on days 1–3 and cisplatin (60 mg/m2 for 2 hours on day 2 every 4 weeks (twelve cycles and sorafenib (from the third to the twelfth cycle of HAIC to treat the remaining HCC. Because a remarkable decrease in the tumor burden that satisfied the University of California, San Francisco criteria was observed after these combination treatments, the patient underwent orthotopic liver transplantation with curative aim and survived for 11 months without evidence of HCC recurrence. Keywords: hepatocellular carcinoma, liver transplantation

  6. Efficacy and safety of sorafenib versus apatinib in the treatment of intermediate and advanced hepatocellular carcinoma: a comparative retrospective study

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    Wang Y

    2018-06-01

    Full Text Available Yizhuo Wang,1,2 Qing Gou,1 Rongde Xu,1 Xiaoming Chen,1 Zejian Zhou1 1Department of Interventional Oncology, Guangdong Academy of Medical Sciences, Guangdong General Hospital, Guangzhou, Guangdong, People’s Republic of China; 2Medical College Shantou University, Shantou, Guangdong, People’s Republic of China Objective: To compare the efficacy and safety profiles of sorafenib and apatinib in patients with intermediate- and advanced-stage hepatocellular carcinoma (HCC. Methods: This was a single-center, retrospective study where we collected the clinical data of 72 patients, diagnosed with intermediate or advanced HCC from January 2014 to December 2016. Depending on the treatment received, 38 patients were categorized into group S (sorafenib group and 34 into group A (apatinib group. The patients in group A received the initial recommended dose of 750 mg once daily (QD, which was reduced to 250 mg QD in the case of any class 3 or 4 adverse event (AE. Sorafenib was administered orally 400 mg twice daily (BID, and dose was modified to 400 mg or 200 mg QD in the case of grade 3 or 4 AEs. The median overall survival (OS, progression-free survival (PFS, and AEs reported in the two groups were analyzed and compared. Results: Among the 38 patients treated with sorafenib, one patient had complete response (CR, 5 patients had partial response (PR, and 10 patients had stable disease (SD, and among the 34 patients treated with apatinib, 6 patients had PR and 7 patients had SD with no cases of CR. PFS in group S was significantly longer compared with that in group A (7.39 vs 4.79 months, respectively, P=0.031. Similar observations were made for median OS (10.4 months in group S vs 7.18 months in group A, P=0.011. However, there was no significant difference in the objective response rates (ORRs among the study population (15.7 vs 17.6%, P=0.829. Common AEs in group S included hand and foot syndrome (HFS and diarrhea, whereas common AEs in group A

  7. Phase II trial of sorafenib and erlotinib in advanced pancreatic cancer

    International Nuclear Information System (INIS)

    Cardin, Dana B; Goff, Laura; Li, Chung-I; Shyr, Yu; Winkler, Charles; DeVore, Russell; Schlabach, Larry; Holloway, Melanie; McClanahan, Pam; Meyer, Krista; Grigorieva, Julia; Berlin, Jordan; Chan, Emily

    2014-01-01

    This trial was designed to assess efficacy and safety of erlotinib with sorafenib in the treatment of patients with advanced pancreatic adenocarcinoma. An exploratory correlative study analyzing pretreatment serum samples using a multivariate protein mass spectrometry-based test (VeriStrat®), previously shown to correlate with outcomes in lung cancer patients treated with erlotinib, was performed. Patients received sorafenib 400 mg daily along with erlotinib 150 mg daily with a primary endpoint of 8-week progression free survival (PFS) rate. Pretreatment serum sample analysis by VeriStrat was done blinded to clinical and outcome data; the endpoints were PFS and overall survival (OS). Difference between groups (by VeriStrat classification) was assessed using log-rank P values; hazard ratios (HR) were obtained from Cox proportional hazards model. Thirty-six patients received study drug and were included in the survival analysis. Eight-week PFS rate of 46% (95% confidence interval (CI): 0.32–0.67) did not meet the primary endpoint of a rate ≥70%. Thirty-two patients were included in the correlative analysis, and VeriStrat “Good” patients had superior PFS (HR = 0.18, 95% CI: 0.06–0.57; P = 0.001) and OS (HR = 0.31 95% CI: 0.13–0.77, P = 0.008) compared to VeriStrat “Poor” patients. Grade 3 toxicities of this regimen included fever, anemia, diarrhea, dehydration, rash, and altered liver function. This study did not meet the primary endpoint, and this combination will not be further pursued. In this small retrospective analysis, the proteomic classification was significantly associated with clinical outcomes and is being further evaluated in ongoing studies

  8. Significant blockade of multiple receptor tyrosine kinases by MGCD516 (Sitravatinib), a novel small molecule inhibitor, shows potent anti-tumor activity in preclinical models of sarcoma.

    Science.gov (United States)

    Patwardhan, Parag P; Ivy, Kathryn S; Musi, Elgilda; de Stanchina, Elisa; Schwartz, Gary K

    2016-01-26

    Sarcomas are rare but highly aggressive mesenchymal tumors with a median survival of 10-18 months for metastatic disease. Mutation and/or overexpression of many receptor tyrosine kinases (RTKs) including c-Met, PDGFR, c-Kit and IGF1-R drive defective signaling pathways in sarcomas. MGCD516 (Sitravatinib) is a novel small molecule inhibitor targeting multiple RTKs involved in driving sarcoma cell growth. In the present study, we evaluated the efficacy of MGCD516 both in vitro and in mouse xenograft models in vivo. MGCD516 treatment resulted in significant blockade of phosphorylation of potential driver RTKs and induced potent anti-proliferative effects in vitro. Furthermore, MGCD516 treatment of tumor xenografts in vivo resulted in significant suppression of tumor growth. Efficacy of MGCD516 was superior to imatinib and crizotinib, two other well-studied multi-kinase inhibitors with overlapping target specificities, both in vitro and in vivo. This is the first report describing MGCD516 as a potent multi-kinase inhibitor in different models of sarcoma, superior to imatinib and crizotinib. Results from this study showing blockade of multiple driver signaling pathways provides a rationale for further clinical development of MGCD516 for the treatment of patients with soft-tissue sarcoma.

  9. Activation of mPTP-dependent mitochondrial apoptosis pathway by a novel pan HDAC inhibitor resminostat in hepatocellular carcinoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Fu, Meili [Department of Infectious Disease, Linyi People’s Hospital, Linyi (China); Shi, Wenhong [Department of Radiotherapy, Linyi Tumor Hospital, Linyi (China); Li, Zhengling [Department of Nursing, Tengzhou Central People’s Hospital, Tengzhou (China); Liu, Haiyan, E-mail: liuhaiyanlinyi5@sina.com [Department of Nursing, Linyi People’s Hospital, No. 27 Jiefang Road, Linyi 276000, Shandong (China)

    2016-09-02

    Over-expression and aberrant activation of histone deacetylases (HDACs) are often associated with poor prognosis of hepatocellular carcinoma (HCC). Here, we evaluated the potential anti-hepatocellular carcinoma (HCC) cell activity by resminostat, a novel pan HDAC inhibitor (HDACi). We demonstrated that resminostat induced potent cytotoxic and anti-proliferative activity against established HCC cell lines (HepG2, HepB3, SMMC-7721) and patient-derived primary HCC cells. Further, resminostat treatment in HCC cells activated mitochondrial permeability transition pore (mPTP)-dependent apoptosis pathway, which was evidenced by physical association of cyclophilin-D and adenine nucleotide translocator 1 (ANT-1), mitochondrial depolarization, cytochrome C release and caspase-9 activation. Intriguingly, the mPTP blockers (sanglifehrin A and cyclosporine A), shRNA knockdown of cyclophilin-D or the caspase-9 inhibitor dramatically attenuated resminostat-induced HCC cell apoptosis and cytotoxicity. Reversely, HCC cells with exogenous cyclophilin-D over-expression were hyper-sensitive to resminostat. Intriguingly, a low concentration of resminostat remarkably potentiated sorafenib-induced mitochondrial apoptosis pathway activation, leading to a profound cytotoxicity in HCC cells. The results of this preclinical study indicate that resminostat (or plus sorafenib) could be further investigated as a valuable anti-HCC strategy. - Highlights: • Resminostat inhibits human HCC cell survival and proliferation. • Resminostat activates mPTP-dependent mitochondrial apoptosis pathway in HCC cells. • Resminostat potentiates sorafenib-induced mitochondrial apoptosis pathway activation. • mPTP or caspase-9 inhibition attenuates apoptosis by resminostat or plus sorafenib.

  10. Efficacy and safety of sorafenib in combination with gemcitabine in patients with advanced hepatocellular carcinoma: a multicenter, open-label, single-arm phase II study.

    Science.gov (United States)

    Srimuninnimit, Vichien; Sriuranpong, Virote; Suwanvecho, Suthida

    2014-09-01

    Currently, the only standard systemic treatment for advanced hepatocellular carcinoma is sorafenib monotherapy. The study was conducted to assess the efficacy and safety of the novel combination of sorafenib and gemcitabine in the treatment of advanced hepatocellular carcinoma. Between March 2008 and October 2010, patients with advanced pathologically proven hepatocellular carcinoma who had not received previous systemic therapy and had Child-Pugh liver function class A or B received sorafenib plus gemcitabine. Treatment included 4-week cycle of gemcitabine (1000 mg/m(2) days 1, 8, 15) to the maximum of six cycles together with sorafenib (400 mg twice daily). Patient continued sorafenib until disease progression or withdrawal from other reasons. The primary end point is progression-free survival. Forty-five patients were enrolled in this study. The median progression-free survival was 3.7 months (95% CI 3.5-3.8). The overall response rate was 4% with no complete responses and the disease control rate was 66%. The median overall survival (OS) was 11.6 months (95% CI 7.4-15.9). The median time to progression was 3.6 months (95% CI 3.4-3.7). The most frequently reported grade 3/4 treatment-related adverse events included thrombocytopenia 33%, neutropenia 16% and hand-foot skin reaction 13%. The study regimen was well tolerated. The combination of sorafenib and gemcitabine in advanced hepatocellular carcinoma is generally well tolerated and has modest clinical efficacy. The median OS is up to 1 year. However, well-designed randomized controlled trials with a sorafenib alone comparator arm are needed to confirm this finding. © 2014 Wiley Publishing Asia Pty Ltd.

  11. Early sorafenib-induced toxicity is associated with drug exposure and UGTIA9 genetic polymorphism in patients with solid tumors: a preliminary study.

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    Pascaline Boudou-Rouquette

    Full Text Available BACKGROUND: Identifying predictive biomarkers of drug response is of key importance to improve therapy management and drug selection in cancer therapy. To date, the influence of drug exposure and pharmacogenetic variants on sorafenib-induced toxicity remains poorly documented. The aim of this pharmacokinetic/pharmacodynamic (PK/PD study was to investigate the relationship between early toxicity and drug exposure or pharmacogenetic variants in unselected adult outpatients treated with single-agent sorafenib for advanced solid tumors. METHODS: Toxicity was recorded in 54 patients on days 15 and 30 after treatment initiation and sorafenib exposure was assessed in 51 patients. The influence of polymorphisms in CYP3A5, UGT1A9, ABCB1 and ABCG2 was examined in relation to sorafenib exposure and toxicity. Clinical characteristics, drug exposure and pharmacogenetic variants were tested univariately for association with toxicities. Candidate variables with p<0.1 were analyzed in a multivariate analysis. RESULTS: Gender was the sole parameter independently associated with sorafenib exposure (p = 0.0008. Multivariate analysis showed that increased cumulated sorafenib (AUC(cum was independently associated with any grade ≥ 3 toxicity (p = 0.037; UGT1A9 polymorphism (rs17868320 with grade ≥ 2 diarrhea (p = 0.015 and female gender with grade ≥ 2 hand-foot skin reaction (p = 0.018. Using ROC curve, the threshold AUC(cum value of 3,161 mg/L.h was associated with the highest risk to develop any grade ≥ 3 toxicity (p = 0.018. CONCLUSION: In this preliminary study, increased cumulated drug exposure and UGT1A9 polymorphism (rs17868320 identified patients at high risk for early sorafenib-induced severe toxicity. Further PK/PD studies on larger population are warranted to confirm these preliminary results.

  12. Clinical observation of transcatheter arterial chemoembolization combined with sorafenib on intermediate-advanced hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Wei Zhaoguang; Lu Ligong; Shao Peijian; Hu Baoshan; Li Yong; Zhang Lei; He Xu; Yu Xianyi; Luo Xiaoning

    2012-01-01

    Objective: To evaluate the treatment effect and security of transcatheter arterial chemoembolization (TACE) combined with sorafenib for intermediate-advanced hepatocellular carcinoma. Methods: From July 2008 to November 2010,the treatment effects of two groups of patients with advanced hepatocellular carcinoma were retrospectively analyzed and compared, including 44 patients treated by sorafenib combined with TACE (test group) and the other 44 patients treated only with TACE (control group). To assess the treatment effect based on mRECIST, the time for patients' tumor progression (TTP), overall survival (OS) time and adverse events were recorded. Survival rate were analyzed using Kaplan-Meier method and Log-rank analysis in SPSS 18.0. Results: Till January 2011, 24 patients (54.5%) survived and 20 patients (include patients lost to visit) died (45.5%) among the test group, 13 patients survived (29.5 %) and 31 patients (include patients lost to visit) died (70.5 %) among the control group. No complete remission condition was observed in all patients. Among the test group, 1 patient got partial remission, 24 ones remain stable and 19 patients got progression. While among the control group, conditions remained stable in 21 patients and progressed in rest 23 ones. The disease control rate (DCR) in the test group and control group were 56.8% (25/44) and 47.7% (21/44) respectively, with no statistical significance (χ 2 =0.729, P=0.393). The median overall survival time (mOS) of test group and control group were 21.0 (95% CI: 14.9-27.1)months and 10.0 (95% CI: 6.4-13.6) months respectively, and the difference reached statistical significance (χ 2 =7.436, P=0.006). The median time to tumor progression (mTTP) of test group and control group was 11.0 (95% CI: 8.7-13.3) and 6.0 (95% CI: 3.9-8.1) months respectively, and the difference had statistical significance (χ 2 =10.437, P=0.001). The adverse events of test group mainly included hand-foot skin reaction, loss of

  13. Phase I dose-finding study of sorafenib with FOLFOX4 as first-line treatment in patients with unresectable locally advanced or metastatic gastric cancer.

    Science.gov (United States)

    Chi, Yihebali; Yang, Jianliang; Yang, Sheng; Sun, Yongkun; Jia, Bo; Shi, Yuankai

    2015-06-01

    To determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and efficacy of sorafenib in combination with FOLFOX4 (oxaliplatin/leucovorin (LV)/5-fluorouracil) as first-line treatment for advanced gastric cancer, we performed a phase I dose-finding study in nine evaluable patients with unresectable locally advanced or metastatic gastric cancer or gastroesophageal junction adenocarcinoma. According to modified Fibonacci method, the design of this study was to guide elevation of the sorafenib dosage to the next level (from 200 mg twice daily to 400 mg twice daily and then, if tolerated, 600 mg twice daily). If the patient achieved complete response (CR), partial response (PR) or stable disease (SD) after eight cycles of treatment, combination chemotherapy was scheduled to be discontinued and sorafenib monotherapy continued at the original dose until either disease progression or unacceptable toxicity. In sorafenib 200 mg twice daily group, DLT was observed in 1 of 6 patients, and in 400 mg twice daily group, it was observed in 2 of 3 patients. Seven of 9 (77.8%) evaluable patients achieved PR, with a median overall survival (OS) of 11.8 [95% confidence interval (CI): 8.9-14.7] months. Common adverse effects include hand-foot syndrome, leukopenia, neutropenia, anorexia, and nausea. Twice-daily dosing of sorafenib 200 mg in combination with FOLFOX4 was proven effective and safe for the treatment of advanced gastric cancer, and could be an appropriate dosage for subsequent phase II clinical studies.

  14. Hand-foot skin reaction is a beneficial indicator of sorafenib therapy for patients with hepatocellular carcinoma: a systemic review and meta-analysis.

    Science.gov (United States)

    Wang, Ping; Tan, Gang; Zhu, Mingxin; Li, Weidong; Zhai, Bo; Sun, Xueying

    2018-01-01

    Sorafenib remains the only standard first-line drug for advanced hepatocellular carcinoma (HCC). Hand-foot skin reaction (HFSR) is a very common side-effect in patients treated with sorafenib, and also affects the treatment schedule and quality of life. However, the association of HFSR and response of HCC to sorafenib remain unclear. Databases including PubMed, EMBASE, Web of Science and Cochrane Central Register of Controlled Trials were searched up to May 7 th , 2017. Review Manager 5.3 software was adopted for performing meta-analyses, Newcastle-Ottawa Scale for assessing the bias of cohort studies, and GRADEprofler software for further assessing outcomes obtained from meta-analyses. 1478 articles were reviewed, and 12 cohort studies with 1017 participants were included in the analyses. The pooled hazard ratio (HR) of overall survival is 0.45 (95% confidence interval (CI) 0.36, 0.55; P The pooled HR of time to progression is 0.41 (95% CI 0.28, 0.60; P The results indicate that HFSR is a beneficial indicator for HCC patients receiving sorafenib therapy. However, molecular mechanisms accounting for sorafenib-induced HFSR in HCC patients remain.

  15. Effective prevention of sorafenib-induced hand–foot syndrome by dried-bonito broth

    Directory of Open Access Journals (Sweden)

    Kamimura K

    2018-04-01

    Full Text Available Kenya Kamimura,1 Yoko Shinagawa-Kobayashi,1 Ryo Goto,1 Kohei Ogawa,1 Takeshi Yokoo,1 Akira Sakamaki,1 Satoshi Abe,1 Hiroteru Kamimura,1 Takeshi Suda,2 Hiroshi Baba,3 Takayuki Tanaka,4 Yoshizu Nozawa,5 Naoto Koyama,6 Masaaki Takamura,1 Hirokazu Kawai,1 Satoshi Yamagiwa,1 Yutaka Aoyagi,1 Shuji Terai1 1Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Niigata, Japan; 2Department of Gastroenterology and Hepatology, Uonuma Institute of Community Medicine, Niigata Medical and Dental Hospital, Minami-Uonuma, Niigata, Japan; 3Division of Anesthesiology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Niigata, Japan; 4Uonuma Eye Clinic, Uonuma, Niigata, Japan; 5Institute of Food Sciences and Technologies, Ajinomoto Co., Inc., Kawasaki, Kanagawa, Japan; 6Institute for Innovation, Ajinomoto Co., Inc., Kawasaki, Kanagawa, Japan Background: Sorafenib (SOR is a molecular medicine that prolongs the survival of patients with hepatocellular carcinoma (HCC. Therefore, the management of side effects is essential for the longer period of continuous medication. Among the various side effects, hand–foot syndrome (HFS is the most common, occurring in 30%–50% of patients, and often results in discontinuation of the SOR medication. However, its mechanism has not been clarified, and no effective prevention method has been reported for the symptoms. Therefore, this study aimed to analyze its mechanism and to develop an effective prevention regimen for the symptoms. Materials and methods: To assess the mechanism of SOR-induced HFS, the peripheral blood flow in the hand and foot was carefully monitored by Doppler ultrasound, thermography, and laser speckle flowgraphy in the cases treated with SOR and its contribution was assessed. Then, the effect of dried-bonito broth (DBB, which was reported to improve peripheral blood flow, on the prevention of the symptom was

  16. A phase I/II trial of AT9283, a selective inhibitor of aurora kinase in children with relapsed or refractory acute leukemia: challenges to run early phase clinical trials for children with leukemia.

    Science.gov (United States)

    Vormoor, B; Veal, G J; Griffin, M J; Boddy, A V; Irving, J; Minto, L; Case, M; Banerji, U; Swales, K E; Tall, J R; Moore, A S; Toguchi, M; Acton, G; Dyer, K; Schwab, C; Harrison, C J; Grainger, J D; Lancaster, D; Kearns, P; Hargrave, D; Vormoor, J

    2017-06-01

    Aurora kinases regulate mitosis and are commonly overexpressed in leukemia. This phase I/IIa study of AT9283, a multikinase inhibitor, was designed to identify maximal tolerated doses, safety, pharmacokinetics, and pharmacodynamic activity in children with relapsed/refractory acute leukemia. The trial suffered from poor recruitment and terminated early, therefore failing to identify its primary endpoints. AT9283 caused tolerable toxicity, but failed to show clinical responses. Future trials should be based on robust preclinical data that provide an indication of which patients may benefit from the experimental agent, and recruitment should be improved through international collaborations and early combination with established treatment strategies. © 2016 Wiley Periodicals, Inc.

  17. Synthesis and conformational analysis of new arylated-diphenylurea derivatives related to sorafenib drug via Suzuki-Miyaura cross-coupling reaction

    Science.gov (United States)

    Al-Masoudi, Najim A.; Essa, Ali Hashem; Alwaaly, Ahmed A. S.; Saeed, Bahjat A.; Langer, Peter

    2017-10-01

    Sorafenib, is a relatively new cytostatic drug approved for the treatment of renal cell and hepatocellular carcinoma. The development of new sorafenib analogues offers the possibility of generating structures of increased potency. To this end, a series of arylated-diphenylurea analogues 17-31 were synthesized via Suzuki-Miyaura coupling reaction, related to sorafenib by treatment of three diarylureas 2-4 having 3-bromo, 4-chloro and 2-iodo groups with various arylboronic acids. Conformational analysis of the new arylated urea analogues has been investigated using MOPAC 2016 of semi empirical PM7 Hamiltonian computational method. Our results showed that all compounds preferred the trans-trans conformations. Compound 17 has been selected to calculate the torsional energy profiles for rotation around the urea bonds and found to be existed predominantly in the trans-trans conformation with only very minimal fluctuation in conformation.

  18. Research advances in regorafenib in treatment of hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    CHEN Weibo

    2017-12-01

    Full Text Available Hepatocellular carcinoma (HCC is the most common malignant liver tumor, and there are limited systemic treatments for patients with advanced HCC. Regorafenib is an oral multi-kinase inhibitor, and phase III clinical trial has shown that regorafenib can significantly extend the median survival of patients with advanced HCC by 2.8 months, which makes it a second-line drug approved by FDA for the treatment of advanced HCC, just after sorafenib. This article reviews the basic and clinical research on regorafenib in the field of HCC.

  19. Bone metastases as initial presentation of hepatocellular carcinoma.

    Science.gov (United States)

    Monteserin, Luzdivina; Mesa, Alicia; Fernandez-Garcia, Maria Soledad; Gadanon-Garcia, Arantza; Rodriguez, Manuel; Varela, María

    2017-10-18

    Extra-hepatic spread is present in 5% to 15% of patients with hepatocellular carcinoma (HCC) at the time of diagnosis. The most frequent sites are lung and regional lymph nodes. Here, we report 3 cases of unsuspected HCC with symptoms due to bone lesions as initial presentation. Morphological characteristics and immunohistochemistry from the examined bone were the key data for diagnosis. None of the patients had an already known chronic liver disease. Differential diagnoses with HCC upon ectopic liver disease or hepatoid adenocarcinoma were shown. Therapy with the orally active multikinase inhibitor sorafenib plus symptomatic treatment was indicated.

  20. Regorafenib for the treatment of unresectable hepatocellular carcinoma.

    Science.gov (United States)

    Rimassa, Lorenza; Pressiani, Tiziana; Personeni, Nicola; Santoro, Armando

    2017-07-01

    Sorafenib is the standard of care for patients with advanced hepatocellular carcinoma (HCC) and well preserved liver function. However, until recent approval of regorafenib by the Food and Drug Administration (FDA), no effective therapeutic options were available for patients resistant to sorafenib. Areas covered: The present article reviews the preclinical and clinical data of regorafenib, putting them into the context of current and future landscape of treatment options for patients with HCC. Recently, the randomized, placebo-controlled, Phase III RESORCE trial, demonstrated a statistically and clinically significant increase in overall survival from 7.8 months with placebo to 10.6 months with regorafenib in patients progressing on sorafenib. Furthermore, the study showed a significant improvement in all the other efficacy endpoints. Main adverse events were hypertension, hand-foot skin reaction, fatigue and diarrhea, with no negative impact on quality of life. Expert commentary: Regorafenib is a recently approved treatment option for HCC patients who have been previously treated with sorafenib. The RESORCE trial demonstrates the beneficial effect of a sequential approach involving two multikinase inhibitors, namely sorafenib and regorafenib, whose antitumor activity extends beyond their antiangiogenic functions.

  1. Fisetin, a dietary flavonoid, augments the anti-invasive and anti-metastatic potential of sorafenib in melanoma.

    Science.gov (United States)

    Pal, Harish C; Diamond, Ariana C; Strickland, Leah R; Kappes, John C; Katiyar, Santosh K; Elmets, Craig A; Athar, Mohammad; Afaq, Farrukh

    2016-01-12

    Melanoma is the most aggressive and deadly form of cutaneous neoplasm due to its propensity to metastasize. Oncogenic BRAF drives sustained activation of the BRAF/MEK/ERK (MAPK) pathway and cooperates with PI3K/AKT/mTOR (PI3K) signaling to induce epithelial to mesenchymal transition (EMT), leading to cell invasion and metastasis. Therefore, targeting these pathways is a promising preventive/therapeutic strategy. We have shown that fisetin, a flavonoid, reduces human melanoma cell invasion by inhibiting EMT. In addition, fisetin inhibited melanoma cell proliferation and tumor growth by downregulating the PI3K pathway. In this investigation, we aimed to determine whether fisetin can potentiate the anti-invasive and anti-metastatic effects of sorafenib in BRAF-mutated melanoma. We found that combination treatment (fisetin + sorafenib) more effectively reduced the migration and invasion of BRAF-mutated melanoma cells both in vitro and in raft cultures compared to individual agents. Combination treatment also effectively inhibited EMT as observed by a decrease in N-cadherin, vimentin and fibronectin and an increase in E-cadherin both in vitro and in xenograft tumors. Furthermore, combination therapy effectively inhibited Snail1, Twist1, Slug and ZEB1 protein expression compared to monotherapy. The expression of MMP-2 and MMP-9 in xenograft tumors was further reduced in combination treatment compared to individual agents. Bioluminescent imaging of athymic mice, intravenously injected with stably transfected CMV-luciferase-ires-puromycin.T2A.EGFP-tagged A375 melanoma cells, demonstrated fewer lung metastases following combination treatment versus monotherapy. Our findings demonstrate that fisetin potentiates the anti-invasive and anti-metastatic effects of sorafenib. Our data suggest that fisetin may be a worthy adjuvant chemotherapy for the management of melanoma.

  2. Predictive factors in patients with hepatocellular carcinoma receiving sorafenib therapy using time-dependent receiver operating characteristic analysis.

    Science.gov (United States)

    Nishikawa, Hiroki; Nishijima, Norihiro; Enomoto, Hirayuki; Sakamoto, Azusa; Nasu, Akihiro; Komekado, Hideyuki; Nishimura, Takashi; Kita, Ryuichi; Kimura, Toru; Iijima, Hiroko; Nishiguchi, Shuhei; Osaki, Yukio

    2017-01-01

    To investigate variables before sorafenib therapy on the clinical outcomes in hepatocellular carcinoma (HCC) patients receiving sorafenib and to further assess and compare the predictive performance of continuous parameters using time-dependent receiver operating characteristics (ROC) analysis. A total of 225 HCC patients were analyzed. We retrospectively examined factors related to overall survival (OS) and progression free survival (PFS) using univariate and multivariate analyses. Subsequently, we performed time-dependent ROC analysis of continuous parameters which were significant in the multivariate analysis in terms of OS and PFS. Total sum of area under the ROC in all time points (defined as TAAT score) in each case was calculated. Our cohort included 175 male and 50 female patients (median age, 72 years) and included 158 Child-Pugh A and 67 Child-Pugh B patients. The median OS time was 0.68 years, while the median PFS time was 0.24 years. On multivariate analysis, gender, body mass index (BMI), Child-Pugh classification, extrahepatic metastases, tumor burden, aspartate aminotransferase (AST) and alpha-fetoprotein (AFP) were identified as significant predictors of OS and ECOG-performance status, Child-Pugh classification and extrahepatic metastases were identified as significant predictors of PFS. Among three continuous variables (i.e., BMI, AST and AFP), AFP had the highest TAAT score for the entire cohort. In subgroup analyses, AFP had the highest TAAT score except for Child-Pugh B and female among three continuous variables. In continuous variables, AFP could have higher predictive accuracy for survival in HCC patients undergoing sorafenib therapy.

  3. Prognosis of patients with hepatocellular carcinoma treated with sorafenib: a comparison of five models in a large Canadian database.

    Science.gov (United States)

    Samawi, Haider H; Sim, Hao-Wen; Chan, Kelvin K; Alghamdi, Mohammad A; Lee-Ying, Richard M; Knox, Jennifer J; Gill, Parneet; Romagnino, Adriana; Batuyong, Eugene; Ko, Yoo-Joung; Davies, Janine M; Lim, Howard J; Cheung, Winson Y; Tam, Vincent C

    2018-05-15

    Several systems (tumor-node-metastasis [TNM], Barcelona Clinic Liver Cancer [BCLC], Okuda, Cancer of the Liver Italian Program [CLIP], and albumin-bilirubin grade [ALBI]) were developed to estimate the prognosis of patients with hepatocellular carcinoma (HCC) mostly prior to the prevalent use of sorafenib. We aimed to compare the prognostic and discriminatory power of these models in predicting survival for HCC patients treated with sorafenib and to identify independent prognostic factors for survival in this population. Patients who received sorafenib for the treatment of HCC between 1 January 2008 and 30 June 2015 in the provinces of British Columbia and Alberta, and two large cancer centers in Toronto, Ontario, were included. Survival was assessed using the Kaplan-Meier method. Multivariate Cox regression was used to identify predictors of survival. The models were compared with respect to homogeneity, discriminatory ability, monotonicity of gradients, time-dependent area under the curve, and Akaike information criterion. A total of 681 patients were included. 80% were males, 86% had Child-Pugh class A, and 37% of patients were East Asians. The most common etiology for liver disease was hepatitis B (34%) and C (31%). In all model comparisons, CLIP performed better while BCLC and TNM7 performed less favorably but the differences were small. The utility of each system in allocating patients into different prognostic groups varied, for example, TNM poorly differentiated patients in advanced stages (8.7 months (m) (95% CI 6.5-11.5) versus 8.4 m (95% CI 7.0-9.6) for stages III and IV, respectively) while ALBI had excellent discrimination of early grades (15.6 m [95% CI 13.0-18.4] versus 8.3 m [95% CI 7.0-9.2] for grades 1 and 2, respectively). On multivariate analysis, hepatitis C, alcoholism, and prior hepatic resection were independently prognostic of better survival (P < 0.01). In conclusion, none of the prognostic systems was optimal in predicting survival

  4. Multi-tyrosine kinase inhibitors in preclinical studies for pediatric CNS AT/RT: Evidence for synergy with Topoisomerase-I inhibition

    Directory of Open Access Journals (Sweden)

    Jayanthan Aarthi

    2011-12-01

    Full Text Available Abstract Background Currently, Atypical Teratoid Rhabdoid Tumor (AT/RT constitutes one of the most difficult to treat malignancies in pediatrics. Hence, new knowledge of potential targets for therapeutics and the development of novel treatment approaches are urgently needed. We have evaluated the presence of cytokine pathways and the effects of two clinically available multi-tyrosine kinase inhibitors for cytotoxicity, target modulation and drug combinability against AT/RT cell lines. Results AT/RT cell lines expressed measurable quantities of VEGF, FGF, PDGF and SDF-1, although the absolute amounts varied between the cell lines. The targeted receptor tyrosine kinase inhibitor sorafenib inhibited the key signaling molecule Erk, which was activated following the addition of own conditioned media, suggesting the existence of autocrine/paracrine growth stimulatory pathways. The multi-tyrosine kinase inhibitors sorafenib and sunitinib also showed significant growth inhibition of AT/RT cells and their activity was enhanced by combination with the topoisomerase inhibitor, irinotecan. The loss of cytoplasmic NF-kappa-B in response to irinotecan was diminished by sorafenib, providing evidence for a possible benefit for this drug combination. Conclusions In addition to previously described involvement of insulin like growth factor (IGF family of cytokines, a multitude of other growth factors may contribute to the growth and survival of AT/RT cells. However, consistent with the heterogeneous nature of this tumor, quantitative and qualitative differences may exist among different tumor samples. Multi-tyrosine kinase inhibitors appear to have effective antitumor activity against all cell lines studied. In addition, the target modulation studies and drug combinability data provide the groundwork for additional studies and support the evaluation of these agents in future treatment protocols.

  5. Paclitaxel/carboplatin with or without sorafenib in the first-line treatment of patients with stage III/IV epithelial ovarian cancer: a randomized phase II study of the Sarah Cannon Research Institute

    International Nuclear Information System (INIS)

    Hainsworth, John D; Thompson, Dana S; Bismayer, John A; Gian, Victor G; Merritt, William M; Whorf, Robert C; Finney, Lindsey H; Dudley, B Stephens

    2015-01-01

    This trial compared the efficacy and toxicity of standard first-line treatment with paclitaxel/carboplatin versus paclitaxel/carboplatin plus sorafenib in patients with advanced ovarian carcinoma. Patients with stage 3 or 4 epithelial ovarian cancer with residual measurable disease or elevated CA-125 levels after maximal surgical cytoreduction were randomized (1:1) to receive treatment with paclitaxel (175 mg/m 2 , 3 h infusion, day 1) and carboplatin (AUC 6.0, IV, day 1) with or without sorafenib 400 mg orally twice daily (PO BID). Patients were reevaluated for response after completing 6 weeks of treatment (two cycles); responding or stable patients received six cycles of paclitaxel/carboplatin. Patients receiving the sorafenib-containing regimen continued sorafenib (400 PO BID) for a total of 52 weeks. Eighty-five patients were randomized and received treatment.Efficacy was similar for patients receiving paclitaxel/carboplatin/sorafenib versus paclitaxel/carboplatin: overall response rates 69% versus 74%; median progression-free survival 15.4 versus 16.3 months; 2 year survival 76% versus 81%. The addition of sorafenib added substantially to the toxicity of the regimen; rash, hand–foot syndrome, mucositis, and hypertension were significantly more common in patients treated with sorafenib. The addition of sorafenib to standard paclitaxel/carboplatin did not improve efficacy and substantially increased toxicity in the first-line treatment of advanced epithelial ovarian cancer. Based on evidence from this study and other completed trials, sorafenib is unlikely to have a role in the treatment of ovarian cancer

  6. CS2164, a novel multi-target inhibitor against tumor angiogenesis, mitosis and chronic inflammation with anti-tumor potency.

    Science.gov (United States)

    Zhou, You; Shan, Song; Li, Zhi-Bin; Xin, Li-Jun; Pan, De-Si; Yang, Qian-Jiao; Liu, Ying-Ping; Yue, Xu-Peng; Liu, Xiao-Rong; Gao, Ji-Zhou; Zhang, Jin-Wen; Ning, Zhi-Qiang; Lu, Xian-Ping

    2017-03-01

    Although inhibitors targeting tumor angiogenic pathway have provided improvement for clinical treatment in patients with various solid tumors, the still very limited anti-cancer efficacy and acquired drug resistance demand new agents that may offer better clinical benefits. In the effort to find a small molecule potentially targeting several key pathways for tumor development, we designed, discovered and evaluated a novel multi-kinase inhibitor, CS2164. CS2164 inhibited the angiogenesis-related kinases (VEGFR2, VEGFR1, VEGFR3, PDGFRα and c-Kit), mitosis-related kinase Aurora B and chronic inflammation-related kinase CSF-1R in a high potency manner with the IC 50 at a single-digit nanomolar range. Consequently, CS2164 displayed anti-angiogenic activities through suppression of VEGFR/PDGFR phosphorylation, inhibition of ligand-dependent cell proliferation and capillary tube formation, and prevention of vasculature formation in tumor tissues. CS2164 also showed induction of G2/M cell cycle arrest and suppression of cell proliferation in tumor tissues through the inhibition of Aurora B-mediated H3 phosphorylation. Furthermore, CS2164 demonstrated the inhibitory effect on CSF-1R phosphorylation that led to the suppression of ligand-stimulated monocyte-to-macrophage differentiation and reduced CSF-1R + cells in tumor tissues. The in vivo animal efficacy studies revealed that CS2164 induced remarkable regression or complete inhibition of tumor growth at well-tolerated oral doses in several human tumor xenograft models. Collectively, these results indicate that CS2164 is a highly selective multi-kinase inhibitor with potent anti-tumor activities against tumor angiogenesis, mitosis and chronic inflammation, which may provide the rationale for further clinical assessment of CS2164 as a therapeutic agent in the treatment of cancer. © 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  7. Effect of histidine on sorafenib-induced vascular damage: Analysis using novel medaka fish model.

    Science.gov (United States)

    Shinagawa-Kobayashi, Yoko; Kamimura, Kenya; Goto, Ryo; Ogawa, Kohei; Inoue, Ryosuke; Yokoo, Takeshi; Sakai, Norihiro; Nagoya, Takuro; Sakamaki, Akira; Abe, Satoshi; Sugitani, Soichi; Yanagi, Masahiko; Fujisawa, Koichi; Nozawa, Yoshizu; Koyama, Naoto; Nishina, Hiroshi; Furutani-Seiki, Makoto; Sakaida, Isao; Terai, Shuji

    2018-02-05

    Sorafenib (SFN) is an anti-angiogenic chemotherapeutic that prolongs survival of patients with hepatocellular carcinoma (HCC); its side effects, including vascular damages such as hand-foot syndrome (HFS), are a major cause of therapy discontinuation. We previously reported that maintenance of peripheral blood flow by intake of dried bonito broth (DBB) significantly prevented HFS and prolonged the administration period. The amino acids contained in DBB probably contribute to its effects, but the mechanism has not been clarified. We hypothesized that histidine, the largest component among the amino acids contained in DBB, has effects on SFN-induced vascular damage, and evaluated this possibility using a novel medaka fish model. The fli::GFP transgenic medaka fish model has a fluorescently visible systemic vasculature. We fed the fish with SFN with and without histidine to compare blood flow and vascular structure among the differently fed models. The vascular cross-sectional area of each fish was measured to determine vascular diameter changes. Our results demonstrated that SFN-fed medaka developed a narrower vascular diameter. In addition, this narrowing was counteracted by addition of histidine to the medaka diet. We observed no positive effect of histidine on regeneration of cut vessels or on cell growth of endothelial cells and HCC cell lines. We proved the efficacy of the medaka model to assess vascular changes after administration of specific chemicals. And our results suggest that SFN causes vascular damage by narrowing peripheral vessel diameter, and that histidine effectively counteracts these changes to maintain blood flow. Copyright © 2018 Elsevier Inc. All rights reserved.

  8. Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells

    NARCIS (Netherlands)

    Mathew, N.R.; Baumgartner, F.; Braun, L.; O'Sullivan, D.; Thomas, S.; Waterhouse, M.; Muller, T.A.; Hanke, K.; Taromi, S.; Apostolova, P.; Illert, A.L.; Melchinger, W.; Duquesne, S.; Schmitt-Graeff, A.; Osswald, L.; Yan, K.L.; Weber, A; Tugues, S.; Spath, S.; Pfeifer, D.; Follo, M.; Claus, R.; Lubbert, M.; Rummelt, C.; Bertz, H.; Wasch, R.; Haag, J.; Schmidts, A.; Schultheiss, M.; Bettinger, D.; Thimme, R.; Ullrich, E.; Tanriver, Y.; Vuong, G.L.; Arnold, R.; Hemmati, P.; Wolf, D.; Ditschkowski, M.; Jilg, C.; Wilhelm, K.; Leiber, C.; Gerull, S.; Halter, J.; Lengerke, C.; Pabst, T.; Schroeder, T.; Kobbe, G.; Rosler, W.; Doostkam, S.; Meckel, S.; Stabla, K.; Metzelder, S.K.; Halbach, S.; Brummer, T.; Hu, Z; Dengjel, J.; Hackanson, B.; Schmid, C.; Holtick, U.; Scheid, C.; Spyridonidis, A.; Stolzel, F.; Ordemann, R.; Muller, L.P.; Sicre-de-Fontbrune, F.; Ihorst, G.; Kuball, J.; Ehlert, J.E.; Feger, D.; Wagner, E.M.; Cahn, J.Y.; Schnell, J.; Kuchenbauer, F.; Bunjes, D.; Chakraverty, R.; Richardson, S.; Gill, S.; Kroger, N.; Ayuk, F.; Vago, L.; Ciceri, F.; Muller, A.M.; Kondo, T.; Teshima, T.; Klaeger, S.; Kuster, B.; Kim, D.D.H.; Weisdorf, D.; Velden, W.J. van der; Dorfel, D.; Bethge, W.; Hilgendorf, I.; Hochhaus, A.; Andrieux, G.; Borries, M.; Busch, H.; Magenau, J.; Reddy, P.; Labopin, M.; Antin, J.H., et al.

    2018-01-01

    Individuals with acute myeloid leukemia (AML) harboring an internal tandem duplication (ITD) in the gene encoding Fms-related tyrosine kinase 3 (FLT3) who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) have a 1-year survival rate below 20%. We observed that sorafenib, a

  9. A comparative study of sorafenib and metronomic chemotherapy for Barcelona Clinic Liver Cancer-stage C hepatocellular carcinoma with poor liver function

    Directory of Open Access Journals (Sweden)

    Hyun Yang

    2017-06-01

    Full Text Available Background/Aims Metronomic chemotherapy (MET is frequently administered in comparatively low doses as a continuous chemotherapeutic agent. The aim of this study was to evaluate the feasibility and overall survival (OS of MET compared to sorafenib for advanced hepatocellular carcinoma (HCC patients with portal vein tumor thrombosis (PVTT. Methods A total of 54 patients with advanced HCC and PVTT who had undergone MET were analyzed between 2005 and 2013. A total of 53 patients who had undergone sorafenib therapy were analyzed as the control group. The primary endpoint of this study was OS. Results The median number of MET cycles was two (1-15. The OS values for the MET group and sorafenib group were 158 days (132-184 and 117 days (92-142, respectively (P=0.029. The Cox proportional-hazard model showed that a higher risk of death was correlated with higher serum alpha fetoprotein level (≥400 mg/dL, hazard ratio [HR]=1.680, P=0.014 and Child-Pugh class B (HR=1.856, P=0.008. Conclusions MET was associated with more favorable outcomes in terms of overall survival than was sorafenib in patients with advanced HCC with PVTT, especially in patients with poor liver function. Therefore, MET can be considered as a treatment option in patients with advanced HCC with PVTT and poor liver function.

  10. Medical treatment of hepatocellular carcinoma.

    Science.gov (United States)

    Granito, Alessandro; Bolondi, Luigi

    2009-12-16

    Hepatocellular carcinoma (HCC) is the fifth most common neoplasm and the third leading cause of cancer-related deaths worldwide. Cirrhosis, most often due to viral hepatitis, is the predominant risk factors for HCC and geographical differences in both risk factors and incidence are largely due to epidemiological variations in hepatitis B and C infection. Hepatic function is a relevant parameter in selecting therapy in HCC. The current clinical classification of HCC split patients into 5 stages, with a specific treatment schedule for any stage. As patients with early stages can receive curative treatments, such as surgical resection, liver transplantation or local ablation, surveillance program in high-risk populations has become mandatory. Sorafenib, a multikinase inhibitor, has recently shown survival benefits in patients at advanced stage of disease. Hopefully, new molecular targeted therapies and their combination with sorafenib or interventional and surgical procedures, should expand the therapeutic armamentarium against HCC.

