WorldWideScience

Sample records for cancer therapeutic agents

  1. Microtubule-binding agents: a dynamic field of cancer therapeutics

    OpenAIRE

    Dumontet, Charles; Jordan, Mary Ann

    2010-01-01

    International audience Microtubules are dynamic filamentous cytoskeletal proteins composed of tubulin and are an important therapeutic target in tumour cells. Agents that bind to microtubules have been part of the pharmacopoeia of anticancer therapy for decades and until the advent of targeted therapy, microtubules were the only alternative to DNA as a therapeutic target in cancer. The screening of a range of botanical species and marine organisms has yielded promising new antitubulin agen...

  2. Terpenoids as potential chemopreventive and therapeutic agents in liver cancer.

    Science.gov (United States)

    Thoppil, Roslin J; Bishayee, Anupam

    2011-09-27

    Despite significant advances in medicine, liver cancer, predominantly hepatocellular carcinoma remains a major cause of death in the United States as well as the rest of the world. As limited treatment options are currently available to patients with liver cancer, novel preventive control and effective therapeutic approaches are considered to be reasonable and decisive measures to combat this disease. Several naturally occurring dietary and non-dietary phytochemicals have shown enormous potential in the prevention and treatment of several cancers, especially those of the gastrointestinal tract. Terpenoids, the largest group of phytochemicals, traditionally used for medicinal purposes in India and China, are currently being explored as anticancer agents in clinical trials. Terpenoids (also called "isoprenoids") are secondary metabolites occurring in most organisms, particularly plants. More than 40 000 individual terpenoids are known to exist in nature with new compounds being discovered every year. A large number of terpenoids exhibit cytotoxicity against a variety of tumor cells and cancer preventive as well as anticancer efficacy in preclinical animal models. This review critically examines the potential role of naturally occurring terpenoids, from diverse origins, in the chemoprevention and treatment of liver tumors. Both in vitro and in vivo effects of these agents and related cellular and molecular mechanisms are highlighted. Potential challenges and future directions involved in the advancement of these promising natural compounds in the chemoprevention and therapy of human liver cancer are also discussed. PMID:21969877

  3. Novel therapeutic agents in the treatment of metastaticcolorectal cancer

    Institute of Scientific and Technical Information of China (English)

    2016-01-01

    Over the past couple of decades considerable progresshas been made in the management of metastaticcolorectal cancers (mCRC) leading to a significant improvementin five-year survival. Although part of thissuccess has been rightly attributed to aggressive surgicalmanagement and advances in other adjunct treatments,our understanding of the pathogenesis of cancer andemergence of newer molecular targets for colon cancerhas created a powerful impact. In this review article wewill discuss various targeted therapies in the managementof mCRC. Newer agents on the horizon soon to beincorporated in clinical practice will be briefly reviewedas well.

  4. Radiation-Therapeutic Agent Clinical Trials: Leveraging Advantages of a National Cancer Institute Programmatic Collaboration.

    Science.gov (United States)

    Takebe, Naoko; Ahmed, Mansoor M; Vikram, Bhadrasain; Bernhard, Eric J; Zwiebel, James; Norman Coleman, C; Kunos, Charles A

    2016-10-01

    A number of oncology phase II radiochemotherapy trials with promising results have been conducted late in the overall experimental therapeutic agent development process. Accelerated development and approval of experimental therapeutic agents have stimulated further interest in much earlier radiation-agent studies to increase the likelihood of success in phase III trials. To sustain this interest, more forward-thinking preclinical radiobiology experimental designs are needed to improve discovery of promising radiochemotherapy plus agent combinations for clinical trial testing. These experimental designs should better inform next-step radiation-agent clinical trial dose, schedule, exposure, and therapeutic effect. Recognizing the need for a better strategy to develop preclinical data supporting radiation-agent phase I or II trials, the National Cancer Institute (NCI)-Cancer Therapy Evaluation Program (CTEP) and the NCI-Molecular Radiation Therapeutics Branch of the Radiation Research Program have partnered to promote earlier radiobiology studies of CTEP portfolio agents. In this Seminars in Radiation Oncology article, four key components of this effort are discussed. First, we outline steps for accessing CTEP agents for preclinical testing. Second, we propose radiobiology studies that facilitate transition from preclinical testing to early phase trial activation. Third, we navigate steps that walk through CTEP agent strategic development paths available for radiation-agent testing. Fourth, we highlight a new NCI-sponsored cooperative agreement grant supporting in vitro and in vivo radiation-CTEP agent testing that informs early phase trial designs. Throughout the article, we include contemporary examples of successful radiation-agent development initiatives.