  11. Targeted therapy for human hepatic carcinoma cells using folate-functionalized polymeric micelles loaded with superparamagnetic iron oxide and sorafenib in vitro

    Directory of Open Access Journals (Sweden)

    Zhang L

    2013-04-01

    Full Text Available Lei Zhang,1 Faming Gong,2 Fang Zhang,3 Jing Ma,1 Peidong Zhang,1 Jun Shen3 1Department of Hepatobiliary and Pancreatic Surgery, 2PCFM Laboratory of Ministry of Education, School of Chemistry and Chemical Engineering, 3Department of Radiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China Background: The purpose of this study was to evaluate the inhibitory effect of targeted folate-functionalized micelles containing superparamagnetic iron oxide nanoparticles (SPIONs and sorafenib on human hepatic carcinoma (HepG2 cells in vitro, and to observe the feasibility of surveillance of this targeting therapeutic effect by magnetic resonance imaging. Methods: Sorafenib and SPIONs were loaded into polymeric micelles. The targeted nanocarrier was synthesized by functionalizing the micelles with folate. Folate-free micelles loaded with sorafenib and SPIONs were used as control (nontargeted micelles. Uptake of the nanocarrier by cells was assessed using Prussian blue staining after 1 hour of incubation with the polymeric micelles. The inhibitory effect of the targeted micelles on HepG2 cell proliferation at various concentrations of sorafenib was assessed in vitro using the methyl thiazolyl tetrazolium (MTT assay and apoptotic analysis using flow cytometry. Magnetic resonance imaging using a clinical 1.5 T scanner was performed to detect changes in the signal intensity of cells after incubation with the targeted micelles. Results: Prussian blue staining showed significantly more intracellular SPIONs in cells incubated with the targeted micelles than those incubated with nontargeted micelles. The MTT assay showed that the average inhibitory ratio in the targeted group was significantly higher than that in the nontargeted group (38.13% versus 22.54%, P = 0.028. The mean apoptotic rate in the targeted cells, nontargeted cells, and untreated cells was 17.01%, 11.04%, and 7.89%, respectively. The apoptotic rate in the

  12. Multikinase activity of fibroblast growth factor receptor (FGFR) inhibitors SU5402, PD173074, AZD1480, AZD4547 and BGJ398 compromises the use of small chemicals targeting FGFR catalytic activity for therapy of short-stature syndromes

    Czech Academy of Sciences Publication Activity Database

    Gudernová, I.; Veselá, Iva; Balek, L.; Buchtová, Marcela; Dosedělová, Hana; Kunová, M.; Pivnička, J.; Jelínková, I.; Roubalová, L.; Kozubík, Alois; Krejčí, P.

    2016-01-01

    Roč. 25, č. 1 (2016), s. 9-23 ISSN 0964-6906 R&D Projects: GA ČR(CZ) GA14-31540S Institutional support: RVO:67985904 ; RVO:68081707 Keywords : fibroblast growth factor receptor * tyrosine kinase domain * ERK MAP kinase Subject RIV: EA - Cell Biology Impact factor: 5.340, year: 2016

  13. IGF-1R tyrosine kinase inhibitors and Vitamin K1 enhance the antitumor effects of Regorafenib in HCC cell lines.

    Science.gov (United States)

    Refolo, Maria Grazia; D'Alessandro, Rosalba; Lippolis, Catia; Carella, Nicola; Cavallini, Aldo; Messa, Caterina; Carr, Brian Irving

    2017-11-28

    The recent RESORCE trial showed that treatment with Regorafenib after Sorafenib failure provided a significant improvement in overall survival in HCC patients. Preclinical and clinical trial data showed that Regorafenib is a more potent drug than Sorafenib. In this study we aimed at improving Regorafenib actions and at reducing its toxicity, by targeting parallel pathways or by combination with Vitamins K (VKs). We investigated the effects of Regorafenib administrated at low concentrations and in combination with either VK1 and/or with GSK1838705A or OSI-906, two IGF1-R inhibitors, on HCC cell growth and motility. Our results showed that both IGF1-R inhibitors potentiated the antiproliferative and pro-apoptotic effects of Regorafenib and/or VK1 in HCC cell lines. Moreover we provide evidence that the combined treatment with IG1-R antagonists and Regorafenib (and/or VK1) also caused a significant reduction and depolymerization of actin resulting in synergistic inhibition exerted on cell migration. Thus, simultaneous blocking of MAPK and PI3K/Akt cascades with IGF1-R inhibitors plus Regorafenib could represent a more potent approach for HCC treatment.

  14. Economic evaluation of everolimus versus sorafenib for the treatment of metastatic renal cell carcinoma after failure of first-line sunitinib.

    Science.gov (United States)

    Casciano, Roman; Chulikavit, Maruit; Di Lorenzo, Giuseppe; Liu, Zhimei; Baladi, Jean-Francois; Wang, Xufang; Robertson, Justin; Garrison, Lou

    2011-01-01

    A recent indirect comparison study showed that sunitinib-refractory metastatic renal cell carcinoma (mRCC) patients treated with everolimus are expected to have improved overall survival outcomes compared to patients treated with sorafenib. This analysis examines the likely cost-effectiveness of everolimus versus sorafenib in this setting from a US payer perspective. A Markov model was developed to simulate a cohort of sunitinib-refractory mRCC patients and to estimate the cost per incremental life-years gained (LYG) and quality-adjusted life-years (QALYs) gained. Markov states included are stable disease without adverse events, stable disease with adverse events, disease progression, and death. Transition probabilities were estimated using a subset of the RECORD-1 patient population receiving everolimus after sunitinib, and a comparable population receiving sorafenib in a single-arm phase II study. Costs of antitumor therapies were based on wholesale acquisition cost. Health state costs accounted for physician visits, tests, adverse events, postprogression therapy, and end-of-life care. The model extrapolated beyond the trial time horizon for up to 6 years based on published trial data. Deterministic and probabilistic sensitivity analyses were conducted. The estimated gain over sorafenib treatment was 1.273 LYs (0.916 QALYs) at an incremental cost of $81,643. The deterministic analysis resulted in an incremental cost-effectiveness ratio (ICER) of $64,155/LYG ($89,160/QALY). The probabilistic sensitivity analysis demonstrated that results were highly consistent across simulations. As the ICER fell within the cost per QALY range for many other widely used oncology medicines, everolimus is projected to be a cost-effective treatment relative to sorafenib for sunitinib-refractory mRCC. Copyright © 2011 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

  15. Cost-effectiveness analysis of antiviral therapy in patients with advanced hepatitis B virus-related hepatocellular carcinoma treated with sorafenib.

    Science.gov (United States)

    Zhang, Pengfei; Yang, Yu; Wen, Feng; Wheeler, John; Fu, Ping; Li, Qiu

    2016-12-01

    Antiviral therapy has been demonstrated to significantly improve the survival in patients with advanced hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). The aim of the study was to investigate the cost-effectiveness of antiviral therapy in patients with advanced HBV-related HCC treated with sorafenib. To conduct the analysis, a Markov model comprising three health states (progression-free survival, progressive disease, and death) was created. The efficacy data were derived from medical records. Cost data were collected based on the Chinese national drug prices. Utility data came from the previously published studies. One-way sensitivity analyses as well as probabilistic sensitivity analyses were performed to explore model uncertainties. In the base-case analysis, addition of antiviral therapy to sorafenib generated an effectiveness of 0.68 quality-adjusted life years (QALYs) at a cost of $25 026.04, while sorafenib monotherapy gained an effectiveness of 0.42 QALYs at a cost of $20 249.64. The incremental cost-effectiveness ratio (ICER) was $18 370.77/QALY for antiviral therapy group versus non-antiviral therapy group. On the other hand, the ICER between the two groups in patients with high or low HBV-DNA load, with or without cirrhosis, normal or elevated alanine aminotransferase/aspartate aminotransferase were $16 613.97/QALY, $19 774.16/QALY, $14 587.66/QALY, $19 873.84/QALY, $17 947.07/QALY, and $18 785.58/QALY, respectively. Based on the cost-effectiveness threshold ($20 301.00/QALY in China), addition of antiviral therapy to sorafenib is considered to be a cost-effective option compared with sorafenib monotherapy in patients with advanced HBV-related HCC in China from the patient's perspective. © 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

  16. Treatment of Recurrent Hepatocellular Carcinoma with Sorafenib in a HIV/HCV Co-Infected patient in HAART: A Case Report

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    De Nardo Pasquale

    2012-06-01

    Full Text Available Abstract Background Liver disease is the second cause of death among HIV patients receiving highly active antiretroviral therapy (HAART in Europe. HIV patients have a high prevalence of chronic HBV (6–10% and HCV (33% co-infection, and accelerated progression of viral hepatitis. Furthermore, the long duration of both HIV and HCV diseases in the HAART era increases the risk of hepatocellular carcinoma. Findings We report the case of a 49 year -old HIV/HCV co-infected male patient who developed hepatocellular carcinoma. The patient underwent a partial hepatectomy, and a few months later was treated with transcatheter arterial chemoembolisation due to hepatocarcinoma recurrence. Two months later, advanced hepatocellular carcinoma was diagnosed and sorafenib therapy was initiated. The patient achieved partial response of the main lesions, complete regression of the smallest lesions and did not experience clinical progression during the 20-month follow-up period. During therapy with sorafenib, the patient was treated with HAART with good viral and immunological responses. We used the therapeutic drug monitoring to assess antiretroviral concentrations during co-administration of sorafenib. Fosamprenavir Ctrough was found under the minimum level recommended by international guidelines. No grade 3 or 4 toxicities were observed. At month 20 of treatment, new liver lesions with portal vein thrombosis were diagnosed. After 28 months of sorafenib therapy, the patient deceased for severe liver insufficiency. Conclusions Sorafenib monotherapy demonstrated a marked delay in HCC disease progression in an HIV/HCV co-infected patient. Fosamprenavir Ctrough was found under the minimum level recommended by international guidelines, suggesting a possible interaction.

  17. The c-Met Inhibitor MSC2156119J Effectively Inhibits Tumor Growth in Liver Cancer Models

    Energy Technology Data Exchange (ETDEWEB)

    Bladt, Friedhelm, E-mail: Friedhelm.Bladt@merckgroup.com; Friese-Hamim, Manja; Ihling, Christian; Wilm, Claudia; Blaukat, Andree [EMD Serono, and Merck Serono Research and Development, Merck KGaA, Darmstadt 64293 (Germany)

    2014-08-19

    The mesenchymal-epithelial transition factor (c-Met) is a receptor tyrosine kinase with hepatocyte growth factor (HGF) as its only high-affinity ligand. Aberrant activation of c-Met is associated with many human malignancies, including hepatocellular carcinoma (HCC). We investigated the in vivo antitumor and antimetastatic efficacy of the c-Met inhibitor MSC2156119J (EMD 1214063) in patient-derived tumor explants. BALB/c nude mice were inoculated with MHCC97H cells or with tumor fragments of 10 patient-derived primary liver cancer explants selected according to c-Met/HGF expression levels. MSC2156119J (10, 30, and 100 mg/kg) and sorafenib (50 mg/kg) were administered orally as single-agent treatment or in combination, with vehicle as control. Tumor response, metastases formation, and alpha fetoprotein (AFP) levels were measured. MSC2156119J inhibited tumor growth and induced complete regression in mice bearing subcutaneous and orthotopic MHCC97H tumors. AFP levels were undetectable after 5 weeks of MSC2156119J treatment, and the number of metastatic lung foci was reduced. Primary liver explant models with strong c-Met/HGF activation showed increased responsiveness to MSC2156119J, with MSC2156119J showing similar or superior activity to sorafenib. Tumors characterized by low c-Met expression were less sensitive to MSC2156119J. MSC2156119J was better tolerated than sorafenib, and combination therapy did not improve efficacy. These findings indicate that selective c-Met/HGF inhibition with MSC2156119J is associated with marked regression of c-Met high-expressing tumors, supporting its clinical development as an antitumor treatment for HCC patients with active c-Met signaling.

  18. Biological and Molecular Effects of Small Molecule Kinase Inhibitors on Low-Passage Human Colorectal Cancer Cell Lines

    Directory of Open Access Journals (Sweden)

    Falko Lange

    2014-01-01

    Full Text Available Low-passage cancer cell lines are versatile tools to study tumor cell biology. Here, we have employed four such cell lines, established from primary tumors of colorectal cancer (CRC patients, to evaluate effects of the small molecule kinase inhibitors (SMI vemurafenib, trametinib, perifosine, and regorafenib in an in vitro setting. The mutant BRAF (V600E/V600K inhibitor vemurafenib, but also the MEK1/2 inhibitor trametinib efficiently inhibited DNA synthesis, signaling through ERK1/2 and expression of genes downstream of ERK1/2 in BRAF mutant cells only. In case of the AKT inhibitor perifosine, three cell lines showed a high or intermediate responsiveness to the drug while one cell line was resistant. The multikinase inhibitor regorafenib inhibited proliferation of all CRC lines with similar efficiency and independent of the presence or absence of KRAS, BRAF, PIK3CA, and TP53 mutations. Regorafenib action was associated with broad-range inhibitory effects at the level of gene expression but not with a general inhibition of AKT or MEK/ERK signaling. In vemurafenib-sensitive cells, the antiproliferative effect of vemurafenib was enhanced by the other SMI. Together, our results provide insights into the determinants of SMI efficiencies in CRC cells and encourage the further use of low-passage CRC cell lines as preclinical models.

  19. Benefit-Risk Summary of Regorafenib for the Treatment of Patients with Advanced Hepatocellular Carcinoma That Has Progressed on Sorafenib.

    Science.gov (United States)

    Pelosof, Lorraine; Lemery, Steven; Casak, Sandra; Jiang, Xiaoping; Rodriguez, Lisa; Pierre, Vadryn; Bi, Youwei; Liu, Jiang; Zirkelbach, Jeanne Fourie; Patel, Anuja; Goldberg, Kirsten B; McKee, Amy E; Keegan, Patricia; Pazdur, Richard

    2018-04-01

    On April 27, 2017, the U.S. Food and Drug Administration approved regorafenib for the treatment of patients with advanced hepatocellular carcinoma (HCC) who had previously been treated with sorafenib. Approval was based on the results of a single, randomized, placebo-controlled trial (RESORCE) that demonstrated an improvement in overall survival (OS). Patients were randomly allocated to receive regorafenib160 mg orally once daily or matching placebo for the first 21 days of each 28-day cycle. The trial demonstrated a significant improvement in OS (hazard ratio [HR] = 0.63; 95% confidence interval [CI], 0.50-0.79, p  regorafenib arm and 7.8 months in the placebo arm. A statistically significant improvement in progression-free survival (PFS) based on modified RECIST for HCC [Semin Liver Dis 2010;30:52-60] (HR = 0.46; 95% CI, 0.37-0.56, p  regorafenib and placebo arms, respectively. The overall response rate, based on modified RECIST for HCC, was 11% in the regorafenib arm and 4% in the placebo arm. The toxicity profile was consistent with that observed in other indications; the most clinically significant adverse reactions were palmar-plantar erythrodysesthesia, diarrhea, and hypertension. Based on the improvement in survival and acceptable toxicity, a favorable benefit-to-risk evaluation led to approval for treatment of patients with advanced HCC. Regorafenib is the first drug approved by the U.S. Food and Drug Administration for the treatment of hepatocellular carcinoma that has progressed on sorafenib and is expected to become a standard of care for these patients. Published 2018. This article is a U.S. Government work and is in the public domain in the USA.

  20. Pre-clinical activity of PR-104 as monotherapy and in combination with sorafenib in hepatocellular carcinoma.

    Science.gov (United States)

    Abbattista, Maria R; Jamieson, Stephen M F; Gu, Yongchuan; Nickel, Jennifer E; Pullen, Susan M; Patterson, Adam V; Wilson, William R; Guise, Christopher P

    2015-01-01

    PR-104 is a clinical stage bioreductive prodrug that is converted in vivo to its cognate alcohol, PR-104A. This dinitrobenzamide mustard is reduced to activated DNA cross-linking metabolites (hydroxylamine PR-104H and amine PR-104M) under hypoxia by one-electron reductases and independently of hypoxia by the 2-electron reductase aldo-keto reductase 1C3 (AKR1C3). High expression of AKR1C3, along with extensive hypoxia, suggested the potential of PR-104 for treatment of hepatocellular carcinoma (HCC). However, a phase IB trial with sorafenib demonstrated significant toxicity that was ascribed in part to reduced PR-104A clearance, likely reflecting compromised glucuronidation in patients with advanced HCC. Here, we evaluate the activity of PR-104 in HCC xenografts (HepG2, PLC/PRF/5, SNU-398, Hep3B) in mice, which do not significantly glucuronidate PR-104A. Cell line differences in sensitivity to PR-104A in vitro under aerobic conditions could be accounted for by differences in both expression of AKR1C3 (high in HepG2 and PLC/PRF/5) and sensitivity to the major active metabolite PR-104H, to which PLC/PRF/5 was relatively resistant, while hypoxic selectivity of PR-104A cytotoxicity and reductive metabolism was greatest in the low-AKR1C3 SNU-398 and Hep3B lines. Expression of AKR1C3 in HepG2 and PLC/PRF/5 xenografts was in the range seen in 21 human HCC specimens. PR-104 monotherapy elicited significant reductions in growth of Hep3B and HepG2 xenografts, and the combination with sorafenib was significantly active in all 4 xenograft models. The results suggest that better-tolerated analogs of PR-104, without a glucuronidation liability, may have the potential to exploit AKR1C3 and/or hypoxia in HCC in humans.

  1. Genetic and pharmacological screens converge in identifying FLIP, BCL2 and IAP proteins as key regulators of sensitivity to the TRAIL-inducing anti-cancer agent ONC201/TIC10

    Science.gov (United States)

    Allen, Joshua E.; Prabhu, Varun V.; Talekar, Mala; van den Heuvel, AP; Lim, Bora; Dicker, David T.; Fritz, Jennifer L.; Beck, Adam; El-Deiry, Wafik S.

    2015-01-01

    ONC201/TIC10 is a small molecule inducer of the TRAIL gene under current investigation as a novel anticancer agent. In this study, we identify critical molecular determinants of ONC201 sensitivity offering potential utility as pharmacodynamic or predictive response markers. By screening a library of kinase siRNAs in combination with a subcytotoxic dose of ONC201, we identified several kinases that ablated tumor cell sensitivity, including the MAPK pathway inducer KSR1. Unexpectedly, KSR1 silencing did not affect MAPK signaling in the presence or absence of ONC201, but instead reduced expression of the anti-apoptotic proteins FLIP, Mcl-1, Bcl-2, cIAP1, cIAP2, and survivin. In parallel to this work, we also conducted a synergy screen in which ONC201 was combined with approved small molecule anticancer drugs. In multiple cancer cell populations, ONC201 synergized with diverse drug classes including the multi-kinase inhibitor sorafenib. Notably, combining ONC201 and sorafenib led to synergistic induction of TRAIL and its receptor DR5 along with a potent induction of cell death. In a mouse xenograft model of hepatocellular carcinoma, we demonstrated that ONC201 and sorafenib cooperatively and safely triggered tumor regressions. Overall, our results established a set of determinants for ONC201 sensitivity that may predict therapeutic response, particularly in settings of sorafenib co-treatment to enhance anticancer responses. PMID:25681273

  2. Genetic and Pharmacological Screens Converge in Identifying FLIP, BCL2, and IAP Proteins as Key Regulators of Sensitivity to the TRAIL-Inducing Anticancer Agent ONC201/TIC10.

    Science.gov (United States)

    Allen, Joshua E; Prabhu, Varun V; Talekar, Mala; van den Heuvel, A Pieter J; Lim, Bora; Dicker, David T; Fritz, Jennifer L; Beck, Adam; El-Deiry, Wafik S

    2015-04-15

    ONC201/TIC10 is a small-molecule inducer of the TRAIL gene under current investigation as a novel anticancer agent. In this study, we identify critical molecular determinants of ONC201 sensitivity offering potential utility as pharmacodynamic or predictive response markers. By screening a library of kinase siRNAs in combination with a subcytotoxic dose of ONC201, we identified several kinases that ablated tumor cell sensitivity, including the MAPK pathway-inducer KSR1. Unexpectedly, KSR1 silencing did not affect MAPK signaling in the presence or absence of ONC201, but instead reduced expression of the antiapoptotic proteins FLIP, Mcl-1, Bcl-2, cIAP1, cIAP2, and survivin. In parallel to this work, we also conducted a synergy screen in which ONC201 was combined with approved small-molecule anticancer drugs. In multiple cancer cell populations, ONC201 synergized with diverse drug classes, including the multikinase inhibitor sorafenib. Notably, combining ONC201 and sorafenib led to synergistic induction of TRAIL and its receptor DR5 along with a potent induction of cell death. In a mouse xenograft model of hepatocellular carcinoma, we demonstrated that ONC201 and sorafenib cooperatively and safely triggered tumor regressions. Overall, our results established a set of determinants for ONC201 sensitivity that may predict therapeutic response, particularly in settings of sorafenib cotreatment to enhance anticancer responses. ©2015 American Association for Cancer Research.

  3. Novel biomarker-based model for the prediction of sorafenib response and overall survival in advanced hepatocellular carcinoma: a prospective cohort study.

    Science.gov (United States)

    Kim, Hwi Young; Lee, Dong Hyeon; Lee, Jeong-Hoon; Cho, Young Youn; Cho, Eun Ju; Yu, Su Jong; Kim, Yoon Jun; Yoon, Jung-Hwan

    2018-03-20

    Prediction of the outcome of sorafenib therapy using biomarkers is an unmet clinical need in patients with advanced hepatocellular carcinoma (HCC). The aim was to develop and validate a biomarker-based model for predicting sorafenib response and overall survival (OS). This prospective cohort study included 124 consecutive HCC patients (44 with disease control, 80 with progression) with Child-Pugh class A liver function, who received sorafenib. Potential serum biomarkers (namely, hepatocyte growth factor [HGF], fibroblast growth factor [FGF], vascular endothelial growth factor receptor-1, CD117, and angiopoietin-2) were tested. After identifying independent predictors of tumor response, a risk scoring system for predicting OS was developed and 3-fold internal validation was conducted. A risk scoring system was developed with six covariates: etiology, platelet count, Barcelona Clinic Liver Cancer stage, protein induced by vitamin K absence-II, HGF, and FGF. When patients were stratified into low-risk (score ≤ 5), intermediate-risk (score 6), and high-risk (score ≥ 7) groups, the model provided good discriminant functions on tumor response (concordance [c]-index, 0.884) and 12-month survival (area under the curve [AUC], 0.825). The median OS was 19.0, 11.2, and 6.1 months in the low-, intermediate-, and high-risk group, respectively (P functions on tumor response (c-index, 0.825) and 12-month survival (AUC, 0.803), and good calibration functions (all P > 0.05 between expected and observed values). This new model including serum FGF and HGF showed good performance in predicting the response to sorafenib and survival in patients with advanced HCC.

  4. In silico design and biological evaluation of a dual specificity kinase inhibitor targeting cell cycle progression and angiogenesis.

    Directory of Open Access Journals (Sweden)

    Antony M Latham

    Full Text Available Protein kinases play a central role in tumor progression, regulating fundamental processes such as angiogenesis, proliferation and metastasis. Such enzymes are an increasingly important class of drug target with small molecule kinase inhibitors being a major focus in drug development. However, balancing drug specificity and efficacy is problematic with off-target effects and toxicity issues.We have utilized a rational in silico-based approach to demonstrate the design and study of a novel compound that acts as a dual inhibitor of vascular endothelial growth factor receptor 2 (VEGFR2 and cyclin-dependent kinase 1 (CDK1. This compound acts by simultaneously inhibiting pro-angiogenic signal transduction and cell cycle progression in primary endothelial cells. JK-31 displays potent in vitro activity against recombinant VEGFR2 and CDK1/cyclin B proteins comparable to previously characterized inhibitors. Dual inhibition of the vascular endothelial growth factor A (VEGF-A-mediated signaling response and CDK1-mediated mitotic entry elicits anti-angiogenic activity both in an endothelial-fibroblast co-culture model and a murine ex vivo model of angiogenesis.We deduce that JK-31 reduces the growth of both human endothelial cells and human breast cancer cells in vitro. This novel synthetic molecule has broad implications for development of similar multi-kinase inhibitors with anti-angiogenic and anti-cancer properties. In silico design is an attractive and innovative method to aid such drug discovery.

  5. In silico design and biological evaluation of a dual specificity kinase inhibitor targeting cell cycle progression and angiogenesis.

    Science.gov (United States)

    Latham, Antony M; Kankanala, Jayakanth; Fearnley, Gareth W; Gage, Matthew C; Kearney, Mark T; Homer-Vanniasinkam, Shervanthi; Wheatcroft, Stephen B; Fishwick, Colin W G; Ponnambalam, Sreenivasan

    2014-01-01

    Protein kinases play a central role in tumor progression, regulating fundamental processes such as angiogenesis, proliferation and metastasis. Such enzymes are an increasingly important class of drug target with small molecule kinase inhibitors being a major focus in drug development. However, balancing drug specificity and efficacy is problematic with off-target effects and toxicity issues. We have utilized a rational in silico-based approach to demonstrate the design and study of a novel compound that acts as a dual inhibitor of vascular endothelial growth factor receptor 2 (VEGFR2) and cyclin-dependent kinase 1 (CDK1). This compound acts by simultaneously inhibiting pro-angiogenic signal transduction and cell cycle progression in primary endothelial cells. JK-31 displays potent in vitro activity against recombinant VEGFR2 and CDK1/cyclin B proteins comparable to previously characterized inhibitors. Dual inhibition of the vascular endothelial growth factor A (VEGF-A)-mediated signaling response and CDK1-mediated mitotic entry elicits anti-angiogenic activity both in an endothelial-fibroblast co-culture model and a murine ex vivo model of angiogenesis. We deduce that JK-31 reduces the growth of both human endothelial cells and human breast cancer cells in vitro. This novel synthetic molecule has broad implications for development of similar multi-kinase inhibitors with anti-angiogenic and anti-cancer properties. In silico design is an attractive and innovative method to aid such drug discovery.

  6. Use of Ultrasmall Superparamagnetic Iron Oxide Enhanced Susceptibility Weighted Imaging and Mean Vessel Density Imaging to Monitor Antiangiogenic Effects of Sorafenib on Experimental Hepatocellular Carcinoma

    Directory of Open Access Journals (Sweden)

    Shuohui Yang

    2017-01-01

    Full Text Available We investigated effectiveness of ultrasmall superparamagnetic iron oxide enhanced susceptibility weighted imaging (USPIO-enhanced SWI and mean vessel density imaging (Q in monitoring antiangiogenic effects of Sorafenib on orthotopic hepatocellular carcinoma (HCC. Thirty-five HCC xenografts were established. USPIO-enhanced SWI and Q were performed on a 1.5 T MR scanner at baseline, 7, 14, and 21 days after Sorafenib treatment. Intratumoral susceptibility signal intensity (ITSS and Q were serially measured and compared between the treated (n = 15 and control groups (n = 15. Both ITSS and Q were significantly lower in the treated group at each time point (P < 0.05. Measurements in the treated group showed that ITSS persisted at 7 days (P = 0.669 and increased at 14 and 21 days (P < 0.05, while Q significantly declined at 7 days (P = 0.028 and gradually increased at 14 and 21 days. In the treated group, significant correlation was found between Q and histologic microvessel density (MVD (r = 0.753, P < 0.001, and ITSS correlated well with MVD (r = 0.742, P = 0.002 after excluding the data from baseline. This study demonstrated that USPIO-enhanced SWI and Q could provide novel biomarkers for evaluating antiangiogenic effects of Sorafenib on HCC.

  7. A pilot study to assess feasibility of value based pricing in Cyprus through pharmacoeconomic modelling and assessment of its operational framework: sorafenib for second line renal cell cancer.

    Science.gov (United States)

    Petrou, Panagiotis; Talias, Michael A

    2014-01-01

    The continuing increase of pharmaceutical expenditure calls for new approaches to pricing and reimbursement of pharmaceuticals. Value based pricing of pharmaceuticals is emerging as a useful tool and possess theoretical attributes to help health system cope with rising pharmaceutical expenditure. To assess the feasibility of introducing a value-based pricing scheme of pharmaceuticals in Cyprus and explore the integrative framework. A probabilistic Markov chain Monte Carlo model was created to simulate progression of advanced renal cell cancer for comparison of sorafenib to standard best supportive care. Literature review was performed and efficacy data were transferred from a published landmark trial, while official pricelists and clinical guidelines from Cyprus Ministry of Health were utilised for cost calculation. Based on proposed willingness to pay threshold the maximum price of sorafenib for the indication of second line renal cell cancer was assessed. Sorafenib value based price was found to be significantly lower compared to its current reference price. Feasibility of Value Based Pricing is documented and pharmacoeconomic modelling can lead to robust results. Integration of value and affordability in the price are its main advantages which have to be weighed against lack of documentation for several theoretical parameters that influence outcome. Smaller countries such as Cyprus may experience adversities in establishing and sustaining essential structures for this scheme.

  8. [Syk inhibitors].

    Science.gov (United States)

    Kimura, Yukihiro; Chihara, Kazuyasu; Takeuchi, Kenji; Sada, Kiyonao

    2013-07-01

    Non-receptor type of protein-tyrosine kinase Syk (spleen tyrosine kinase) was isolated in the University of Fukui in 1991. Syk is known to be essential for the various physiological functions, especially in hematopoietic lineage cells. Moreover, ectopic expression of Syk by epigenetic changes is reported to cause retinoblastoma. Recently, novel Syk inhibitors were developed and its usefulness has been evaluated in the treatment of allergic rhinitis, rheumatoid arthritis, and idiopathic thrombocytopenic purpura. In this review, we will summarize the history, structure, and function of Syk, and then describe the novel Syk inhibitors and their current status. Furthermore, we will introduce our findings of the adaptor protein 3BP2 (c-Abl SH3 domain-binding protein-2), as a novel target of Syk.

  9. Syk inhibitors.

    Science.gov (United States)

    Chihara, Kazuyasu; Kimura, Yukihiro; Honjo, Chisato; Takeuchi, Kenji; Sada, Kiyonao

    2013-01-01

    Non-receptor type of protein-tyrosine kinase Syk (spleen tyrosine kinase) was isolated in University of Fukui in 1991. Syk is most highly expressed by haemopoietic cells and known to play crucial roles in the signal transduction through various immunoreceptors of the adaptive immune response. However, recent reports demonstrate that Syk also mediates other biological functions, such as innate immune response, osteoclast maturation, platelet activation and cellular adhesion. Moreover, ectopic expression of Syk by epigenetic changes is reported to cause retinoblastoma. Because of its critical roles on the cellular functions, the development of Syk inhibitors for clinical use has been desired. Although many candidate compounds were produced, none of them had progressed to clinical trials. However, novel Syk inhibitors were finally developed and its usefulness has been evaluated in the treatment of allergic rhinitis, rheumatoid arthritis and idiopathic thrombocytopenic purpura. In this review, we will summarize the history, structure and function of Syk, and then the novel Syk inhibitors and their current status. In addition, we will introduce our research focused on the functions of Syk on Dectin-1-mediated mast cell activation.

  10. Identification of selective inhibitors of RET and comparison with current clinical candidates through development and validation of a robust screening cascade [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Amanda J. Watson

    2016-05-01

    Full Text Available RET (REarranged during Transfection is a receptor tyrosine kinase, which plays pivotal roles in regulating cell survival, differentiation, proliferation, migration and chemotaxis. Activation of RET is a mechanism of oncogenesis in medullary thyroid carcinomas where both germline and sporadic activating somatic mutations are prevalent.   At present, there are no known specific RET inhibitors in clinical development, although many potent inhibitors of RET have been opportunistically identified through selectivity profiling of compounds initially designed to target other tyrosine kinases. Vandetanib and cabozantinib, both multi-kinase inhibitors with RET activity, are approved for use in medullary thyroid carcinoma, but additional pharmacological activities, most notably inhibition of vascular endothelial growth factor - VEGFR2 (KDR, lead to dose-limiting toxicity. The recent identification of RET fusions present in ~1% of lung adenocarcinoma patients has renewed interest in the identification and development of more selective RET inhibitors lacking the toxicities associated with the current treatments.   In an earlier publication [Newton et al, 2016; 1] we reported the discovery of a series of 2-substituted phenol quinazolines as potent and selective RET kinase inhibitors. Here we describe the development of the robust screening cascade which allowed the identification and advancement of this chemical series.  Furthermore we have profiled a panel of RET-active clinical compounds both to validate the cascade and to confirm that none display a RET-selective target profile.

  11. Immunostimulatory monoclonal antibodies for hepatocellular carcinoma therapy. Trends and perspectives

    Directory of Open Access Journals (Sweden)

    Guillermo D. Mazzolini

    2018-01-01

    Full Text Available Hepatocellular carcinoma (HCC is the second cause of cancer-related death in the world and is the main cause of death in cirrhotic patients. Unfortunately, the incidence of HCC has grown significantly in the last decade. Curative treatments such as surgery, liver transplantation or percutaneous ablation can only be applied in less than 30% of cases. The multikinase inhibitor sorafenib is the first line therapy for advanced HCC. Regorafenib is the standard of care for second-line patients. However, novel and more specific potent therapeutic approaches for advanced HCC are still needed. The liver constitutes a unique immunological microenvironment, although anti-tumor immunity seems to be feasible with the use of checkpoint inhibitors such as nivolumab. Efficacy may be further increased by combining checkpoint inhibitors or by applying loco-regional treatments. The success of immune checkpoint blockade has renewed interest in immunotherapy in HCC

  12. Sub-classification of Advanced-Stage Hepatocellular Carcinoma: A Cohort Study Including 612 Patients Treated with Sorafenib.

    Science.gov (United States)

    Yoo, Jeong-Ju; Chung, Goh Eun; Lee, Jeong-Hoon; Nam, Joon Yeul; Chang, Young; Lee, Jeong Min; Lee, Dong Ho; Kim, Hwi Young; Cho, Eun Ju; Yu, Su Jong; Kim, Yoon Jun; Yoon, Jung-Hwan

    2018-04-01

    Advanced hepatocellular carcinoma (HCC) is associated with various clinical conditions including major vessel invasion, metastasis, and poor performance status. The aim of this study was to establish a prognostic scoring system and to propose a sub-classification of the Barcelona-Clinic Liver Cancer (BCLC) stage C. This retrospective study included consecutive patientswho received sorafenib for BCLC stage C HCC at a single tertiary hospital in Korea. A Cox proportional hazard model was used to develop a scoring system, and internal validationwas performed by a 5-fold cross-validation. The performance of the model in predicting risk was assessed by the area under the curve and the Hosmer-Lemeshow test. A total of 612 BCLC stage C HCC patients were sub- classified into strata depending on their performance status. Five independent prognostic factors (Child-Pugh score, α-fetoprotein, tumor type, extrahepatic metastasis, and portal vein invasion) were identified and used in the prognostic scoring system. This scoring system showed good discrimination (area under the receiver operating characteristic curve, 0.734 to 0.818) and calibration functions (both p advanced HCC. A prognostic scoring system with five independent factors is useful in predicting the survival of patients with BCLC stage C HCC.

  13. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial.

    Science.gov (United States)

    Bruix, Jordi; Qin, Shukui; Merle, Philippe; Granito, Alessandro; Huang, Yi-Hsiang; Bodoky, György; Pracht, Marc; Yokosuka, Osamu; Rosmorduc, Olivier; Breder, Valeriy; Gerolami, René; Masi, Gianluca; Ross, Paul J; Song, Tianqiang; Bronowicki, Jean-Pierre; Ollivier-Hourmand, Isabelle; Kudo, Masatoshi; Cheng, Ann-Lii; Llovet, Josep M; Finn, Richard S; LeBerre, Marie-Aude; Baumhauer, Annette; Meinhardt, Gerold; Han, Guohong

    2017-01-07

    There are no systemic treatments for patients with hepatocellular carcinoma (HCC) whose disease progresses during sorafenib treatment. We aimed to assess the efficacy and safety of regorafenib in patients with HCC who have progressed during sorafenib treatment. In this randomised, double-blind, parallel-group, phase 3 trial done at 152 sites in 21 countries, adults with HCC who tolerated sorafenib (≥400 mg/day for ≥20 of last 28 days of treatment), progressed on sorafenib, and had Child-Pugh A liver function were enrolled. Participants were randomly assigned (2:1) by a computer-generated randomisation list and interactive voice response system and stratified by geographical region, Eastern Cooperative Oncology Group performance status, macrovascular invasion, extrahepatic disease, and α-fetoprotein level to best supportive care plus oral regorafenib 160 mg or placebo once daily during weeks 1-3 of each 4-week cycle. Investigators, patients, and the funder were masked to treatment assignment. The primary endpoint was overall survival (defined as time from randomisation to death due to any cause) and analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01774344. Between May 14, 2013, and Dec 31, 2015, 843 patients were screened, of whom 573 were enrolled and randomised (379 to regorafenib and 194 to placebo; population for efficacy analyses), and 567 initiated treatment (374 received regorafenib and 193 received placebo; population for safety analyses). Regorafenib improved overall survival with a hazard ratio of 0·63 (95% CI 0·50-0·79; one-sided p<0·0001); median survival was 10·6 months (95% CI 9·1-12·1) for regorafenib versus 7·8 months (6·3-8·8) for placebo. Adverse events were reported in all regorafenib recipients (374 [100%] of 374) and 179 (93%) of 193 placebo recipients. The most common clinically relevant grade 3 or 4 treatment-emergent events were hypertension (57 patients [15%] in the regorafenib group

  14. Identification of a unique hepatocellular carcinoma line, Li-7, with CD13(+) cancer stem cells hierarchy and population change upon its differentiation during culture and effects of sorafenib.

    Science.gov (United States)

    Yamada, Takeshi; Abei, Masato; Danjoh, Inaho; Shirota, Ryoko; Yamashita, Taro; Hyodo, Ichinosuke; Nakamura, Yukio

    2015-04-11

    Cancer stem cell (CSC) research has highlighted the necessity of developing drugs targeting CSCs. We investigated a hepatocellular carcinoma (HCC) cell line that not only has CSC hierarchy but also shows phenotypic changes (population changes) upon differentiation of CSC during culture and can be used for screening drugs targeting CSC. Based on a hypothesis that the CSC proportion should decrease upon its differentiation into progenitors (population change), we tested HCC cell lines (HuH-7, Li-7, PLC/PRF/5, HLF, HLE) before and after 2 months culture for several markers (CD13, EpCAM, CD133, CD44, CD90, CD24, CD166). Tumorigenicity was tested using nude mice. To evaluate the CSC hierarchy, we investigated reconstructivity, proliferation, ALDH activity, spheroid formation, chemosensitivity and microarray analysis of the cell populations sorted by FACS. Only Li-7 cells showed a population change during culture: the proportion of CD13 positive cells decreased, while that of CD166 positive cells increased. The high tumorigenicity of the Li-7 was lost after the population change. CD13(+)/CD166(-) cells showed slow growth and reconstructed the bulk Li-7 populations composed of CD13(+)/CD166(-), CD13(-)/CD166(-) and CD13(-)/CD166(+) fractions, whereas CD13(-)/CD166(+) cells showed rapid growth but could not reproduce any other population. CD13(+)/CD166(-) cells showed high ALDH activity, spheroid forming ability and resistance to 5-fluorouracil. Microarray analysis demonstrated higher expression of stemness-related genes in CD166(-) than CD166(+) fraction. These results indicated a hierarchy in Li-7 cells, in which CD13(+)/CD166(-) and CD13(-)/CD166(+) cells serve as slow growing CSCs and rapid growing progenitors, respectively. Sorafenib selectively targeted the CD166(-) fraction, including CD13(+) CSCs, which exhibited higher mRNA expression for FGF3 and FGF4, candidate biomarkers for sorafenib. 5-fluorouracil followed by sorafenib inhibited the growth of bulk Li-7

  15. Simultaneous analysis of regorafenib and sorafenib and three of their metabolites in human plasma using LC-MS/MS.

    Science.gov (United States)

    Allard, Marie; Khoudour, Nihel; Rousseau, Benoît; Joly, Charlotte; Costentin, Charlotte; Blanchet, Benoît; Tournigand, Christophe; Hulin, Anne

    2017-08-05

    A new liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, performed by electrospray ionization in positive mode using a triple quadrupole mass spectrometry, has been developed and validated for the simultaneous determination of regorafenib (REGO), its two metabolites regorafenib-M2 and regorafenib-M5, sorafenib (SORA), and its N-oxide metabolite in human plasma. Separation is achieved on an Hypersil Gold ® column using a gradient elution of 10mM ammonium formate containing 0.1% formic acid (A) and acetonitrile containing 0.1% formic acid (B) at a flow rate of 0.3mL/min. After addition of two internal standards and a protein precipitation, the supernatant is diluted two-fold in a 0.1% (v/v) formic acid solution. Two selected reaction monitoring transitions are used, for each analyte, one for quantitation and the second one for confirmation. The standard curves are ranged from 50 to 5 000ng/mL for REGO and its metabolites and 80 to 5 000ng/mL for SORA and its metabolite and were fitted to a 1/x weighted linear regression model. The method also showed satisfactory results in terms of sensitivity, specificity, precision (intra- and inter-day CV from 2.4 to 10.2%), accuracy (from 91.0 to 111.7%), recovery as well as stability of the analytes under various conditions. The method is usually used in clinical practice in order to improve the SORA treatment for renal carcinoma, REGO treatment for colorectal cancer and both for hepatocellular carcinoma. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Role of anti-angiogenesis therapy in the management of hepatocellular carcinoma: The jury is still out

    Institute of Scientific and Technical Information of China (English)

    Hong; Sun; Man-Sheng; Zhu; Wen-Rui; Wu; Xiang-De; Shi; Lei-Bo; Xu

    2014-01-01

    As the leading cause of disease-related deaths,cancer is a major public health threat worldwide.Surgical resection is still the first-line therapy for patients with early-stage cancers.However,postoperative relapse and metastasis remain the cause of 90%of deaths of patients with solid organ malignancies,including hepatocellular carcinoma(HCC).With the rapid development of molecular biology techniques in recent years,molecularly targeted therapies using monoclonal antibodies,small molecules,and vaccines have become a milestone in cancer therapeutic by significantly improv-ing the survival of cancer patients,and have opened a window of hope for patients with advanced cancer.Hypervascularization is a major characteristic of HCC.It has been reported that anti-angiogenic treatments,which inhibit blood vessel formation,are highly effective for treating HCC.However,the efficacy and safety of anti-angiogenesis therapies remain controversial.Sorafenib is an oral multikinase inhibitor with antiproliferative and anti-angiogenic effects and is the first molecular target drug approved for the treatment of advanced HCC.While sorafenib has shown promising therapeutic effects,substantial evidence of primary and acquired resistance to sorafenib has been reported.Numerous clinical trials have been conducted to evaluate a large number of molecularly targeted drugs for treating HCC,but most drugs exhibited less efficacy and/or higher toxicity compared to sorafenib.Therefore,understanding the mechanism(s)underlying sorafenib resistance of cancer cells is highlighted for efficiently treating HCC.This concise review aims to provide an overview of anti-angiogenesis therapy in the management of HCC and to discuss the common mechanisms of resistance to anti-angiogenesis therapies.

  17. Aspirin disrupts the mTOR-Raptor complex and potentiates the anti-cancer activities of sorafenib via mTORC1 inhibition.

    Science.gov (United States)

    Sun, Danni; Liu, Hongchun; Dai, Xiaoyang; Zheng, Xingling; Yan, Juan; Wei, Rongrui; Fu, Xuhong; Huang, Min; Shen, Aijun; Huang, Xun; Ding, Jian; Geng, Meiyu

    2017-10-10

    Aspirin is associated with a reduced risk of cancer and delayed progression of malignant disease. Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)-mTOR signaling is believed to partially contribute to these anticancer effects, although the mechanism is unclear. In this study, we revealed the mechanism underlying the effects of aspirin on AMPK-mTOR signaling, and described a mechanism-based rationale for the use of aspirin in cancer therapy. We found that aspirin inhibited mTORC1 signaling through AMPK-dependent and -independent manners. Aspirin inhibited the AMPK-TSC pathway, thus resulting in the suppression of mTORC1 activity. In parallel, it directly disrupted the mTOR-raptor interaction. Additionally, the combination of aspirin and sorafenib showed synergetic effects via inhibiting mTORC1 signaling and the PI3K/AKT, MAPK/ERK pathways. Aspirin and sorafenib showed synergetic anticancer efficacy in the SMMC-7721 model. Our study provides mechanistic insights and a mechanism-based rationale for the roles of aspirin in cancer treatment. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. ANGIOGENESIS INHIBITORS FOR THE TREATMENT OF HEPATOCELLULAR CARCINOMA

    Directory of Open Access Journals (Sweden)

    Massimiliano Berretta

    2016-11-01

    Full Text Available Background: Angiogenesis inhibitors have become an important therapeutic approach in the treatment of hepatocellular carcinoma (HCC patients. The achievement of Sorafenib in prolonging overall survival of patients with HCC makes therapeutic inhibition of angiogenesis a fundamental element of the treatment of HCC. Considering the heterogeneous aspects of HCC and to enhance therapeutic efficacy, overcome drug resistance and reduce toxicity, the combination of antiangiogenic drugs with antiblastic chemotherapy (AC, radiotherapy or other targeted drugs have been evaluated. The issue is further complicated by the combination of antiangiogenesis with other AC or biologic drugs. To date, there is no planned approach to determine which patients are more responsive to a given type of antiangiogenic treatment. Conclusion: Large investments in the clinical research are essential to improve treatment response and minimize toxicities for patients with HCC. Future investigations will need to focus on utilizing patterns of genetic information to classify HCC into groups that display similar prognosis and treatment sensitivity, and combining targeted therapies with AC producing enhanced anti-tumor effect. In this review the current panel of available antiangiogenic therapies for the treatment of HCC have been analyzed. In addition current clinical trials are also reported herein.

  19. Efficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locally advanced and inoperable hepatocellular carcinoma (SARAH): an open-label randomised controlled phase 3 trial.

    Science.gov (United States)

    Vilgrain, Valérie; Pereira, Helena; Assenat, Eric; Guiu, Boris; Ilonca, Alina Diana; Pageaux, Georges-Philippe; Sibert, Annie; Bouattour, Mohamed; Lebtahi, Rachida; Allaham, Wassim; Barraud, Hélène; Laurent, Valérie; Mathias, Elodie; Bronowicki, Jean-Pierre; Tasu, Jean-Pierre; Perdrisot, Rémy; Silvain, Christine; Gerolami, René; Mundler, Olivier; Seitz, Jean-Francois; Vidal, Vincent; Aubé, Christophe; Oberti, Frédéric; Couturier, Olivier; Brenot-Rossi, Isabelle; Raoul, Jean-Luc; Sarran, Anthony; Costentin, Charlotte; Itti, Emmanuel; Luciani, Alain; Adam, René; Lewin, Maïté; Samuel, Didier; Ronot, Maxime; Dinut, Aurelia; Castera, Laurent; Chatellier, Gilles

    2017-12-01

    Sorafenib is the recommended treatment for patients with advanced hepatocellular carcinoma. We aimed to compare the efficacy and safety of sorafenib to that of selective internal radiotherapy (SIRT) with yttrium-90 ( 90 Y) resin microspheres in patients with hepatocellular carcinoma. SARAH was a multicentre, open-label, randomised, controlled, investigator-initiated, phase 3 trial done at 25 centres specialising in liver diseases in France. Patients were eligible if they were aged at least 18 years with a life expectancy greater than 3 months, had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, Child-Pugh liver function class A or B score of 7 or lower, and locally advanced hepatocellular carcinoma (Barcelona Clinic Liver Cancer [BCLC] stage C), or new hepatocellular carcinoma not eligible for surgical resection, liver transplantation, or thermal ablation after a previously cured hepatocellular carcinoma (cured by surgery or thermoablative therapy), or hepatocellular carcinoma with two unsuccessful rounds of transarterial chemoembolisation. Patients were randomly assigned (1:1) by a permutated block method with block sizes two and four to receive continuous oral sorafenib (400 mg twice daily) or SIRT with 90 Y-loaded resin microspheres 2-5 weeks after randomisation. Patients were stratified according to randomising centre, ECOG performance status, previous transarterial chemoembolisation, and presence of macroscopic vascular invasion. The primary endpoint was overall survival. Analyses were done on the intention-to-treat population; safety was assessed in all patients who received at least one dose of sorafenib or underwent at least one of the SIRT work-up exams. This study has been completed and the final results are reported here. The trial is registered with ClinicalTrials.gov, number NCT01482442. Between Dec 5, 2011, and March 12, 2015, 467 patients were randomly assigned; after eight patients withdrew consent, 237 were assigned to

  20. Targeting tumorigenesis: development and use of mTOR inhibitors in cancer therapy

    Directory of Open Access Journals (Sweden)

    Kay Andrea

    2009-10-01

    Full Text Available Abstract The mammalian target of rapamycin (mTOR is an intracellular serine/threonine protein kinase positioned at a central point in a variety of cellular signaling cascades. The established involvement of mTOR activity in the cellular processes that contribute to the development and progression of cancer has identified mTOR as a major link in tumorigenesis. Consequently, inhibitors of mTOR, including temsirolimus, everolimus, and ridaforolimus (formerly deforolimus have been developed and assessed for their safety and efficacy in patients with cancer. Temsirolimus is an intravenously administered agent approved by the US Food and Drug Administration (FDA and the European Medicines Agency (EMEA for the treatment of advanced renal cell carcinoma (RCC. Everolimus is an oral agent that has recently obtained US FDA and EMEA approval for the treatment of advanced RCC after failure of treatment with sunitinib or sorafenib. Ridaforolimus is not yet approved for any indication. The use of mTOR inhibitors, either alone or in combination with other anticancer agents, has the potential to provide anticancer activity in numerous tumor types. Cancer types in which these agents are under evaluation include neuroendocrine tumors, breast cancer, leukemia, lymphoma, hepatocellular carcinoma, gastric cancer, pancreatic cancer, sarcoma, endometrial cancer, and non-small-cell lung cancer. The results of ongoing clinical trials with mTOR inhibitors, as single agents and in combination regimens, will better define their activity in cancer.

  1. Antileukemic activity of the HSP70 inhibitor pifithrin-μ in acute leukemia

    International Nuclear Information System (INIS)

    Kaiser, M; Kühnl, A; Reins, J; Fischer, S; Ortiz-Tanchez, J; Schlee, C; Mochmann, L H; Heesch, S; Benlasfer, O; Hofmann, W-K; Thiel, E; Baldus, C D

    2011-01-01

    Heat shock protein (HSP) 70 is aberrantly expressed in different malignancies and has emerged as a promising new target for anticancer therapy. Here, we analyzed the in vitro antileukemic effects of pifithrin-μ (PFT-μ), an inhibitor of inducible HSP70, in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) cell lines, as well as in primary AML blasts. PFT-μ significantly inhibited cell viability at low micromolar concentrations in all cell lines tested, with IC50 values ranging from 2.5 to 12.7 μ, and was highly active in primary AML blasts with a median IC50 of 8.9 μ (range 5.7–37.2). Importantly, higher IC50 values were seen in normal hematopoietic cells. In AML and ALL, PFT-μ induced apoptosis and cell cycle arrest in a dose-dependent fashion. PFT-μ also led to an increase of the active form of caspase-3 and reduced the intracellular concentrations of AKT and ERK1/2 in NALM-6 cells. Moreover, PFT-μ enhanced cytotoxicity of cytarabine, 17-(allylamino)-17-desmethoxygeldanamycin, suberoylanilide hydroxamic acid, and sorafenib in NALM-6, TOM-1 and KG-1a cells. This is the first study demonstrating significant antileukemic effects of the HSP70 inhibitor PFT-μ, alone and in combination with different antineoplastic drugs in both AML and ALL. Our results suggest a potential therapeutic role for PFT-μ in acute leukemias

  2. Ilexgenin A exerts anti-inflammation and anti-angiogenesis effects through inhibition of STAT3 and PI3K pathways and exhibits synergistic effects with Sorafenib on hepatoma growth

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Hao [Medical and Pharmaceutical Institute, Yangzhou University, Yangzhou 225001, Jiangsu (China); College of Medicine, Yangzhou University, Yangzhou 225001, Jiangsu (China); Institute of Pharmacology and Toxicology, Jiangsu Kanion Pharmaceutical Co., Ltd., Lianyungang 222000, Jiangsu (China); Wang, Juan [Medical and Pharmaceutical Institute, Yangzhou University, Yangzhou 225001, Jiangsu (China); College of Medicine, Yangzhou University, Yangzhou 225001, Jiangsu (China); Fan, Jin-hong; Zhang, Ya-qi; Zhao, Jun-xian [Medical and Pharmaceutical Institute, Yangzhou University, Yangzhou 225001, Jiangsu (China); Dai, Xiao-jun [Medical and Pharmaceutical Institute, Yangzhou University, Yangzhou 225001, Jiangsu (China); Chinese Medicine Hospital of Yangzhou City, Yangzhou 225009, Jiangsu (China); Liu, Qi; Shen, Yan-jun [Medical and Pharmaceutical Institute, Yangzhou University, Yangzhou 225001, Jiangsu (China); College of Medicine, Yangzhou University, Yangzhou 225001, Jiangsu (China); Liu, Chang [Medical and Pharmaceutical Institute, Yangzhou University, Yangzhou 225001, Jiangsu (China); Sun, Wei-dong, E-mail: zyykjc@sina.com [Medical and Pharmaceutical Institute, Yangzhou University, Yangzhou 225001, Jiangsu (China); Chinese Medicine Hospital of Yangzhou City, Yangzhou 225009, Jiangsu (China); Sun, Yun, E-mail: ysun@yzu.edu.cn [Medical and Pharmaceutical Institute, Yangzhou University, Yangzhou 225001, Jiangsu (China); College of Medicine, Yangzhou University, Yangzhou 225001, Jiangsu (China)

    2017-01-15

    Recently, we reported that Ilexgenin A exhibits anti-cancer activities and induces cell arrest. Here, we investigated the effect of Ilexgenin A on the inflammation, angiogenesis and tumor growth of hepatocellular carcinoma (HCC). Our current study revealed that Ilexgenin A significantly inhibited the inflammatory cytokines TNF-α and IL-6 levels and downregulated pro-angiogenic factor VEGF production and transcription in HepG2 cells. The underlying mechanism for Ilexgenin A effects appears to be through inhibiting STAT3 and PI3K pathways. Furthermore, we found that not only Ilexgenin A inhibited STAT3 and PI3K pathways in HepG2 cells but also blocked these signaling pathways in HUVECs. Most importantly, by employing two HCC xenografts models - HepG2 and H22, we showed that Ilexgenin A reduced tumor growth and exhibited synergy effect with Sorafenib. ELISA assay, histological analysis and immunohistochemistry examination revealed that the expression of VEGF and MVD was significantly decreased after the treatment with Ilexgenin A and the combination. Moreover, Ilexgenin A could enhance caspase-3/7 activity in vitro and transmission electron microscope indicated that the combination induced evident apoptosis of tumor cells and caused the structural changes of mitochondria in vivo. Although no apparent adverse effects occurred during the treatment period, Sorafenib monotherapy elicited hepatotoxicity for specific expression in the increased level of AST and the ratio of AST/ALT. However, the combination could remedy this adverse effect. In conclusion, the results described in the present study identifies Ilexgenin A as a promising therapeutic candidate that modulates inflammation, angiogenesis, and HCC growth. - Highlights: • Ilexgenin A exerts anti-inflammatory and anti-angiogenesis effects in hepatoma. • Ilexgenin A may exert these effects through inhibition of STAT3 and PI3K pathways. • Ilexgenin A exhibits synergistic effects with Sorafenib on hepatoma growth

  3. Quantitative therapy response assessment by volumetric iodine-uptake measurement: Initial experience in patients with advanced hepatocellular carcinoma treated with sorafenib

    International Nuclear Information System (INIS)

    Dai, Xu; Schlemmer, Heinz-Peter; Schmidt, Bernhard; Höh, Karolin; Xu, Ke; Ganten, Tom M.; Ganten, Maria-Katharina

    2013-01-01

    Objectives: To investigate the volumetric iodine-uptake (VIU) changes by dual-energy CT (DECT) in assessing the response to sorafenib treated hepatocellular carcinoma (HCC) patients, compared with AASLD (American Association for the Study of Liver Diseases) and Choi criteria. Materials and methods: Fifteen patients with HCC receiving sorafenib, monitored with contrast-enhanced DECT scans at baseline and a minimum of one follow-up (8–12 weeks) were retrospectively evaluated. 30 target lesions in total were analyzed for tumor response according to VIU and adapted Choi criteria and compared with the standard AASLD. Results: According to AASLD criteria, 67% target lesions showed disease control: partial response (PR) in 3% and stable disease (SD) in 63%. 33% lesions progressed (PD). Disease control rate presented by VIU (60%) was similar to AASLD (67%) and Choi (63%) (P > 0.05). For disease control group, change in mean VIU was from 149.5 ± 338.3 mg to 108.5 ± 284.1 mg (decreased 19.1 ± 42.9%); and for progressive disease group, change in mean VIU was from 163.7 ± 346.7 mg to 263.9 ± 537.2 mg (increased 230.5 ± 253.1%). Compared to AASLD (PR, 3%), VIU and Choi presented more PR (33% and 30%, respectively) in disease control group (P < 0.05). VIU has moderate consistency with both AASLD (kappa = 0.714; P < 0.005) and Choi (kappa = 0.648; P < 0.005), while VIU showed a better consistency and correlation with AASLD (kappa = 0.714; P < 0.005; r = 0.666, P < 0.005) than Choi with AASLD (kappa = 0.634, P < 0.005; r = 0.102, P = 0.296). Conclusion: VIU measurements by DECT can evaluate the disease control consistent with the current standard AASLD. Measurements are semi-automatic and therefore easy and robust to apply. As VIU reflects vital tumor burden in HCC, it is likely to be an optimal tumor response biomarker in HCC

  4. Inhibitory effects of regorafenib, a multiple tyrosine kinase inhibitor, on corneal neovascularization

    Directory of Open Access Journals (Sweden)

    Halil Ibrahim Onder

    2014-04-01

    Full Text Available AIM:To evaluate the inhibitory effects of regorafenib (BAY 73-4506, a multikinase inhibitor, on corneal neovascularization (NV.METHODS:Thirty adult male Sprague-Dawley rats weighing 250-300 g, were used. Corneal NV was induced by NaOH in the left eyes of each rat. Following the establishment of alkali burn, the animals were randomized into five groups according to topical treatment. Group 1 (n = 6 received 0.9% NaCl, Group 2 (n = 6 received dimethyl sulfoxide, Group 3 (n = 6 received regorafenib 1 mg/mL, Group 4 (n =6 received bevacizumab 5 mg/mL and Group 5 (n = 6 received 0.1% dexamethasone phosphate. On the 7d, the corneal surface covered with neovascular vessels was measured on photographs as the percentage of the cornea’s total area using computer-imaging analysis. The corneas obtained from rats were semiquantitatively evaluated for caspase-3 and vascular endothelial growth factor by immunostaining.RESULTS:A statistically significant difference in the percent area of corneal NV was found among the groups (P <0.001. Although the Group 5 had the smallest percent area of corneal NV, there was no difference among Groups 3, 4 and 5 (P >0.005. There was a statistically significant difference among the groups in apoptotic cell density (P = 0.002. The staining intensity of vascular endothelial growth factor in the epithelial and endothelial layers of cornea was significantly different among the groups (P <0.05. The staining intensity of epithelial and endothelial vascular endothelial growth factor was significantly weaker in Groups 3, 4 and 5 than in Groups 1 and 2.CONCLUSION: Topical administration of regorafenib 1 mg/mL is partly effective for preventing alkali-induced corneal NV in rats.

  5. A Miniaturized Chemical Proteomic Approach for Target Profiling of Clinical Kinase Inhibitors in Tumor Biopsies

    Science.gov (United States)

    Chamrád, Ivo; Rix, Uwe; Stukalov, Alexey; Gridling, Manuela; Parapatics, Katja; Müller, André C.; Altiok, Soner; Colinge, Jacques; Superti-Furga, Giulio; Haura, Eric B.; Bennett, Keiryn L.

    2014-01-01

    While targeted therapy based on the idea of attenuating the activity of a preselected, therapeutically relevant protein has become one of the major trends in modern cancer therapy, no truly specific targeted drug has been developed and most clinical agents have displayed a degree of polypharmacology. Therefore, the specificity of anticancer therapeutics has emerged as a highly important but severely underestimated issue. Chemical proteomics is a powerful technique combining postgenomic drug-affinity chromatography with high-end mass spectrometry analysis and bioinformatic data processing to assemble a target profile of a desired therapeutic molecule. Due to high demands on the starting material, however, chemical proteomic studies have been mostly limited to cancer cell lines. Herein, we report a down-scaling of the technique to enable the analysis of very low abundance samples, as those obtained from needle biopsies. By a systematic investigation of several important parameters in pull-downs with the multikinase inhibitor bosutinib, the standard experimental protocol was optimized to 100 µg protein input. At this level, more than 30 well-known targets were detected per single pull-down replicate with high reproducibility. Moreover, as presented by the comprehensive target profile obtained from miniaturized pull-downs with another clinical drug, dasatinib, the optimized protocol seems to be extendable to other drugs of interest. Sixty distinct human and murine targets were finally identified for bosutinib and dasatinib in chemical proteomic experiments utilizing core needle biopsy samples from xenotransplants derived from patient tumor tissue. Altogether, the developed methodology proves robust and generic and holds many promises for the field of personalized health care. PMID:23901793

  6. Selective and Irreversible Induction of Necroptotic Cell Death in Lung Tumorspheres by Short-Term Exposure to Verapamil in Combination with Sorafenib

    Directory of Open Access Journals (Sweden)

    Juan Sebastian Yakisich

    2017-01-01

    Full Text Available The presence of highly resistant cancer cells and the toxicity to normal cells are key factors that limit chemotherapy. Here, we used two models of highly resistant lung cancer cells: (1 adherent cells growing under prolonged periods of serum starvation (PPSS and (2 cells growing as floating tumorspheres (FTs to evaluate the effect of Verapamil (VP in combination with Sorafenib (SF. Compared to cells growing under routine culture conditions (RCCs, PPPS cells or FTs were highly sensitive to short-term exposure (24 h to VP 100 μM + SF 5 μM (VP100 + SF5. Recovery experiments exposing cells to VP100 + SF5 for 24 h followed by incubation in drug-free media for 48 h demonstrated that while PPSS as well as FT cells were unable to recover, cancer cells and the noncancerous cell line Beas-2B growing under RCCs were less sensitive and were also able to recover significantly. VP100 + SF5 induced significant changes in the expression of protein associated with apoptosis, autophagy, and to a lesser extent necroptosis. Coincubation experiments with z-VAD-FMK, necrostatin 1, or chloroquine showed evidence that necroptosis played a central role. Our data demonstrates that highly resistant cancer cells can be selectively eliminated by VP + SF and that necroptosis plays a central role.

  7. Monoamine Oxidase Inhibitors (MAOIs)

    Science.gov (United States)

    ... health-medications/index.shtml. Accessed May 16, 2016. Hirsch M, et al. Monoamine oxidase inhibitors (MAOIs) for ... www.uptodate.com/home. Accessed May 16, 2016. Hirsch M, et al. Discontinuing antidepressant medications in adults. ...

  8. Intrinsic resistance to tyrosine kinase inhibitors is associated with poor clinical outcome in metastatic renal cell carcinoma

    International Nuclear Information System (INIS)

    Busch, Jonas; Grünwald, Viktor; Seidel, Christoph; Weikert, Steffen; Wolff, Ingmar; Kempkensteffen, Carsten; Weinkauf, Lisa; Hinz, Stefan; Magheli, Ahmed; Miller, Kurt

    2011-01-01

    Data on sequential therapy in patients with metastatic renal cell carcinoma (mRCC) and intrinsic resistance to receptor tyrosine kinase inhibitor (rTKI) treatment remains vague. We retrospectively studied treatment characteristics and outcome of mRCC patients refractory to first rTKI therapy. Thirty-five mRCC patients (male, 18; female, 11) with primary resistance to first rTKI therapy (sunitinib, n = 28; sorafenib, n = 7) and a median treatment interval of 2.4 months (1 - 4.6) were identified. In 22 patients, progressive disease (PD) was determined by a new metastatic lesion. Of these, 16 patients received subsequent therapy with 12 patients remaining refractory and 4 patients achieving disease stabilization. In 13 patients continuous growth of existing metastatic lesions determined PD. Of these, 9 received sequential therapy with 6 achieving disease stabilization. Altogether, 25 patients were treated sequentially (rTKI: n = 15; mTOR-inhibitor: n = 10) and achieved a median PFS of 3.2 months (range, 1-16.6). Fifteen patients failed to respond to either line of therapy. Disease control was not associated with type of subsequent therapy. Median OS was 14.9 months (CI: 5.5-24.4). Intrinsic resistance to rTKI is associated with a low chance of response to sequential therapy and a poor prognosis in mRCC patients

  9. BFD-22 a new potential inhibitor of BRAF inhibits the metastasis of B16F10 melanoma cells and simultaneously increased the tumor immunogenicity

    Energy Technology Data Exchange (ETDEWEB)

    Ferreira, Adilson Kleber, E-mail: ferreira-kleber@usp.br [Laboratory of Tumor Immunology, University of São Paulo, São Paulo, SP (Brazil); Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, Groningen (Netherlands); Pasqualoto, Kerly Fernanda Mesquita [Biochemistry and Biophysics Laboratory, Butantan Institute, São Paulo, SP (Brazil); Kruyt, Frank A.E. [Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, Groningen (Netherlands); Palace-Berl, Fanny [Laboratory of Drug Design and Development, University of São Paulo, São Paulo, SP (Brazil); Azevedo, Ricardo Alexandre [Laboratory of Tumor Immunology, University of São Paulo, São Paulo, SP (Brazil); Turra, Kely Medeiros [Laboratory of Cytopathology, Department of Clinical Chemistry and Toxicology, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP (Brazil); Rodrigues, Cecilia Pessoa; Ferreira, Ana Carolina Franco; Salomón, Maria Alejandra Clavijo [Laboratory of Tumor Immunology, University of São Paulo, São Paulo, SP (Brazil); Sá, Paulo Luiz de [Laboratory of Genetics, Butantan Institute, São Paulo, SP (Brazil); Farias, Camyla Fernandes; Figueiredo, Carlos Rogerio [Experimental Oncology Section, The Federal University of São Paulo, São Paulo, SP (Brazil); and others

    2016-03-15

    Benzofuroxan is an interesting ring system, which has shown a wide spectrum of biological responses against tumor cell lines. We investigated, herein, the antitumor effects of benzofuroxan derivatives (BFDs) in vitro and in a melanoma mouse model. Cytotoxic effects of twenty-two BFDs were determined by MTT assay. Effects of BFD-22 in apoptosis and cell proliferation were evaluated using Annexin V-FITC/PI and CFSE staining. In addition, the effects in the cell cycle were assessed. Flow cytometry, western blot, and fluorescence microscopy analysis were employed to investigate the apoptosis-related proteins and the BRAF signaling. Cell motility was also exploited through cell invasion and migration assays. Molecular docking approach was performed in order to verify the BFD-22 binding mode into the ATP catalytic site of BRAF kinase. Moreover, the BFD-22 antitumor effects were evaluated in a melanoma murine model using B16F10. BFD-22 was identified as a potential hit against melanoma cells. BFD-22 induced apoptosis and inhibited cell proliferation of B16F10 cells. BFD-22 has suppressed, indeed, the migratory and invasive behavior of B16F10 cells. Cyclin D1 and CDK4 expression were reduced leading to cell cycle arrest at G0/G1 phase. Of note, phosphorylation of BRAF at Ser338 was strongly down-regulated by BFD-22 in B16F10 cells. The accommodation/orientation into the binding site of BRAF was similar of BAY43-9006 (co-crystallized inhibitor of BRAF, sorafenib). Importantly, BFD-22 presented in vivo antimetastatic effects and showed better therapeutic efficacy than sorafenib and taxol. BFD-22 can be considered as a new lead compound and, then, can be helpful for the designing of novel drug candidates to treat melanoma. - Highlights: • BFD-22 induces apoptosis effects of B16F10 cells by mitochondrial pathway. • BFD-22 provokes downstream in the MAPK/ERK kinase signaling cascade. • Molecular docking trials supported BRAF protein as potential target for BDF-22. • BFD

  10. Phase II and Biomarker Study of the Dual MET/VEGFR2 Inhibitor Foretinib in Patients With Papillary Renal Cell Carcinoma

    Science.gov (United States)

    Choueiri, Toni K.; Vaishampayan, Ulka; Rosenberg, Jonathan E.; Logan, Theodore F.; Harzstark, Andrea L.; Bukowski, Ronald M.; Rini, Brian I.; Srinivas, Sandy; Stein, Mark N.; Adams, Laurel M.; Ottesen, Lone H.; Laubscher, Kevin H.; Sherman, Laurie; McDermott, David F.; Haas, Naomi B.; Flaherty, Keith T.; Ross, Robert; Eisenberg, Peter; Meltzer, Paul S.; Merino, Maria J.; Bottaro, Donald P.; Linehan, W. Marston; Srinivasan, Ramaprasad

    2013-01-01

    Purpose Foretinib is an oral multikinase inhibitor targeting MET, VEGF, RON, AXL, and TIE-2 receptors. Activating mutations or amplifications in MET have been described in patients with papillary renal cell carcinoma (PRCC). We aimed to evaluate the efficacy and safety of foretinib in patients with PRCC. Patients and Methods Patients were enrolled onto the study in two cohorts with different dosing schedules of foretinib: cohort A, 240 mg once per day on days 1 through 5 every 14 days (intermittent arm); cohort B, 80 mg daily (daily dosing arm). Patients were stratified on the basis of MET pathway activation (germline or somatic MET mutation, MET [7q31] amplification, or gain of chromosome 7). The primary end point was overall response rate (ORR). Results Overall, 74 patients were enrolled, with 37 in each dosing cohort. ORR by Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 was 13.5%, median progression-free survival was 9.3 months, and median overall survival was not reached. The presence of a germline MET mutation was highly predictive of a response (five of 10 v five of 57 patients with and without germline MET mutations, respectively). The most frequent adverse events of any grade associated with foretinib were fatigue, hypertension, gastrointestinal toxicities, and nonfatal pulmonary emboli. Conclusion Foretinib demonstrated activity in patients with advanced PRCC with a manageable toxicity profile and a high response rate in patients with germline MET mutations. PMID:23213094

  11. Complications of hyperglycaemia with PI3K–AKT–mTOR inhibitors in patients with advanced solid tumours on Phase I clinical trials

    Science.gov (United States)

    Geuna, E; Roda, D; Rafii, S; Jimenez, B; Capelan, M; Rihawi, K; Montemurro, F; Yap, T A; Kaye, S B; De Bono, J S; Molife, L R; Banerji, U

    2015-01-01

    Background: PI3K–AKT–mTOR inhibitors (PAMi) are promising anticancer treatments. Hyperglycaemia is a mechanism-based toxicity of these agents and is becoming increasingly important with their use in larger numbers of patients. Methods: Retrospective case-control study comparing incidence and severity of hyperglycaemia (all grades) between a case group of 387 patients treated on 18 phase I clinical trials with PAMi (78 patients with PI3Ki, 138 with mTORi, 144 with AKTi and 27 with PI3K/mTORi) and a control group of 109 patients treated on 10 phase I clinical trials with agents not directly targeting the PAM pathway. Diabetic patients were excluded in both groups. Results: The incidence of hyperglycaemia was not significantly different between cases and controls (86.6% vs 80.7%, respectively, P=0.129). However, high grade (grade 3–4) hyperglycaemia was more frequent in the PAMi group than in controls (6.7% vs 0%, respectively, P=0.005). The incidence of grade 3–4 hyperglycaemia was greater with AKT and multikinase inhibitors compared with other PAMi (P<0.001). All patients with high-grade hyperglycaemia received antihyperglycemic treatment and none developed severe metabolic complications (diabetic ketoacidosis or hyperosmolar hyperglycemic nonketotic state). High-grade hyperglycaemia was the cause of permanent PAMi discontinuation in nine patients. Conclusions: PI3K–AKT–mTOR inhibitors are associated with small (6.7%) but statistically significant increased risk of high-grade hyperglycaemia compared with non-PAM targeting agents. However, PAMi-induced hyperglycaemia was not found to be associated with severe metabolic complications in this non-diabetic population of patients with advanced cancers. PMID:26554652

  12. Tyrosine and aurora kinase inhibitors diminish transport function of multidrug resistance-associated protein (MRP 4 and breast cancer resistance protein (BCRP

    Directory of Open Access Journals (Sweden)

    Rhiannon N. Hardwick

    2016-12-01

    Full Text Available Tyrosine and aurora kinases are important effectors in signal transduction pathways that are often involved in aberrant cancer cell growth. Tyrosine (TKI and aurora (AKI kinase inhibitors are anti-cancer agents specifically designed to target such signaling pathways through TKI/AKI binding to the ATP-binding pocket of kinases thereby leading to diminished kinase activity. Some TKIs have been identified as inhibitors of ATP-binding cassette (ABC transporters such as P-glycoprotein and breast cancer resistance protein (BCRP, which are commonly upregulated in malignant cells. TKI/AKIs have been investigated as ABC transporter inhibitors in order to facilitate the accumulation of concomitantly administered chemo-therapeutics within cancer cells. However, ABC transporters are prominently expressed in the liver and other eliminating organs, and their inhibition has been linked to intracellular accumulation of drugs, altered disposition, and toxicity. The potential for TKIs/AKIs to inhibit other important hepatic efflux transporters, particularly multidrug resistance-associated proteins (MRPs, remains unknown. The aim of the current study was to compare the inhibitory potency of 20 selected TKI/AKIs against MRP4 and BCRP through the use of inverted membrane vesicle assays. Relative IC50 values were estimated by determining TKI/AKI inhibition of MRP4-mediated [3H]-dehydroepiandrosterone sulfate uptake and BCRP-mediated [3H]-estrone sulfate uptake. To provide insight to the clinical relevance of TKI/AKI inhibition of ABC efflux transporters, the ratio of the steady-state maximum total plasma concentration (Css to the IC50 for each compound was calculated with Css/IC50 ratio >0.1 deemed potentially clinically relevant. Such analysis identified several potentially clinically relevant inhibitors of MRP4: alisertib, danusertib, erlotinib, lapatinib, neratinib, nilotinib, pazopanib, sorafenib, and tozasertib. The potentially clinically relevant inhibition of

  13. SGLT2 inhibitors.

    Science.gov (United States)

    Dardi, I; Kouvatsos, T; Jabbour, S A

    2016-02-01

    Diabetes mellitus is a serious health issue and an economic burden, rising in epidemic proportions over the last few decades worldwide. Although several treatment options are available, only half of the global diabetic population achieves the recommended or individualized glycemic targets. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of antidiabetic agents with a novel insulin-independent action. SGLT2 is a transporter found in the proximal renal tubules, responsible for the reabsorption of most of the glucose filtered by the kidney. Inhibition of SGLT2 lowers the blood glucose level by promoting the urinary excretion of excess glucose. Due to their insulin-independent action, SGLT2 inhibitors can be used with any degree of beta-cell dysfunction or insulin resistance, related to a very low risk of hypoglycemia. In addition to improving glycemic control, SGLT2 inhibitors have been associated with a reduction in weight and blood pressure when used as monotherapy or in combination with other antidiabetic agents in patients with type 2 diabetes mellitus (T2DM). Treatment with SGLT2 inhibitors is usually well tolerated; however, they have been associated with an increased incidence of urinary tract and genital infections, although these infections are usually mild and easy to treat. SGLT2 inhibitors are a promising new option in the armamentarium of drugs for patients with T2DM. Copyright © 2015 Elsevier Inc. All rights reserved.

  14. Aromatase inhibitors in pediatrics.

    Science.gov (United States)

    Wit, Jan M; Hero, Matti; Nunez, Susan B

    2011-10-25

    Aromatase, an enzyme located in the endoplasmic reticulum of estrogen-producing cells, catalyzes the rate-limiting step in the conversion of androgens to estrogens in many tissues. The clinical features of patients with defects in CYP19A1, the gene encoding aromatase, have revealed a major role for this enzyme in epiphyseal plate closure, which has promoted interest in the use of inhibitors of aromatase to improve adult height. The availability of the selective aromatase inhibitors letrozole and anastrozole--currently approved as adjuvant therapy for breast cancer--have stimulated off-label use of aromatase inhibitors in pediatrics for the following conditions: hyperestrogenism, such as aromatase excess syndrome, Peutz-Jeghers syndrome, McCune-Albright syndrome and functional follicular ovarian cysts; hyperandrogenism, for example, testotoxicosis (also known as familial male-limited precocious puberty) and congenital adrenal hyperplasia; pubertal gynecomastia; and short stature and/or pubertal delay in boys. Current data suggest that aromatase inhibitors are probably effective in the treatment of patients with aromatase excess syndrome or testotoxicosis, partially effective in Peutz-Jeghers and McCune-Albright syndrome, but probably ineffective in gynecomastia. Insufficient data are available in patients with congenital adrenal hyperplasia or functional ovarian cysts. Although aromatase inhibitors appear effective in increasing adult height of boys with short stature and/or pubertal delay, safety concerns, including vertebral deformities, a decrease in serum HDL cholesterol levels and increase of erythrocytosis, are reasons for caution.

  15. JAK inhibitors in autoinflammation.

    Science.gov (United States)

    Hoffman, Hal M; Broderick, Lori

    2018-06-11

    Interferonopathies are a subset of autoinflammatory disorders with a prominent type I IFN gene signature. Treatment of these patients has been challenging, given the lack of response to common autoinflammatory therapeutics including IL-1 and TNF blockade. JAK inhibitors (Jakinibs) are a family of small-molecule inhibitors that target the JAK/STAT signaling pathway and have shown clinical efficacy, with FDA and European Medicines Agency (EMA) approval for arthritic and myeloproliferative syndromes. Sanchez and colleagues repurposed baricitinib to establish a significant role for JAK inhibition as a novel therapy for patients with interferonopathies, demonstrating the power of translational rare disease research with lifesaving effects.

  16. Cathepsin D inhibitors

    Directory of Open Access Journals (Sweden)

    M. Gacko

    2007-11-01

    Full Text Available Inhibitors of cathepsin D belong to chemical compounds that estrify carboxyl groups of the Asp33 and Asp231residues of its catalytic site, penta-peptides containing statin, i.e. the amino acid similar in structure to the tetraedric indirectproduct, and polypeptides found in the spare organs of many plants and forming permanent noncovalent complexes withcathepsin. Cathepsin D activity is also inhibited by alpha2-macroglobulin and antibodies directed against this enzyme.Methods used to determine the activity and concentration of these inhibitors and their analytical, preparative and therapeuticapplications are discussed.

  17. Transglutaminase inhibitor from milk

    NARCIS (Netherlands)

    Jong, G.A.H. de; Wijngaards, G.; Koppelman, S.J.

    2003-01-01

    Cross-linking experiments of skimmed bovine milk with bacterial transglutaminase isolated from Streptoverticillium mobaraense showed only some degree of formation of high-molecular-weight casein polymers. Studies on the nature of this phenomenon revealed that bovine milk contains an inhibitor of

  18. Inhibitors of histone demethylases

    DEFF Research Database (Denmark)

    Lohse, Brian; Kristensen, Jesper L; Kristensen, Line H

    2011-01-01

    Methylated lysines are important epigenetic marks. The enzymes involved in demethylation have recently been discovered and found to be involved in cancer development and progression. Despite the relative recent discovery of these enzymes a number of inhibitors have already appeared. Most of the i...

  19. A Natural CCR2 Antagonist Relieves Tumor-associated Macrophage-mediated Immunosuppression to Produce a Therapeutic Effect for Liver Cancer

    Directory of Open Access Journals (Sweden)

    Wenbo Yao

    2017-08-01

    Full Text Available Hepatocellular carcinoma (HCC is a common malignant tumor in the digestive tract with limited therapeutic choices. Although sorafenib, an orally administered multikinase inhibitor, has produced survival benefits for patients with advanced HCC, favorable clinical outcomes are limited due to individual differences and resistance. The application of immunotherapy, a promising approach for HCC is urgently needed. Macrophage infiltration, mediated by the CCL2/CCR2 axis, is a potential immunotherapeutic target. Here, we report that a natural product from Abies georgei, named 747 and related in structure to kaempferol, exhibits sensitivity and selectivity as a CCR2 antagonist. The specificity of 747 on CCR2 was demonstrated via calcium flux, the binding domain of CCR2 was identified in an extracellular loop by chimera binding assay, and in vivo antagonistic activity of 747 was confirmed through a thioglycollate-induced peritonitis model. In animals, 747 elevated the number of CD8+ T cells in tumors via blocking tumor-infiltrating macrophage-mediated immunosuppression and inhibited orthotopic and subcutaneous tumor growth in a CD8+ T cell-dependent manner. Further, 747 enhanced the therapeutic efficacy of low-dose sorafenib without obvious toxicity, through elevating the numbers of intra-tumoral CD8+ T cells and increasing death of tumor cells. Thus, we have discovered a natural CCR2 antagonist and have provided a new perspective on development of this antagonist for treatment of HCC. In mouse models of HCC, 747 enhanced the tumor immunosuppressive microenvironment and potentiated the therapeutic effect of sorafenib, indicating that the combination of an immunomodulator with a chemotherapeutic drug could be a new approach for treating HCC.

  20. Acid corrosion inhibitor

    Energy Technology Data Exchange (ETDEWEB)

    Chen, N G

    1964-04-28

    An acid corrosion inhibitor is prepared by a 2-stage vacuum evaporation of effluents obtained from the ammonia columns of the coking oven plant. The effluent, leaving a scrubber in which the phenols are removed at a temperature of 98$C, passes through a quartz filter and flows into a heated chamber in which it is used for preheating a solution circulating through a vacuum unit, maintaining the temperature of the solution at 55$ to 60$C. The effluent enters a large tank in which it is boiled at 55$ to 60$C under 635 to 640 mm Hg pressure. Double evaporation of this solution yields a very effective acid corrosion inhibitor. Its corrosion-preventing effect is 97.9% compared with 90.1% for thiourea and 88.5% for urotropin under identical conditions.

  1. Benzoylurea Chitin Synthesis Inhibitors.

    Science.gov (United States)

    Sun, Ranfeng; Liu, Chunjuan; Zhang, Hao; Wang, Qingmin

    2015-08-12

    Benzoylurea chitin synthesis inhibitors are widely used in integrated pest management (IPM) and insecticide resistance management (IRM) programs due to their low toxicity to mammals and predatory insects. In the past decades, a large number of benzoylurea derivatives have been synthesized, and 15 benzoylurea chitin synthesis inhibitors have been commercialized. This review focuses on the history of commercial benzolyphenylureas (BPUs), synthetic methods, structure-activity relationships (SAR), action mechanism research, environmental behaviors, and ecotoxicology. Furthermore, their disadvantages of high risk to aquatic invertebrates and crustaceans are pointed out. Finally, we propose that the para-substituents at anilide of benzoylphenylureas should be the functional groups, and bipartite model BPU analogues are discussed in an attempt to provide new insight for future development of BPUs.

  2. DGAT inhibitors for obesity.

    Science.gov (United States)

    Matsuda, Daisuke; Tomoda, Hiroshi

    2007-10-01

    Obesity is characterized by the accumulation of triacylglycerol in adipocytes. Diacylglycerol acyltransferase (DGAT) catalyzes the final reaction of triacylgycerol synthesis. Two isozymes of DGAT, DGAT1 and DGAT2, have been reported. Increased DGAT2 activity has a role in steatosis, while DGAT1 plays a role in very (V)LDL synthesis; increased plasma VLDL concentrations may promote obesity and thus DGAT1 is considered a potential therapeutic target of inhibition for obesity control. Several DGAT inhibitors of natural and synthetic origin have been reported, and their future prospect as anti-obesity drugs is discussed in this review.

  3. Pulmonary Toxicity of Cholinesterase Inhibitors

    National Research Council Canada - National Science Library

    Hilmas, Corey; Adler, Michael; Baskin, Steven I; Gupta, Ramesh C

    2006-01-01

    .... Whereas nerve agents were produced primarily for military deployment, other cholinesterase inhibitors were used for treating conditions such as myasthenia gravis and as pretreaunents for nerve agent exposure...

  4. Sequence‑dependent effect of sorafenib in combination with natural phenolic compounds on hepatic cancer cells and the possible mechanism of action.

    Science.gov (United States)

    Bahman, Abdulmajeed A; Abaza, Mohamed Salah I; Khoushiash, Sarah I; Al-Attiyah, Rajaa J

    2018-06-08

    Sorafenib (Nexavar, BAY43‑9006 or Sora) is the first molecular targeted agent that has exhibited significant therapeutic benefits in advanced hepatocellular carcinoma (HCC). However, not all HCC patients respond well to Sora and novel therapeutic strategies to optimize the efficacy of Sora are urgently required. Plant‑based drugs have received increasing attention owing to their excellent chemotherapeutic and chemopreventive activities; they are also well tolerated, non‑toxic, easily available and inexpensive. It is well known that certain biologically active natural products act synergistically with synthetic drugs used in clinical applications. The present study aimed to investigate whether a combination therapy with natural phenolic compounds (NPCs), including curcumin (Cur), quercetin (Que), kaempherol (Kmf) and resveratrol (Rsv), would allow a dose reduction of Sora without concomitant loss of its effectiveness. Furthermore, the possible molecular mechanisms of this synergy were assessed. The hepatic cancer cell lines Hep3b and HepG2 were treated with Sora alone or in combination with NPCs in concomitant, sequential, and inverted sequential regimens. Cell proliferation, cell cycle, apoptosis and expression of proteins associated with the cell cycle and apoptosis were investigated. NPCs markedly potentiated the therapeutic efficacy of Sora in a sequence‑, type‑, NPC dose‑ and cell line‑dependent manner. Concomitant treatment with Sora and Cur [sensitization ratio (SR)=28], Kmf (SR=18) or Que (SR=8) was associated with the highest SRs in Hep3b cells. Rsv markedly potentiated the effect of Sora (SR=17) on Hep3b cells when administered in a reverse sequential manner. By contrast, Rsv and Que did not improve the efficacy of Sora against HepG2 cells, while concomitant treatment with Cur (SR=10) or Kmf (SR=4.01) potentiated the cytotoxicity of Sora. Concomitant treatment with Sora and Cur or Kmf caused S‑phase and G2/M phase arrest of liver cancer

  5. Visceral fat area predicts survival in patients with advanced hepatocellular carcinoma treated with tyrosine kinase inhibitors.

    Science.gov (United States)

    Nault, Jean-Charles; Pigneur, Frédéric; Nelson, Anaïs Charles; Costentin, Charlotte; Tselikas, Lambros; Katsahian, Sandrine; Diao, Guoqing; Laurent, Alexis; Mallat, Ariane; Duvoux, Christophe; Luciani, Alain; Decaens, Thomas

    2015-10-01

    Anthropometric measurements have been linked to resistance to anti-angiogenic treatment and survival. Patients with advanced hepatocellular carcinoma treated with sorafenib or brivanib in 2008-2011 were included in this retrospective study. Anthropometric measurements were assessed using computed tomography and were correlated with drug toxicity, radiological response, and overall survival. 52 patients were included, Barcelona Clinic Liver Classification B (38%) and C (62%), with a mean value of α-fetoprotein of 29,554±85,654 ng/mL, with a median overall survival of 10.5 months. Sarcopenia was associated with a greater rate of hand-foot syndrome (P=0.049). Modified Response Evaluation Criteria In Solid Tumours (mRECIST) and Choi criteria were significantly associated with survival, but RECIST criteria were not. An absence of hand-foot syndrome and high-visceral fat area were associated with progressive disease as assessed by RECIST and mRECIST criteria. In multivariate analyses, high visceral fat area (HR=3.6; P=0.002), low lean body mass (HR=2.4; P=0.015), and presence of hand-foot syndrome (HR=1.8; P=0.004) were significantly associated with overall survival. In time-dependent multivariate analyses; only high visceral fat area was associated with survival. Visceral fat area is associated with survival and seems to be a predictive marker for primary resistance to tyrosine kinase inhibitors in patients with advanced hepatocellular carcinoma. Copyright © 2015 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

  6. Immune Consequences of Decreasing Tumor Vasculature with Antiangiogenic Tyrosine Kinase Inhibitors in Combination with Therapeutic Vaccines

    Science.gov (United States)

    Farsaci, Benedetto; Donahue, Renee N.; Coplin, Michael A.; Grenga, Italia; Lepone, Lauren M.; Molinolo, Alfredo A.; Hodge, James W.