  5. Nutraceuticals as potential therapeutic agents for colon cancer: a review

    OpenAIRE

    Palaniselvam Kuppusamy; Yusoff, Mashitah M.; Gaanty Pragas Maniam; Solachuddin Jauhari Arief Ichwan; Ilavenil Soundharrajan; Natanamurugaraj Govindan

    2014-01-01

    Colon cancer is a world-wide health problem and the second-most dangerous type of cancer, affecting both men and women. The modern diet and lifestyles, with high meat consumption and excessive alcohol use, along with limited physical activity has led to an increasing mortality rate for colon cancer worldwide. As a result, there is a need to develop novel and environmentally benign drug therapies for colon cancer. Currently, nutraceuticals play an increasingly important role in the treatment o...

  6. Nutraceuticals as potential therapeutic agents for colon cancer: a review

    Directory of Open Access Journals (Sweden)

    Palaniselvam Kuppusamy

    2014-06-01

    Full Text Available Colon cancer is a world-wide health problem and the second-most dangerous type of cancer, affecting both men and women. The modern diet and lifestyles, with high meat consumption and excessive alcohol use, along with limited physical activity has led to an increasing mortality rate for colon cancer worldwide. As a result, there is a need to develop novel and environmentally benign drug therapies for colon cancer. Currently, nutraceuticals play an increasingly important role in the treatment of various chronic diseases such as colon cancer, diabetes and Alzheimer׳s disease. Nutraceuticals are derived from various natural sources such as medicinal plants, marine organisms, vegetables and fruits. Nutraceuticals have shown the potential to reduce the risk of colon cancer and slow its progression. These dietary substances target different molecular aspects of colon cancer development. Accordingly, this review briefly discusses the medicinal importance of nutraceuticals and their ability to reduce the risk of colorectal carcinogenesis.

  7. Flavonoids as Chemopreventive and Therapeutic Agents Against Lung Cancer

    Directory of Open Access Journals (Sweden)

    Albert Cabrera

    2014-05-01

    Full Text Available The objective of the present review is to study the relationship between flavonoids and lung cancer, proposing that their regular consumption in Western diets could be beneficial for protecting patients against lung cancer. An extensive search of the scientific literature was performed in the following electronic specialized databases (PubMed central (PMC-NBCI, Elsevier Journal, SciELO Spain, Scirus, Science Direct, including studies in animals, cells, and humans, in order to establish the effect of flavonoids in the prevention and development of lung cancer. Although in vitro and animal studies show the potential ability of flavonoids to act against different types of cancers, especially against lung cancers, the diverse results reported within epidemiological studies, together with the lack of experiments in humans, are the major factors in limiting making dietary recommendations based on scientific evidence for the management of patients with lung cancer. Therefore, the authors of the present study recommend following the dietary health practice guidelines which promotes the consumption of food enriched in flavonoids and reflects the current state of knowledge of an effective and appropriate diet in lung cancer patients.Erratum in: Rev Esp Nutr Hum Diet. 2013;17(2:91-92Link: http://www.renhyd.org/index.php/renhyd/article/view/6/17

  8. Radiation-Therapeutic Agent Clinical Trials: Leveraging Advantages of a National Cancer Institute Programmatic Collaboration.

    Science.gov (United States)

    Takebe, Naoko; Ahmed, Mansoor M; Vikram, Bhadrasain; Bernhard, Eric J; Zwiebel, James; Norman Coleman, C; Kunos, Charles A

    2016-10-01

    A number of oncology phase II radiochemotherapy trials with promising results have been conducted late in the overall experimental therapeutic agent development process. Accelerated development and approval of experimental therapeutic agents have stimulated further interest in much earlier radiation-agent studies to increase the likelihood of success in phase III trials. To sustain this interest, more forward-thinking preclinical radiobiology experimental designs are needed to improve discovery of promising radiochemotherapy plus agent combinations for clinical trial testing. These experimental designs should better inform next-step radiation-agent clinical trial dose, schedule, exposure, and therapeutic effect. Recognizing the need for a better strategy to develop preclinical data supporting radiation-agent phase I or II trials, the National Cancer Institute (NCI)-Cancer Therapy Evaluation Program (CTEP) and the NCI-Molecular Radiation Therapeutics Branch of the Radiation Research Program have partnered to promote earlier radiobiology studies of CTEP portfolio agents. In this Seminars in Radiation Oncology article, four key components of this effort are discussed. First, we outline steps for accessing CTEP agents for preclinical testing. Second, we propose radiobiology studies that facilitate transition from preclinical testing to early phase trial activation. Third, we navigate steps that walk through CTEP agent strategic development paths available for radiation-agent testing. Fourth, we highlight a new NCI-sponsored cooperative agreement grant supporting in vitro and in vivo radiation-CTEP agent testing that informs early phase trial designs. Throughout the article, we include contemporary examples of successful radiation-agent development initiatives. PMID:27619249