    2014-01-01

    This study investigated the effects on the tumor microenvironment of combining antiangiogenic tyrosine kinase inhibitors (TKI) with therapeutic vaccines, and in particular, how vascular changes affect tumor-infiltrating immune cells. We conducted studies using a TKI (sunitinib or sorafenib) in combination with recombinant vaccines in 2 murine tumor models: colon carcinoma (MC38-CEA) and breast cancer (4T1). Tumor vasculature was measured by immunohistochemistry using 3 endothelial cell markers: CD31 (mature), CD105 (immature/proliferating), and CD11b (monocytic). We assessed oxygenation, tight junctions, compactness, and pressure within tumors, along with the frequency and phenotype of tumor-infiltrating T lymphocytes (TIL), myeloid-derived suppressor cells (MDSC), and tumor-associated macrophages (TAM) following treatment with antiangiogenic TKIs alone, vaccine alone, or the combination of a TKI with vaccine. The combined regimen decreased tumor vasculature, compactness, tight junctions, and pressure, leading to vascular normalization and increased tumor oxygenation. This combination therapy also increased TILs, including tumor antigen-specific CD8 T cells, and elevated the expression of activation markers FAS-L, CXCL-9, CD31, and CD105 in MDSCs and TAMs, leading to reduced tumor volumes and an increase in the number of tumor-free animals. The improved antitumor activity induced by combining antiangiogenic TKIs with vaccine may be the result of activated lymphoid and myeloid cells in the tumor microenvironment, resulting from vascular normalization, decreased tumor-cell density, and the consequent improvement in vascular perfusion and oxygenation. Therapies that alter tumor architecture can thus have a dramatic impact on the effectiveness of cancer immunotherapy. PMID:25092771

  7. Effects of 31 FDA approved small-molecule kinase inhibitors on isolated rat liver mitochondria.

    Science.gov (United States)

    Zhang, Jun; Salminen, Alec; Yang, Xi; Luo, Yong; Wu, Qiangen; White, Matthew; Greenhaw, James; Ren, Lijun; Bryant, Matthew; Salminen, William; Papoian, Thomas; Mattes, William; Shi, Qiang

    2017-08-01

    The FDA has approved 31 small-molecule kinase inhibitors (KIs) for human use as of November 2016, with six having black box warnings for hepatotoxicity (BBW-H) in product labeling. The precise mechanisms and risk factors for KI-induced hepatotoxicity are poorly understood. Here, the 31 KIs were tested in isolated rat liver mitochondria, an in vitro system recently proposed to be a useful tool to predict drug-induced hepatotoxicity in humans. The KIs were incubated with mitochondria or submitochondrial particles at concentrations ranging from therapeutic maximal blood concentrations (Cmax) levels to 100-fold Cmax levels. Ten endpoints were measured, including oxygen consumption rate, inner membrane potential, cytochrome c release, swelling, reactive oxygen species, and individual respiratory chain complex (I-V) activities. Of the 31 KIs examined only three including sorafenib, regorafenib and pazopanib, all of which are hepatotoxic, caused significant mitochondrial toxicity at concentrations equal to the Cmax, indicating that mitochondrial toxicity likely contributes to the pathogenesis of hepatotoxicity associated with these KIs. At concentrations equal to 100-fold Cmax, 18 KIs were found to be toxic to mitochondria, and among six KIs with BBW-H, mitochondrial injury was induced by regorafenib, lapatinib, idelalisib, and pazopanib, but not ponatinib, or sunitinib. Mitochondrial liability at 100-fold Cmax had a positive predictive power (PPV) of 72% and negative predictive power (NPV) of 33% in predicting human KI hepatotoxicity as defined by product labeling, with the sensitivity and specificity being 62% and 44%, respectively. Similar predictive power was obtained using the criterion of Cmax ≥1.1 µM or daily dose ≥100 mg. Mitochondrial liability at 1-2.5-fold Cmax showed a 100% PPV and specificity, though the NPV and sensitivity were 32% and 14%, respectively. These data provide novel mechanistic insights into KI hepatotoxicity and indicate that

  8. Pazopanib for the treatment of soft-tissue sarcoma

    Directory of Open Access Journals (Sweden)

    Heudel P

    2012-10-01

    Full Text Available Pierre Heudel,1 Philippe Cassier,1 Olfa Derbel,1 Armelle Dufresne,1 Pierre Meeus,2 Philippe Thiesse,3 Dominique Ranchère-Vince,4 Jean Yves Blay,1 Isabelle Ray-Coquard1,51Department of Medical Oncology, 2Department of Surgical Oncology, 3Department of Radiology, 4Department of Pathology, Leon Berard Center, Lyon, 5EAM 4128 Sante-Individu-Societe, Lyon University, Lyon, FranceAbstract: Pazopanib is a multikinase inhibitor which potently inhibits the activity of major receptor tyrosine kinases, including vascular endothelial growth factor receptor-1, vascular endothelial growth factor receptor-2, vascular endothelial growth factor receptor-3, platelet-derived growth factor receptor-a, platelet-derived growth factor receptor-a, and c-Kit. Approved by the Food and Drug Administration in 2009 in the United States for the treatment of metastatic renal cell carcinoma, pazopanib has been tested in advanced or metastatic soft-tissue sarcoma. Unlike other tyrosine kinase inhibitors, a statistically significant efficacy in phase II but also in randomized phase III studies has been shown. In comparison with sunitinib or sorafenib, pazopanib has a similar toxicity profile and is generally well tolerated. This review details the development of this new therapeutic class in the treatment of metastatic soft-tissue sarcomas.Keywords: soft-tissue sarcoma, pazopanib, tyrosine kinase inhibitor

  9. Biological abatement of cellulase inhibitors

    Science.gov (United States)

    Bio-abatement uses a fungus to metabolize and remove fermentation inhibitors. To determine whether bio-abatement could alleviate enzyme inhibitor effects observed in biomass liquors after pretreatment, corn stover at 10% (w/v) solids was pretreated with either dilute acid or liquid hot water. The ...

  10. Proteinaceous alpha-araylase inhibitors

    DEFF Research Database (Denmark)

    Svensson, Birte; Fukuda, Kenji; Nielsen, P.K.

    2004-01-01

    -amylase inhibitors belong to seven different protein structural families, most of which also contain evolutionary related proteins without inhibitory activity. Two families include bifunctional inhibitors acting both on alpha-amylases and proteases. High-resolution structures are available of target alpha...

  11. Corrosion inhibitors. Manufacture and technology

    International Nuclear Information System (INIS)

    Ranney, M.W.

    1976-01-01

    Detailed information is presented relating to corrosion inhibitors. Areas covered include: cooling water, boilers and water supply plants; oil well and refinery operations; fuel and lubricant additives for automotive use; hydraulic fluids and machine tool lubes; grease compositions; metal surface treatments and coatings; and general processes for corrosion inhibitors

  12. Regorafenib-associated hand-foot skin reaction: practical advice on diagnosis, prevention, and management.

    Science.gov (United States)

    McLellan, B; Ciardiello, F; Lacouture, M E; Segaert, S; Van Cutsem, E

    2015-10-01

    Regorafenib is an orally available, small-molecule multikinase inhibitor with international marketing authorizations for use in colorectal cancer and gastrointestinal stromal tumors. In clinical trials, regorafenib showed a consistent and predictable adverse-event profile, with hand-foot skin reaction (HFSR) among the most clinically significant toxicities. This review summarizes the clinical characteristics of regorafenib-related HFSR and provides practical advice on HFSR management to enable health care professionals to recognize, pre-empt, and effectively manage the symptoms, thereby allowing patients to remain on active therapy for as long as possible. This review is based on a systematic literature search of the PubMed database (using synonyms of HFSR, regorafenib, and skin toxicities associated with targeted therapies or cytotoxic chemotherapy). However, as this search identified very few articles, the authors also use their clinical experience as oncologists and dermatologists managing patients with treatment-related HFSR to provide recommendations on recognition and management of HFSR in regorafenib-treated patients. Regorafenib-related HFSR is similar to that seen with other multikinase inhibitors (e.g. sorafenib, sunitinib, cabozantinib, axitinib, and pazopanib) but differs from the hand-foot syndrome seen with cytotoxic chemotherapies (e.g. fluoropyrimidines, anthracyclines, and taxanes). There have been no controlled trials of symptomatic management of regorafenib-related HFSR, and limited good-quality evidence from randomized clinical trials of effective interventions for HFSR associated with other targeted therapies. Recommendations on prevention and management of regorafenib-related HFSR in this review are therefore based on the expert opinion of the authors (dermatologists and oncologists with expertise in the management of treatment-related skin toxicities and oncologists involved in clinical trials of regorafenib) and tried-and-tested empirical

  13. Regorafenib-associated hand–foot skin reaction: practical advice on diagnosis, prevention, and management

    Science.gov (United States)

    McLellan, B.; Ciardiello, F.; Lacouture, M. E.; Segaert, S.; Van Cutsem, E.

    2015-01-01

    Background Regorafenib is an orally available, small-molecule multikinase inhibitor with international marketing authorizations for use in colorectal cancer and gastrointestinal stromal tumors. In clinical trials, regorafenib showed a consistent and predictable adverse-event profile, with hand–foot skin reaction (HFSR) among the most clinically significant toxicities. This review summarizes the clinical characteristics of regorafenib-related HFSR and provides practical advice on HFSR management to enable health care professionals to recognize, pre-empt, and effectively manage the symptoms, thereby allowing patients to remain on active therapy for as long as possible. Design This review is based on a systematic literature search of the PubMed database (using synonyms of HFSR, regorafenib, and skin toxicities associated with targeted therapies or cytotoxic chemotherapy). However, as this search identified very few articles, the authors also use their clinical experience as oncologists and dermatologists managing patients with treatment-related HFSR to provide recommendations on recognition and management of HFSR in regorafenib-treated patients. Results Regorafenib-related HFSR is similar to that seen with other multikinase inhibitors (e.g. sorafenib, sunitinib, cabozantinib, axitinib, and pazopanib) but differs from the hand–foot syndrome seen with cytotoxic chemotherapies (e.g. fluoropyrimidines, anthracyclines, and taxanes). There have been no controlled trials of symptomatic management of regorafenib-related HFSR, and limited good-quality evidence from randomized clinical trials of effective interventions for HFSR associated with other targeted therapies. Recommendations on prevention and management of regorafenib-related HFSR in this review are therefore based on the expert opinion of the authors (dermatologists and oncologists with expertise in the management of treatment-related skin toxicities and oncologists involved in clinical trials of regorafenib) and

  14. A pilot study of JI-101, an inhibitor of VEGFR-2, PDGFR-β, and EphB4 receptors, in combination with everolimus and as a single agent in an ovarian cancer expansion cohort.

    Science.gov (United States)

    Werner, Theresa L; Wade, Mark L; Agarwal, Neeraj; Boucher, Kenneth; Patel, Jesal; Luebke, Aaron; Sharma, Sunil

    2015-12-01

    JI-101 is an oral multi-kinase inhibitor that targets vascular endothelial growth factor receptor type 2 (VEGFR-2), platelet derived growth factor receptor β (PDGFR-β), and ephrin type-B receptor 4 (EphB4). None of the currently approved angiogenesis inhibitors have been reported to inhibit EphB4, and therefore, JI-101 has a novel mechanism of action. We conducted a pilot trial to assess the pharmacokinetics (PK), tolerability, and efficacy of JI-101 in combination with everolimus in advanced cancers, and pharmacodynamics (PD), tolerability, and efficacy of JI-101 in ovarian cancer. This was the first clinical study assessing anti-tumor activity of JI-101 in a combinatorial regimen. In the PK cohort, four patients received single agent 10 mg everolimus on day 1, 10 mg everolimus and 200 mg JI-101 combination on day 8, and single agent 200 mg JI-101 on day 15. In the PD cohort, eleven patients received single agent JI-101 at 200 mg twice daily for 28 day treatment cycles. JI-101 was well tolerated as a single agent and in combination with everolimus. No serious adverse events were observed. Common adverse events were hypertension, nausea, and abdominal pain. JI-101 increased exposure of everolimus by approximately 22%, suggestive of drug-drug interaction. The majority of patients had stable disease at their first set of restaging scans (two months), although no patients demonstrated a response to the drug per RECIST criteria. The novel mechanism of action of JI-101 is promising in ovarian cancer treatment and further prospective studies of this agent may be pursued in a less refractory patient population or in combination with cytotoxic chemotherapy.

  15. The FDA approved PI3K inhibitor GDC-0941 enhances in vitro the anti-neoplastic efficacy of Axitinib against c-myc-amplified high-risk medulloblastoma.

    Science.gov (United States)

    Ehrhardt, Michael; Craveiro, Rogerio B; Velz, Julia; Olschewski, Martin; Casati, Anna; Schönberger, Stefan; Pietsch, Torsten; Dilloo, Dagmar

    2018-04-01

    Aberrant receptor kinase signalling and tumour neovascularization are hallmarks of medulloblastoma development and are both considered valuable therapeutic targets. In addition to VEGFR1/2, expression of PDGFR α/β in particular has been documented as characteristic of metastatic disease correlating with poor prognosis. Therefore, we have been suggested that the clinically approved multi-kinase angiogenesis inhibitor Axitinib, which specifically targets these kinases, might constitute a promising option for medulloblastoma treatment. Indeed, our results delineate anti-neoplastic activity of Axitinib in medulloblastoma cell lines modelling the most aggressive c-myc-amplified Non-WNT/Non-SHH and SHH-TP53-mutated tumours. Exposure of medulloblastoma cell lines to Axitinib results in marked inhibition of proliferation and profound induction of cell death. The differential efficacy of Axitinib is in line with target expression of medulloblastoma cells identifying VEGFR 1/2, PDGFR α/β and c-kit as potential markers for drug application. The high specificity of Axitinib and the consequential low impact on the haematopoietic and immune system render this drug ideal multi-modal treatment approaches. In this context, we demonstrate that the clinically available PI3K inhibitor GDC-0941 enhances the anti-neoplastic efficacy of Axitinib against c-myc-amplified medulloblastoma. Our findings provide a rational to further evaluate Axitinib alone and in combination with other therapeutic agents for the treatment of most aggressive medulloblastoma subtypes. © 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  16. Phosphorylation-dependent signaling controls degradation of DNA mismatch repair protein PMS2.

    Science.gov (United States)

    Hinrichsen, Inga; Weßbecher, Isabel M; Huhn, Meik; Passmann, Sandra; Zeuzem, Stefan; Plotz, Guido; Biondi, Ricardo M; Brieger, Angela

    2017-12-01

    MutLα, a heterodimer consisting of MLH1 and PMS2, plays an important role in DNA mismatch repair and has been shown to be additionally involved in several other important cellular mechanisms. Previous work indicated that AKT could modulate PMS2 stability by phosphorylation. Still, the mechanisms of regulation of MutLα remain unclear. The stability of MutLα subunits was investigated by transiently overexpression of wild type and mutant forms of MLH1 and PMS2 using immunoblotting for measuring the protein levels after treatment. We found that treatment with the cell-permeable serine/threonine phosphatase inhibitor, Calyculin, leads to degradation of PMS2 when MLH1 or its C-terminal domain is missing or if amino acids of MLH1 essential for PMS2 interaction are mutated. In addition, we discovered that the C-terminal tail of PMS2 is relevant for this Calyculin-dependent degradation. A direct involvement of AKT, which was previously described to be responsible for PMS2 degradation, could not be detected. The multi-kinase inhibitor Sorafenib, in contrast, was able to avoid the degradation of PMS2 which postulates that cellular phosphorylation is involved in this process. Together, we show that pharmacologically induced phosphorylation by Calyculin can induce the selective proteasome-dependent degradation of PMS2 but not of MLH1 and that the PMS2 degradation could be blocked by Sorafenib treatment. Curiously, the C-terminal Lynch Syndrome-variants MLH1 L749P and MLH1 Y750X make PMS2 prone to Calyculin induced degradation. Therefore, we conclude that the specific degradation of PMS2 may represent a new mechanism to regulate MutLα. © 2017 Wiley Periodicals, Inc.

  17. [ACE inhibitors and the kidney].

    Science.gov (United States)

    Hörl, W H

    1996-01-01

    Treatment with ACE inhibitors results in kidney protection due to reduction of systemic blood pressure, intraglomerular pressure, an antiproliferative effect, reduction of proteinuria and a lipid-lowering effect in proteinuric patients (secondary due to reduction of protein excretion). Elderly patients with diabetes melitus, coronary heart disease or peripheral vascular occlusion are at risk for deterioration of kidney function due to a high frequency of renal artery stenosis in these patients. In patients with renal insufficiency dose reduction of ACE inhibitors is necessary (exception: fosinopril) but more important is the risk for development of hyperkalemia. Patients at risk for renal artery stenosis and patients pretreated with diuretics should receive a low ACE inhibitor dosage initially ("start low - go slow"). For compliance reasons once daily ACE inhibitor dosage is recommended.

  18. Tyrosine kinase inhibitors directed against the vascular endothelial growth factor receptor (VEGFR) have distinct cutaneous toxicity profiles: a meta-analysis and review of the literature.

    Science.gov (United States)

    Massey, Paul R; Okman, Jonathan S; Wilkerson, Julia; Cowen, Edward W

    2015-06-01

    Inhibition of the vascular endothelial growth factor receptor (VEGFR) with tyrosine kinase inhibitors (TKIs) is associated with cutaneous adverse effects that increase patient morbidity. Our objective was to examine the skin toxicity profile of anti-VEGFR TKIs and determine the changing incidence in clinical trials. PubMed was queried for phase II or III trials of anti-VEGFR TKIs between 2000 and 2013 involving ≥50 patients. Adverse events were abstracted, with results presented in both fixed and random effects models. Odds ratios (OR) and 95 % confidence intervals (CIs) were estimated for studies with at least two arms. Across 82 included studies, all grades rash (OR, 2.68; 95 % CI, 2.45-2.94), hand-foot skin reaction (HFSR) (OR, 2.70; 95 % CI, 2.43-3.00), and pruritus (OR, 1.25; 95 % CI, 1.12-1.39) were associated with anti-VEGFR TKIs. Vandetanib had the highest incidence of rash (41 %), while sorafenib was most commonly associated with HFSR (37 %) and pruritus (14 %). The incidence of HFSR from 2000 to 2013 showed an upward trend (r (2) = 0.042, p = 0.10) and in sunitinib therapy increased significantly (r (2) = 0.237, p = 0.04). The incidence of HFSR, rash, and pruritus varies considerably by drug. Our data suggest a continued need to address skin toxicities and improve reporting strategies.

  19. Drosophila Cancer Models Identify Functional Differences between Ret Fusions.

    Science.gov (United States)

    Levinson, Sarah; Cagan, Ross L

    2016-09-13

    We generated and compared Drosophila models of RET fusions CCDC6-RET and NCOA4-RET. Both RET fusions directed cells to migrate, delaminate, and undergo EMT, and both resulted in lethality when broadly expressed. In all phenotypes examined, NCOA4-RET was more severe than CCDC6-RET, mirroring their effects on patients. A functional screen against the Drosophila kinome and a library of cancer drugs found that CCDC6-RET and NCOA4-RET acted through different signaling networks and displayed distinct drug sensitivities. Combining data from the kinome and drug screens identified the WEE1 inhibitor AZD1775 plus the multi-kinase inhibitor sorafenib as a synergistic drug combination that is specific for NCOA4-RET. Our work emphasizes the importance of identifying and tailoring a patient's treatment to their specific RET fusion isoform and identifies a multi-targeted therapy that may prove effective against tumors containing the NCOA4-RET fusion. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  20. Simultaneous inhibition of aberrant cancer kinome using rationally designed polymer-protein core-shell nanomedicine.

    Science.gov (United States)

    Chandran, Parwathy; Gupta, Neha; Retnakumari, Archana Payickattu; Malarvizhi, Giridharan Loghanathan; Keechilat, Pavithran; Nair, Shantikumar; Koyakutty, Manzoor

    2013-11-01

    Simultaneous inhibition of deregulated cancer kinome using rationally designed nanomedicine is an advanced therapeutic approach. Herein, we have developed a polymer-protein core-shell nanomedicine to inhibit critically aberrant pro-survival kinases (mTOR, MAPK and STAT5) in primitive (CD34(+)/CD38(-)) Acute Myeloid Leukemia (AML) cells. The nanomedicine consists of poly-lactide-co-glycolide core (~250 nm) loaded with mTOR inhibitor, everolimus, and albumin shell (~25 nm thick) loaded with MAPK/STAT5 inhibitor, sorafenib and the whole construct was surface conjugated with monoclonal antibody against CD33 receptor overexpressed in AML. Electron microscopy confirmed formation of core-shell nanostructure (~290 nm) and flow cytometry and confocal studies showed enhanced cellular uptake of targeted nanomedicine. Simultaneous inhibition of critical kinases causing synergistic lethality against leukemic cells, without affecting healthy blood cells, was demonstrated using immunoblotting, cytotoxicity and apoptosis assays. This cell receptor plus multi-kinase targeted core-shell nanomedicine was found better specific and tolerable compared to current clinical regime of cytarabine and daunorubicin. These authors demonstrate simultaneous inhibition of critical kinases causing synergistic lethality against leukemic cells, without affecting healthy blood cells by using rationally designed polymer-protein core-shell nanomedicine, provoding an advanced method to eliminate cancer cells, with the hope of future therapeutic use. Copyright © 2013 Elsevier Inc. All rights reserved.

  1. Metal corrosion inhibitors and ecology

    International Nuclear Information System (INIS)

    Krasts, H.; Svarce, J.; Berge, B.

    1999-01-01

    The use of metal corrosion inhibitors in water is one of the cheapest method to protect metals against corrosion. However, the used inhibitors can come to surface water in the course of time and can become as source of environmental pollution. It is important to co-ordinate amount of substances in the elaborated inhibitors not only with demands for metal protection, but also with demands for quality of surface water and drinking water according to normative statements: 3.5 mg/l (as PO 4 ) for hexametaphosphate, tripolyphosphate and phosphonate; 40 mg/l (as SiO 2 for silicate, up to 1 mg/l for CU 2+ ; up to 5 mg/l for Zn 2+ ; up to 1 mg/l for B; up to 0.5 mg/l for Mo 2+ . The examples of the elaborated inhibitors are given. Many organic substances can be used as corrosion inhibitors, but there is shortage of standard methods for their analysis in water in Latvia. Removing of salt's deposits from boilers needs elaboration of a separate normative statement for dispersing waste water which content chloride at high concentration and heavy metals. (authors)

  2. Positron emitter labeled enzyme inhibitors

    International Nuclear Information System (INIS)

    Fowler, J.S.; MacGregor, R.R.; Wolf, A.P.; Langstrom, B.

    1990-01-01

    This invention involves a new strategy for imagining and mapping enzyme activity in the living human and animal body using positron emitter-labeled suicide enzyme inactivators or inhibitors which become covalently bound to the enzyme as a result of enzymatic catalysis. Two such suicide inactivators for monoamine oxidase have been labeled with carbon-11 and used to map the enzyme subtypes in the living human and animal body using PET. By using positron emission tomography to image the distribution of radioactivity produced by the body penetrating radiation emitted by carbon-11, a map of functionally active monoamine oxidase activity is obtained. Clorgyline and L-deprenyl are suicide enzyme inhibitors and irreversibly inhibit monoamine oxidase. When these inhibitors are labeled with carbon-11 they provide selective probes for monoamine oxidase localization and reactivity in vivo using positron emission tomography

  3. ROCK inhibitors in ocular disease

    Directory of Open Access Journals (Sweden)

    Eva Halasz

    2016-12-01

    Full Text Available Rho kinases (ROCKs have a crucial role in actin-cytoskeletal reorganization and thus are involved in broad aspects of cell motility, from smooth muscle contraction to neurite outgrowth. The first marketed ROCK inhibitor, called fasudil, has been used safely for treatment of cerebral vasospasm since 1995 in Japan. During the succeeding decades ROCK inhibitors have been applied in many pathological conditions from central nervous system disorders to cardiovascular disease as potential therapeutic agents or experimental tools to help understand the underlying (pathomechanisms. In 2014, a fasudil derivate named ripasudil was accepted for clinical use in glaucoma and ocular hypertension. Since ROCK kinases are widely expressed in ocular tissues, they have been implicated in the pathology of many ocular conditions such as corneal dysfunction, glaucoma, cataract, diabetic retinopathy, age-related macular degeneration, and retinal detachment. This paper aims to provide an overview of the most recent status/application of ROCK inhibitors in the field of eye disease.

  4. Increased Bowel Toxicity in Patients Treated With a Vascular Endothelial Growth Factor Inhibitor (VEGFI) After Stereotactic Body Radiation Therapy (SBRT)

    Energy Technology Data Exchange (ETDEWEB)

    Barney, Brandon M., E-mail: barney.brandon@mayo.edu [Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (United States); Markovic, Svetomir N. [Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota (United States); Laack, Nadia N.; Miller, Robert C.; Sarkaria, Jann N. [Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (United States); Macdonald, O. Kenneth [Therapeutic Radiologists Incorporated, Kansas City, Kansas (United States); Bauer, Heather J.; Olivier, Kenneth R. [Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (United States)

    2013-09-01

    Purpose: Gastrointestinal injury occurs rarely with agents that affect the vascular endothelial growth factor receptor and with abdominal stereotactic body radiation therapy (SBRT). We explored the incidence of serious bowel injury (SBI) in patients treated with SBRT with or without vascular endothelial growth factor inhibitor (VEGFI) therapy. Methods and Materials: Seventy-six patients with 84 primary or metastatic intra-abdominal lesions underwent SBRT (median dose, 50 Gy in 5 fractions). Of the patients, 20 (26%) received VEGFI within 2 years after SBRT (bevacizumab, n=14; sorafenib, n=4; pazopanib, n=1; sunitinib, n=1). The incidence of SBI (Common Terminology Criteria for Adverse Events, version 4.0, grade 3-5 ulceration or perforation) after SBRT was obtained, and the relationship between SBI and VEGFI was examined. Results: In the combined population, 7 patients (9%) had SBI at a median of 4.6 months (range, 3-17 months) from SBRT. All 7 had received VEGFI before SBI and within 13 months of completing SBRT, and 5 received VEGFI within 3 months of SBRT. The 6-month estimate of SBI in the 26 patients receiving VEGFI within 3 months of SBRT was 38%. No SBIs were noted in the 63 patients not receiving VEGFI. The log–rank test showed a significant correlation between SBI and VEGFI within 3 months of SBRT (P=.0006) but not between SBI and radiation therapy bowel dose (P=.20). Conclusions: The combination of SBRT and VEGFI results in a higher risk of SBI than would be expected with either treatment independently. Local therapies other than SBRT may be considered if a patient is likely to receive a VEGFI in the near future.

  5. Modulation of Regorafenib effects on HCC cell lines by epidermal growth factor.

    Science.gov (United States)

    D'Alessandro, Rosalba; Refolo, Maria Grazia; Lippolis, Catia; Carella, Nicola; Messa, Caterina; Cavallini, Aldo; Carr, Brian Irving

    2015-06-01

    Blood platelet numbers are correlated to growth and aggressiveness of several tumor types, including hepatocellular carcinoma (HCC). We previously found that platelet lysates (hPLs) also stimulated growth and migration, and antagonized the growth-inhibitory and apoptotic effects of both Sorafenib and Regorafenib, two multikinase inhibitors, on three HCC cell lines. In this study, in vitro function of human epidermal growth factor (EGF) with and without Sorafenib or Regorafenib was investigated. An ELISA kit was used to evaluate the EGF concentrations in hPLs. In vitro function of EGF was assessed with proliferation MTT test. Apoptosis assay, scratch assays, and Transwell assays were performed for apoptosis, invasion, and migration, respectively. MAPK Activation Kit was used to explore MAPK phosphorylation. EGF antagonized the growth inhibition of Regorafenib on three HCC cell lines. Regorafenib-mediated growth inhibition was blocked by 70 % when the cells were pre-treated with EGF. EGF also blocked Regorafenib-induced apoptosis, as well as Regorafenib-induced decreases in cell migration and invasion. The EGF effects were in turn antagonized by concomitant addition to the cultures of EGF receptor antagonist Erlotinib, showing that the EGF receptor was involved in the mechanisms of EGF-mediated blocking of Regorafenib effects. Erlotinib also partially blocked the effects of hPLs in antagonizing Regorafenib-mediated growth inhibition, showing that EGF was an important component of hPL actions. All these results show that EGF antagonized Regorafenib-mediated growth and migration inhibition and apoptosis induction in HCC cells and reinforce the idea that microenvironment can influence cancer drug actions.

  6. Azidoblebbistatin, a photoreactive myosin inhibitor

    Science.gov (United States)

    Képiró, Miklós; Várkuti, Boglárka H.; Bodor, Andrea; Hegyi, György; Drahos, László; Kovács, Mihály; Málnási-Csizmadia, András

    2012-01-01

    Photoreactive compounds are important tools in life sciences that allow precisely timed covalent crosslinking of ligands and targets. Using a unique technique we have synthesized azidoblebbistatin, which is a derivative of blebbistatin, the most widely used myosin inhibitor. Without UV irradiation azidoblebbistatin exhibits identical inhibitory properties to those of blebbistatin. Using UV irradiation, azidoblebbistatin can be covalently crosslinked to myosin, which greatly enhances its in vitro and in vivo effectiveness. Photo-crosslinking also eliminates limitations associated with the relatively low myosin affinity and water solubility of blebbistatin. The wavelength used for photo-crosslinking is not toxic for cells and tissues, which confers a great advantage in in vivo tests. Because the crosslink results in an irreversible association of the inhibitor to myosin and the irradiation eliminates the residual activity of unbound inhibitor molecules, azidoblebbistatin has a great potential to become a highly effective tool in both structural studies of actomyosin contractility and the investigation of cellular and physiological functions of myosin II. We used azidoblebbistatin to identify previously unknown low-affinity targets of the inhibitor (EC50 ≥ 50 μM) in Dictyostelium discoideum, while the strongest interactant was found to be myosin II (EC50 = 5 μM). Our results demonstrate that azidoblebbistatin, and potentially other azidated drugs, can become highly useful tools for the identification of strong- and weak-binding cellular targets and the determination of the apparent binding affinities in in vivo conditions. PMID:22647605

  7. Biological abatement of cellulase inhibitors.

    Science.gov (United States)

    Cao, Guangli; Ximenes, Eduardo; Nichols, Nancy N; Zhang, Leyu; Ladisch, Michael

    2013-10-01

    Removal of enzyme inhibitors released during lignocellulose pretreatment is essential for economically feasible biofuel production. We tested bio-abatement to mitigate enzyme inhibitor effects observed in corn stover liquors after pretreatment with either dilute acid or liquid hot water at 10% (w/v) solids. Bio-abatement of liquors was followed by enzymatic hydrolysis of cellulose. To distinguish between inhibitor effects on enzymes and recalcitrance of the substrate, pretreated corn stover solids were removed and replaced with 1% (w/v) Solka Floc. Cellulose conversion in the presence of bio-abated liquors from dilute acid pretreatment was 8.6% (0.1x enzyme) and 16% (1x enzyme) higher than control (non-abated) samples. In the presence of bio-abated liquor from liquid hot water pretreated corn stover, 10% (0.1x enzyme) and 13% (1x enzyme) higher cellulose conversion was obtained compared to control. Bio-abatement yielded improved enzyme hydrolysis in the same range as that obtained using a chemical (overliming) method for mitigating inhibitors. Copyright © 2013 Elsevier Ltd. All rights reserved.

  8. Phosphodiesterase inhibitors in clinical urology.

    Science.gov (United States)

    Ückert, Stefan; Kuczyk, Markus A; Oelke, Matthias

    2013-05-01

    To date, benign diseases of the male and female lower urinary and genital tract, such as erectile dysfunction, bladder overactivity, lower urinary tract symptomatology secondary to benign prostatic hyperplasia and symptoms of female sexual dysfunction (including arousal and orgasmic disorders), can be therapeutically approached by influencing the function of the smooth musculature of the respective tissues. The use of isoenzyme-selective phosphodiesterase (PDE) inhibitors is considered a great opportunity to treat various diseases of the human urogenital tract. PDE inhibitors, in particular the PDE5 (cyclic GMP PDE) inhibitors avanafil, lodenafil, sildenafil, tadalafil, udenafil and vardenafil, are regarded as efficacious, having a fast onset of drug action and an improved effect-to-adverse event ratio, combining a high response rate with the advantage of an on-demand intake. The purpose of this review is to summarize recent as well as potential future indications, namely, erectile dysfunction, Peyronie's disease, overactive bladder, urinary stone disease, lower urinary tract symptomatology secondary to benign prostatic hyperplasia and premature ejaculation, for the use of PDE inhibitors in clinical urology.

  9. Inhibitors of mTOR

    NARCIS (Netherlands)

    Klümpen, Heinz-Josef; Beijnen, Jos H.; Gurney, Howard; Schellens, Jan H. M.

    2010-01-01

    Inhibitors of mammalian target of rapamycin (mTOR) have been approved for the treatment of renal cell carcinoma and appear to have a role in the treatment of other malignancies. The primary objective of this drug review is to provide pharmacokinetic and dynamic properties of the commonly used drugs

  10. Retroviral proteinases and their inhibitors

    Czech Academy of Sciences Publication Activity Database

    Sedláček, Juraj

    2000-01-01

    Roč. 3, 3,4 (2000), s. 23-24 [ Proteolytic enzymes and their inhibitors in physiology and pathogenesis. 14.09.2000, Plzen] Institutional research plan: CEZ:AV0Z5052915 Subject RIV: EB - Genetics ; Molecular Biology

  11. Monoamine depletion by reuptake inhibitors

    Directory of Open Access Journals (Sweden)

    Hinz M

    2011-10-01

    Full Text Available Marty Hinz1, Alvin Stein2, Thomas Uncini31Clinical Research, NeuroResearch Clinics Inc, Cape Coral, FL; 2Stein Orthopedic Associates, Plantation, FL; 3DBS Labs Inc, Duluth, MN, USABackground: Disagreement exists regarding the etiology of cessation of the observed clinical results with administration of reuptake inhibitors. Traditionally, when drug effects wane, it is known as tachyphylaxis. With reuptake inhibitors, the placebo effect is significantly greater than the drug effect in the treatment of depression and attention deficit hyperactivity disorder, leading some to assert that waning of drug effects is placebo relapse, not tachyphylaxis.Methods: Two groups were retrospectively evaluated. Group 1 was composed of subjects with depression and Group 2 was composed of bariatric subjects treated with reuptake inhibitors for appetite suppression.Results: In Group 1, 200 subjects with depression were treated with citalopram 20 mg per day. A total of 46.5% (n = 93 achieved relief of symptoms (Hamilton-D rating score ≤ 7, of whom 37 (39.8% of whom experienced recurrence of depression symptoms, at which point an amino acid precursor formula was started. Within 1–5 days, 97.3% (n = 36 experienced relief of depression symptoms. In Group 2, 220 subjects were treated with phentermine 30 mg in the morning and citalopram 20 mg at 4 pm. In this group, 90.0% (n = 198 achieved adequate appetite suppression. The appetite suppression ceased in all 198 subjects within 4–48 days. Administration of an amino acid precursor formula restored appetite suppression in 98.5% (n = 195 of subjects within 1–5 days.Conclusion: Reuptake inhibitors do not increase the total number of monoamine molecules in the central nervous system. Their mechanism of action facilitates redistribution of monoamines from one place to another. In the process, conditions are induced that facilitate depletion of monoamines. The "reuptake inhibitor monoamine depletion theory" of this paper

  12. Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs)

    Science.gov (United States)

    Serotonin and norepinephrine reuptake inhibitors (SNRIs) Antidepressant SNRIs help relieve depression symptoms, such as irritability and sadness, ... effects they may cause. By Mayo Clinic Staff Serotonin and norepinephrine reuptake inhibitors (SNRIs) are a class ...

  13. Contemporary protease inhibitors and cardiovascular risk

    DEFF Research Database (Denmark)

    Lundgren, Jens; Mocroft, Amanda; Ryom, Lene

    2018-01-01

    PURPOSE OF REVIEW: To review the evidence linking use of HIV protease inhibitors with excess risk of cardiovascular disease (CVD) in HIV+ populations. RECENT FINDINGS: For the two contemporary most frequently used protease inhibitors, darunavir and atazanavir [both pharmacologically boosted...

  14. Reduction rules for reset/inhibitor nets

    NARCIS (Netherlands)

    Verbeek, H.M.W.; Wynn, M.T.; Aalst, van der W.M.P.; Hofstede, ter A.H.M.

    2010-01-01

    Reset/inhibitor nets are Petri nets extended with reset arcs and inhibitor arcs. These extensions can be used to model cancellation and blocking. A reset arc allows a transition to remove all tokens from a certain place when the transition fires. An inhibitor arc can stop a transition from being

  15. Allosteric small-molecule kinase inhibitors

    DEFF Research Database (Denmark)

    Wu, Peng; Clausen, Mads Hartvig; Nielsen, Thomas E.

    2015-01-01

    current barriers of kinase inhibitors, including poor selectivity and emergence of drug resistance. In spite of the small number of identified allosteric inhibitors in comparison with that of inhibitors targeting the ATP pocket, encouraging results, such as the FDA-approval of the first small...

  16. Investigation of the effect of plasma albumin levels on regorafenib-induced hepatotoxicity using a validated liquid chromatography-tandem mass spectrometry method.

    Science.gov (United States)

    Pang, Yi Yun; Tan, Yeong Lan; Ho, Han Kiat

    2017-09-01

    Regorafenib is an oral multikinase inhibitor indicated for metastatic colorectal cancer and gastrointestinal stromal tumour. Due to its extensive plasma protein binding and low calculated hepatic extraction ratio, the hepatotoxicity observed with usage of the drug may be related to its plasma exposure. To investigate the highly dynamic free:bound drug concentration for regorafenib in the plasma, a bioanalytical liquid chromatography-tandem mass spectrometric assay was developed and validated in human plasma. The concentration range of the assay was 2-1000ng/mL. Sample preparation was via protein precipitation using acetonitrile with sorafenib as the internal standard. The supernatant was injected into an ultra-performance liquid chromatographic system coupled to a triple quadrupole mass spectrometer. The analytes were separated on an AQUITY UPLC BEH C 18 column (120Å, 1.7μm, 2.1mm×50mm) and eluted with a gradient elution system. The ions were detected in multiple reaction monitoring mode. The linearity, lower limit of quantification, intra-day and inter-day precision and accuracy conformed to FDA guidelines. The validated method was successfully applied to determine the effect of albumin levels in plasma on the extent of protein binding of regorafenib. The results indicated that physiologically-relevant levels of albumin were found to have no significant effect on the extent of protein binding of regorafenib, hence imposing minimal effect on drug disposition. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Transcatheter Arterial Chemoembolization Based on Hepatic Hemodynamics for Hepatocellular Carcinoma

    Directory of Open Access Journals (Sweden)

    Satoru Murata

    2013-01-01

    Full Text Available Hepatocellular carcinoma (HCC is the sixth most common cancer and the third leading cause of cancer-related deaths in the world. The Barcelona Clinic Liver Cancer (BCLC classification has recently emerged as the standard classification system for clinical management of patients with HCC. According to the BCLC staging system, curative therapies (resection, transplantation, and percutaneous ablation can improve survival in HCC patients diagnosed at an early stage and offer potential long-term curative effects. Patients with intermediate-stage HCC benefit from transcatheter arterial chemoembolization (TACE, and those diagnosed at an advanced stage receive sorafenib, a multikinase inhibitor, or conservative therapy. Most patients receive palliative or conservative therapy only, and approximately 50% of patients with HCC are candidates for systemic therapy. TACE is often recommended for advanced-stage HCC patients all over the world because these patients desire therapy that is more effective than systemic chemotherapy or conservative treatment. This paper aims to summarize both the published data and important ongoing studies for TACE and to discuss technical improvements in TACE for advanced-stage HCC.

  18. Venom from Cuban Blue Scorpion has tumor activating effect in hepatocellular carcinoma.

    Science.gov (United States)

    Giovannini, Catia; Baglioni, Michele; Baron Toaldo, Marco; Cescon, Matteo; Bolondi, Luigi; Gramantieri, Laura

    2017-03-21

    Complementary and alternative medicine (CAM) is the term used to describe many kinds of products, practices, and systems that are not part of conventional medicine. Cancer patients usually do everything they can to combat the disease, manage its symptoms, and cope with the side effects of treatment. Unfortunately, patients who use CAM underestimate the risk of interaction with cancer therapy or worse they omit conventional therapy thus reducing the possibility of cancer remission. Herein we analyzed the effects of Vidatox 30 CH (venom extracted from the Junceus Rhopalurus scorpion) on hepatocellular carcinoma (HCC), the second leading cause of cancer-related deaths. We found out that Vidatox increases HCC proliferation and invasion whereas it does not seem to interact with sorafenib, the orally active multikinase inhibitor approved for the treatment of advanced hepatocellular carcinoma. Our results suggest that the concentration of Vidatox used in the present study has not anti-neoplastic effects and care must be taken in hiring Vidatox in patients with HCC.

  19. Novel Phenotypic Outcomes Identified for a Public Collection of Approved Drugs from a Publicly Accessible Panel of Assays.

    Directory of Open Access Journals (Sweden)

    Jonathan A Lee

    Full Text Available Phenotypic assays have a proven track record for generating leads that become first-in-class therapies. Whole cell assays that inform on a phenotype or mechanism also possess great potential in drug repositioning studies by illuminating new activities for the existing pharmacopeia. The National Center for Advancing Translational Sciences (NCATS pharmaceutical collection (NPC is the largest reported collection of approved small molecule therapeutics that is available for screening in a high-throughput setting. Via a wide-ranging collaborative effort, this library was analyzed in the Open Innovation Drug Discovery (OIDD phenotypic assay modules publicly offered by Lilly. The results of these tests are publically available online at www.ncats.nih.gov/expertise/preclinical/pd2 and via the PubChem Database (https://pubchem.ncbi.nlm.nih.gov/ (AID 1117321. Phenotypic outcomes for numerous drugs were confirmed, including sulfonylureas as insulin secretagogues and the anti-angiogenesis actions of multikinase inhibitors sorafenib, axitinib and pazopanib. Several novel outcomes were also noted including the Wnt potentiating activities of rotenone and the antifolate class of drugs, and the anti-angiogenic activity of cetaben.

  20. Stabilization versus inhibition of TAFIa by competitive inhibitors in vitro

    NARCIS (Netherlands)

    Walker, J.B.; Hughes, B.; James, I.; Haddock, P.; Kluft, C.; Bajzar, L.

    2003-01-01

    Two competitive inhibitors of TAFIa (activated thrombin-activable fibrinolysis inhibitor), 2-guanidinoethyl-mercaptosuccinic acid and potato tuber carboxypeptidase inhibitor, variably affect fibrinolysis of clotted human plasma. Depending on their concentration, the inhibitors shortened, prolonged,

  1. Histone deacetylase inhibitors (HDACIs): multitargeted anticancer agents.

    Science.gov (United States)

    Ververis, Katherine; Hiong, Alison; Karagiannis, Tom C; Licciardi, Paul V

    2013-01-01

    Histone deacetylase (HDAC) inhibitors are an emerging class of therapeutics with potential as anticancer drugs. The rationale for developing HDAC inhibitors (and other chromatin-modifying agents) as anticancer therapies arose from the understanding that in addition to genetic mutations, epigenetic changes such as dysregulation of HDAC enzymes can alter phenotype and gene expression, disturb homeostasis, and contribute to neoplastic growth. The family of HDAC inhibitors is large and diverse. It includes a range of naturally occurring and synthetic compounds that differ in terms of structure, function, and specificity. HDAC inhibitors have multiple cell type-specific effects in vitro and in vivo, such as growth arrest, cell differentiation, and apoptosis in malignant cells. HDAC inhibitors have the potential to be used as monotherapies or in combination with other anticancer therapies. Currently, there are two HDAC inhibitors that have received approval from the US FDA for the treatment of cutaneous T-cell lymphoma: vorinostat (suberoylanilide hydroxamic acid, Zolinza) and depsipeptide (romidepsin, Istodax). More recently, depsipeptide has also gained FDA approval for the treatment of peripheral T-cell lymphoma. Many more clinical trials assessing the effects of various HDAC inhibitors on hematological and solid malignancies are currently being conducted. Despite the proven anticancer effects of particular HDAC inhibitors against certain cancers, many aspects of HDAC enzymes and HDAC inhibitors are still not fully understood. Increasing our understanding of the effects of HDAC inhibitors, their targets and mechanisms of action will be critical for the advancement of these drugs, especially to facilitate the rational design of HDAC inhibitors that are effective as antineoplastic agents. This review will discuss the use of HDAC inhibitors as multitargeted therapies for malignancy. Further, we outline the pharmacology and mechanisms of action of HDAC inhibitors while

  2. Calcineurin-inhibitor pain syndrome.

    Science.gov (United States)

    Prommer, Eric

    2012-07-01

    There has been increased recognition of calcineurin, a phosphoprotein serine/threonine phosphatase enzyme, in the regulation of many physiologic systems. Calcineurin mediates activation of lymphocytes, which play a role in immune response. Widely distributed in the central nervous system, calcinuerin also plays an important role in sensory neural function, via its role in the regulation of newly discovered 2-pore potassium channels, which greatly influence neuronal resting membrane potentials. Calcinuerin inhibition is the mechanism of action of immunomodulatory drugs such as cyclosporine and tacrolimus, which are widely used in transplantation medicine to prevent rejection. While important for immunosuppression, the use of calcineurin inhibitors has been associated with the development of a new pain syndrome called the calcineurin pain syndrome, which appears to be an untoward complication of the interruption of the physiologic function of calcineurin. This is a narrative review focusing on the epidemiology, pathophysiology, characterization of a newly recognized pain syndrome associated with the use of calcineurin inhibitors. The use of immunosuppressants however is associated with several well-known toxicities to which the calcineurin pain syndrome can be added. The development of this syndrome most likely involves altered nociceptive processing due to the effect of calcineurin inhibition on neuronal firing, as well as effects of calcineurin on vascular tone. The most striking aspect of the treatment of this syndrome is the response to calcium channel blockers, which suggest that the effects of calcineurin inhibition on vascular tone play an important role in the development of the calcineurin pain syndrome. The calcineurin syndrome is a newly recognized complication associated with the use of calcineurin inhibitors. There is no standard therapy at this time but anecdotal reports suggest the effectiveness of calcium channel blockers.

  3. Crystallization inhibitors for amorphous oxides

    International Nuclear Information System (INIS)

    Reznitskij, L.A.; Filippova, S.E.

    1993-01-01

    Data for the last 10 years, in which experimental results of studying the temperature stabilization of x-ray amorphous oxides (including R 3 Fe 5 O 12 R-rare earths, ZrO 2 , In 2 O 3 , Sc 2 O 3 ) and their solid solution are presented, are generalized. Processes of amorphous oxide crystallization with the production of simple oxides, solid solutions and chemical compounds with different polyhedral structure, are investigated. Energy and crystallochemical criteria for selecting the doping inhibitor-components stabilizing the amorphous state are ascertained, temperatures and enthalpies of amorpous oxide crystallization are determined, examination of certain provisions of iso,orphous miscibility theory is conducted

  4. Inhibitors of plant hormone transport

    Czech Academy of Sciences Publication Activity Database

    Klíma, Petr; Laňková, Martina; Zažímalová, Eva

    2016-01-01

    Roč. 253, č. 6 (2016), s. 1391-1404 ISSN 0033-183X R&D Projects: GA MŠk(CZ) LD15088 Institutional support: RVO:61389030 Keywords : polar auxin transport * acid-binding protein * gnom arf-gef * equilibrative nucleoside transporter * efflux carrier polarity * plasma-membrane-protein * cultured tobacco cells * arabidopsis-thaliana * gravitropic response * brefeldin-a * Plant hormones * Transport * Inhibitors * Auxin * Cytokinins * Strigolactones * Abscisic acid * Cell biology Subject RIV: ED - Physiology Impact factor: 2.870, year: 2016

  5. Laura: Soybean variety lacking Kunitz trypsin inhibitor

    Directory of Open Access Journals (Sweden)

    Srebrić Mirjana

    2010-01-01

    Full Text Available Grain of conventional soybean varieties requires heat processing to break down trypsin inhibitor's activity before using as food or animal feed. At the same time, protein denaturation and other qualitative changes occur in soybean grain, especially if the temperature of heating is not controlled. Two types of trypsin inhibitor were found in soybean grain the Kunitz trypsin inhibitor and the Bowman-Birk inhibitor. Mature grain of soybean Laura is lacking Kunitz trypsin inhibitor. Grain yield of variety Laura is equal to high yielding varieties from the maturity group I, where it belongs. Lacking of Kunitz-trypsin inhibitor makes soybean grain suitable for direct feeding in adult non ruminant animals without previous thermal processing. Grain of variety Laura can be processed for a shorter period of time than conventional soybeans. This way we save energy, and preserve valuable nutritional composition of soybean grain, which is of interest in industrial processing.

  6. Vanadium Compounds as PTP Inhibitors

    Directory of Open Access Journals (Sweden)

    Elsa Irving

    2017-12-01

    Full Text Available Phosphotyrosine signaling is regulated by the opposing actions of protein tyrosine kinases (PTKs and protein tyrosine phosphatases (PTPs. Here we discuss the potential of vanadium derivatives as PTP enzyme inhibitors and metallotherapeutics. We describe how vanadate in the V oxidized state is thought to inhibit PTPs, thus acting as a pan-inhibitor of this enzyme superfamily. We discuss recent developments in the biological and biochemical actions of more complex vanadium derivatives, including decavanadate and in particular the growing number of oxidovanadium compounds with organic ligands. Pre-clinical studies involving these compounds are discussed in the anti-diabetic and anti-cancer contexts. Although in many cases PTP inhibition has been implicated, it is also clear that many such compounds have further biochemical effects in cells. There also remain concerns surrounding off-target toxicities and long-term use of vanadium compounds in vivo in humans, hindering their progress through clinical trials. Despite these current misgivings, interest in these chemicals continues and many believe they could still have therapeutic potential. If so, we argue that this field would benefit from greater focus on improving the delivery and tissue targeting of vanadium compounds in order to minimize off-target toxicities. This may then harness their full therapeutic potential.

  7. Proton pump inhibitors and osteoporosis

    DEFF Research Database (Denmark)

    Andersen, Bjarne Nesgaard; Johansen, Per Birger; Abrahamsen, Bo

    2016-01-01

    PURPOSE OF REVIEW: The purpose of the review is to provide an update on recent advances in the evidence based on proton pump inhibitors (PPI) as a possible cause of osteoporosis and osteoporotic fractures. This review focuses, in particular, on new studies published in the last 18 months and a di......PURPOSE OF REVIEW: The purpose of the review is to provide an update on recent advances in the evidence based on proton pump inhibitors (PPI) as a possible cause of osteoporosis and osteoporotic fractures. This review focuses, in particular, on new studies published in the last 18 months...... and a discussion of these findings and how this has influenced our understanding of this association, the clinical impact and the underlying pathophysiology. RECENT FINDINGS: New studies have further strengthened existing evidence linking use of PPIs to osteoporosis. Short-term use does not appear to pose a lower...... risk than long-term use. There is a continued lack of conclusive studies identifying the pathogenesis. Direct effects on calcium absorption or on osteoblast or osteoclast action cannot at present plausibly explain the mechanism. SUMMARY: The use of PPIs is a risk factor for development of osteoporosis...

  8. Development of a validated liquid chromatographic method for quantification of sorafenib tosylate in the presence of stress-induced degradation products and in biological matrix employing analytical quality by design approach.

    Science.gov (United States)

    Sharma, Teenu; Khurana, Rajneet Kaur; Jain, Atul; Katare, O P; Singh, Bhupinder

    2018-05-01

    The current research work envisages an analytical quality by design-enabled development of a simple, rapid, sensitive, specific, robust and cost-effective stability-indicating reversed-phase high-performance liquid chromatographic method for determining stress-induced forced-degradation products of sorafenib tosylate (SFN). An Ishikawa fishbone diagram was constructed to embark upon analytical target profile and critical analytical attributes, i.e. peak area, theoretical plates, retention time and peak tailing. Factor screening using Taguchi orthogonal arrays and quality risk assessment studies carried out using failure mode effect analysis aided the selection of critical method parameters, i.e. mobile phase ratio and flow rate potentially affecting the chosen critical analytical attributes. Systematic optimization using response surface methodology of the chosen critical method parameters was carried out employing a two-factor-three-level-13-run, face-centered cubic design. A method operable design region was earmarked providing optimum method performance using numerical and graphical optimization. The optimum method employed a mobile phase composition consisting of acetonitrile and water (containing orthophosphoric acid, pH 4.1) at 65:35 v/v at a flow rate of 0.8 mL/min with UV detection at 265 nm using a C 18 column. Response surface methodology validation studies confirmed good efficiency and sensitivity of the developed method for analysis of SFN in mobile phase as well as in human plasma matrix. The forced degradation studies were conducted under different recommended stress conditions as per ICH Q1A (R2). Mass spectroscopy studies showed that SFN degrades in strongly acidic, alkaline and oxidative hydrolytic conditions at elevated temperature, while the drug was per se found to be photostable. Oxidative hydrolysis using 30% H 2 O 2 showed maximum degradation with products at retention times of 3.35, 3.65, 4.20 and 5.67 min. The absence of any

  9. TYROSINE KINASE INHIBITORS AND PREGNANCY

    Directory of Open Access Journals (Sweden)

    Elisabetta Abruzzese

    2014-04-01

    Full Text Available The management of patients with chronic myeloid leukemia (CML during pregnancy has became recently a matter of continuous debate.  The introduction of the Tyrosine Kinase Inhibitors (TKIs in clinical practice has dramatically changed the prognosis of CML patients.  Patients diagnosed in chronic phase can reasonably expect many years of excellent disease control and good quality of life, as well as a normal life expectancy.  This fact has come the necessity to address issues relating to fertility and pregnancy. Physicians are not infrequently being asked for advice regarding the need for, and or the appropriateness of, stopping treatment in order to conceive. In this report we will review the data published in terms of fertility, conception, pregnancy, pregnancy outcome and illness control for all the approved TKIs, as well as suggest how to manage a planned and/or unplanned pregnancy.

  10. PARP Inhibitors in Ovarian Cancer.

    Science.gov (United States)

    Mittica, Gloria; Ghisoni, Eleonora; Giannone, Gaia; Genta, Sofia; Aglietta, Massimo; Sapino, Anna; Valabrega, Giorgio

    2018-03-05

    Treatment of Epithelial Ovarian Cancer (EOC), historically based on surgery and platinum doublet chemotherapy, is associated with high risk of relapse and poor prognosis for recurrent disease. In this landscape, the innovative treatment with PARP inhibitors (PARPis) demonstrated an outstanding activity in EOC, and is currently changing clinical practice in BRCA mutant patients. To highlight the mechanism of action, pharmacokinetics, clinical activity, indications and current strategies of development of Olaparib, Niraparib, Rucaparib, Talazoparib and Veliparib, the 5 most relevant PARPis. We performed a review on Pubmed using 'ovarian cancer' and the name of each PARPi (PARP inhibitor) discussed in the review as Medical Subject Headings (MeSH) keywords. The same search was performed on "clinicaltrial.gov" to identify ongoing clinical trials and on "google.com/patents" and "uspto.gov" for recent patents exploring PARPIs in ovarian cancer. Olaparib, Niraparib and Rucaparib are already approved for treatment of recurrent EOC and their indications are partially overlapping. Talazoparib and Veliparib are promising PARPis, but currently under investigation in early phase trials. Several studies are evaluating PARPis in monotherapy or in associations, in a wide range of settings (i.e. first line, neoadjuvant, platinum-sensitive and resistant disease). PARPis are valuable options in patients with recurrent ovarian cancer with promising activity in different stages of this disease. Further studies are required to better define optimal clinical settings, predictors of response beyond BRCA mutations and strategies to overcome secondary resistance of PARPis therapy in EOC. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  11. Discovery and SAR of hydantoin TACE inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Wensheng; Guo, Zhuyan; Orth, Peter; Madison, Vincent; Chen, Lei; Dai, Chaoyang; Feltz, Robert J.; Girijavallabhan, Vinay M.; Kim, Seong Heon; Kozlowski, Joseph A.; Lavey, Brian J.; Li, Dansu; Lundell, Daniel; Niu, Xiaoda; Piwinski, John J.; Popovici-Muller, Janeta; Rizvi, Razia; Rosner, Kristin E.; Shankar, Bandarpalle B.; Shih, Neng-Yang; Siddiqui, M.A.; Sun, J.; Tong, L.; Umland, S.; Wong, M.K.; Yang, D.Y.; Zhou, G. (Merck)

    2010-09-03

    We disclose inhibitors of TNF-{alpha} converting enzyme (TACE) designed around a hydantoin zinc binding moiety. Crystal structures of inhibitors bound to TACE revealed monodentate coordination of the hydantoin to the zinc. SAR, X-ray, and modeling designs are described. To our knowledge, these are the first reported X-ray structures of TACE with a hydantoin zinc ligand.

  12. Does plasminogen activator inhibitor-1 drive lymphangiogenesis?

    DEFF Research Database (Denmark)

    Bruyère, Françoise; Melen-Lamalle, Laurence; Blacher, Silvia

    2010-01-01

    The purpose of this study is to explore the function of plasminogen activator inhibitor-1 (PAI-1) during pathological lymphangiogenesis. PAI-1, the main physiological inhibitor of plasminogen activators is involved in pathological angiogenesis at least by controlling extracellular proteolysis and...

  13. Electrochemical Behaviour of Environmentally Friendly Inhibitor of ...

    African Journals Online (AJOL)

    Electrochemical Behaviour of Environmentally Friendly Inhibitor of Aloe Secundiflora Extract in Corrosion Control of Carbon Steel in Soft Water Media. ... The investigation was performed at different inhibitor concentrations under static and dynamic conditions using a Rotating Disk Electrode (RDE). The impedance and ...

  14. Histone deacetylase inhibitors (HDACIs: multitargeted anticancer agents

    Directory of Open Access Journals (Sweden)

    Ververis K

    2013-02-01

    Full Text Available Katherine Ververis,1 Alison Hiong,1 Tom C Karagiannis,1,* Paul V Licciardi2,*1Epigenomic Medicine, Alfred Medical Research and Education Precinct, 2Allergy and Immune Disorders, Murdoch Childrens Research Institute, Melbourne, VIC, Australia*These authors contributed equally to this workAbstract: Histone deacetylase (HDAC inhibitors are an emerging class of therapeutics with potential as anticancer drugs. The rationale for developing HDAC inhibitors (and other chromatin-modifying agents as anticancer therapies arose from the understanding that in addition to genetic mutations, epigenetic changes such as dysregulation of HDAC enzymes can alter phenotype and gene expression, disturb homeostasis, and contribute to neoplastic growth. The family of HDAC inhibitors is large and diverse. It includes a range of naturally occurring and synthetic compounds that differ in terms of structure, function, and specificity. HDAC inhibitors have multiple cell type-specific effects in vitro and in vivo, such as growth arrest, cell differentiation, and apoptosis in malignant cells. HDAC inhibitors have the potential to be used as monotherapies or in combination with other anticancer therapies. Currently, there are two HDAC inhibitors that have received approval from the US FDA for the treatment of cutaneous T-cell lymphoma: vorinostat (suberoylanilide hydroxamic acid, Zolinza and depsipeptide (romidepsin, Istodax. More recently, depsipeptide has also gained FDA approval for the treatment of peripheral T-cell lymphoma. Many more clinical trials assessing the effects of various HDAC inhibitors on hematological and solid malignancies are currently being conducted. Despite the proven anticancer effects of particular HDAC inhibitors against certain cancers, many aspects of HDAC enzymes and HDAC inhibitors are still not fully understood. Increasing our understanding of the effects of HDAC inhibitors, their targets and mechanisms of action will be critical for the

  15. Potential physiological role of plant glycosidase inhibitors

    DEFF Research Database (Denmark)

    Bellincampi, D.; Carmadella, L.; Delcour, J.A.

    2004-01-01

    Carbohydrate-active enzymes including glycosidases, transglycosidases, glycosyltransferases, polysaccharide lyases and carbohydrate esterases are responsible for the enzymatic processing of carbohydrates in plants. A number of carbohydrate-active enzymes are produced by microbial pathogens...... and insects responsible of severe crop losses. Plants have evolved proteinaceous inhibitors to modulate the activity of several of these enzymes. The continuing discovery of new inhibitors indicates that this research area is still unexplored and may lead to new exciting developments. To date, the role...... of the inhibitors is not completely understood. Here we review recent results obtained on the best characterised inhibitors, pointing to their possible biological role in vivo. Results recently obtained with plant transformation technology indicate that this class of inhibitors has potential biotechnological...

  16. The Wonders of Phosphodiesterase‑5 Inhibitors: A Majestic History

    African Journals Online (AJOL)

    A milestone in drug discovery was the selective inhibitors of. PDE‑5 that ... the pharmacotherapeutics of PDE‑5 inhibitors and the majestic history that led to their discovery. ..... including HIV protease inhibitors, ketoconazole, itraconazole,.

  17. Squash inhibitor family of serine proteinases

    International Nuclear Information System (INIS)

    Otlewski, J.; Krowarsch, D.

    1996-01-01

    Squash inhibitors of serine proteinases form an uniform family of small proteins. They are built of 27-33 amino-acid residues and cross-linked with three disulfide bridges. The reactive site peptide bond (P1-P1') is between residue 5 (Lys, Arg or Leu) and 6 (always Ile). High resolution X-ray structures are available for two squash inhibitors complexed with trypsin. NMR solution structures have also been determined for free inhibitors. The major structural motif is a distorted, triple-stranded antiparallel beta-sheet. A similar folding motif has been recently found in a number of proteins, including: conotoxins from fish-hunting snails, carboxypeptidase inhibitor from potato, kalata B1 polypeptide, and in some growth factors (e.g. nerve growth factor, transforming growth factor β2, platelet-derived growth factor). Squash inhibitors are highly stable and rigid proteins. They inhibit a number of serine proteinases: trypsin, plasmin, kallikrein, blood clotting factors: X a and XII a , cathepsin G. The inhibition spectrum can be much broadened if specific amino-acid substitutions are introduced, especially at residues which contact proteinase. Squash inhibitors inhibit proteinases via the standard mechanism. According to the mechanism, inhibitors are substrates which exhibit at neutral pH a high k cat /K m index for hydrolysis and resynthesis of the reactive site, and a low value of the hydrolysis constant. (author)

  18. Histone Deacetylase Inhibitors as Anticancer Drugs.

    Science.gov (United States)

    Eckschlager, Tomas; Plch, Johana; Stiborova, Marie; Hrabeta, Jan

    2017-07-01

    Carcinogenesis cannot be explained only by genetic alterations, but also involves epigenetic processes. Modification of histones by acetylation plays a key role in epigenetic regulation of gene expression and is controlled by the balance between histone deacetylases (HDAC) and histone acetyltransferases (HAT). HDAC inhibitors induce cancer cell cycle arrest, differentiation and cell death, reduce angiogenesis and modulate immune response. Mechanisms of anticancer effects of HDAC inhibitors are not uniform; they may be different and depend on the cancer type, HDAC inhibitors, doses, etc. HDAC inhibitors seem to be promising anti-cancer drugs particularly in the combination with other anti-cancer drugs and/or radiotherapy. HDAC inhibitors vorinostat, romidepsin and belinostat have been approved for some T-cell lymphoma and panobinostat for multiple myeloma. Other HDAC inhibitors are in clinical trials for the treatment of hematological and solid malignancies. The results of such studies are promising but further larger studies are needed. Because of the reversibility of epigenetic changes during cancer development, the potency of epigenetic therapies seems to be of great importance. Here, we summarize the data on different classes of HDAC inhibitors, mechanisms of their actions and discuss novel results of preclinical and clinical studies, including the combination with other therapeutic modalities.

  19. Histone Deacetylase Inhibitors as Anticancer Drugs

    Directory of Open Access Journals (Sweden)

    Tomas Eckschlager

    2017-07-01

    Full Text Available Carcinogenesis cannot be explained only by genetic alterations, but also involves epigenetic processes. Modification of histones by acetylation plays a key role in epigenetic regulation of gene expression and is controlled by the balance between histone deacetylases (HDAC and histone acetyltransferases (HAT. HDAC inhibitors induce cancer cell cycle arrest, differentiation and cell death, reduce angiogenesis and modulate immune response. Mechanisms of anticancer effects of HDAC inhibitors are not uniform; they may be different and depend on the cancer type, HDAC inhibitors, doses, etc. HDAC inhibitors seem to be promising anti-cancer drugs particularly in the combination with other anti-cancer drugs and/or radiotherapy. HDAC inhibitors vorinostat, romidepsin and belinostat have been approved for some T-cell lymphoma and panobinostat for multiple myeloma. Other HDAC inhibitors are in clinical trials for the treatment of hematological and solid malignancies. The results of such studies are promising but further larger studies are needed. Because of the reversibility of epigenetic changes during cancer development, the potency of epigenetic therapies seems to be of great importance. Here, we summarize the data on different classes of HDAC inhibitors, mechanisms of their actions and discuss novel results of preclinical and clinical studies, including the combination with other therapeutic modalities.

  20. Reverse transcriptase inhibitors as microbicides.

    Science.gov (United States)

    Lewi, Paul; Heeres, Jan; Ariën, Kevin; Venkatraj, Muthusamy; Joossens, Jurgen; Van der Veken, Pieter; Augustyns, Koen; Vanham, Guido

    2012-01-01

    The CAPRISA 004 study in South Africa has accelerated the development of vaginal and rectal microbicides containing antiretrovirals that target specific enzymes in the reproduction cycle of HIV, especially reverse transcriptase inhibitors (RTI). In this review we discuss the potential relevance of HIV-1 RTIs as microbicides, focusing in the nucleotide RTI tenofovir and six classes of nonnucleoside RTIs (including dapivirine, UC781, urea and thiourea PETTs, DABOs and a pyrimidinedione). Although tenofovir and dapivirine appear to be most advanced in clinical trials as potential microbicides, several issues remain unresolved, e.g., the importance of nonhuman primates as a "gatekeeper" for clinical trials, the emergence and spread of drug-resistant mutants, the combination of microbicides that target different phases of viral reproduction and the accessibility to microbicides in low-income countries. Thus, here we discuss the latest research on RTI as microbicides in the light of the continuing spread of the HIV pandemic from the point of view of medicinal chemistry, virological, and pharmaceutical studies.

  1. AZT as a telomerase inhibitor

    International Nuclear Information System (INIS)

    Gomez, Daniel E.; Armando, Romina G.; Alonso, Daniel F.

    2012-01-01

    Telomerase is a highly specialized reverse transcriptase (RT) and the maintenance of telomeric length is determined by this specific enzyme. The human holoenzyme telomerase is a ribonucleoprotein composed by a catalytic subunit, hTERT, an RNA component, hTR, and a group of associated proteins. Telomerase is normally expressed in embryonic cells and is repressed during adulthood. The enzyme is reexpressed in around 85% of solid tumors. This observation makes it a potential target for developing drugs that could be developed for therapeutic purposes. The identification of the hTERT as a functional catalytic RT prompted studies of inhibiting telomerase with the HIV RT inhibitor azidothymidine (AZT). Previously, we have demonstrated that AZT binds preferentially to telomeres, inhibits telomerase and enhances tumor cell senescence, and apoptosis after AZT treatment in breast mammary adenocarcinoma cells. Since then, several studies have considered AZT for telomerase inhibition and have led to potential clinical strategies for anticancer therapy. This review covers present thinking of the inhibition of telomerase by AZT and future treatment protocols using the drug.

  2. Proton pump inhibitors and gastroenteritis

    International Nuclear Information System (INIS)

    Hassing, Robert-Jan; Verbon, Annelies; Visser, Herman de; Hofman, Albert; Stricker, Bruno H.

    2016-01-01

    An association between proton pump inhibitor (PPI) therapy and bacterial gastroenteritis has been suggested as well as contradicted. The aim of this study was to examine the association between the use of PPIs and occurrence of bacterial gastroenteritis in the prospective Rotterdam Study. The Rotterdam Study is a population-based cohort study among 14,926 subjects aged 45 years and older with up to 24 years of follow-up. Analyses were performed with a generalized estimating equations method in participants who handed-in a diagnostic stool sample. Furthermore, a nested case–control analysis was performed using the total cohort as a reference group. A bacterial microorganism was isolated in 125 samples, whereas 1174 samples were culture negative. In the generalized estimating equations analysis, we found that participants with a bacterial gastroenteritis were more likely than controls to be current users of PPIs (adjusted OR 1.94; 95 % CI 1.15–3.25). Different sensitivity analyses did not change this result. A considerably higher effect was observed (adjusted OR 6.14; 95 % CI 3.81–9.91), using the total cohort as a reference in a nested case–control analysis. Current PPI therapy is associated with an increased risk of bacterial gastroenteritis. However, by reducing the risk of selection and information bias in our study design, we demonstrated that the effect is lower than previously assumed.

  3. ALK inhibitors, a pharmaceutical perspective

    Directory of Open Access Journals (Sweden)

    Arturo eGalvani

    2012-02-01

    Full Text Available In 2007, the ALK tyrosine kinase, already known to be translocated and activated in Anaplastic Large Cell Lymphoma, and a few other rare cancers, was described as a potential therapeutic target for a subset of non small-cell lung cancer (NSCLC patients. Clinical proof of concept, culminating in the recent approval by the FDA of the Pfizer drug Xalkori (crizotinib, formerly known as PF-02341066 followed in record time. The drug was approved together with a companion diagnostic, the Vysis ALK Break Apart FISH Probe Kit (Abbott Molecular, Inc. for detection of eligible patients. This remarkable example of the coming of age of personalized medicine in cancer therapy is hopefully only an auspice of things to come in this rapidly developing field. Perhaps unsurprisingly, however, the appearance of clinical acquired resistance to crizotinib has already been observed early on in clinical testing, with the identification of several ALK secondary point mutations which diminish drug efficacy, and which open the way for development of second-generation inhibitors. It is also emerging that acquired resistance to crizotinib may also occur through ALK-independent mechanisms, which still need to be elucidated in detail.

  4. SGLT2 Inhibitors May Predispose to Ketoacidosis.

    Science.gov (United States)

    Taylor, Simeon I; Blau, Jenny E; Rother, Kristina I

    2015-08-01

    Sodium glucose cotransporter 2 (SGLT2) inhibitors are antidiabetic drugs that increase urinary excretion of glucose, thereby improving glycemic control and promoting weight loss. Since approval of the first-in-class drug in 2013, data have emerged suggesting that these drugs increase the risk of diabetic ketoacidosis. In May 2015, the Food and Drug Administration issued a warning that SGLT2 inhibitors may lead to ketoacidosis. Using PubMed and Google, we conducted Boolean searches including terms related to ketone bodies or ketoacidosis with terms for SGLT2 inhibitors or phlorizin. Priority was assigned to publications that shed light on molecular mechanisms whereby SGLT2 inhibitors could affect ketone body metabolism. SGLT2 inhibitors trigger multiple mechanisms that could predispose to diabetic ketoacidosis. When SGLT2 inhibitors are combined with insulin, it is often necessary to decrease the insulin dose to avoid hypoglycemia. The lower dose of insulin may be insufficient to suppress lipolysis and ketogenesis. Furthermore, SGLT2 is expressed in pancreatic α-cells, and SGLT2 inhibitors promote glucagon secretion. Finally, phlorizin, a nonselective inhibitor of SGLT family transporters decreases urinary excretion of ketone bodies. A decrease in the renal clearance of ketone bodies could also increase the plasma ketone body levels. Based on the physiology of SGLT2 and the pharmacology of SGLT2 inhibitors, there are several biologically plausible mechanisms whereby this class of drugs has the potential to increase the risk of developing diabetic ketoacidosis. Future research should be directed toward identifying which patients are at greatest risk for this side effect and also to optimizing pharmacotherapy to minimize the risk to patients.

  5. Enzyme structure and interaction with inhibitors

    International Nuclear Information System (INIS)

    London, R.E.

    1983-01-01

    This article reviews some of the results of studies on the 13 C-labeled enzyme dihydrofolate reductase (DHFR). Nuclear magnetic resonance (NMR) techniques are used in combination with isotopic labeling to learn about the structure and dynamics of this enzyme. 13 C-labeling is used for the purpose of studying enzyme/substrate and enzyme/inhibitor interactions. A second set of studies with DHFR was designed to investigate the basis for the high affinity between the inhibitor methotrexate and DHFR. The label was placed on the inhibitor, rather than the enzyme

  6. An Updated Review of Tyrosinase Inhibitors

    Directory of Open Access Journals (Sweden)

    Te-Sheng Chang

    2009-05-01

    Full Text Available Tyrosinase is a multifunctional, glycosylated, and copper-containing oxidase, which catalyzes the first two steps in mammalian melanogenesis and is responsible for enzymatic browning reactions in damaged fruits during post-harvest handling and processing. Neither hyperpigmentation in human skin nor enzymatic browning in fruits are desirable. These phenomena have encouraged researchers to seek new potent tyrosinase inhibitors for use in foods and cosmetics. This article surveys tyrosinase inhibitors newly discovered from natural and synthetic sources. The inhibitory strength is compared with that of a standard inhibitor, kojic acid, and their inhibitory mechanisms are discussed.

  7. Strategies for discontinuation of proton pump inhibitors

    DEFF Research Database (Denmark)

    Haastrup, Peter; Paulsen, Maja S; Begtrup, Luise M

    2014-01-01

    PURPOSE: Proton pump inhibitors (PPIs) are considered to be overprescribed. Consensus on how to attempt discontinuation is, however, lacking. We therefore conducted a systematic review of clinical studies on discontinuation of PPIs. METHODS: Systematic review based on clinical studies investigating...

  8. Predicting the Performance of Organic Corrosion Inhibitors

    Directory of Open Access Journals (Sweden)

    David A. Winkler

    2017-12-01

    Full Text Available The withdrawal of effective but toxic corrosion inhibitors has provided an impetus for the discovery of new, benign organic compounds to fill that role. Concurrently, developments in the high-throughput synthesis of organic compounds, the establishment of large libraries of available chemicals, accelerated corrosion inhibition testing technologies, and the increased capability of machine learning methods have made discovery of new corrosion inhibitors much faster and cheaper than it used to be. We summarize these technical developments in the corrosion inhibition field and describe how data-driven machine learning methods can generate models linking molecular properties to corrosion inhibition that can be used to predict the performance of materials not yet synthesized or tested. We briefly summarize the literature on quantitative structure–property relationships models of small organic molecule corrosion inhibitors. The success of these models provides a paradigm for rapid discovery of novel, effective corrosion inhibitors for a range of metals and alloys in diverse environments.

  9. Novel diamide-based inhibitors of IMPDH.

    Science.gov (United States)

    Gu, Henry H; Iwanowicz, Edwin J; Guo, Junqing; Watterson, Scott H; Shen, Zhongqi; Pitts, William J; Dhar, T G Murali; Fleener, Catherine A; Rouleau, Katherine; Sherbina, N Z; Witmer, Mark; Tredup, Jeffrey; Hollenbaugh, Diane

    2002-05-06

    A series of novel amide-based small molecule inhibitors of inosine monophosphate dehydrogenase is described. The synthesis and the structure-activity relationships (SARs) derived from in vitro studies are presented.

  10. Monoamine Oxidase B Inhibitors in Parkinson's Disease.

    Science.gov (United States)

    Dezsi, Livia; Vecsei, Laszlo

    2017-01-01

    Parkinson's disease (PD) is a neurodegenerative disorder with a prevalence increasing with age. Oxidative stress and glutamate toxicity are involved in its pathomechanism. There are still many unmet needs of PD patients, including the alleviation of motor fluctuations and dyskinesias, and the development of therapies with neuroprotective potential. To give an overview of the pharmacological properties, the efficacy and safety of the monoamine oxidase B (MAO-B) inhibitors in the treatment of PD, with special focus on the results of randomized clinical trials. A literature search was conducted in PubMed for 'PD treatment', 'MAO-B inhibitors', 'selegiline', 'rasagiline', 'safinamide' and 'clinical trials' with 'MAO-B inhibitors' in 'Parkinson' disease'. MAO-B inhibitors have a favorable pharmacokinetic profile, improve the dopamine deficient state and may have neuroprotective properties. Safinamide exhibits an anti-glutamatergic effect as well. When applied as monotherapy, MAO-B inhibitors provide a modest, but significant improvement of motor function and delay the need for levodopa. Rasagiline and safinamide were proven safe and effective when added to a dopamine agonist in early PD. As add-on to levodopa, MAO-B inhibitors significantly reduced off-time and were comparable in efficacy to COMT inhibitors. Improvements were achieved as regards certain non-motor symptoms as well. Due to the efficacy shown in clinical trials and their favorable side-effect profile, MAO-B inhibitors are valuable drugs in the treatment of PD. They are recommended as monotherapy in the early stages of the disease and as add-on therapy to levodopa in advanced PD. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  11. The effect of chemical anti-inhibitors on fibrinolytic enzymes and inhibitors

    DEFF Research Database (Denmark)

    Sidelmann, Johannes Jakobsen; Jespersen, J; Kluft, C

    1997-01-01

    proteases. We studied the influence of chemical anti-inhibitors (chloramine T, flufenamate, sodium lauryl sulfate, and methylamine) on fibrinolytic serine proteases and fibrinolytic enzyme inhibitors using the physiological substrate fibrin as plasmin substrate. Low concentrations of chloramine T (0.01 mmol......%) and plasminogen activators (apparent recovery > 200%). Sodium lauryl sulfate eliminates the major fibrinolytic enzyme inhibitors, but increases the activity of plasmin (apparent recovery > 200%) and plasminogen activator, urokinase type (apparent recovery 130%). Methylamine affects only plasmin inhibition. We...

  12. Development of Radiosensitizer using farnesyltransferase inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Lim, Jong Seok; Choe, Yong Kyung; Han, Mi Young; Kim, Kwang Dong [Korea Research Institute of Bioscience and Biotechnology, Taejon (Korea)

    1999-03-01

    We selected some compounds that were reported to have an activity of farneyltransferase inhibitor and tested the hypothesis that they might be used to radiosensitize cells transformed by ras oncogenes. The inhibition of ras processing using some, but not all, inhibitors resulted in higher levels of cell death after {gamma}-irradiation and increased radiosensitivity in H-ras-transformed NIH3T3 cells and MCF-10A human tumor cells. They did not induce additional cell death in control cells that doe not have ras mutation. Furthermore, the treatment of inhibitors alone induced a weak G0/G1 block, whereas inhibitors in combination with {gamma}-irradiation induced an additional enrichment in the G2/M phase of the cell cycle that typically represents irradiation-induced growth arrest. At present, the underling mechanism by which the farnesylltransferase inhibitors exert radiosensitizing effect is not known. In summary, our results suggest and lead to the possibility that some of farnesylation inhibitors may prove clinically useful not only as antitumor agents, but also radiosensitizers of tumors whose growth is dependent on ras function. (author). 15 refs., 10 figs., 4 tabs.

  13. Natural inhibitors of tumor-associated proteases

    International Nuclear Information System (INIS)

    Magdolen, U.; Krol, J.; Sato, S.; Schmitt, M.; Magdolen, V.; Krueger, A.; Mueller, M.M.; Sperl, S.

    2002-01-01

    The turnover and remodelling of extracellular matrix (ECM) is an essential part of many normal biological processes including development, morphogenesis, and wound healing. ECM turnover also occurs in severe pathological situations like artherosclerosis, fibrosis, tumor invasion and metastasis. The major proteases involved in this turnover are serine proteases (especially the urokinase-type plasminogen activator/plasmin system), matrix metalloproteases (a family of about 20 zinc-dependent endopeptidases including collagenases, gelatinases, stromelysins, and membrane-type metalloproteases), and cysteine proteases. In vivo, the activity of these proteases is tightly regulated in the extracellular space by zymogen activation and/or controlled inhibition. In the present review, we give an overview on the structure and biochemical properties of important tumor-associated protease inhibitors such as plasminogen activator inhibitor type 1 and type 2 (PAI-1, PAI-2), tissue inhibitors of metalloproteinases (TIMP-1, -2, -3, and -4), and the cysteine protease inhibitor cystatin C. Interestingly, some of these inhibitors of tumor-associated proteases display multiple functions which rather promote than inhibit tumor progression, when the presence of inhibitors in the tumor tissue is not balanced. (author)

  14. Emerging Corrosion Inhibitors for Interfacial Coating

    Directory of Open Access Journals (Sweden)

    Mona Taghavikish

    2017-12-01

    Full Text Available Corrosion is a deterioration of a metal due to reaction with environment. The use of corrosion inhibitors is one of the most effective ways of protecting metal surfaces against corrosion. Their effectiveness is related to the chemical composition, their molecular structures and affinities for adsorption on the metal surface. This review focuses on the potential of ionic liquid, polyionic liquid (PIL and graphene as promising corrosion inhibitors in emerging coatings due to their remarkable properties and various embedment or fabrication strategies. The review begins with a precise description of the synthesis, characterization and structure-property-performance relationship of such inhibitors for anti-corrosion coatings. It establishes a platform for the formation of new generation of PIL based coatings and shows that PIL corrosion inhibitors with various heteroatoms in different form can be employed for corrosion protection with higher barrier properties and protection of metal surface. However, such study is still in its infancy and there is significant scope to further develop new structures of PIL based corrosion inhibitors and coatings and study their behaviour in protection of metals. Besides, it is identified that the combination of ionic liquid, PIL and graphene could possibly contribute to the development of the ultimate corrosion inhibitor based coating.

  15. Discovery of natural mouse serum derived HIV-1 entry inhibitor(s).

    Science.gov (United States)

    Wei, M; Chen, Y; Xi, J; Ru, S; Ji, M; Zhang, D; Fang, Q; Tang, B

    Among rationally designed human immunodeficiency virus 1 (HIV-1) inhibitors, diverse natural factors have showed as potent anti-HIV activity in human blood. We have discovered that the boiled supernatant of healthy mouse serum could suppress HIV-1 entry, and exhibited reduced inhibitory activity after trypsin digestion. Further analysis demonstrated that only the fraction containing 10-25 K proteins could inhibit HIV-1 mediated cell-cell fusion. These results suggest that the 10-25 K protein(s) is novel natural HIV-1 entry inhibitor(s). Our findings provide important information about novel natural HIV entry inhibitors in mouse serum.

  16. Inactivation of proteinaceous protease inhibitors of soybeans by isolated fungi

    NARCIS (Netherlands)

    Meijer, M.M.T.; Spekking, W.T.J.; Sijtsma, L.; Bont, de J.A.M.

    1995-01-01

    Proteinaceous protease inhibitors, Kunitz Soybean Trypsin Inhibitor (KSTI) and Bowman Birk Inhibitor (BBI), in legume seeds reduce the digestibility of proteins in feed of monogastric animals. Enzymatic inactivation of these inhibitors will increase the nutritional value of the feed. The aim of this

  17. Combined effects of EGFR tyrosine kinase inhibitors and vATPase inhibitors in NSCLC cells

    Energy Technology Data Exchange (ETDEWEB)

    Jin, Hyeon-Ok [KIRAMS Radiation Biobank, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 139–706 (Korea, Republic of); Hong, Sung-Eun [Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 139–706 (Korea, Republic of); Kim, Chang Soon [Department of Microbiological Engineering, Kon-Kuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 143–701 (Korea, Republic of); Park, Jin-Ah; Kim, Jin-Hee; Kim, Ji-Young; Kim, Bora [KIRAMS Radiation Biobank, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 139–706 (Korea, Republic of); Chang, Yoon Hwan; Hong, Seok-Il; Hong, Young Jun [Department of Laboratory Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 139–706 (Korea, Republic of); Park, In-Chul, E-mail: parkic@kirams.re.kr [Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 139–706 (Korea, Republic of); Lee, Jin Kyung, E-mail: jklee@kirams.re.kr [KIRAMS Radiation Biobank, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 139–706 (Korea, Republic of); Department of Laboratory Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 139–706 (Korea, Republic of)

    2015-08-15

    Despite excellent initial clinical responses of non-small cell lung cancer (NSCLC) patients to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), many patients eventually develop resistance. According to a recent report, vacuolar H + ATPase (vATPase) is overexpressed and is associated with chemotherapy drug resistance in NSCLC. We investigated the combined effects of EGFR TKIs and vATPase inhibitors and their underlying mechanisms in the regulation of NSCLC cell death. We found that combined treatment with EGFR TKIs (erlotinib, gefitinib, or lapatinib) and vATPase inhibitors (bafilomycin A1 or concanamycin A) enhanced synergistic cell death compared to treatments with each drug alone. Treatment with bafilomycin A1 or concanamycin A led to the induction of Bnip3 expression in an Hif-1α dependent manner. Knock-down of Hif-1α or Bnip3 by siRNA further enhanced cell death induced by bafilomycin A1, suggesting that Hif-1α/Bnip3 induction promoted resistance to cell death induced by the vATPase inhibitors. EGFR TKIs suppressed Hif-1α and Bnip3 expression induced by the vATPase inhibitors, suggesting that they enhanced the sensitivity of the cells to these inhibitors by decreasing Hif-1α/Bnip3 expression. Taken together, we conclude that EGFR TKIs enhance the sensitivity of NSCLC cells to vATPase inhibitors by decreasing Hif-1α/Bnip3 expression. We suggest that combined treatment with EGFR TKIs and vATPase inhibitors is potentially effective for the treatment of NSCLC. - Highlights: • Co-treatment with EGFR TKIs and vATPase inhibitors induces synergistic cell death • EGFR TKIs enhance cell sensitivity to vATPase inhibitors via Hif-1α downregulation • Co-treatment of these inhibitors is potentially effective for the treatment of NSCLC.

  18. Screening of protein kinase inhibitors identifies PKC inhibitors as inhibitors of osteoclastic acid secretion and bone resorption

    Directory of Open Access Journals (Sweden)

    Boutin Jean A

    2010-10-01

    Full Text Available Abstract Background Bone resorption is initiated by osteoclastic acidification of the resorption lacunae. This process is mediated by secretion of protons through the V-ATPase and chloride through the chloride antiporter ClC-7. To shed light on the intracellular signalling controlling extracellular acidification, we screened a protein kinase inhibitor library in human osteoclasts. Methods Human osteoclasts were generated from CD14+ monocytes. The effect of different kinase inhibitors on lysosomal acidification in human osteoclasts was investigated using acridine orange for different incubation times (45 minutes, 4 and 24 hours. The inhibitors were tested in an acid influx assay using microsomes isolated from human osteoclasts. Bone resorption by human osteoclasts on bone slices was measured by calcium release. Cell viability was measured using AlamarBlue. Results Of the 51 compounds investigated only few inhibitors were positive in both acidification and resorption assays. Rottlerin, GF109203X, Hypericin and Ro31-8220 inhibited acid influx in microsomes and bone resorption, while Sphingosine and Palmitoyl-DL-carnitine-Cl showed low levels of inhibition. Rottlerin inhibited lysosomal acidification in human osteoclasts potently. Conclusions In conclusion, a group of inhibitors all indicated to inhibit PKC reduced acidification in human osteoclasts, and thereby bone resorption, indicating that acid secretion by osteoclasts may be specifically regulated by PKC in osteoclasts.

  19. SGLT2 Inhibitors and the Diabetic Kidney.

    Science.gov (United States)

    Fioretto, Paola; Zambon, Alberto; Rossato, Marco; Busetto, Luca; Vettor, Roberto

    2016-08-01

    Diabetic nephropathy (DN) is the most common cause of end-stage renal disease worldwide. Blood glucose and blood pressure control reduce the risk of developing this complication; however, once DN is established, it is only possible to slow progression. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, the most recent glucose-lowering oral agents, may have the potential to exert nephroprotection not only through improving glycemic control but also through glucose-independent effects, such as blood pressure-lowering and direct renal effects. It is important to consider, however, that in patients with impaired renal function, given their mode of action, SGLT2 inhibitors are less effective in lowering blood glucose. In patients with high cardiovascular risk, the SGLT2 inhibitor empagliflozin lowered the rate of cardiovascular events, especially cardiovascular death, and substantially reduced important renal outcomes. Such benefits on DN could derive from effects beyond glycemia. Glomerular hyperfiltration is a potential risk factor for DN. In addition to the activation of the renin-angiotensin-aldosterone system, renal tubular factors, including SGLT2, contribute to glomerular hyperfiltration in diabetes. SGLT2 inhibitors reduce sodium reabsorption in the proximal tubule, causing, through tubuloglomerular feedback, afferent arteriole vasoconstriction and reduction in hyperfiltration. Experimental studies showed that SGLT2 inhibitors reduced hyperfiltration and decreased inflammatory and fibrotic responses of proximal tubular cells. SGLT2 inhibitors reduced glomerular hyperfiltration in patients with type 1 diabetes, and in patients with type 2 diabetes, they caused transient acute reductions in glomerular filtration rate, followed by a progressive recovery and stabilization of renal function. Interestingly, recent studies consistently demonstrated a reduction in albuminuria. Although these data are promising, only dedicated renal outcome trials will clarify whether

  20. The treatment landscape in thyroid cancer: a focus on cabozantinib

    Directory of Open Access Journals (Sweden)

    Weitzman SP

    2015-08-01

    Full Text Available Steven P Weitzman, Maria E Cabanillas Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Abstract: Although patients with thyroid cancer generally fare well, there is a subset for which this is not necessarily true. Progress in understanding the molecular aberrations in thyroid cancer has led to a change in the management of these cases. Since 2011, four multikinase inhibitors (MKIs have been approved by the US Food and Drug Administration for thyroid cancer – cabozantinib and vandetanib for medullary thyroid cancer and sorafenib and lenvatinib for differentiated thyroid cancer. This change in the treatment landscape has raised challenges for practitioners who may not be familiar with the use of MKIs or with the treatment and natural history of advanced thyroid cancer in general. This article reviews the epidemiology, molecular drivers, and initial treatment of patients with thyroid cancer and offers practical guidance to assist with the determination of when to appropriately start an MKI. As an example, cabozantinib and its efficacy are discussed in detail. Close monitoring is required for all patients on targeted agents to assess for adverse effects and response to therapy. An approach to managing drug-related adverse events is detailed. Since these drugs are not curative and have not yet proven to prolong overall survival, it is critical to weigh the risks and benefits of treatment at every visit. The potential value of changing to a different agent following failure of an MKI is also addressed. Keywords: chemotherapy, adverse event, targeted therapy, kinase inhibitor, VEGF, RET

  1. Molecular targeted therapies of aggressive thyroid cancer

    Directory of Open Access Journals (Sweden)

    Silvia Martina eFerrari

    2015-11-01

    Full Text Available Differentiated thyroid carcinomas (DTC that arise from follicular cells account > 90% of thyroid cancer (TC [papillary thyroid cancer (PTC 90%, follicular thyroid cancer (FTC 10%], while medullary thyroid cancer (MTC accounts < 5%. Complete total thyroidectomy is the treatment of choice for PTC, FTC and MTC. Radioiodine is routinely recommended in high-risk patients and considered in intermediate risk DTC patients. DTC cancer cells, during tumor progression, may lose the iodide uptake ability, becoming resistant to radioiodine, with a significant worsening of the prognosis. The lack of specific and effective drugs for aggressive and metastatic DTC and MTC leads to additional efforts towards the development of new drugs.Several genetic alterations in different molecular pathways in TC have been shown in the last decades, associated with TC development and progression. Rearranged during transfection (RET/PTC gene rearrangements, RET mutations, BRAF mutations, RAS mutations, and vascular endothelial growth factor receptor 2 angiogenesis pathways are some of the known pathways determinant in the development of TC. Tyrosine kinase inhibitors (TKIs are small organic compounds inhibiting tyrosine kinases auto-phosphorylation and activation, most of them are multikinase inhibitors. TKIs act on the above-mentioned molecular pathways involved in growth, angiogenesis, local and distant spread of TC. TKIs are emerging as new therapies of aggressive TC, including DTC, MTC and anaplastic thyroid cancer (ATC, being capable of inducing clinical responses and stabilization of disease. Vandetanib and cabozantinib have been approved for the treatment of MTC, while sorafenib and lenvatinib for DTC refractory to radioiodine. These drugs prolong median progression-free survival, but until now no significant increase has been observed on overall survival; side effects are common. New efforts are made to find new more effective and safe compounds, and to personalize

  2. Inhibitor chymotrypsynowy nasion wiechliny łąkowej (Poa pratensis [Chymotrypsin inhibitor from Poa pratensis seeds

    Directory of Open Access Journals (Sweden)

    I. Lorenc-Kubis

    2015-01-01

    Full Text Available A chymotrypsin inhibitor was isolated from Poa pratensis seeds. The inhibitor showed also antytriptic activity. It is a termostable protein, soluble in water, sodium chloride, but insoluble in 5% trichloracetic acid and 0.15 M sulphosalicylic acid.

  3. SGLT2 inhibitors: are they safe?

    Science.gov (United States)

    Filippas-Ntekouan, Sebastian; Filippatos, Theodosios D; Elisaf, Moses S

    2018-01-01

    Sodium-glucose linked transporter type 2 (SGLT2) inhibitors are a relatively new class of antidiabetic drugs with positive cardiovascular and kidney effects. The aim of this review is to present the safety issues associated with SGLT2 inhibitors. Urogenital infections are the most frequently encountered adverse events, although tend to be mild to moderate and are easily manageable with standard treatment. Although no increased acute kidney injury risk was evident in the major trials, the mechanism of action of these drugs requires caution when they are administered in patients with extracellular volume depletion or with drugs affecting renal hemodynamics. Canagliflozin raised the risk of amputations and the rate of fractures in the CANVAS trial, although more data are necessary before drawing definite conclusions. The risk of euglycemic diabetic ketoacidosis seems to be minimal when the drugs are prescribed properly. Regarding other adverse events, SGLT2 inhibitors do not increase the risk of hypoglycemia even when co-administered with insulin, but a decrease in the dose of sulphonylureas may be needed. The available data do not point to a causative role of SGLT2 inhibitors on malignancy risk, however, these drugs should be used with caution in patients with known hematuria or history of bladder cancer. SGLT2 inhibitors seem to be safe and effective in the treatment of diabetes but more studies are required to assess their long-term safety.

  4. Aromatase inhibitors and breast cancer prevention.

    Science.gov (United States)

    Litton, Jennifer Keating; Arun, Banu K; Brown, Powel H; Hortobagyi, Gabriel N

    2012-02-01

    Endocrine therapy with selective estrogen receptor modulators (SERMs) has been the mainstay of breast cancer prevention trials to date. The aromatase inhibitors, which inhibit the final chemical conversion of androgens to estrogens, have shown increased disease-free survival benefit over tamoxifen in patients with primary hormone receptor-positive breast cancer, as well as reducing the risk of developing contralateral breast cancers. The aromatase inhibitors are being actively evaluated as prevention agents for women with a history of ductal carcinoma in situ as well as for women who are considered to be at high risk for developing primary invasive breast cancer. This review evaluates the available prevention data, as evidenced by the decrease in contralateral breast cancers, when aromatase inhibitors are used in the adjuvant setting, as well as the emerging data of the aromatase inhibitors specifically tested in the prevention setting for women at high risk. Exemestane is a viable option for breast cancer prevention. We continue to await further follow-up on exemestane as well as other aromatase inhibitors in the prevention setting for women at high risk of developing breast cancer or with a history of ductal carcinoma in situ.

  5. Janus kinase inhibitors: jackpot or potluck?

    Directory of Open Access Journals (Sweden)

    Pavithran Keechilat

    2012-06-01

    Full Text Available The reports of a unique mutation in the Janus kinase-2 gene (JAK2 in polycythemia vera by several independent groups in 2005 quickly spurred the development of the Janus kinase inhibitors. In one of the great victories of translational research in recent times, the first smallmolecule Janus kinase inhibitor ruxolitinib entered a phase I trial in 2007. With the approval of ruxolitinib by the US Federal Drug Administration in November 2011 for high-risk and intermediate-2 risk myelofibrosis, a change in paradigm has occurred in the management of a subset of myeloproliferative neoplasms (MPN: primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. Whereas the current evidence for ruxolitinib only covers high-risk and intermediate-2 risk myelofibrosis, inhibitors with greater potency are likely to offer better disease control and survival advantage in patients belonging to these categories, and possibly to the low-risk and intermediate-1 risk categories of MPN as well. But use of the Janus kinase inhibitors also probably has certain disadvantages, such as toxicity, resistance, withdrawal phenomenon, non-reversal of histology, and an implausible goal of disease clone eradication, some of which could offset the gains. In spite of this, Janus kinase inhibitors are here to stay, and for use in more than just myeloproliferative neoplasms.

  6. A cyclic peptidic serine protease inhibitor

    DEFF Research Database (Denmark)

    Zhao, Baoyu; Xu, Peng; Jiang, Longguang

    2014-01-01

    Peptides are attracting increasing interest as protease inhibitors. Here, we demonstrate a new inhibitory mechanism and a new type of exosite interactions for a phage-displayed peptide library-derived competitive inhibitor, mupain-1 (CPAYSRYLDC), of the serine protease murine urokinase...... pocket, its carbonyl group aligning improperly relative to Ser195 and the oxyanion hole, explaining why the peptide is an inhibitor rather than a substrate. Substitution of the P1 Arg with novel unnatural Arg analogues with aliphatic or aromatic ring structures led to an increased affinity, depending......, in spite of a less favorable binding entropy and loss of a polar interaction. We conclude that increased flexibility of the peptide allows more favorable exosite interactions, which, in combination with the use of novel Arg analogues as P1 residues, can be used to manipulate the affinity and specificity...

  7. SGLT-2 Inhibitors and Cardiovascular Risk

    DEFF Research Database (Denmark)

    Cavender, Matthew A; Norhammar, Anna; Birkeland, Kåre I

    2018-01-01

    BACKGROUND: Prior studies found patients treated with sodium-glucose co-transporter-2 inhibitors (SGLT-2i) had lower rates of death and heart failure (HF). Whether the benefits of SGLT-2i vary based upon the presence of cardiovascular disease (CVD) is unknown. OBJECTIVES: This study sought...... to determine the association between initiation of SGLT-2i therapy and HF or death in patients with and without CVD. METHODS: The CVD-REAL (Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors) study was a multinational, observational study in which adults with type 2 diabetes...... evidence regarding the benefit of SGLT-2i in patients without established CVD. (Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors [CVD-REAL]; NCT02993614)....

  8. New halogenated phenylcoumarins as tyrosinase inhibitors.

    Science.gov (United States)

    Matos, Maria João; Santana, Lourdes; Uriarte, Eugenio; Delogu, Giovanna; Corda, Marcella; Fadda, Maria Benedetta; Era, Benedetta; Fais, Antonella

    2011-06-01

    With the aim to find out structural features for the tyrosinase inhibitory activity, in the present communication we report the synthesis and pharmacological evaluation of a new series of phenylcoumarin derivatives with different number of hydroxyl or ether groups and bromo substituent in the scaffold. The synthesized compounds 5-12 were evaluated as mushroom tyrosinase inhibitors showing, two of them, lower IC(50) than the umbelliferone. Compound 12 (IC(50)=215 μM) is the best tyrosinase inhibitor of this series. Copyright © 2011 Elsevier Ltd. All rights reserved.

  9. Green inhibitors. Rare Earth based systems

    International Nuclear Information System (INIS)

    Aballe, A.; Bethencourt, M.; Botana, F.J.; Perez, J.; Rodriguez, M.A.; Marcos, M.

    1997-01-01

    Lanthanum, Cerium and Samarium chlorides have been investigated as uniform and pitting corrosion inhibitors of AISI 434 and AISI 304 stainless steels and AA 5083 Al-Mg alloy in 3.5% Na Cl aerated aqueous solutions. Their inhibitor power was evaluated by using electrochemical techniques such as Linear and Cyclic Polarisation. In each case, the highest protection degree was found in the solution dropped with 500 ppm of CeCl 3 . Similar results were obtained for additions of 500 ppm of LaCl 3 . Scanning Electron Microscopy and Energy Dispersive Spectroscopy allowed us to confirm the cathodic nature of the inhibition process. (Author) 27 refs

  10. 2-Aminobenzimidazoles as potent Aurora kinase inhibitors.

    Science.gov (United States)

    Zhong, Min; Bui, Minna; Shen, Wang; Baskaran, Subramanian; Allen, Darin A; Elling, Robert A; Flanagan, W Michael; Fung, Amy D; Hanan, Emily J; Harris, Shannon O; Heumann, Stacey A; Hoch, Ute; Ivy, Sheryl N; Jacobs, Jeffrey W; Lam, Stuart; Lee, Heman; McDowell, Robert S; Oslob, Johan D; Purkey, Hans E; Romanowski, Michael J; Silverman, Jeffrey A; Tangonan, Bradley T; Taverna, Pietro; Yang, Wenjin; Yoburn, Josh C; Yu, Chul H; Zimmerman, Kristin M; O'Brien, Tom; Lew, Willard

    2009-09-01

    This Letter describes the discovery and key structure-activity relationship (SAR) of a series of 2-aminobenzimidazoles as potent Aurora kinase inhibitors. 2-Aminobenzimidazole serves as a bioisostere of the biaryl urea residue of SNS-314 (1c), which is a potent Aurora kinase inhibitor and entered clinical testing in patients with solid tumors. Compared to SNS-314, this series of compounds offers better aqueous solubility while retaining comparable in vitro potency in biochemical and cell-based assays; in particular, 6m has also demonstrated a comparable mouse iv PK profile to SNS-314.

  11. Synergistic apoptosis induction in leukemic cells by the phosphatase inhibitor salubrinal and proteasome inhibitors.

    Directory of Open Access Journals (Sweden)

    Hannes C A Drexler

    Full Text Available Cells adapt to endoplasmic reticulum (ER-stress by arresting global protein synthesis while simultaneously activating specific transcription factors and their downstream targets. These processes are mediated in part by the phosphorylation-dependent inactivation of the translation initiation factor eIF2alpha. Following restoration of homeostasis protein synthesis is resumed when the serine/threonine-protein phosphatase PP1 dephosphorylates and reactivates eIF2alpha. Proteasome inhibitors, used to treat multiple myeloma patients evoke ER-stress and apoptosis by blocking the ER-associated degradation of misfolded proteins (ERAD, however, the role of eIF2alpha phosphorylation in leukemic cells under conditions of proteasome inhibitor-mediated ER stress is currently unclear.Bcr-Abl-positive and negative leukemic cell lines were used to investigate the functional implications of PP1-related phosphatase activities on eIF2alpha phosphorylation in proteasome inhibitor-mediated ER stress and apoptosis. Rather unexpectedly, salubrinal, a recently identified PP1 inhibitor capable to protect against ER stress in various model systems, strongly synergized with proteasome inhibitors to augment apoptotic death of different leukemic cell lines. Salubrinal treatment did not affect the phosphorlyation status of eIF2alpha. Furthermore, the proapoptotic effect of salubrinal occurred independently from the chemical nature of the proteasome inhibitor, was recapitulated by a second unrelated phosphatase inhibitor and was unaffected by overexpression of a dominant negative eIF2alpha S51A variant that can not be phosphorylated. Salubrinal further aggravated ER-stress and proteotoxicity inflicted by the proteasome inhibitors on the leukemic cells since characteristic ER stress responses, such as ATF4 and CHOP synthesis, XBP1 splicing, activation of MAP kinases and eventually apoptosis were efficiently abrogated by the translational inhibitor cycloheximide.Although PP1

  12. Structural Characterization of LRRK2 Inhibitors

    NARCIS (Netherlands)

    Gilsbach, Bernd K; Messias, Ana C; Ito, Genta; Sattler, Michael; Alessi, Dario R; Wittinghofer, Alfred; Kortholt, Arjan

    2015-01-01

    Kinase inhibition is considered to be an important therapeutic target for LRRK2 mediated Parkinson's disease (PD). Many LRRK2 kinase inhibitors have been reported but have yet to be optimized in order to qualify as drug candidates for the treatment of the disease. In order to start a

  13. Rational Design of Rho Protein Inhibitors

    National Research Council Canada - National Science Library

    Rojas, Rafael J

    2006-01-01

    ... nucleotide exchange factors (RhoGEFs). We have developed a high throughput screening strategy identify novel inhibitors of Rho activation are currently following up on several compounds which appear to selectively inhibit Rho activation. These compounds may form the basis of future drug development strategies for the treatment of metastatic breast cancer.

  14. Rational Design of Rho Protein Inhibitors

    National Research Council Canada - National Science Library

    Rojas, Rafael J

    2005-01-01

    ... nucleotide exchange factors (RhoGEFs). We have developed a high throughput screening strategy identify novel inhibitors of Rho activation are currently following up on several compounds which appear to selectively inhibit Rho activation. These compounds may form the basis of future drug development strategies for the treatment of metastatic breast cancer.

  15. [Mechanisms and efficacy of SGLT2 inhibitors].

    Science.gov (United States)

    Shiba, Teruo

    2015-03-01

    SGLT2 is a low affinity, high capacity glucose co-transporter, almost exclusively expressed in the kidney cortex. Inhibition of SGLT2 has been shown to increase the daily 50g or more urinary glucose excretion, as compared to placebo, leading to a reduction in blood glucose levels and indicated only for the treatment of type 2 diabetes. In Japan 6 species of SGLT2 inhibitors have already been sold and reported to results in a decrease of FPG by 14.4 to 45.8 (mg/dL), in a reduction of HbA1c by 0.35 to 1.24% and in loss of body weight by 1.29 to 2.50(kg). There is less effect of the SGLT2 inhibitor in diabetic subjects with renal impairment and the reduction in HbA1c and FPG will be approximately half of the average in those with 30 ≤ eGFR ≤ 59. The position of SGLT2 inhibitors would be considered as the drug administered in combination or add-on therapy when the young obese type 2 diabetics without renal impairment has not yet reached to the glycemic target with other drugs although in AACE consensus statement of 2013, it has been shelved for inexperienced use with respect to the positioning of the SGLT2 inhibitors.

  16. Th17 Inhibitors in Active Psoriatic Arthritis

    DEFF Research Database (Denmark)

    Naik, Girish S; Ming, Wai K; Magodoro, Itai M

    2018-01-01

    BACKGROUND: Several biologics targeting the Th17 pathway have been developed for the treatment of psoriatic arthritis (PsA), a disabling disease with moderate response and an increased incidence of serious infections to first-line biologics (TNF-α antagonists). Th17 inhibitors could replace TNF-α...

  17. Vildagliptin: the first innovative DDP-4 inhibitor

    Directory of Open Access Journals (Sweden)

    Edvin Villkhauer

    2010-09-01

    Full Text Available A review of the main stages of investigation undertaken by Novartis Pharmaceuticals in search of a new molecule for the treatment of type 2 diabetesmellitus, dipeptidyl peptidase-4 (DPP-4 inhibitor (Vildaglyptin. The data on specificity and selectivity of the action of this molecule are presentedalong with the results of its comparison with another agent of this group (sitagliptin.

  18. Curcumin derivatives as HIV-1 protease inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Sui, Z.; Li, J.; Craik, C.S.; Ortiz de Montellano, P.R. [Univ. of California, San Francisco, CA (United States)

    1993-12-31

    Curcumin, a non-toxic natural compound from Curcuma longa, has been found to be an HIV-1 protease inhibitor. Some of its derivatives were synthesized and their inhibitory activity against the HIV-1 protease was tested. Curcumin analogues containing boron enhanced the inhibitory activity. At least of the the synthesized compounds irreversibly inhibits the HIV-1 protease.

  19. Dissolution properties of cerium dibutylphosphate corrosion inhibitors

    NARCIS (Netherlands)

    Soestbergen, van M.; Erich, S.J.F.; Huinink, H.P.; Adan, O.C.G.

    2013-01-01

    The corrosion inhibitor cerium dibutylphosphate, Ce(dbp)3, prevents corrosion by cerium and dbp deposition at the alkaline cathode and acidic anode respectively. The pH dependent Ce(dbp)3 solubility seems to play an essential role in the inhibition degree. We found that Ce(dbp)3 scarcely dissolves

  20. SEARCH OF NEW SYNTHETIC INHIBITORS OF TYROSINASE

    Directory of Open Access Journals (Sweden)

    Yu. Shesterenko

    2017-11-01

    Full Text Available Melanin pigmentation of skin plays the most important role in the protection of organism against UV-irradiation, but the excessive accumulation of melanin brings to toxic melanodermia, melasma, lentigo and other skin lesions. Tyrosinase is the key enzyme of skin melanin pigment biosynthesis. In spite of certain progress in investigation of natural and synthetic tyrosinase inhibitors, actuality of such studies is of a high level, because the existing inhibitors are in some cases unstable, expensive, toxic, requires complex methods of synthesis or isolation from natural sources. The aim of the work is screening of new tyrosinase inhibitors, using the enzyme, isolated from Agaricus bisporus. Tyrosinase was isolated from Agaricus bisporus mushrooms by a modified method. It was found, that the introduction of polyethylene glycol 4000 in the extraction process promotes 3-fold reduction of polyphenol content, which leads to increase purity of enzyme with an increase in its activity by 25%. A search for new tyrosinase inhibitors among a wide range of compounds, including derivatives of 3-chloro-1,4-naphthoquinone, isatin, 3-hydroxy-2-naphthoic acid, etc was conducted. The studied substances did not displayed inhibitory effect at concentration of 0,1-0,5 mmol/dm3.

  1. Peptide aldehyde inhibitors of bacterial peptide deformylases.

    Science.gov (United States)

    Durand, D J; Gordon Green, B; O'Connell, J F; Grant, S K

    1999-07-15

    Bacterial peptide deformylases (PDF, EC 3.5.1.27) are metalloenzymes that cleave the N-formyl groups from N-blocked methionine polypeptides. Peptide aldehydes containing a methional or norleucinal inhibited recombinant peptide deformylase from gram-negative Escherichia coli and gram-positive Bacillus subtilis. The most potent inhibitor was calpeptin, N-CBZ-Leu-norleucinal, which was a competitive inhibitor of the zinc-containing metalloenzymes, E. coli and B. subtilis PDF with Ki values of 26.0 and 55.6 microM, respectively. Cobalt-substituted E. coli and B. subtilis deformylases were also inhibited by these aldehydes with Ki values for calpeptin of 9.5 and 12.4 microM, respectively. Distinct spectral changes were observed upon binding of calpeptin to the Co(II)-deformylases, consistent with the noncovalent binding of the inhibitor rather than the formation of a covalent complex. In contrast, the chelator 1,10-phenanthroline caused the time-dependent inhibition of B. subtilis Co(II)-PDF activity with the loss of the active site metal. The fact that calpeptin was nearly equipotent against deformylases from both gram-negative and gram-positive bacterial sources lends further support to the idea that a single deformylase inhibitor might have broad-spectrum antibacterial activity. Copyright 1999 Academic Press.

  2. Immune checkpoint inhibitors for metastatic bladder cancer.

    Science.gov (United States)

    Massari, Francesco; Di Nunno, Vincenzo; Cubelli, Marta; Santoni, Matteo; Fiorentino, Michelangelo; Montironi, Rodolfo; Cheng, Liang; Lopez-Beltran, Anto; Battelli, Nicola; Ardizzoni, Andrea

    2018-03-01

    Chemotherapy has represented the standard therapy for unresectable or metastatic urothelial carcinoma for more than 20 years. The growing knowledge of the interaction between tumour and immune system has led to the advent of new classes of drugs, the immune-checkpoints inhibitors, which are intended to change the current scenario. To date, immunotherapy is able to improve the overall responses and survival. Moreover, thanks to its safety profile immune-checkpoint inhibitors could be proposed also to patients unfit for standard chemotherapy. No doubts that these agents have started a revolution expected for years, but despite this encouraging results it appears clear that not all subjects respond to these agents and requiring the development of reliable predictive response factors able to isolate patients who can more benefit from these treatments as well as new strategies aimed to improve immunotherapy clinical outcome. In this review we describe the active or ongoing clinical trials involving Programmed Death Ligand 1 (PD-L1), Programmed Death receptor 1 (PD-1) and Cytotoxic-T Lymphocyte Antigen 4 (CTLA 4) inhibitors in urothelial carcinoma focusing our attention on the developing new immune-agents and combination strategies with immune-checkpoint inhibitors. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. Current and Novel Inhibitors of HIV Protease

    Czech Academy of Sciences Publication Activity Database

    Pokorná, Jana; Machala, L.; Řezáčová, Pavlína; Konvalinka, Jan

    2009-01-01

    Roč. 1, č. 3 (2009), s. 1209-1239 ISSN 1999-4915 R&D Projects: GA MŠk 1M0508 Grant - others:GA AV ČR(CZ) IAAX00320901 Program:IA Institutional research plan: CEZ:AV0Z40550506 Keywords : HIV protease * protease inhibitor * HAART Subject RIV: CE - Biochemistry

  4. Proton pump inhibitors affect the gut microbiome

    NARCIS (Netherlands)

    Imhann, Floris; Bonder, Marc Jan; Vich Vila, Arnau; Fu, Jingyuan; Mujagic, Zlatan; Vork, Lisa; Feenstra, Ettje T.; Jankipersadsing, Soesma A; Cenit, Maria Carmen; Harmsen, Hermie J M; Dijkstra, Gerard; Franke, Lude; Xavier, Ramnik J; Jonkers, Daisy; Wijmenga, Cisca; Weersma, Rinse K; Zhernakova, Alexandra

    BACKGROUND AND AIMS: Proton pump inhibitors (PPIs) are among the top 10 most widely used drugs in the world. PPI use has been associated with an increased risk of enteric infections, most notably Clostridium difficile. The gut microbiome plays an important role in enteric infections, by resisting or

  5. Pharmacological caspase inhibitors: Research towards therapeutic perspectives

    Czech Academy of Sciences Publication Activity Database

    Kudělová, J.; Fleischmannová, J.; Adamová, E.; Matalová, Eva

    2015-01-01

    Roč. 66, č. 4 (2015), s. 473-482 ISSN 0867-5910 R&D Projects: GA ČR(CZ) GA14-28254S Institutional support: RVO:68081715 Keywords : caspase * caspase inhibitor * apoptosis Subject RIV: CB - Analytical Chemistry, Separation Impact factor: 2.804, year: 2015

  6. Pharmacological caspase inhibitors: Research towards therapeutic perspectives

    Czech Academy of Sciences Publication Activity Database

    Kudělová, J.; Fleischmannová, Jana; Adamová, Eva; Matalová, Eva

    2015-01-01

    Roč. 66, č. 4 (2015), s. 473-482 ISSN 0867-5910 R&D Projects: GA ČR GB14-37368G Institutional support: RVO:67985904 Keywords : caspase * caspase inhibitor * apoptosis Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.804, year: 2015

  7. Discovery of inhibitors of bacterial histidine kinases

    NARCIS (Netherlands)

    Velikova, N.R.

    2014-01-01

    Discovery of Inhibitors of Bacterial Histidine Kinases Summary

    The thesis is on novel antibacterial drug discovery (http://youtu.be/NRMWOGgeysM). Using structure-based and fragment-based drug discovery approach, we have identified small-molecule histidine-kinase

  8. Novel peptide-based protease inhibitors

    DEFF Research Database (Denmark)

    Roodbeen, Renée

    of novel peptide-based protease inhibitors, efforts were made towards improved methods for peptide synthesis. The coupling of Fmoc-amino acids onto N-methylated peptidyl resins was investigated. These couplings can be low yielding and the effect of the use of microwave heating combined with the coupling...

  9. Oestrogen, testosterone, cytotoxin and cholinesterase inhibitor ...

    African Journals Online (AJOL)

    Oestrogen, testosterone, cytotoxin and cholinesterase inhibitor removal during reclamation of sewage to drinking water. ... Risks associated with sewage effluent and reclaimed sewage should be closely monitored; therefore water at the Gammams Sewage Treatment Plant (GSTP) inlet and outlet, as well as reclaimed water ...

  10. Dry eye syndrome in aromatase inhibitor users.

    Science.gov (United States)

    Turaka, Kiran; Nottage, Jennifer M; Hammersmith, Kristin M; Nagra, Parveen K; Rapuano, Christopher J

    2013-04-01

    Aromatase inhibitors are frequently used as an adjuvant therapy in the treatment of breast cancer. We observed that several patients taking aromatase inhibitors presented with severe dry eye symptoms, and we investigated whether there is a relationship between aromatase inhibitors and dry eyes in these patients. Retrospective chart review. Forty-one women. A computerized search of health records was performed to identify patients using anastrazole, letrozole and exemestane seen by the Cornea Service from August 2008 to March 2011. The results were compared with age-matched controls. Ocular surface changes among aromatase inhibitors users. Of the 41 women, 39 were Caucasians. Thirty-nine patients had breast cancer (95%), one patient had ovarian cancer (2.5%) and one had an unknown primary cancer. Mean age was 68 ± 11.3 years (range 47-95). Most common presenting symptoms were blurred vision in 28 (68%) patients, irritation/foreign body sensation in 12 (29%) patients, redness in 9 (22%) patients, tearing in 6 (22%) patients and photosensitivity in 2 (5%) patients. Mean Schirmer's test measurement was 11 ± 5.8 mm (range 0.5-20 mm). Blepharitis was noted in 68 of 82 eyes (73%), decreased or poor tear function in 24 eyes (29%), conjunctival injection in 18 eyes (22%) and superficial punctate keratitis in 12 eyes (29%). Among an age-matched population (45-95 years), dry eye syndrome was found in only 9.5% of patients. Because the prevalence of ocular surface disease signs and symptoms appears to be higher in study group than control patients, aromatase inhibitors might be a contributing factor to the dry eye symptoms. © 2012 The Authors. Clinical and Experimental Ophthalmology © 2012 Royal Australian and New Zealand College of Ophthalmologists.

  11. RENAL SAFETY OF PROTON PUMP INHIBITORS

    Directory of Open Access Journals (Sweden)

    A. I. Dyadyk

    2017-01-01

    Full Text Available Proton pump inhibitors are a widely used in clinical practice, and are taken by millions of patients around the world for a long time. While proton pump inhibitors are well-tolerated class of drugs, the number of publications has been raised about adverse renal effects, specially their association with acute tubulointerstitial nephritis. It is one of the leading causes of acute renal injury and have catastrophic long-term consequences called chronic kidney disease. In this review, we consider epidemiology, pathogenesis, diagnostic criteria (including biopsy and morphological pattern, clinical manifestations and treatment of proton pump inhibitors-induced acute tubulointerstitial nephritis. A subclinical course without classical manifestations of a cell-mediated hypersensitivity reaction (fever, skin rash, eosinophilia, arthralgia is characteristic of acute tubulointerstitial nephritis. Increased serum creatinine, decreased glomerular filtration rate, electrolyte disorders, pathological changes in urine tests are not highly specific indicators, but allow to suspect the development of acute tubulointerstitial nephritis. The “gold” standard of diagnosis is the intravital morphological examination of the kidney tissue. Timely diagnosis and immediate discontinuation of the potentially causative drug is the mainstay of therapy and the first necessary step in the early management of suspected or biopsy-proven drug-induced acute tubulointerstitial nephritis. The usage of proton pump inhibitors should be performed only on strict indications with optimal duration of treatment and careful monitoring of kidney function. Multiple comorbidities (older age, heart failure, diabetes, cirrhosis, chronic kidney disease, hypovolemia increase potential nephrotoxicity. Awareness of this iatrogenic complication will improve diagnosis of proton pump inhibitors-induced acute tubulointerstitial nephritis by multidisciplinary specialists and increase the possibility

  12. Cost of care of haemophilia with inhibitors.

    Science.gov (United States)

    Di Minno, M N D; Di Minno, G; Di Capua, M; Cerbone, A M; Coppola, A

    2010-01-01

    In Western countries, the treatment of patients with inhibitors is presently the most challenging and serious issue in haemophilia management, direct costs of clotting factor concentrates accounting for >98% of the highest economic burden absorbed for the healthcare of patients in this setting. Being designed to address questions of resource allocation and effectiveness, decision models are the golden standard to reliably assess the overall economic implications of haemophilia with inhibitors in terms of mortality, bleeding-related morbidity, and severity of arthropathy. However, presently, most data analyses stem from retrospective short-term evaluations, that only allow for the analysis of direct health costs. In the setting of chronic diseases, the cost-utility analysis, that takes into account the beneficial effects of a given treatment/healthcare intervention in terms of health-related quality of life, is likely to be the most appropriate approach. To calculate net benefits, the quality adjusted life year, that significantly reflects such health gain, has to be compared with specific economic impacts. Differences in data sources, in medical practice and/or in healthcare systems and costs, imply that most current pharmacoeconomic analyses are confined to a narrow healthcare payer perspective. Long-term/lifetime prospective or observational studies, devoted to a careful definition of when to start a treatment; of regimens (dose and type of product) to employ, and of inhibitor population (children/adults, low-responding/high responding inhibitors) to study, are thus urgently needed to allow for newer insights, based on reliable data sources into resource allocation, effectiveness and cost-utility analysis in the treatment of haemophiliacs with inhibitors.

  13. ROS inhibitor N-acetyl-L-cysteine antagonizes the activity of proteasome inhibitors.

    Science.gov (United States)

    Halasi, Marianna; Wang, Ming; Chavan, Tanmay S; Gaponenko, Vadim; Hay, Nissim; Gartel, Andrei L

    2013-09-01

    NAC (N-acetyl-L-cysteine) is commonly used to identify and test ROS (reactive oxygen species) inducers, and to inhibit ROS. In the present study, we identified inhibition of proteasome inhibitors as a novel activity of NAC. Both NAC and catalase, another known scavenger of ROS, similarly inhibited ROS levels and apoptosis associated with H₂O₂. However, only NAC, and not catalase or another ROS scavenger Trolox, was able to prevent effects linked to proteasome inhibition, such as protein stabilization, apoptosis and accumulation of ubiquitin conjugates. These observations suggest that NAC has a dual activity as an inhibitor of ROS and proteasome inhibitors. Recently, NAC was used as a ROS inhibitor to functionally characterize a novel anticancer compound, piperlongumine, leading to its description as a ROS inducer. In contrast, our own experiments showed that this compound depicts features of proteasome inhibitors including suppression of FOXM1 (Forkhead box protein M1), stabilization of cellular proteins, induction of ROS-independent apoptosis and enhanced accumulation of ubiquitin conjugates. In addition, NAC, but not catalase or Trolox, interfered with the activity of piperlongumine, further supporting that piperlongumine is a proteasome inhibitor. Most importantly, we showed that NAC, but not other ROS scavengers, directly binds to proteasome inhibitors. To our knowledge, NAC is the first known compound that directly interacts with and antagonizes the activity of proteasome inhibitors. Taken together, the findings of the present study suggest that, as a result of the dual nature of NAC, data interpretation might not be straightforward when NAC is utilized as an antioxidant to demonstrate ROS involvement in drug-induced apoptosis.

  14. Cytogenetic study of Ascaris trypsin inhibitor in cultured human ...

    Indian Academy of Sciences (India)

    2009-04-01

    Apr 1, 2009 ... Although the physical and chemical properties of Ascaris trypsin inhibitors ... male of Ascaris suum according to the method of Pudles and. Rola (1967). ..... inhibitor isolated from Ascaris resulted in the appearance of dominant ...

  15. SGLT2 inhibitors: molecular design and potential differences in effect.

    Science.gov (United States)

    Isaji, Masayuki

    2011-03-01

    The physiological and pathological handling of glucose via sodium-glucose cotransporter-2 (SGLT2) in the kidneys has been evolving, and SGLT2 inhibitors have been focused upon as a novel drug for treating diabetes. SGLT2 inhibitors enhance renal glucose excretion by inhibiting renal glucose reabsorption. Consequently, SGLT2 inhibitors reduce plasma glucose insulin independently and improve insulin resistance in diabetes. To date, various SGLT2 inhibitors have been developed and evaluated in clinical studies. The potency and positioning of SGLT2 inhibitors as an antidiabetic drug are dependent on their characteristic profile, which induces selectivity, efficacy, pharmacokinetics, and safety. This profile decides which SGLT2 inhibitors can be expected for application of the theoretical concept of reducing renal glucose reabsorption for the treatment of diabetes. I review the structure and advancing profile of various SGLT2 inhibitors, comparing their similarities and differences, and discuss the expected SGLT2 inhibitors for an emerging category of antidiabetic drugs.

  16. Environmental life cycle analysis of potato sprout inhibitors

    NARCIS (Netherlands)

    Kerstholt, R.P.V.; Ree, C.M.; Moll, H.C.

    Potato sprout inhibitors are generally applied to suppress sprouting during winter storage. This study presents the compared environmental profiles of the two sprout inhibitors available on the Dutch market: A traditional chemical product with isopropyl-3-chlorophenylcarbamate (CIPC) and

  17. [Inhibitors of proteolytic enzymes under abiotic stresses in plants (review)].

    Science.gov (United States)

    Mosolov, V V; Valueva, T A

    2011-01-01

    Data on the role of proteolytic enzyme inhibitors in plant adaptation to various unfavorable environmental abiotic factors--water deficiency, salinization of soil, extreme temperatures, etc.--and also probable functions of proteinases inhibitors in natural plant senescense are considered.

  18. Levels of circulating CD45dimCD34+VEGFR2+ progenitor cells correlate with outcome in metastatic renal cell carcinoma patients treated with tyrosine kinase inhibitors

    Science.gov (United States)

    Farace, F; Gross-Goupil, M; Tournay, E; Taylor, M; Vimond, N; Jacques, N; Billiot, F; Mauguen, A; Hill, C; Escudier, B

    2011-01-01

    Background: Predicting the efficacy of antiangiogenic therapy would be of clinical value in patients (pts) with metastatic renal cell carcinoma (mRCC). We tested the hypothesis that circulating endothelial cell (CEC), bone marrow-derived CD45dimCD34+VEGFR2+ progenitor cell or plasma angiogenic factor levels are associated with clinical outcome in mRCC pts undergoing treatment with tyrosine kinase inhibitors (TKI). Methods: Fifty-five mRCC pts were prospectively monitored at baseline (day 1) and day 14 during treatment (46 pts received sunitinib and 9 pts received sorafenib). Circulating endothelial cells (CD45−CD31+CD146+7-amino-actinomycin (7AAD)− cells) were measured in 1 ml whole blood using four-color flow cytometry (FCM). Circulating CD45dimCD34+VEGFR2+7AAD− progenitor cells were measured in progenitor-enriched fractions by four-color FCM. Plasma VEGF, sVEGFR2, SDF-1α and sVCAM-1 levels were determined by ELISA. Correlations between baseline CEC, CD45dimCD34+VEGFR2+7AAD− progenitor cells, plasma factors, as well as day 1–day 14 changes in CEC, CD45dimCD34+VEGFR2+7AAD− progenitor, plasma factor levels, and response to TKI, progression-free survival (PFS) and overall survival (OS) were examined. Results: No significant correlation between markers and response to TKI was observed. No association between baseline CEC, plasma VEGF, sVEGFR-2, SDF-1α, sVCAM-1 levels with PFS and OS was observed. However, baseline CD45dimCD34+VEGFR2+7AAD− progenitor cell levels were associated with PFS (P=0.01) and OS (P=0.006). Changes in this population and in SDF-1α levels between day 1 and day 14 were associated with PFS (P=0.03, P=0.002). Changes in VEGF and SDF-1α levels were associated with OS (P=0.02, P=0.007). Conclusion: Monitoring CD45dimCD34+VEGFR2+ progenitor cells, plasma VEGF and SDF-1α levels could be of clinical interest in TKI-treated mRCC pts to predict outcome. PMID:21386843

  19. Cellular growth kinetics distinguish a cyclophilin inhibitor from an HSP90 inhibitor as a selective inhibitor of hepatitis C virus.

    Directory of Open Access Journals (Sweden)

    Rudolf K F Beran

    Full Text Available During antiviral drug discovery, it is critical to distinguish molecules that selectively interrupt viral replication from those that reduce virus replication by adversely affecting host cell viability. In this report we investigate the selectivity of inhibitors of the host chaperone proteins cyclophilin A (CypA and heat-shock protein 90 (HSP90 which have each been reported to inhibit replication of hepatitis C virus (HCV. By comparing the toxicity of the HSP90 inhibitor, 17-(Allylamino-17-demethoxygeldanamycin (17-AAG to two known cytostatic compounds, colchicine and gemcitabine, we provide evidence that 17-AAG exerts its antiviral effects indirectly through slowing cell growth. In contrast, a cyclophilin inhibitor, cyclosporin A (CsA, exhibited selective antiviral activity without slowing cell proliferation. Furthermore, we observed that 17-AAG had little antiviral effect in a non-dividing cell-culture model of HCV replication, while CsA reduced HCV titer by more than two orders of magnitude in the same model. The assays we describe here are useful for discriminating selective antivirals from compounds that indirectly affect virus replication by reducing host cell viability or slowing cell growth.

  20. SGLT2 Inhibitors: Benefit/Risk Balance.

    Science.gov (United States)

    Scheen, André J

    2016-10-01

    Inhibitors of sodium-glucose cotransporters type 2 (SGLT2) reduce hyperglycemia by increasing urinary glucose excretion. They have been evaluated in patients with type 2 diabetes treated with diet/exercise, metformin, dual oral therapy or insulin. Three agents are available in Europe and the USA (canagliflozin, dapagliflozin, empagliflozin) and others are commercialized in Japan or in clinical development. SGLT2 inhibitors reduce glycated hemoglobin, with a minimal risk of hypoglycemia. They exert favorable effects beyond glucose control with consistent body weight, blood pressure, and serum uric acid reductions. Empagliflozin showed remarkable reductions in cardiovascular/all-cause mortality and in hospitalization for heart failure in patients with previous cardiovascular disease. Positive renal outcomes were also shown with empagliflozin. Mostly reported adverse events are genital mycotic infections, while urinary tract infections and events linked to volume depletion are rather rare. Concern about a risk of ketoacidosis and bone fractures has been recently raised, which deserves caution and further evaluation.

  1. Serine protease inhibitors of parasitic helminths.

    Science.gov (United States)

    Molehin, Adebayo J; Gobert, Geoffrey N; McManus, Donald P

    2012-05-01

    Serine protease inhibitors (serpins) are a superfamily of structurally conserved proteins that inhibit serine proteases and play key physiological roles in numerous biological systems such as blood coagulation, complement activation and inflammation. A number of serpins have now been identified in parasitic helminths with putative involvement in immune regulation and in parasite survival through interference with the host immune response. This review describes the serpins and smapins (small serine protease inhibitors) that have been identified in Ascaris spp., Brugia malayi, Ancylostoma caninum Onchocerca volvulus, Haemonchus contortus, Trichinella spiralis, Trichostrongylus vitrinus, Anisakis simplex, Trichuris suis, Schistosoma spp., Clonorchis sinensis, Paragonimus westermani and Echinococcus spp. and discusses their possible biological functions, including roles in host-parasite interplay and their evolutionary relationships.

  2. Secreted and Transmembrane Wnt Inhibitors and Activators

    Science.gov (United States)

    Cruciat, Cristina-Maria; Niehrs, Christof

    2013-01-01

    Signaling by the Wnt family of secreted glycoproteins plays important roles in embryonic development and adult homeostasis. Wnt signaling is modulated by a number of evolutionarily conserved inhibitors and activators. Wnt inhibitors belong to small protein families, including sFRP, Dkk, WIF, Wise/SOST, Cerberus, IGFBP, Shisa, Waif1, APCDD1, and Tiki1. Their common feature is to antagonize Wnt signaling by preventing ligand–receptor interactions or Wnt receptor maturation. Conversely, the Wnt activators, R-spondin and Norrin, promote Wnt signaling by binding to Wnt receptors or releasing a Wnt-inhibitory step. With few exceptions, these antagonists and agonists are not pure Wnt modulators, but also affect additional signaling pathways, such as TGF-β and FGF signaling. Here we discuss their interactions with Wnt ligands and Wnt receptors, their role in developmental processes, as well as their implication in disease. PMID:23085770

  3. Raltegravir: first in class HIV integrase inhibitor

    Directory of Open Access Journals (Sweden)

    Zelalem Temesgen

    2008-06-01

    Full Text Available Zelalem Temesgen1, Dawd S Siraj21Mayo Clinic, Rochester, MN, USA; 2East Carolina University Greenville, NC, USAAbstract: On October 16, 2007, the US Food and Drug Administration (FDA approved raltegravir for treatment of human immunodeficiency virus (HIV-1 infection in combination with other antiretroviral agents in treatment-experienced adult patients who have evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral agents. Raltegravir is first in a novel class of antiretroviral drugs known as integrase inhibitors. It has demonstrated potent anti HIV activity in both antiretroviral treatment-naïve and experienced patients. The most common adverse events reported with raltegravir during phase 2 and 3 clinical trials were diarrhea, nausea, and headache. Laboratory abnormalities include mild elevations in liver transaminases and creatine phosphokinase.Keywords: raltegravir, HIV, antiretroviral agents, integrase inhibitors

  4. Small molecule inhibitors of anthrax edema factor.

    Science.gov (United States)

    Jiao, Guan-Sheng; Kim, Seongjin; Moayeri, Mahtab; Thai, April; Cregar-Hernandez, Lynne; McKasson, Linda; O'Malley, Sean; Leppla, Stephen H; Johnson, Alan T

    2018-01-15

    Anthrax is a highly lethal disease caused by the Gram-(+) bacteria Bacillus anthracis. Edema toxin (ET) is a major contributor to the pathogenesis of disease in humans exposed to B. anthracis. ET is a bipartite toxin composed of two proteins secreted by the vegetative bacteria, edema factor (EF) and protective antigen (PA). Our work towards identifying a small molecule inhibitor of anthrax edema factor is the subject of this letter. First we demonstrate that the small molecule probe 5'-Fluorosulfonylbenzoyl 5'-adenosine (FSBA) reacts irreversibly with EF and blocks enzymatic activity. We then show that the adenosine portion of FSBA can be replaced to provide more drug-like molecules which are up to 1000-fold more potent against EF relative to FSBA, display low cross reactivity when tested against a panel of kinases, and are nanomolar inhibitors of EF in a cell-based assay of cAMP production. Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. Novel nonpeptidic inhibitors of peptide deformylase.

    Science.gov (United States)

    Jayasekera, M M; Kendall, A; Shammas, R; Dermyer, M; Tomala, M; Shapiro, M A; Holler, T P

    2000-09-15

    A novel series of nonpeptidic compounds structurally related to the known anticholesteremic thyropropic acid were found to inhibit Escherichia coli peptide deformylase (PDF), with IC50 values in the low-micromolar range. Kinetic analysis of [4-(4-hydroxyphenoxy)-3,5-diiodophenyl]acetic acid reveals competitive inhibition, with a Ki value of 0.66 +/- 0.007 microM. A structure-activity relationship study demonstrates that the carboxylate is required for activity, while the distal phenolic function can be methylated without significant effect. Either decreasing the number of iodine atoms on the molecule to one or increasing the number of iodine atoms to four results in the loss of an order of magnitude in potency. These compounds are the first nonpeptidic inhibitors disclosed and represent a template from which better inhibitors might be designed.

  6. Potent peptidic fusion inhibitors of influenza virus

    Energy Technology Data Exchange (ETDEWEB)

    Kadam, Rameshwar U.; Juraszek, Jarek; Brandenburg, Boerries; Buyck, Christophe; Schepens, Wim B. G.; Kesteleyn, Bart; Stoops, Bart; Vreeken, Rob J.; Vermond, Jan; Goutier, Wouter; Tang, Chan; Vogels, Ronald; Friesen, Robert H. E.; Goudsmit, Jaap; van Dongen, Maria J. P.; Wilson, Ian A.

    2017-09-28

    Influenza therapeutics with new targets and mechanisms of action are urgently needed to combat potential pandemics, emerging viruses, and constantly mutating strains in circulation. We report here on the design and structural characterization of potent peptidic inhibitors of influenza hemagglutinin. The peptide design was based on complementarity-determining region loops of human broadly neutralizing antibodies against the hemagglutinin (FI6v3 and CR9114). The optimized peptides exhibit nanomolar affinity and neutralization against influenza A group 1 viruses, including the 2009 H1N1 pandemic and avian H5N1 strains. The peptide inhibitors bind to the highly conserved stem epitope and block the low pH–induced conformational rearrangements associated with membrane fusion. These peptidic compounds and their advantageous biological properties should accelerate the development of new small molecule– and peptide-based therapeutics against influenza virus.

  7. Corrosion protection with eco-friendly inhibitors

    Science.gov (United States)

    Shahid, Muhammad

    2011-12-01

    Corrosion occurs as a result of the interaction of a metal with its environment. The extent of corrosion depends on the type of metal, the existing conditions in the environment and the type of aggressive ions present in the medium. For example, CO3-2 and NO-3 produce an insoluble deposit on the surface of iron, resulting in the isolation of metal and consequent decrease of corrosion. On the other hand, halide ions are adsorbed selectively on the metal surface and prevent formation of the oxide phase on the metal surface, resulting in continuous corrosion. Iron, aluminum and their alloys are widely used, both domestically and industrially. Linear alkylbenzene and linear alkylbenzene sulfonate are commonly used as detergents. They have also been found together in waste water. It is claimed that these chemicals act as inhibitors for stainless steel and aluminum. Release of toxic gases as a result of corrosion in pipelines may lead in certain cases to air pollution and possible health hazards. Therefore, there are two ways to look at the relationship between corrosion and pollution: (i) corrosion of metals and alloys due to environmental pollution and (ii) environmental pollution as a result of corrosion protection. This paper encompasses the two scenarios and possible remedies for various cases, using 'green' inhibitors obtained either from plant extracts or from pharmaceutical compounds. In the present study, the effect of piperacillin sodium as a corrosion inhibitor for mild steel was investigated using a weight-loss method as well as a three-electrode dc electrochemical technique. It was found that the corrosion rate decreased as the concentration of the inhibitor increased up to 9×10-4 M 93% efficiency was exhibited at this concentration.

  8. Acrosin inhibitor detecting along the boar epididymis

    Czech Academy of Sciences Publication Activity Database

    Maňásková-Postlerová, Pavla; Cozlová, Nina; Dorosh, Andriy; Šulc, Miroslav; Guyonet, B.; Jonáková, Věra

    2016-01-01

    Roč. 82, Jan 2016 (2016), s. 733-739 ISSN 0141-8130 R&D Projects: GA ČR(CZ) GAP503/12/1834; GA MŠk(CZ) ED1.1.00/02.0109; GA ČR GA14-05547S Institutional support: RVO:86652036 ; RVO:61388971 Keywords : Acrosin inhibitor * Boar epididymis * Spermatozoa Subject RIV: CE - Biochemistry Impact factor: 3.671, year: 2016

  9. Cyclooxygenase-2 inhibitors and knee prosthesis surgery

    OpenAIRE

    Meunier, Andreas

    2008-01-01

    Adverse effects of cyclooxygenase (COX) inhibitors on bone healing have previously been demonstrated in diaphyseal fracture models in animals. In spite of that, they are widely used as postoperative analgesics in orthopaedic surgery. After joint replacement, a bone repair process starts at the interface between bone and cement. If this process is disturbed, the prosthesis may never become rigidly fixed to the bone, leading to migration and with time loosening. This thesis investigates the eff...

  10. Aurora kinase inhibitors: Progress towards the clinic

    Czech Academy of Sciences Publication Activity Database

    Kollareddy, M.; Zheleva, D.; Dzubak, P.; Brahmkshatriya, Pathik; Lepšík, Martin; Hajduch, M.

    2012-01-01

    Roč. 30, č. 6 (2012), s. 2411-2432 ISSN 0167-6997 Grant - others:GA ČR(CZ) GA301/08/1649; GA ČR(CZ) GD303/09/H048 Program:GA; GD Institutional research plan: CEZ:AV0Z40550506 Keywords : Aurora kinases * cancer * inhibitors Subject RIV: CF - Physical ; Theoretical Chemistry Impact factor: 3.498, year: 2012

  11. GSK-3 inhibitors induce chromosome instability

    Directory of Open Access Journals (Sweden)

    Staples Oliver D

    2007-08-01

    Full Text Available Abstract Background Several mechanisms operate during mitosis to ensure accurate chromosome segregation. However, during tumour evolution these mechanisms go awry resulting in chromosome instability. While several lines of evidence suggest that mutations in adenomatous polyposis coli (APC may promote chromosome instability, at least in colon cancer, the underlying mechanisms remain unclear. Here, we turn our attention to GSK-3 – a protein kinase, which in concert with APC, targets β-catenin for proteolysis – and ask whether GSK-3 is required for accurate chromosome segregation. Results To probe the role of GSK-3 in mitosis, we inhibited GSK-3 kinase activity in cells using a panel of small molecule inhibitors, including SB-415286, AR-A014418, 1-Azakenpaullone and CHIR99021. Analysis of synchronised HeLa cells shows that GSK-3 inhibitors do not prevent G1/S progression or cell division. They do, however, significantly delay mitotic exit, largely because inhibitor-treated cells have difficulty aligning all their chromosomes. Although bipolar spindles form and the majority of chromosomes biorient, one or more chromosomes often remain mono-oriented near the spindle poles. Despite a prolonged mitotic delay, anaphase frequently initiates without the last chromosome aligning, resulting in chromosome non-disjunction. To rule out the possibility of "off-target" effects, we also used RNA interference to selectively repress GSK-3β. Cells deficient for GSK-3β exhibit a similar chromosome alignment defect, with chromosomes clustered near the spindle poles. GSK-3β repression also results in cells accumulating micronuclei, a hallmark of chromosome missegregation. Conclusion Thus, not only do our observations indicate a role for GSK-3 in accurate chromosome segregation, but they also raise the possibility that, if used as therapeutic agents, GSK-3 inhibitors may induce unwanted side effects by inducing chromosome instability.

  12. FAITH - Fast Assembly Inhibitor Test for HIV

    Czech Academy of Sciences Publication Activity Database

    Hadravová, Romana; Rumlová, Michaela; Ruml, T.

    2015-01-01

    Roč. 486, Dec (2015), s. 78-87 ISSN 0042-6822 R&D Projects: GA ČR(CZ) GA14-15326S; GA MŠk LO1302; GA MŠk(CZ) LO1304 Institutional support: RVO:61388963 Keywords : retrovirus * HIV * assembly * assay * inhibitor Subject RIV: EE - Microbiology, Virology Impact factor: 3.200, year: 2015 http://www.sciencedirect.com/science/article/pii/S0042682215003864

  13. Monoamine oxidase inhibitors from Gentiana lutea.

    Science.gov (United States)

    Haraguchi, Hiroyuki; Tanaka, Yasumasa; Kabbash, Amal; Fujioka, Toshihiro; Ishizu, Takashi; Yagi, Akira

    2004-08-01

    Three monoamine oxidase (MAO) inhibitors were isolated from Gentiana lutea. Their structures were elucidated to be 3-3''linked-(2'-hydroxy-4-O-isoprenylchalcone)-(2'''-hydroxy-4''-O-isoprenyldihydrochalcone) (1), 2-methoxy-3-(1,1'-dimethylallyl)-6a,10a-dihydrobenzo(1,2-c)chroman-6-one and 5-hydroxyflavanone. These compounds, and the hydrolysis product of 1, displayed competitive inhibitory properties against MAO-B which was more effective than MAO-A.

  14. Trial Watch: Proteasomal inhibitors for anticancer therapy.

    Science.gov (United States)

    Obrist, Florine; Manic, Gwenola; Kroemer, Guido; Vitale, Ilio; Galluzzi, Lorenzo

    2015-01-01

    The so-called "ubiquitin-proteasome system" (UPS) is a multicomponent molecular apparatus that catalyzes the covalent attachment of several copies of the small protein ubiquitin to other proteins that are generally (but not always) destined to proteasomal degradation. This enzymatic cascade is crucial for the maintenance of intracellular protein homeostasis (both in physiological conditions and in the course of adaptive stress responses), and regulates a wide array of signaling pathways. In line with this notion, defects in the UPS have been associated with aging as well as with several pathological conditions including cardiac, neurodegenerative, and neoplastic disorders. As transformed cells often experience a constant state of stress (as a result of the hyperactivation of oncogenic signaling pathways and/or adverse microenvironmental conditions), their survival and proliferation are highly dependent on the integrity of the UPS. This rationale has driven an intense wave of preclinical and clinical investigation culminating in 2003 with the approval of the proteasomal inhibitor bortezomib by the US Food and Drug Administration for use in multiple myeloma patients. Another proteasomal inhibitor, carfilzomib, is now licensed by international regulatory agencies for use in multiple myeloma patients, and the approved indications for bortezomib have been extended to mantle cell lymphoma. This said, the clinical activity of bortezomib and carfilzomib is often limited by off-target effects, innate/acquired resistance, and the absence of validated predictive biomarkers. Moreover, the antineoplastic activity of proteasome inhibitors against solid tumors is poor. In this Trial Watch we discuss the contribution of the UPS to oncogenesis and tumor progression and summarize the design and/or results of recent clinical studies evaluating the therapeutic profile of proteasome inhibitors in cancer patients.

  15. Adverse Effects of COX-2 Inhibitors

    Directory of Open Access Journals (Sweden)

    Jagdish N. Sharma

    2005-01-01

    Full Text Available Cyclooxygenase-2 selective inhibitors (COXIBs were developed with the prime object of minimizing gastrointestinal adverse effects, which are seen with the use of traditional nonsteroidal anti-inflammatory drugs (NSAIDs. Their long-term use is limited by the development of hypertension, edema, and congestive heart failure in a significant proportion of patients. NSAIDs block the activity of both COX isozymes, COX-1 and COX-2, which mediate the enzymatic conversion of arachidonate to prostaglandin H2 (PGH2 and other prostaglandin (PG metabolites. It is well established that the cardiovascular profile of COX-2 inhibitors can be accounted for by inhibition of COX-dependent PG synthesis. Following the COX-mediated synthesis of PGH2 from arachidonate, PGH2 is metabolized to one of at least five bioactive PGs, including PGE2, PGI2, PGF2, PGD2, or thromboxane A2 (TXA2. These prostanoids have pleiotropic cardiovascular effects, altering platelet function and renal function, and they are acting either as vasodilators or vasoconstrictors. Although COX-1 and COX-2 exhibit similar biochemical activity in converting arachidonate to PGH2in vitro, the ultimate prostanoids they produce in vivo may be different due to differential regulation of COX-1 and COX-2, tissue distribution, and availability of the prostanoid synthases. PGs have been established as being critically involved in mitigating hypertension, helping to maintain medullary blood flow (MBF, promoting urinary salt excretion, and preserving the normal homeostasis of thrombosis, and the researchers found that the use of COX-2 inhibitors caused many serious complications in altering the normal body homeostasis. The purpose of the present research is to explain briefly the side effects of COX-2 inhibitors on the renal and cardiovascular system.

  16. Rust Inhibitor And Fungicide For Cooling Systems

    Science.gov (United States)

    Adams, James F.; Greer, D. Clay

    1988-01-01

    Mixture of benzotriazole, benzoic acid, and fungicide prevents growth of rust and fungus. Water-based cooling mixture made from readily available materials prevents formation of metallic oxides and growth of fungi in metallic pipes. Coolant remains clear and does not develop thick sludge tending to collect in low points in cooling systems with many commercial rust inhibitors. Coolant compatible with iron, copper, aluminum, and stainless steel. Cannot be used with cadmium or cadmium-plated pipes.

  17. Luminometric method for screening retroviral protease inhibitors

    Czech Academy of Sciences Publication Activity Database

    Horáková, D.; Rumlová, Michaela; Pichová, Iva; Ruml, Tomáš

    2005-01-01

    Roč. 345, č. 1 (2005), s. 96-101 ISSN 0003-2697 R&D Projects: GA AV ČR(CZ) IAA4055304; GA MŠk(CZ) 1M0508; GA MŠk(CZ) 1M0520 Institutional research plan: CEZ:AV0Z40550506 Keywords : retroviral protease * inhibitors * luminescent assay Subject RIV: CE - Biochemistry Impact factor: 2.670, year: 2005

  18. Serine proteinases and their inhibitors in fertilization

    Czech Academy of Sciences Publication Activity Database

    Jonáková, Věra

    2000-01-01

    Roč. 3, 3,4 (2000), s. 23 [ Proteolytic enzymes and their inhibitors in physiology and pathogenesis. 14.09.2000, Plzen] R&D Projects: GA ČR GV524/96/K162; GA ČR GA303/99/0357; GA MŠk VS96141 Grant - others:GA UK(CZ) 12/1998 Institutional research plan: CEZ:AV0Z5052915 Subject RIV: EB - Genetics ; Molecular Biology

  19. Cost effectiveness of regorafenib as second-line therapy for patients with advanced hepatocellular carcinoma.

    Science.gov (United States)

    Parikh, Neehar D; Singal, Amit G; Hutton, David W

    2017-10-01

    Regorafenib, a multikinase inhibitor, has demonstrated prolonged survival by 2.8 months as a second-line agent in patients with hepatocellular carcinoma (HCC) who progress on sorafenib therapy. The objective of the current study was to examine the cost effectiveness of regorafenib for the treatment of HCC. The authors constructed a Markov simulation model of patients with unresectable HCC and Child-Pugh A cirrhosis who received treatment with regorafenib versus best supportive care. Model inputs for regorafenib effectiveness and rates of adverse events in patients with HCC were based on published clinical trial data and literature review. Quality-adjusted life years (QALYs) were calculated along with the incremental cost-effectiveness ratio (ICER) of regorafenib therapy. One-way sensitivity analyses also were conducted simultaneously on all model parameters and on various Monte-Carlo simulation parameters, and the regorafenib cost threshold at which cost effectiveness would be achieved was determined. Regorafenib provided an increase of 0.18 QALYs at a cost of $47,112. The ICER for regorafenib, compared with best supportive care, was $224,362. In 1-way sensitivity analyses, there were no scenarios in which regorafenib was cost effective. In cost threshold analysis, regorafenib would have to be priced at or below $67 per pill to be cost effective at an ICER of $100,000. Regorafenib is not cost effective as a second-line agent in the treatment of HCC, with a marginal increase in QALYs at a high cost. Lowering the cost of regorafenib or improving the selection of patients who can achieve maximal survival benefit would improve its value as a second-line treatment option for patients with HCC. Cancer 2017;123:3725-3731. © 2017 American Cancer Society. © 2017 American Cancer Society.

  20. Eukaryotic elongation factor 2 is a prognostic marker and its kinase a potential therapeutic target in HCC.

    Science.gov (United States)

    Pott, Leona L; Hagemann, Sascha; Reis, Henning; Lorenz, Kristina; Bracht, Thilo; Herold, Thomas; Skryabin, Boris V; Megger, Dominik A; Kälsch, Julia; Weber, Frank; Sitek, Barbara; Baba, Hideo A

    2017-02-14

    Hepatocellular carcinoma is a cancer with increasing incidence and largely refractory to current anticancer drugs. Since Sorafenib, a multikinase inhibitor has shown modest efficacy in advanced hepatocellular carcinoma additional treatments are highly needed. Protein phosphorylation via kinases is an important post-translational modification to regulate cell homeostasis including proliferation and apoptosis. Therefore kinases are valuable targets in cancer therapy. To this end we performed 2D differential gel electrophoresis and mass spectrometry analysis of phosphoprotein-enriched lysates of tumor and corresponding non-tumorous liver samples to detect differentially abundant phosphoproteins to screen for novel kinases as potential drug targets. We identified 34 differentially abundant proteins in phosphoprotein enriched lysates. Expression and distribution of the candidate protein eEF2 and its phosphorylated isoform was validated immunohistochemically on 78 hepatocellular carcinoma and non-tumorous tissue samples. Validation showed that total eEF2 and phosphorylated eEF2 at threonine 56 are prognostic markers for overall survival of HCC-patients. The activity of the regulating eEF2 kinase, compared between tumor and non-tumorous tissue lysates by in vitro kinase assays, is more than four times higher in tumor tissues. Functional analyzes regarding eEF2 kinase were performed in JHH5 cells with CRISPR/Cas9 mediated eEF2 kinase knock out. Proliferation and growth is decreased in eEF2 kinase knock out cells. eEF2 and phosphorylated eEF2 are prognostic markers for survival of hepatocellular carcinoma patients and the regulating eEF2 kinase is a potential drug target for tumor therapy.

  1. Modelling of potentially promising SARS protease inhibitors

    International Nuclear Information System (INIS)

    Plewczynski, Dariusz; Hoffmann, Marcin; Grotthuss, Marcin von; Knizewski, Lukasz; Rychewski, Leszek; Eitner, Krystian; Ginalski, Krzysztof

    2007-01-01

    In many cases, at the beginning of a high throughput screening experiment some information about active molecules is already available. Active compounds (such as substrate analogues, natural products and inhibitors of related proteins) are often identified in low throughput validation studies on a biochemical target. Sometimes the additional structural information is also available from crystallographic studies on protein and ligand complexes. In addition, the structural or sequence similarity of various protein targets yields a novel possibility for drug discovery. Co-crystallized compounds from homologous proteins can be used to design leads for a new target without co-crystallized ligands. In this paper we evaluate how far such an approach can be used in a real drug campaign, with severe acute respiratory syndrome (SARS) coronavirus providing an example. Our method is able to construct small molecules as plausible inhibitors solely on the basis of the set of ligands from crystallized complexes of a protein target, and other proteins from its structurally homologous family. The accuracy and sensitivity of the method are estimated here by the subsequent use of an electronic high throughput screening flexible docking algorithm. The best performing ligands are then used for a very restrictive similarity search for potential inhibitors of the SARS protease within the million compounds from the Ligand.Info small molecule meta-database. The selected molecules can be passed on for further experimental validation

  2. Inhibitors of polyamine metabolism: review article.

    Science.gov (United States)

    Wallace, H M; Fraser, A V

    2004-07-01

    The identification of increased polyamine concentrations in a variety of diseases from cancer and psoriasis to parasitic infections has led to the hypothesis that manipulation of polyamine metabolism is a realistic target for therapeutic or preventative intervention in the treatment of certain diseases. The early development of polyamine biosynthetic single enzyme inhibitors such as alpha-difluoromethylornithine (DFMO) and methylglyoxal bis(guanylhydrazone) showed some interesting early promise as anticancer drugs, but ultimately failed in vivo. Despite this, DFMO is currently in use as an effective anti-parasitic agent and has recently also been shown to have further potential as a chemopreventative agent in colorectal cancer. The initial promise in vitro led to the development and testing of other potential inhibitors of the pathway namely the polyamine analogues. The analogues have met with greater success than the single enzyme inhibitors possibly due to their multiple targets. These include down regulation of polyamine biosynthesis through inhibition of ornithine decarboxylase and S-adenosylmethionine decarboxylase and decreased polyamine uptake. This coupled with increased activity of the catabolic enzymes, polyamine oxidase and spermidine/spermine N1-acetyltransferase, and increased polyamine export has made the analogues more effective in depleting polyamine pools. Recently, the identification of a new oxidase (PAO-h1/SMO) in polyamine catabolism and evidence of induction of both PAO and PAO-h1/SMO in response to polyamine analogue treatment, suggests the analogues may become an important part of future chemotherapeutic and/or chemopreventative regimens.

  3. Recent advances in botulinum neurotoxin inhibitor development.

    Science.gov (United States)

    Kiris, Erkan; Burnett, James C; Kane, Christopher D; Bavari, Sina

    2014-01-01

    Botulinum neurotoxins (BoNTs) are endopeptidases that target motor neurons and block acetylcholine neurotransmitter release. This action results in the muscle paralysis that defines the disease botulism. To date, there are no FDA-approved therapeutics to treat BoNT-mediated paralysis after intoxication of the motor neuron. Importantly, the rationale for pursuing treatments to counter these toxins is driven by their potential misuse. Current drug discovery efforts have mainly focused on small molecules, peptides, and peptidomimetics that can directly and competitively inhibit BoNT light chain proteolytic activity. Although this is a rational approach, direct inhibition of the Zn(2+) metalloprotease activity has been elusive as demonstrated by the dearth of candidates undergoing clinical evaluation. Therefore, broadening the scope of viable targets beyond that of active site protease inhibitors represents an additional strategy that could move the field closer to the clinic. Here we review the rationale, and discuss the outcomes of earlier approaches and highlight potential new targets for BoNT inhibition. These include BoNT uptake and processing inhibitors, enzymatic inhibitors, and modulators of neuronal processes associated with toxin clearance, neurotransmitter potentiation, and other pathways geared towards neuronal recovery and repair.

  4. A porphodimethene chemical inhibitor of uroporphyrinogen decarboxylase.

    Directory of Open Access Journals (Sweden)

    Kenneth W Yip

    Full Text Available Uroporphyrinogen decarboxylase (UROD catalyzes the conversion of uroporphyrinogen to coproporphyrinogen during heme biosynthesis. This enzyme was recently identified as a potential anticancer target; its inhibition leads to an increase in reactive oxygen species, likely mediated by the Fenton reaction, thereby decreasing cancer cell viability and working in cooperation with radiation and/or cisplatin. Because there is no known chemical UROD inhibitor suitable for use in translational studies, we aimed to design, synthesize, and characterize such a compound. Initial in silico-based design and docking analyses identified a potential porphyrin analogue that was subsequently synthesized. This species, a porphodimethene (named PI-16, was found to inhibit UROD in an enzymatic assay (IC50 = 9.9 µM, but did not affect porphobilinogen deaminase (at 62.5 µM, thereby exhibiting specificity. In cellular assays, PI-16 reduced the viability of FaDu and ME-180 cancer cells with half maximal effective concentrations of 22.7 µM and 26.9 µM, respectively, and only minimally affected normal oral epithelial (NOE cells. PI-16 also combined effectively with radiation and cisplatin, with potent synergy being observed in the case of cisplatin in FaDu cells (Chou-Talalay combination index <1. This work presents the first known synthetic UROD inhibitor, and sets the foundation for the design, synthesis, and characterization of higher affinity and more effective UROD inhibitors.

  5. Emicizumab Prophylaxis in Hemophilia A with Inhibitors.

    Science.gov (United States)

    Oldenburg, Johannes; Mahlangu, Johnny N; Kim, Benjamin; Schmitt, Christophe; Callaghan, Michael U; Young, Guy; Santagostino, Elena; Kruse-Jarres, Rebecca; Negrier, Claude; Kessler, Craig; Valente, Nancy; Asikanius, Elina; Levy, Gallia G; Windyga, Jerzy; Shima, Midori

    2017-08-31

    Emicizumab (ACE910) bridges activated factor IX and factor X to restore the function of activated factor VIII, which is deficient in persons with hemophilia A. This phase 3, multicenter trial assessed once-weekly subcutaneous emicizumab prophylaxis in persons with hemophilia A with factor VIII inhibitors. We enrolled participants who were 12 years of age or older. Those who had previously received episodic treatment with bypassing agents were randomly assigned in a 2:1 ratio to emicizumab prophylaxis (group A) or no prophylaxis (group B). The primary end point was the difference in bleeding rates between group A and group B. Participants who had previously received prophylactic treatment with bypassing agents received emicizumab prophylaxis in group C. A total of 109 male participants with hemophilia A with inhibitors were enrolled. The annualized bleeding rate was 2.9 events (95% confidence interval [CI], 1.7 to 5.0) among participants who were randomly assigned to emicizumab prophylaxis (group A, 35 participants) versus 23.3 events (95% CI, 12.3 to 43.9) among those assigned to no prophylaxis (group B, 18 participants), representing a significant difference of 87% in favor of emicizumab prophylaxis (Phemophilia A with inhibitors. (Funded by F. Hoffmann-La Roche and Chugai Pharmaceutical; HAVEN 1 ClinicalTrials.gov number, NCT02622321 .).

  6. Modelling of potentially promising SARS protease inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Plewczynski, Dariusz [Interdisciplinary Centre for Mathematical and Computational Modelling, ICM, Warsaw University, Pawinskiego 5a Street, 02-106 Warsaw (Poland); Hoffmann, Marcin [BioInfoBank Institute, Limanowskiego 24A/16, 60-744 Poznan (Poland); Grotthuss, Marcin von [BioInfoBank Institute, Limanowskiego 24A/16, 60-744 Poznan (Poland); Knizewski, Lukasz [Interdisciplinary Centre for Mathematical and Computational Modelling, ICM, Warsaw University, Pawinskiego 5a Street, 02-106 Warsaw (Poland); Rychewski, Leszek [BioInfoBank Institute, Limanowskiego 24A/16, 60-744 Poznan (Poland); Eitner, Krystian [BioInfoBank Institute, Limanowskiego 24A/16, 60-744 Poznan (Poland); Ginalski, Krzysztof [Interdisciplinary Centre for Mathematical and Computational Modelling, ICM, Warsaw University, Pawinskiego 5a Street, 02-106 Warsaw (Poland)

    2007-07-18

    In many cases, at the beginning of a high throughput screening experiment some information about active molecules is already available. Active compounds (such as substrate analogues, natural products and inhibitors of related proteins) are often identified in low throughput validation studies on a biochemical target. Sometimes the additional structural information is also available from crystallographic studies on protein and ligand complexes. In addition, the structural or sequence similarity of various protein targets yields a novel possibility for drug discovery. Co-crystallized compounds from homologous proteins can be used to design leads for a new target without co-crystallized ligands. In this paper we evaluate how far such an approach can be used in a real drug campaign, with severe acute respiratory syndrome (SARS) coronavirus providing an example. Our method is able to construct small molecules as plausible inhibitors solely on the basis of the set of ligands from crystallized complexes of a protein target, and other proteins from its structurally homologous family. The accuracy and sensitivity of the method are estimated here by the subsequent use of an electronic high throughput screening flexible docking algorithm. The best performing ligands are then used for a very restrictive similarity search for potential inhibitors of the SARS protease within the million compounds from the Ligand.Info small molecule meta-database. The selected molecules can be passed on for further experimental validation.

  7. Structure-Based Search for New Inhibitors of Cholinesterases

    Directory of Open Access Journals (Sweden)

    Barbara Malawska

    2013-03-01

    Full Text Available Cholinesterases are important biological targets responsible for regulation of cholinergic transmission, and their inhibitors are used for the treatment of Alzheimer’s disease. To design new cholinesterase inhibitors, of different structure-based design strategies was followed, including the modification of compounds from a previously developed library and a fragment-based design approach. This led to the selection of heterodimeric structures as potential inhibitors. Synthesis and biological evaluation of selected candidates confirmed that the designed compounds were acetylcholinesterase inhibitors with IC50 values in the mid-nanomolar to low micromolar range, and some of them were also butyrylcholinesterase inhibitors.

  8. ELISA analysis of soybean trypsin inhibitors in processed foods.

    Science.gov (United States)

    Brandon, D L; Bates, A H; Friedman, M

    1991-01-01

    Soybean proteins are widely used in human foods in a variety of forms, including infant formulas, flour, protein concentrates, protein isolates, soy sauces, textured soy fibers, and tofu. The presence of inhibitors of digestive enzymes in soy proteins impairs the nutritional quality and possibly the safety of soybeans and other legumes. Processing, based on the use of heat or fractionation of protein isolates, does not completely inactivate or remove these inhibitors, so that residual amounts of inhibitors are consumed by animals and humans. New monoclonal antibody-based immunoassays can measure low levels of the soybean Kunitz trypsin inhibitor (KTI) and the Bowman-Birk trypsin and chymotrypsin inhibitor (BBI) and the Bowman-Birk foods. The enzyme-linked immunosorbent assay (ELISA) was used to measure the inhibitor content of soy concentrates, isolates, and flours, both heated and unheated; a commercial soy infant formula; KTI and BBI with rearranged disulfide bonds; browning products derived from heat-treatment of KTI with glucose and starch; and KTI exposed to high pH. The results indicate that even low inhibitor isolates contain significant amounts of specific inhibitors. Thus, infants on soy formula consume about 10 mg of KTI plus BBI per day. The immunoassays complement the established enzymatic assays of trypsin and chymotrypsin inhibitors, and have advantages in (a) measuring low levels of inhibitors in processed foods; and (b) differentiating between the Kunitz and Bowman-Birk inhibitors. The significance of our findings for food safety are discussed.

  9. Pathophysiological significance and therapeutic applications of snake venom protease inhibitors.

    Science.gov (United States)

    Thakur, Rupamoni; Mukherjee, Ashis K

    2017-06-01

    Protease inhibitors are important constituents of snake venom and play important roles in the pathophysiology of snakebite. Recently, research on snake venom protease inhibitors has provided valuable information to decipher the molecular details of various biological processes and offer insight for the development of some therapeutically important molecules from snake venom. The process of blood coagulation and fibrinolysis, in addition to affecting platelet function, are well known as the major targets of several snake venom protease inhibitors. This review summarizes the structure-functional aspects of snake venom protease inhibitors that have been described to date. Because diverse biological functions have been demonstrated by protease inhibitors, a comparative overview of their pharmacological and pathophysiological properties is also highlighted. In addition, since most snake venom protease inhibitors are non-toxic on their own, this review evaluates the different roles of individual protease inhibitors that could lead to the identification of drug candidates and diagnostic molecules. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. Evaluation of Encapsulated Inhibitor for Autonomous Corrosion Protection

    Science.gov (United States)

    Johnsey, M. N.; Li, W.; Buhrow, J. W.; Calle, L. M.; Pearman, B. P.; Zhang, X.

    2015-01-01

    This work concerns the development of smart coating technologies based on microencapsulation for the autonomous control of corrosion. Microencapsulation allows the incorporation of corrosion inhibitors into coating which provides protection through corrosion-controlled release of these inhibitors.One critical aspect of a corrosion protective smart coating is the selection of corrosion inhibitor for encapsulation and comparison of the inhibitor function before and after encapsulation. For this purpose, a systematic approach is being used to evaluate free and encapsulated corrosion inhibitors by salt immersion. Visual, optical microscope, and Scanning Electron Microscope (with low-angle backscatter electron detector) are used to evaluate these inhibitors. It has been found that the combination of different characterization tools provide an effective method for evaluation of early stage localized corrosion and the effectiveness of corrosion inhibitors.

  11. The "SWOT" of BRAF inhibition in melanoma: RAF inhibitors, MEK inhibitors or both?

    Science.gov (United States)

    Nissan, Moriah H; Solit, David B

    2011-12-01

    Activating mutations in the BRAF gene are among the most prevalent kinase mutations in human cancer. BRAF mutations are most frequent in patients with melanoma where they occur in approximately 50% of patients with advanced disease. Remarkable clinical activity has recently been reported with highly selective RAF inhibitors in melanoma patients whose tumors harbor V600E BRAF mutations. The response rates of RAF inhibitors in patients with BRAF-mutant melanomas far exceed the activity level of any prior therapy studied in this disease. The results suggest that we have entered an era of personalized therapy for patients with metastatic melanoma in which treatment selection will be guided by BRAF mutational status. This review will discuss the strengths, weaknesses, opportunities and threats ("SWOT") of developing RAF and MEK selective inhibitors as anti-cancer therapies, recent insights into the mechanisms of intrinsic and acquired resistance to these agents, and current efforts to develop mechanism-based combination therapies.

  12. F8 haplotype and inhibitor risk: results from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort

    Science.gov (United States)

    Schwarz, John; Astermark, Jan; Menius, Erika D.; Carrington, Mary; Donfield, Sharyne M.; Gomperts, Edward D.; Nelson, George W.; Oldenburg, Johannes; Pavlova, Anna; Shapiro, Amy D.; Winkler, Cheryl A.; Berntorp, Erik

    2012-01-01

    Background Ancestral background, specifically African descent, confers higher risk for development of inhibitory antibodies to factor VIII (FVIII) in hemophilia A. It has been suggested that differences in the distribution of factor VIII gene (F8) haplotypes, and mismatch between endogenous F8 haplotypes and those comprising products used for treatment could contribute to risk. Design and Methods Data from the HIGS Combined Cohort were used to determine the association between F8 haplotype 3 (H3) vs. haplotypes 1 and 2 (H1+H2) and inhibitor risk among individuals of genetically-determined African descent. Other variables known to affect inhibitor risk including type of F8 mutation and HLA were included in the analysis. A second research question regarding risk related to mismatch in endogenous F8 haplotype and recombinant FVIII products used for treatment was addressed. Results H3 was associated with higher inhibitor risk among those genetically-identified (N=49) as of African ancestry, but the association did not remain significant after adjustment for F8 mutation type and the HLA variables. Among subjects of all racial ancestries enrolled in HIGS who reported early use of recombinant products (N=223), mismatch in endogenous haplotype and the FVIII proteins constituting the products used did not confer greater risk for inhibitor development. Conclusion H3 was not an independent predictor of inhibitor risk. Further, our findings did not support a higher risk of inhibitors in the presence of a haplotype mismatch between the FVIII molecule infused and that of the individual. PMID:22958194

  13. Sifuvirtide, a potent HIV fusion inhibitor peptide

    International Nuclear Information System (INIS)

    Wang, Rui-Rui; Yang, Liu-Meng; Wang, Yun-Hua; Pang, Wei; Tam, Siu-Cheung; Tien, Po; Zheng, Yong-Tang

    2009-01-01

    Enfuvirtide (ENF) is currently the only FDA approved HIV fusion inhibitor in clinical use. Searching for more drugs in this category with higher efficacy and lower toxicity seems to be a logical next step. In line with this objective, a synthetic peptide with 36 amino acid residues, called Sifuvirtide (SFT), was designed based on the crystal structure of gp41. In this study, we show that SFT is a potent anti-HIV agent with relatively low cytotoxicity. SFT was found to inhibit replication of all tested HIV strains. The effective concentrations that inhibited 50% viral replication (EC 50 ), as determined in all tested strains, were either comparable or lower than benchmark values derived from well-known anti-HIV drugs like ENF or AZT, while the cytotoxic concentrations causing 50% cell death (CC 50 ) were relatively high, rendering it an ideal anti-HIV agent. A GST-pull down assay was performed to confirm that SFT is a fusion inhibitor. Furthermore, the activity of SFT on other targets in the HIV life cycle was also investigated, and all assays showed negative results. To further understand the mechanism of action of HIV peptide inhibitors, resistant variants of HIV-1 IIIB were derived by serial virus passage in the presence of increasing doses of SFT or ENF. The results showed that there was cross-resistance between SFT and ENF. In conclusion, SFT is an ideal anti-HIV agent with high potency and low cytotoxicity, but may exhibit a certain extent of cross-resistance with ENF.

  14. [Cholinesterase inhibitors for treating dementia. Review].

    Science.gov (United States)

    Kremer, Janus

    2010-01-01

    Alzheimer's disease is the most common form of dementia seen in the clinical practice. The principal risk factor is aging. There is not currently any available curative medication. However, there a family of drugs call the cholinesterase inhibitors (donepezile, galantamine and rivastigmine) the enhances cholinergic activity in the CNS. Also, memantine is available is a NMDA receptor modulator. A new transdermal way of administration is available now for rivastigmine. The rivastigmines patches are now a rational alternative focusing in getting more tolerance, better blood levels of the drug and compliance to treatment in Alzheimer's disease patients.

  15. Serine proteinases and their inhibitors in fertilization

    Czech Academy of Sciences Publication Activity Database

    Jonáková, Věra; Jelínková-Slavíčková, Petra

    2004-01-01

    Roč. 8, 3,4 (2004), s. 108-110 ISSN 1211-8869. [Central European Conference on Human Tumor Markers /5./. Praha, 01.10.2004-03.10.2004] R&D Projects: GA ČR GA303/02/0433; GA ČR GP303/02/P069; GA ČR GP303/04/P070; GA MZd NJ7463 Institutional research plan: CEZ:AV0Z5052915 Keywords : serine proteinase * proteinase inhibitors * fertilization Subject RIV: CE - Biochemistry

  16. A New Urease Inhibitor from Viola betonicifolia

    Directory of Open Access Journals (Sweden)

    Naveed Muhammad

    2014-10-01

    Full Text Available Urease has attracted much attention, as it is directly involved in the formation of infection stones and contributes to the pathogenesis of urolithiasis, pyelonephritis, ammonia and hepatic encephalopathy, hepatic coma and urinary catheter encrustation. Moreover, urease is the major cause of pathologies induced by H. pylori, such as gastritis and peptic ulcer. In the present work, the new natural compound, 3-methoxydalbergione, was isolated from Viola betonicifolia. A mechanistic study of this compound as a natural urease inhibitor was performed by using enzyme kinetics and docking studies. 3-Methoxydalbergione could be considered as a lead molecule for drugs useful in the urease associated diseases.

  17. Tetomilast: new promise for phosphodiesterase-4 inhibitors?

    Science.gov (United States)

    Bickston, Stephen J; Snider, Kenneth R; Kappus, Matthew R

    2012-12-01

    Tetomilast is a novel thiazole phosphodiesterase-4 (PDE-4) inhibitor, which may prove useful in both the treatment of inflammatory bowel disease (IBD) and chronic obstructive pulmonary disease (COPD). Here, the authors review the pharmacology of the drug, and offer critical review of the available data for use of tetomilast in the treatment of IBD. Peer-reviewed publications, including Phase I and II clinical trials, all other formats included. Tetomilast may be beneficial in IBD. Small differences in molecules and in recombinant proteins can translate into substantial differences in clinical effects and toxicity in IBD. This is a reasonable approach when exploring new options like tetomilast.

  18. Potential mechanisms of resistance to microtubule inhibitors.

    Science.gov (United States)

    Kavallaris, Maria; Annereau, Jean-Philippe; Barret, Jean-Marc

    2008-06-01

    Antimitotic drugs targeting the microtubules, such as the taxanes and vinca alkaloids, are widely used in the treatment of neoplastic diseases. Development of drug resistance over time, however, limits the efficacy of these agents and poses a clinical challenge to long-term improvement of patient outcomes. Understanding the mechanism(s) of drug resistance becomes paramount to allowing for alternative, if not improved, therapeutic options that might circumvent this challenge. Vinflunine, a novel microtubule inhibitor, has shown superior preclinical antitumor activity, and displays a different pattern of resistance, compared with other agents in the vinca alkaloid class.

  19. Larvicides and acetylcholinesterase inhibitors from Kalanchoe species

    International Nuclear Information System (INIS)

    Trevisan, Maria Teresa Salles; Bezerra, Maria Zeneide Barbosa; Santiago, Gilvandete Maria Pinheiro; Feitosa, Chistiane Mendes; Verpoorte, Robert; Gorlaeus Laboratories, Leiden; Braz Filho, Raimundo

    2006-01-01

    Acetylcholine esterase inhibitors are successfully used to treat the symptoms of Alzheimer's disease. Extracts of three Kalanchoe species (K. brasiliensis, K. pinnata and K. gastonis-bornieri) showed acetylcholine esterase inhibitory effects and a toxic effect on Aedes aegypti larvae. Here we describe the bioassay guided fractionation of extracts of the most active extracts (K. brasiliensis) which resulted in the isolation of an active mixture of three flavonoids: 8-methoxyquercetin, 3,7-di-O-rhamnopyranoside and 8-methoxykaempferol-3,7-di-O-rhamnopyranoside. On TLC these flavonoids showed an acetylcholine esterase inhibitory effect. (author)

  20. Hepatitis C Virus NS3 Inhibitors: Current and Future Perspectives

    Directory of Open Access Journals (Sweden)

    Kazi Abdus Salam

    2013-01-01

    Full Text Available Currently, hepatitis C virus (HCV infection is considered a serious health-care problem all over the world. A good number of direct-acting antivirals (DAAs against HCV infection are in clinical progress including NS3-4A protease inhibitors, RNA-dependent RNA polymerase inhibitors, and NS5A inhibitors as well as host targeted inhibitors. Two NS3-4A protease inhibitors (telaprevir and boceprevir have been recently approved for the treatment of hepatitis C in combination with standard of care (pegylated interferon plus ribavirin. The new therapy has significantly improved sustained virologic response (SVR; however, the adverse effects associated with this therapy are still the main concern. In addition to the emergence of viral resistance, other targets must be continually developed. One such underdeveloped target is the helicase portion of the HCV NS3 protein. This review article summarizes our current understanding of HCV treatment, particularly with those of NS3 inhibitors.

  1. HTCC: Broad Range Inhibitor of Coronavirus Entry.

    Directory of Open Access Journals (Sweden)

    Aleksandra Milewska

    Full Text Available To date, six human coronaviruses have been known, all of which are associated with respiratory infections in humans. With the exception of the highly pathogenic SARS and MERS coronaviruses, human coronaviruses (HCoV-NL63, HCoV-OC43, HCoV-229E, and HCoV-HKU1 circulate worldwide and typically cause the common cold. In most cases, infection with these viruses does not lead to severe disease, although acute infections in infants, the elderly, and immunocompromised patients may progress to severe disease requiring hospitalization. Importantly, no drugs against human coronaviruses exist, and only supportive therapy is available. Previously, we proposed the cationically modified chitosan, N-(2-hydroxypropyl-3-trimethylammonium chitosan chloride (HTCC, and its hydrophobically-modified derivative (HM-HTCC as potent inhibitors of the coronavirus HCoV-NL63. Here, we show that HTCC inhibits interaction of a virus with its receptor and thus blocks the entry. Further, we demonstrate that HTCC polymers with different degrees of substitution act as effective inhibitors of all low-pathogenic human coronaviruses.

  2. Lonafarnib is a potential inhibitor for neovascularization.

    Directory of Open Access Journals (Sweden)

    Linlin Sun

    Full Text Available Atherosclerosis is a common cardiovascular disease that involves the build-up of plaque on the inner walls of the arteries. Intraplaque neovacularization has been shown to be essential in the pathogenesis of atherosclerosis. Previous studies showed that small-molecule compounds targeting farnesyl transferase have the ability to prevent atherosclerosis in apolipoprotein E-deficient mice, but the underlying mechanism remains to be elucidated. In this study, we found that lonafarnib, a specific inhibitor of farnesyl transferase, elicits inhibitory effect on vascular endothelial capillary assembly in vitro in a dose-dependent manner. In addition, we showed that lonafarnib treatment led to a dose-dependent decrease in scratch wound closure in vitro, whereas it had little effect on endothelial cell proliferation. These data indicate that lonafarnib inhibits neovascularization via directly targeting endothelial cells and disturbing their motility. Moreover, we demonstrated that pharmacological inhibition of farnesyl transferase by lonafarnib significantly impaired centrosome reorientation toward the leading edge of endothelial cells. Mechanistically, we found that the catalytic β subunit of farnesyl transferase associated with a cytoskeletal protein important for the establishment and maintenance of cell polarity. Additionally, we showed that lonafarnib remarkably inhibited the expression of the cytoskeletal protein and interrupted its interaction with farnesyl transferase. Our findings thus offer novel mechanistic insight into the protective effect of farnesyl transferase inhibitors on atherosclerosis and provide encouraging evidence for the potential use of this group of agents in inhibiting plaque neovascularization.

  3. Proton Pump Inhibitors and Risk of Rhabdomyolysis.

    Science.gov (United States)

    Duncan, Scott J; Howden, Colin W

    2017-01-01

    Proton pump inhibitors (PPIs) have been associated with a variety of adverse events, although the level of evidence for many of these is weak at best. Recently, one national regulatory authority has mandated a change to the labeling of one PPI based on reports of possible associated rhabdomyolysis. Thus, in this review we summarize the available evidence linking PPI use with rhabdomyolysis. The level of evidence is insufficient to establish a causal relationship and is largely based on sporadic case reports. In general, patients with suspected PPI-associated rhabdomyolysis have not been re-challenged with a PPI after recovery. The mechanism whereby PPIs might have been associated with rhabdomyolysis is unclear but possibly related to interaction with concomitantly administered drugs such as HMG-CoA reductase inhibitors (statins). For patients with rhabdomyolysis, a careful search must be made for possible etiological factors. In patients who recover from an episode of possible PPI-related rhabdomyolysis but do not have a genuine requirement for PPI treatment, the PPI should not be re-introduced. For those with a definite indication for ongoing PPI treatment, the PPI can be re-introduced but should preferably not be administered with a statin.

  4. Polyphenol Compound as a Transcription Factor Inhibitor

    Directory of Open Access Journals (Sweden)

    Seyeon Park

    2015-10-01

    Full Text Available A target-based approach has been used to develop novel drugs in many therapeutic fields. In the final stage of intracellular signaling, transcription factor–DNA interactions are central to most biological processes and therefore represent a large and important class of targets for human therapeutics. Thus, we focused on the idea that the disruption of protein dimers and cognate DNA complexes could impair the transcriptional activation and cell transformation regulated by these proteins. Historically, natural products have been regarded as providing the primary leading compounds capable of modulating protein–protein or protein-DNA interactions. Although their mechanism of action is not fully defined, polyphenols including flavonoids were found to act mostly as site-directed small molecule inhibitors on signaling. There are many reports in the literature of screening initiatives suggesting improved drugs that can modulate the transcription factor interactions responsible for disease. In this review, we focus on polyphenol compound inhibitors against dimeric forms of transcription factor components of intracellular signaling pathways (for instance, c-jun/c-fos (Activator Protein-1; AP-1, c-myc/max, Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB and β-catenin/T cell factor (Tcf.

  5. Polyphenol Compound as a Transcription Factor Inhibitor.

    Science.gov (United States)

    Park, Seyeon

    2015-10-30

    A target-based approach has been used to develop novel drugs in many therapeutic fields. In the final stage of intracellular signaling, transcription factor-DNA interactions are central to most biological processes and therefore represent a large and important class of targets for human therapeutics. Thus, we focused on the idea that the disruption of protein dimers and cognate DNA complexes could impair the transcriptional activation and cell transformation regulated by these proteins. Historically, natural products have been regarded as providing the primary leading compounds capable of modulating protein-protein or protein-DNA interactions. Although their mechanism of action is not fully defined, polyphenols including flavonoids were found to act mostly as site-directed small molecule inhibitors on signaling. There are many reports in the literature of screening initiatives suggesting improved drugs that can modulate the transcription factor interactions responsible for disease. In this review, we focus on polyphenol compound inhibitors against dimeric forms of transcription factor components of intracellular signaling pathways (for instance, c-jun/c-fos (Activator Protein-1; AP-1), c-myc/max, Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and β-catenin/T cell factor (Tcf)).

  6. PD-1 Checkpoint Inhibitor Associated Autoimmune Encephalitis

    Directory of Open Access Journals (Sweden)

    Stephanie Schneider

    2017-05-01

    Full Text Available Objective: To report first-hand narrative experience of autoimmune encephalitis and to briefly review currently available evidence of autoimmune encephalitis in cancer patients treated with immune checkpoint inhibitors. Setting: A case study is presented on the management of a patient who developed autoimmune encephalitis during nivolumab monotherapy occurring after 28 weeks on anti-PD-1 monotherapy (nivolumab 3 mg/kg every 2 weeks for non-small cell lung cancer. Results: No substantial improvement was observed by antiepileptic treatment. After administration of 80 mg methylprednisolone, neurologic symptoms disappeared within 24 h and the patient fully recovered. Conclusions: Immune checkpoint inhibitor treatment can lead to autoimmune encephalitis. Clinical trial data indicate a frequency of autoimmune encephalitis of ≥0.1 to <1% with a higher probability during combined or sequential anti-CTLA-4/anti-PD-1 therapy than during anti-PD-1 or anti-PD-L1 monotherapy. Further collection of evidence and translational research is warranted.

  7. Synthesis of Novel Chalcones as Acetylcholinesterase Inhibitors

    Directory of Open Access Journals (Sweden)

    Thanh-Dao Tran

    2016-07-01

    Full Text Available A new series of benzylaminochalcone derivatives with different substituents on ring B were synthesized and evaluated as inhibitors of acetylcholinesterase. The study is aimed at identification of novel benzylaminochalcones capable of blocking acetylcholinesterase activity for further development of an approach to Alzheimer’s disease treatment. These compounds were produced in moderate to good yields via Claisen-Schmidt condensation and subjected to an in vitro acetylcholinesterase inhibition assay, using Ellman’s method. The in silico docking procedure was also employed to identify molecular interactions between the chalcone compounds and the enzyme. Compounds with ring B bearing pyridin-4-yl, 4-nitrophenyl, 4-chlorophenyl and 3,4-dimethoxyphenyl moieties were discovered to exhibit significant inhibitory activities against acetylcholinesterase, with IC50 values ranging from 23 to 39 µM. The molecular modeling studies are consistent with the hypothesis that benzylaminochalcones could exert their effects as dual-binding-site acetylcholinesterase inhibitors, which might simultaneously enhance cholinergic neurotransmission and inhibit β-amyloid aggregation through binding to both catalytic and peripheral sites of the enzyme. These derivatives could be further developed to provide novel leads for the discovery of new anti-Alzheimer drugs in the future.

  8. Replication and Inhibitors of Enteroviruses and Parechoviruses

    Directory of Open Access Journals (Sweden)

    Lonneke van der Linden

    2015-08-01

    Full Text Available The Enterovirus (EV and Parechovirus genera of the picornavirus family include many important human pathogens, including poliovirus, rhinovirus, EV-A71, EV-D68, and human parechoviruses (HPeV. They cause a wide variety of diseases, ranging from a simple common cold to life-threatening diseases such as encephalitis and myocarditis. At the moment, no antiviral therapy is available against these viruses and it is not feasible to develop vaccines against all EVs and HPeVs due to the great number of serotypes. Therefore, a lot of effort is being invested in the development of antiviral drugs. Both viral proteins and host proteins essential for virus replication can be used as targets for virus inhibitors. As such, a good understanding of the complex process of virus replication is pivotal in the design of antiviral strategies goes hand in hand with a good understanding of the complex process of virus replication. In this review, we will give an overview of the current state of knowledge of EV and HPeV replication and how this can be inhibited by small-molecule inhibitors.

  9. Flavonoids as Inhibitors of Human Butyrylcholinesterase Variants

    Directory of Open Access Journals (Sweden)

    Maja Katalinić

    2014-01-01

    Full Text Available The inhibition of butyrylcholinesterase (BChE, EC 3.1.1.8 appears to be of interest in treating diseases with symptoms of reduced neurotransmitter levels, such as Alzheimer’s disease. However, BCHE gene polymorphism should not be neglected in research since it could have an effect on the expected outcome. Several well-known cholinergic drugs (e.g. galantamine, huperzine and rivastigmine originating from plants, or synthesised as derivatives of plant compounds, have shown that herbs could serve as a source of novel target-directed compounds. We focused our research on flavonoids, biologically active polyphenolic compounds found in many plants and plant-derived products, as BChE inhibitors. All of the tested flavonoids: galangin, quercetin, fisetin and luteolin reversibly inhibited usual, atypical, and fluoride-resistant variants of human BChE. The inhibition potency increased in the following order, identically for all three BChE variants: luteolininhibitor dissociation constants (Ki ranged from 10 to 170 mmol/L. We showed that no significant change in the inhibition potency of selected flavonoids exists in view of BChE polymorphism. Our results suggested that flavonoids could assist the further development of new BChE-targeted drugs for treating symptoms of neurodegenerative diseases and dementia.

  10. Matrix Metalloproteinase Responsive Delivery of Myostatin Inhibitors.

    Science.gov (United States)

    Braun, Alexandra C; Gutmann, Marcus; Ebert, Regina; Jakob, Franz; Gieseler, Henning; Lühmann, Tessa; Meinel, Lorenz

    2017-01-01

    The inhibition of myostatin - a member of the transforming growth factor (TGF-β) family - drives regeneration of functional skeletal muscle tissue. We developed a bioresponsive drug delivery system (DDS) linking release of a myostatin inhibitor (MI) to inflammatory flares of myositis to provide self-regulated MI concentration gradients within tissues of need. A protease cleavable linker (PCL) - responding to MMP upregulation - is attached to the MI and site-specifically immobilized on microparticle surfaces. The PCL disintegrated in a matrix metalloproteinase (MMP) 1, 8, and particularly MMP-9 concentration dependent manner, with MMP-9 being an effective surrogate biomarker correlating with the activity of myositis. The bioactivity of particle-surface bound as well as released MI was confirmed by luciferase suppression in stably transfected HEK293 cells responding to myostatin induced SMAD phosphorylation. We developed a MMP-responsive DDS for MI delivery responding to inflammatory flare of a diseased muscle matching the kinetics of MMP-9 upregulation, with MMP-9 kinetics matching (patho-) physiological myostatin levels. ᅟ: Graphical Abstract Schematic illustration of the matrix metalloproteinase responsive delivery system responding to inflammatory flares of muscle disease. The protease cleavable linker readily disintegrates upon entry into the diseased tissue, therby releasing the mystatin inhibitor.

  11. Nontoxic corrosion inhibitors for N80 steel in hydrochloric acid

    OpenAIRE

    M. Yadav; Debasis Behera; Usha Sharma

    2016-01-01

    The purpose of this paper is to evaluate the protective ability of 1-(2-aminoethyl)-2-oleylimidazoline (AEOI) and 1-(2-oleylamidoethyl)-2-oleylimidazoline (OAEOI) as corrosion inhibitors for N80 steel in 15% hydrochloric acid, which may find application as eco-friendly corrosion inhibitors in acidizing processes in petroleum industry. Different concentrations of synthesized inhibitors AEOI and OAEOI were added to the test solution (15% HCl) and the corrosion inhibition of N80 steel in hydroch...

  12. Aromatase inhibitors in men: effects and therapeutic options

    Directory of Open Access Journals (Sweden)

    de Jong Frank H

    2011-06-01

    Full Text Available Abstract Aromatase inhibitors effectively delay epiphysial maturation in boys and improve testosterone levels in adult men Therefore, aromatase inhibitors may be used to increase adult height in boys with gonadotropin-independent precocious puberty, idiopathic short stature and constitutional delay of puberty. Long-term efficacy and safety of the use of aromatase inhibitors has not yet been established in males, however, and their routine use is therefore not yet recommended.

  13. Inhibitors of Fatty Acid Synthase for Prostate Cancer. Revision

    Science.gov (United States)

    2013-05-01

    acetyl- cholinesterase inhibitors have been developed, many with femtomolar binding affinities (7). This body of literature also confirms that the...AD_________________ Award Number: W81XWH-09-1-0204 TITLE: Inhibitors of Fatty Acid Synthase for...May 2013 2. REPORT TYPE Revised Final 3. DATES COVERED 01 May 2009-30 Apr 2013 4. TITLE AND SUBTITLE Inhibitors of Fatty Acid Synthase for

  14. Inhibitors of Fatty Acid Synthase for Prostate Cancer

    Science.gov (United States)

    2012-05-01

    compounds. For example, numerous classes of acetyl- cholinesterase inhibitors have been developed, m any with fe mtomolar binding affinities (7). This...AD_________________ Award Number: W81XWH-09-1-0204 TITLE: Inhibitors of Fatty Acid Synthase for...CONTRACT NUMBER Inhibitors of Fatty Acid Synthase for Prostate Cancer 5b. GRANT NUMBER W81XWH-09-1-0204 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR

  15. Natural compounds as corrosion inhibitors for highly cycled systems

    Energy Technology Data Exchange (ETDEWEB)

    Quraishi, M.A.; Farooqi, I.H.; Saini, P.A. [Corrosion Research Lab., Aligarh (India)

    1999-11-01

    Strict environmental legislations have led to the development of green inhibitors in recent years. In continuation of the authors` research work on development of green inhibitors, they have investigated the aqueous extracts of three plants namely: Azadirachta indica, Punica Granatum and Momordica charantia as corrosion inhibitors for mild steel in 3% NaCl using weight loss and electrochemical methods. All the investigated compounds exhibited excellent corrosion inhibition properties comparable to that of HEDP. Azadirachta showed better scale inhibition effect than HEDP.

  16. Invertase proteinaceous inhibitor of Cyphomandra betacea Sendt fruits.

    Science.gov (United States)

    Ordóñez, R M; Isla, M I; Vattuone, M A; Sampietro, A R

    2000-01-01

    This work describes a new invertase proteinaceous inhibitor from Cyphomandra betacea Sendt. (tomate de arbol) fruits. The proteinaceous inhibitor was isolated and purified from a cell wall preparation. The pH stability, kinetics of the inhibition of the C. betacea invertase, inhibition of several higher plant invertases and lectin nature of the inhibitor were studied. The inhibitor structure involves a single polypeptide (Mr = 19000), as shown by gel filtration and SDS-PAGE determinations. N-terminal aminoacid sequence was determined. The properties and some structural features of the inhibitor are compared with the proteinaceous inhibitors from several plant species (Beta vulgaris L., Ipomoea batatas L. and Lycopersicon esculentum Mill.). All these inhibitors share lectinic properties, some common epitopes, some aminoacid sequences and a certain lack of specificity towards invertases of different species, genera and even plant family. In consequence, the inhibitors appear to belong to the same lectin family. It is now known that some lectins are part of the defence mechanism of higher plants against fungi and bacteria and this is a probable role of the proteinaceous inhibitors.

  17. Predicting DPP-IV inhibitors with machine learning approaches

    Science.gov (United States)

    Cai, Jie; Li, Chanjuan; Liu, Zhihong; Du, Jiewen; Ye, Jiming; Gu, Qiong; Xu, Jun

    2017-04-01

    Dipeptidyl peptidase IV (DPP-IV) is a promising Type 2 diabetes mellitus (T2DM) drug target. DPP-IV inhibitors prolong the action of glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP), improve glucose homeostasis without weight gain, edema, and hypoglycemia. However, the marketed DPP-IV inhibitors have adverse effects such as nasopharyngitis, headache, nausea, hypersensitivity, skin reactions and pancreatitis. Therefore, it is still expected for novel DPP-IV inhibitors with minimal adverse effects. The scaffolds of existing DPP-IV inhibitors are structurally diversified. This makes it difficult to build virtual screening models based upon the known DPP-IV inhibitor libraries using conventional QSAR approaches. In this paper, we report a new strategy to predict DPP-IV inhibitors with machine learning approaches involving naïve Bayesian (NB) and recursive partitioning (RP) methods. We built 247 machine learning models based on 1307 known DPP-IV inhibitors with optimized molecular properties and topological fingerprints as descriptors. The overall predictive accuracies of the optimized models were greater than 80%. An external test set, composed of 65 recently reported compounds, was employed to validate the optimized models. The results demonstrated that both NB and RP models have a good predictive ability based on different combinations of descriptors. Twenty "good" and twenty "bad" structural fragments for DPP-IV inhibitors can also be derived from these models for inspiring the new DPP-IV inhibitor scaffold design.

  18. Experimental and theoretical studies of benzoxazines corrosion inhibitors

    Directory of Open Access Journals (Sweden)

    Abdulhadi Kadhim

    Full Text Available 2-Methyl-4H-benzo[d][1,3]oxazin-4-one (BZ1 and 3-amino-2-methylquinazolin-4(3H-one (BZ2 were evaluated for their corrosion inhibition properties on mild steel (MS in hydrochloric acid solution by weight loss technique and scanning electron microscopy. Results show the inhibition efficiency values depend on the amount of nitrogen in the inhibitor, the inhibitor concentration and the inhibitor molecular weight with maximum inhibition efficiency of 89% and 65% for BZ2 and BZ1 at highest concentration of the compounds. Keywords: Methylquinazoline, Benzoxazines, Corrosion, Inhibitors

  19. Cysteine peptidases and their inhibitors in breast and genital cancer.

    Directory of Open Access Journals (Sweden)

    Magdalena Milan

    2010-11-01

    Full Text Available Cysteine proteinases and their inhibitors probably play the main role in carcinogenesis and metastasis. The metastasis process need external proteolytic activities that pass several barriers which are membranous structures of the connective tissue which includes, the basement membrane of blood vessels. Activities of the proteinases are regulated by endogenous inhibitors and activators. The imbalance between cysteine proteinases and cystatins seems to be associated with an increase in metastatic potential in some tumors. It has also been reported that proteinase inhibitors, specific antibodies for these enzymes and inhibition of the urokinase receptor may prevent cancer cell invasion. Some proteinase inhibitor could serve as agents for cancer treatment.

  20. Insights into the molecular evolution of peptidase inhibitors in arthropods.

    Science.gov (United States)

    Alonso, Joaquin; Martinez, Manuel

    2017-01-01

    Peptidase inhibitors are key proteins involved in the control of peptidases. In arthropods, peptidase inhibitors modulate the activity of peptidases involved in endogenous physiological processes and peptidases of the organisms with which they interact. Exploring available arthropod genomic sequences is a powerful way to obtain the repertoire of peptidase inhibitors in every arthropod species and to understand the evolutionary mechanisms involved in the diversification of this kind of proteins. A genomic comparative analysis of peptidase inhibitors in species belonging to different arthropod taxonomic groups was performed. The results point out: i) species or clade-specific presence is shown for several families of peptidase inhibitors; ii) multidomain peptidase inhibitors are commonly found in many peptidase inhibitor families; iii) several families have a wide range of members in different arthropod species; iv) several peptidase inhibitor families show species-specific (or clade-specific) gene family expansions; v) functional divergence may be assumed for particular clades; vi) passive expansions may be used by natural selection to fix adaptations. In conclusion, conservation and divergence of duplicated genes and the potential recruitment as peptidase inhibitors of proteins from other families are the main mechanisms used by arthropods to fix diversity. This diversity would be associated to the control of target peptidases and, as consequence, to adapt to specific environments.

  1. The safety of proton pump inhibitors in pregnancy

    DEFF Research Database (Denmark)

    Nielsen, Gunnar Lauge; Sørensen, Henrik Toft; Thulstrup, Ane Marie

    1999-01-01

    AIM: To assess the safety of proton pump inhibitors during pregnancy. METHODS: Fifty-one pregnant women exposed to proton pump inhibitors around the time of conception or during pregnancy were compared with 13 327 controls without exposure to any prescribed drug in a population-based study based...... birth weight or number of preterm deliveries in pregnancies exposed to proton pump inhibitors. However, further monitoring is warranted in order to establish or rule out a potential association between the use of proton pump inhibitors and increased risk of either cardiac malformations or preterm birth....

  2. Inhibitory Effects of Respiration Inhibitors on Aflatoxin Production

    Directory of Open Access Journals (Sweden)

    Shohei Sakuda

    2014-03-01

    Full Text Available Aflatoxin production inhibitors, which do not inhibit the growth of aflatoxigenic fungi, may be used to control aflatoxin without incurring a rapid spread of resistant strains. A respiration inhibitor that inhibits aflatoxin production was identified during a screening process for natural, aflatoxin-production inhibitors. This prompted us to evaluate respiration inhibitors as potential aflatoxin control agents. The inhibitory activities of four natural inhibitors, seven synthetic miticides, and nine synthetic fungicides were evaluated on aflatoxin production in Aspergillus parasiticus. All of the natural inhibitors (rotenone, siccanin, aptenin A5, and antimycin A inhibited fungal aflatoxin production with IC50 values around 10 µM. Among the synthetic miticides, pyridaben, fluacrypyrim, and tolfenpyrad exhibited strong inhibitory activities with IC50 values less than 0.2 µM, whereas cyflumetofen did not show significant inhibitory activity. Of the synthetic fungicides, boscalid, pyribencarb, azoxystrobin, pyraclostrobin, and kresoxim-methyl demonstrated strong inhibitory activities, with IC50 values less than 0.5 µM. Fungal growth was not significantly affected by any of the inhibitors tested at concentrations used. There was no correlation observed between the targets of respiration inhibitors (complexes I, II, and III and their IC50 values for aflatoxin-production inhibitory activity. This study suggests that respiration inhibitors, including commonly used pesticides, are useful for aflatoxin control.

  3. Inhibitory Effects of Respiration Inhibitors on Aflatoxin Production

    Science.gov (United States)

    Sakuda, Shohei; Prabowo, Diyan Febri; Takagi, Keiko; Shiomi, Kazuro; Mori, Mihoko; Ōmura, Satoshi; Nagasawa, Hiromichi

    2014-01-01

    Aflatoxin production inhibitors, which do not inhibit the growth of aflatoxigenic fungi, may be used to control aflatoxin without incurring a rapid spread of resistant strains. A respiration inhibitor that inhibits aflatoxin production was identified during a screening process for natural, aflatoxin-production inhibitors. This prompted us to evaluate respiration inhibitors as potential aflatoxin control agents. The inhibitory activities of four natural inhibitors, seven synthetic miticides, and nine synthetic fungicides were evaluated on aflatoxin production in Aspergillus parasiticus. All of the natural inhibitors (rotenone, siccanin, aptenin A5, and antimycin A) inhibited fungal aflatoxin production with IC50 values around 10 µM. Among the synthetic miticides, pyridaben, fluacrypyrim, and tolfenpyrad exhibited strong inhibitory activities with IC50 values less than 0.2 µM, whereas cyflumetofen did not show significant inhibitory activity. Of the synthetic fungicides, boscalid, pyribencarb, azoxystrobin, pyraclostrobin, and kresoxim-methyl demonstrated strong inhibitory activities, with IC50 values less than 0.5 µM. Fungal growth was not significantly affected by any of the inhibitors tested at concentrations used. There was no correlation observed between the targets of respiration inhibitors (complexes I, II, and III) and their IC50 values for aflatoxin-production inhibitory activity. This study suggests that respiration inhibitors, including commonly used pesticides, are useful for aflatoxin control. PMID:24674936

  4. Inga laurina trypsin inhibitor (ILTI) obstructs Spodoptera frugiperda trypsins expressed during adaptive mechanisms against plant protease inhibitors.

    Science.gov (United States)

    Machado, Suzy Wider; de Oliveira, Caio Fernando Ramalho; Zério, Neide Graciano; Parra, José Roberto Postali; Macedo, Maria Lígia Rodrigues

    2017-08-01

    Plant protease inhibitors (PIs) are elements of a common plant defense mechanism induced in response to herbivores. The fall armyworm, Spodoptera frugiperda, a highly polyphagous lepidopteran pest, responds to various PIs in its diet by expressing genes encoding trypsins. This raises the question of whether the PI-induced trypsins are also inhibited by other PIs, which we posed as the hypothesis that Inga laurina trypsin inhibitor (ILTI) inhibits PI-induced trypsins in S. frugiperda. In the process of testing our hypothesis, we compared its properties with those of selected PIs, soybean Kunitz trypsin inhibitor (SKTI), Inga vera trypsin inhibitor (IVTI), Adenanthera pavonina trypsin inhibitor (ApTI), and Entada acaciifolia trypsin inhibitor (EATI). We report that ILTI is more effective in inhibiting the induced S. frugiperda trypsins than SKTI and the other PIs, which supports our hypothesis. ILTI may be more appropriate than SKTI for studies regarding adaptive mechanisms to dietary PIs. © 2017 Wiley Periodicals, Inc.

  5. Identification of fermentation inhibitors in wood hydrolyzates and removal of inhibitors by ion exchange and liquid-liquid extraction

    Science.gov (United States)

    Luo, Caidian

    1998-12-01

    Common methods employed in the ethanol production from biomass consist of chemical or enzymatic degradation of biomass into sugars and then fermentation of sugars into ethanol or other chemicals. However, some degradation products severely inhibit the fermentation processes and substantially reduce the efficiency of ethanol production. How to remove inhibitors from the reaction product mixture and increase the production efficiency are critical in the commercialization of any processes of energy from biomass. The present study has investigated anion exchange and liquid-liquid extraction as potential methods for inhibitor removal. An analytical method has been developed to identify the fermentation inhibitors in a hydrolyzate. The majority of inhibitors present in hybrid poplar hydrolyzate have positively been identified. Ion exchange with weak basic Dowex-MWA-1 resin has been proved to be an effective mean to remove fermentation inhibitors from hybrid poplar hydrolyzate and significantly increase the fermentation productivity. Extraction with n-butanol might be a preferred way to remove inhibitors from wood hydrolyzates and improve the fermentability of sugars in the hydrolyzates. n-Butanol also removes some glucose, mannose and xylose from the hydrolyzate. Inhibitor identification reveals that lignin and sugar degradation compounds including both aromatic and aliphatic aldehydes and carboxylic acids formed in hydrolysis, plus fatty acids and other components from wood extractives are major fermentation inhibitors in Sacchromyces cerevisiae fermentation. There are 35 components identified as fermentation inhibitors. Among them, 4-hydroxy benzoic acid, 3,4-dihydroxy benzoic acid, syringic acid, syringaldehyde, and ferulic acid are among the most abundant aromatic inhibitors in hybrid poplar hydrolyzate. The conversion of aldehyde groups into carboxylic acid groups in the nitric acid catalyzed hydrolysis reduces the toxicity of the hydrolyzate. A wide spectrum of

  6. The effects of residual platelets in plasma on plasminogen activator inhibitor-1 and plasminogen activator inhibitor-1-related assays.

    Directory of Open Access Journals (Sweden)

    Marlien Pieters

    Full Text Available Due to controversial evidence in the literature pertaining to the activity of plasminogen activator inhibitor-1 in platelets, we examined the effects of residual platelets present in plasma (a potential pre-analytical variable on various plasminogen activator inhibitor-1 and plasminogen activator inhibitor-1-related assays. Blood samples were collected from 151 individuals and centrifuged at 352 and 1500 g to obtain plasma with varying numbers of platelet. In a follow-up study, blood samples were collected from an additional 23 individuals, from whom platelet-poor (2000 g, platelet-containing (352 g and platelet-rich plasma (200 g were prepared and analysed as fresh-frozen and after five defrost-refreeze cycles (to determine the contribution of in vitro platelet degradation. Plasminogen activator inhibitor-1 activity, plasminogen activator inhibitor-1 antigen, tissue plasminogen activator/plasminogen activator inhibitor-1 complex, plasma clot lysis time, β-thromboglobulin and plasma platelet count were analysed. Platelet α-granule release (plasma β-thromboglobulin showed a significant association with plasminogen activator inhibitor-1 antigen levels but weak associations with plasminogen activator inhibitor-1 activity and a functional marker of fibrinolysis, clot lysis time. Upon dividing the study population into quartiles based on β-thromboglobulin levels, plasminogen activator inhibitor-1 antigen increased significantly across the quartiles while plasminogen activator inhibitor-1 activity and clot lysis time tended to increase in the 4th quartile only. In the follow-up study, plasma plasminogen activator inhibitor-1 antigen was also significantly influenced by platelet count in a concentration-dependent manner. Plasma plasminogen activator inhibitor-1 antigen levels increased further after complete platelet degradation. Residual platelets in plasma significantly influence plasma plasminogen activator inhibitor-1 antigen levels mainly

  7. Proton pump inhibitors inhibit pancreatic secretion

    DEFF Research Database (Denmark)

    Wang, Jing; Barbuskaite, Dagne; Tozzi, Marco

    2015-01-01

    +/K+-ATPases are expressed and functional in human pancreatic ducts and whether proton pump inhibitors (PPIs) have effect on those. Here we show that the gastric HKα1 and HKβ subunits (ATP4A; ATP4B) and non-gastric HKα2 subunits (ATP12A) of H+/K+-ATPases are expressed in human pancreatic cells. Pumps have similar...... of major ions in secretion follow similar excretory curves in control and PPI treated animals. In addition to HCO3-, pancreas also secretes K+. In conclusion, this study calls for a revision of the basic model for HCO3- secretion. We propose that proton transport is driving secretion, and that in addition...

  8. Neuromuscular complications of immune checkpoint inhibitor therapy.

    Science.gov (United States)

    Kolb, Noah A; Trevino, Christopher R; Waheed, Waqar; Sobhani, Fatemeh; Landry, Kara K; Thomas, Alissa A; Hehir, Mike

    2018-01-17

    Immune checkpoint inhibitor (ICPI) therapy unleashes the body's natural immune system to fight cancer. ICPIs improve overall cancer survival, however, the unbridling of the immune system may induce a variety of immune-related adverse events. Neuromuscular immune complications are rare but they can be severe. Myasthenia gravis and inflammatory neuropathy are the most common neuromuscular adverse events but a variety of others including inflammatory myopathy are reported. The pathophysiologic mechanism of these autoimmune disorders may differ from that of non-ICPI-related immune diseases. Accordingly, while the optimal treatment for ICPI-related neuromuscular disorders generally follows a traditional paradigm, there are important novel considerations in selecting appropriate immunosuppressive therapy. This review presents 2 new cases, a summary of neuromuscular ICPI complications, and an approach to the diagnosis and treatment of these disorders. Muscle Nerve, 2018. © 2018 Wiley Periodicals, Inc.

  9. Phosphodiesterase Type 5 Inhibitors, Sport and Doping.

    Science.gov (United States)

    Di Luigi, Luigi; Sansone, Massimiliano; Sansone, Andrea; Ceci, Roberta; Duranti, Guglielmo; Borrione, Paolo; Crescioli, Clara; Sgrò, Paolo; Sabatini, Stefania

    Phosphodiesterase type 5 inhibitors (PDE5i) (e.g., sildenafil, tadalafil, vardenafil, and avanafil) are drugs commonly used to treat erectile dysfunction, pulmonary arterial hypertension, and benign prostatic hyperplasia. PDE5i are not prohibited by the World Anti-Doping Agency (WADA) but are alleged to be frequently misused by healthy athletes to improve sporting performance. In vitro and in vivo studies have reported various effects of PDE5i on cardiovascular, muscular, metabolic, and neuroendocrine systems and the potential, therefore, to enhance performance of healthy athletes during training and competition. This suggests well-controlled research studies to examine the ergogenic effects of PDE5i on performance during activities that simulate real sporting situations are warranted to determine if PDE5i should be included on the prohibited WADA list. In the meantime, there is concern that some otherwise healthy athletes will continue to misuse PDE5i to gain an unfair competitive advantage over their competitors.

  10. Developing BACE-1 inhibitors for FXS

    Directory of Open Access Journals (Sweden)

    Cara J Westmark

    2013-05-01

    Full Text Available Fragile X syndrome (FXS is a debilitating genetic disorder with no cure and few therapeutic options. Excessive signaling through metabotropic glutamate receptor 5 (mGluR5 in FXS leads to increased translation of numerous synaptic proteins and exaggerated long-term depression (LTD. Two of the overexpressed proteins are amyloid-beta protein precursor (APP and its metabolite amyloid-beta (Aβ, which have been well-studied in Alzheimer’s disease (AD. Here we discus the possibility that pharmaceuticals under study for the modulation of these proteins in AD might be viable therapeutic strategies for FXS. Specifically, a recently identified acetyltransferase (ATase inhibitor that reduces the levels and activity of β-site APP cleaving enzyme (BACE-1 has strong potential to attenuate BACE-1 activity and maintain homeostatic levels APP catabolites in FXS.

  11. Coumarins as cholinesterase inhibitors: A review.

    Science.gov (United States)

    de Souza, Luana G; Rennã, Magdalena N; Figueroa-Villar, Jose D

    2016-07-25

    The first report in literature of the isolation of coumarin was in the year 1820. After this report, other papers were published demonstrating the isolation and synthesis of coumarin and analogues. These compounds have been studying along the years for several different pathologies. One of these pathologies was Alzheimer's disease (AD), being the main cause of dementia in the contemporary world. There are two hypotheses to explain the pathogenesis mechanism and disease symptoms, then having the "amyloid hypothesis" and the "cholinergic hypothesis". Some drugs for AD are based on the theory of "cholinergic hypothesis", which objective is to increase the concentration of ACh in the synaptic cleft by the inhibition of cholinesterases. Over the last twenty years, many studies with coumarins compounds were reported as cholinesterases inhibitors. The aim of the present review is to discuss the studies and development of new compounds for AD treatment. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  12. New Acetylcholinesterase Inhibitors for Alzheimer's Disease

    Directory of Open Access Journals (Sweden)

    Mona Mehta

    2012-01-01

    Full Text Available Acetylcholinesterase (AChE remains a highly viable target for the symptomatic improvement in Alzheimer's disease (AD because cholinergic deficit is a consistent and early finding in AD. The treatment approach of inhibiting peripheral AchE for myasthenia gravis had effectively proven that AchE inhibition was a reachable therapeutic target. Subsequently tacrine, donepezil, rivastigmine, and galantamine were developed and approved for the symptomatic treatment of AD. Since then, multiple cholinesterase inhibitors (ChEI continue to be developed. These include newer ChEIs, naturally derived ChEIs, hybrids, and synthetic analogues. In this paper, we summarize the different types of ChEIs in development and their respective mechanisms of actions. This pharmacological approach continues to be active with many promising compounds.

  13. Endogenous Natural Complement Inhibitor Regulates Cardiac Development

    DEFF Research Database (Denmark)

    Mortensen, Simon A; Skov, Louise L; Kjaer-Sorensen, Kasper

    2017-01-01

    mechanisms during fetal development and adult homeostasis. In this article, we describe the function of an endogenous complement inhibitor, mannan-binding lectin (MBL)-associated protein (MAp)44, in regulating the composition of a serine protease-pattern recognition receptor complex, MBL-associated serine...... of MAp44 caused impaired cardiogenesis, lowered heart rate, and decreased cardiac output. These defects were associated with aberrant neural crest cell behavior. We found that MAp44 competed with MASP-3 for pattern recognition molecule interaction, and knockdown of endogenous MAp44 expression could...... be rescued by overexpression of wild-type MAp44. Our observations provide evidence that immune molecules are centrally involved in the orchestration of cardiac tissue development....

  14. Histone deacetylase inhibitors in multiple myeloma

    Directory of Open Access Journals (Sweden)

    Sarah Deleu

    2009-06-01

    Full Text Available Novel drugs such as bortezomib and high dose chemotherapy combined with stem cell transplantation improved the outcome of multiple myeloma patients in the past decade. However, multiple myeloma often remains incurable due to the development of drug resistance governed by the bone marrow micro-environment. Therefore targeting new pathways to overcome this resistance is needed. Histone deacetylase (HDAC inhibitors represent a new class of anti-myeloma agents. Inhibiting HDACs results in histone hyperacetylation and alterations in chromatine structure, which, in turn, cause growth arrest differentiation and/or apoptosis in several tumor cells. Here we summarize the molecular actions of HDACi as a single agent or in combination with other drugs in different in vitro and in vivo myeloma models and in (preclinical trials.

  15. Molecular modeling of auxin transport inhibitors

    International Nuclear Information System (INIS)

    Gardner, G.; Black-Schaefer, C.; Bures, M.G.

    1990-01-01

    Molecular modeling techniques have been used to study the chemical and steric properties of auxin transport inhibitors. These bind to a specific site on the plant plasma membrane characterized by its affinity for N-1-naphthylphthalamic acid (NPA). A three-dimensional model was derived from critical features of ligands for the NPA receptor, and a suggested binding conformation is proposed. This model, along with three-dimensional structural searching techniques, was then used to search the Abbott corporate database of chemical structures. Of the 467 compounds that satisfied the search criteria, 77 representative molecules were evaluated for their ability to compete for [ 3 H]NPA binding to corn microsomal membranes. Nineteen showed activity that ranged from 16 to 85% of the maximum NPA binding. Four of the most active of these, from chemical classes not included in the original compound set, also inhibited polar auxin transport through corn coleoptile sections

  16. Carbocyclic Carbohydrate Mimics as Potential Glycosidase Inhibitors

    DEFF Research Database (Denmark)

    Fanefjord, Mette; Lundt, Inge

    It has been proven that aminocyclopentanols having the aminogroup adjacent to a carbon sidechain could be potential anomer-selective glycosidase inhibitors [1]. A successful pathway for synthesising mimics to L-carbohydrates 2, by introducing nitrogen to the C6 position in compound 1, has been...... developed in our group. A similar strategy has been used for synthesising mimics of D-carbohydrates. The α,β-unsaturated lactone 3 was cyclised to compound 4 which was further transformed into 5. The nitrogen functionality in compound 7 is introduced by an Overman rearrangement of 6 and the hydroxyl...... functionalities was introduced by either epoxidation or dihydroxylation of 7. Finally, reduction of the lactone ring led to the sugar mimics 8. The synthesis of several isomers of 8 will be presented. [1] a) Kleban, M. ; Hilgers, P. ; Greul, J.N. ; Kugler, R.D. ; Li, J. ; Picasso, S. ; Vogel, P. ; Jäger, V. Chem...

  17. Use of proteasome inhibitors in anticancer therapy

    Directory of Open Access Journals (Sweden)

    Sara M. Schmitt

    2011-10-01

    Full Text Available The importance of the ubiquitin-proteasome pathway to cellular function has brought it to the forefront in the search for new anticancer therapies. The ubiquitin-proteasome pathway has proven promising in targeting various human cancers. The approval of the proteasome inhibitor bortezomib for clinical treatment of relapsed/refractory multiple myeloma and mantle cell lymphoma has validated the ubiquitin-proteasome as a rational target. Bortezomib has shown positive results in clinical use but some toxicity and side effects, as well as resistance, have been observed, indicating that further development of novel, less toxic drugs is necessary. Because less toxic drugs are necessary and drug development can be expensive and time-consuming, using existing drugs that can target the ubiquitin-proteasome pathway in new applications, such as cancer therapy, may be effective in expediting the regulatory process and bringing new drugs to the clinic. Toward this goal, previously approved drugs, such as disulfiram, as well as natural compounds found in common foods, such as green tea polyphenol (--EGCG and the flavonoid apigenin, have been investigated for their possible proteasome inhibitory and cell death inducing abilities. These compounds proved quite promising in preclinical studies and have now moved into clinical trials, with preliminary results that are encouraging. In addition to targeting the catalytic activity of the proteasome pathway, upstream regulators, such as the 19S regulatory cap, as well as E1, E2, and E3, are now being investigated as potential drug targets. This review outlines the development of novel proteasome inhibitors from preclinical to clinical studies, highlighting their abilities to inhibit the tumor proteasome and induce apoptosis in several human cancers.

  18. Molecular Dynamics simulations of Inhibitor of Apoptosis Proteins and identification of potential small molecule inhibitors.

    Science.gov (United States)

    Jayakumar, Jayanthi; Anishetty, Sharmila

    2014-05-01

    Chemotherapeutic resistance due to over expression of Inhibitor of Apoptosis Proteins (IAPs) XIAP, survivin and livin has been observed in various cancers. In the current study, Molecular Dynamics (MD) simulations were carried out for all three IAPs and a common ligand binding scaffold was identified. Further, a novel sequence based motif specific to these IAPs was designed. SMAC is an endogenous inhibitor of IAPs. Screening of ChemBank for compounds similar to lead SMAC-non-peptidomimetics yielded a cemadotin related compound NCIMech_000654. Cemadotin is a derivative of natural anti-tumor peptide dolastatin-15; hence these compounds were docked against all three IAPs. Based on our analysis, we propose that NCIMech_000654/dolastatin-15/cemadotin derivatives may be investigated for their potential in inhibiting XIAP, survivin and livin. Copyright © 2014 Elsevier Ltd. All rights reserved.

  19. Effect of biocides and anionic homopolymeric inhibitors on the ...

    African Journals Online (AJOL)

    This paper describes the effect of biocides and of the anionic homopolymeric inhibitors on the precipitation behavior of calcium fluoride (CaF2).The efficiency of inhibitors in the presence and absence of biocides was calculated using the half-life (t1/2) approach, where 50% of the concentration has been precipitated.

  20. High throughput in vivo protease inhibitor selection platform

    DEFF Research Database (Denmark)

    2017-01-01

    The invention relates to a recombinant microbial cell comprising a selection platform for screening for a protease inhibitor, wherein the platform comprises transgenes encoding a protease having selective peptide bond cleavage activity at a recognition site amino acid sequence; and transgenes...... platform for screening for a protease inhibitor....

  1. Regulation of collagenase inhibitor production in chondrosarcoma chondrocytes

    International Nuclear Information System (INIS)

    Harper, J.; Harper, E.

    1987-01-01

    Swarm rat chondrosarcoma chondrocytes produce an inhibitor of collagenase. This inhibitor is similar to those isolated from normal cartilage tissues. These cells will synthesize proteins in the absence of serum. Since serum contains inhibitors of collagenase, it is necessary to culture cells without serum in order to obtain accurate measurements of enzyme and inhibitor levels. They examined the effect of insulin on inhibitor secretion by cultures of Swarm rat chondrosarcoma chondrocytes. They observed a 2.5 to 3.5 fold stimulation of inhibitory activity in the presence of as little as 10 ng/ml insulin as compared to controls in serum free Dulbecco's modified Eagle's medium supplemented with 4.5 g/l glucose. The units of inhibitor were determined over a 7 day culture period. Medium was harvested daily and assayed for collagenase activity and for inhibition of a known collagenase from rabbit skin or human skin, using the 14 C-glycine peptide release assay. The amount of inhibitor obtained from days 2 through 7 were: 1.4 unit (control), 3.8 units (10 ng/ml insulin), 5.2 units (1 μg/ml insulin). The addition of 1 mM dibutyryl cyclic AMP to these chondrocytes in the presence of 1 μg/ml insulin caused a decrease in the level of inhibitor, suggesting that a dephosphorylation event may be necessary for this stimulation by insulin to occur

  2. Nontoxic corrosion inhibitors for N80 steel in hydrochloric acid

    Directory of Open Access Journals (Sweden)

    M. Yadav

    2016-11-01

    Full Text Available The purpose of this paper is to evaluate the protective ability of 1-(2-aminoethyl-2-oleylimidazoline (AEOI and 1-(2-oleylamidoethyl-2-oleylimidazoline (OAEOI as corrosion inhibitors for N80 steel in 15% hydrochloric acid, which may find application as eco-friendly corrosion inhibitors in acidizing processes in petroleum industry. Different concentrations of synthesized inhibitors AEOI and OAEOI were added to the test solution (15% HCl and the corrosion inhibition of N80 steel in hydrochloric acid medium containing inhibitors was tested by weight loss, potentiodynamic polarization and AC impedance measurements. Influence of temperature (298–323 K on the inhibition behavior was studied. Surface studies were performed by using FTIR spectra and SEM. Both the inhibitors, AEOI and OAEOI at 150 ppm concentration show maximum efficiency 90.26% and 96.23%, respectively at 298 K in 15% HCl solution. Both the inhibitors act as mixed corrosion inhibitors. The adsorption of the corrosion inhibitors at the surface of N80 steel is the root cause of corrosion inhibition.