  9. Encapsulation of Cancer Therapeutic Agent Dacarbazine Using Nanostructured Lipid Carrier.

    Science.gov (United States)

    Almoussalam, Musallam; Zhu, Huijun

    2016-01-01

    The only formula of dacarbazine (Dac) in clinical use is intravenous infusion, presenting a poor therapeutic profile due to the low dispersity of the drug in aqueous solution. To overcome this, a nanostructured lipid carrier (NLC) consisting of glyceryl palmitostearate and isopropyl myristate was developed to encapsulate Dac. NLCs with controlled size were achieved using high shear dispersion (HSD) following solidification of oil-in-water emulsion. The synthesis parameters, including surfactant concentration, the speed and time of HSD were optimized to achieve the smallest NLC with size, polydispersion index and zeta potential of 155 ± 10 nm, 0.2 ± 0.01, and -43.4 ± 2 mV, respectively. The optimal parameters were also employed for Dac-loaded NLC preparation. The resultant NLC loaded with Dac possessed size, polydispersion index and zeta potential of 190 ± 10 nm, 0.2 ± 0.01, and -43.5 ± 1.2 mV, respectively. The drug encapsulation efficiency and drug loading reached 98% and 14%, respectively. This is the first report on encapsulation of Dac using NLC, implying that NLC could be a new potential candidate as drug carrier to improve the therapeutic profile of Dac. PMID:27168058

  10. Recent Progress and Advances in HGF/MET-Targeted Therapeutic Agents for Cancer Treatment

    Directory of Open Access Journals (Sweden)

    Yilong Zhang

    2015-03-01

    Full Text Available The hepatocyte growth factor (HGF: MET axis is a ligand-mediated receptor tyrosine kinase pathway that is involved in multiple cellular functions, including proliferation, survival, motility, and morphogenesis. Aberrancy in the HGF/MET pathway has been reported in multiple tumor types and is associated with tumor stage and prognosis. Thus, targeting the HGF/MET pathway has become a potential therapeutic strategy in oncology development in the last two decades. A number of novel therapeutic agents—either as therapeutic proteins or small molecules that target the HGF/MET pathway—have been tested in patients with different tumor types in clinical studies. In this review, recent progress in HGF/MET pathway-targeted therapy for cancer treatment, the therapeutic potential of HGF/MET-targeted agents, and challenges in the development of such agents will be discussed.

  11. New candidate therapeutic agents for endometrial cancer: potential for clinical practice (review).

    Science.gov (United States)

    Umene, Kiyoko; Banno, Kouji; Kisu, Iori; Yanokura, Megumi; Nogami, Yuya; Tsuji, Kosuke; Masuda, Kenta; Ueki, Arisa; Kobayashi, Yusuke; Yamagami, Wataru; Tominaga, Eiichiro; Susumu, Nobuyuki; Aoki, Daisuke

    2013-03-01

    Cases of endometrial cancer have increased in recent years, but the prognosis of patients with this disease has also been improved by combined modality therapy with surgery, radiotherapy and chemotherapy. However, the development of new therapy is required from the perspectives of conservation of fertility and efficacy for recurrent and intractable cancer. New candidate therapeutic agents for endometrial cancer include fourth-generation progestins for inhibition of growth and differentiation of endometrial glands; metformin for reduction of hTERT expression in the endometrium and inhibition of the mTOR pathway by activation of AMPK, with consequent inhibition of the cell cycle; mTOR inhibitors for supressing growth of cancer cells by G1 cell cycle arrest; microRNAs involved in the molecular mechanisms of oncogenesis and progression; and HDAC inhibitors that block the growth of cancer cells by transcriptional elevation of tumor-suppressor genes, cell cycle arrest and induction of apoptosis. In this study, we review the background and early clinical evidence for these agents as new therapeutic candidates for endometrial cancer. PMID:23291663

  12. Preclinical therapeutic potential of a nitrosylating agent in the treatment of ovarian cancer.

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    Shailendra Giri

    Full Text Available This study examines the role of s-nitrosylation in the growth of ovarian cancer using cell culture based and in vivo approaches. Using the nitrosylating agent, S-nitrosoglutathione (GSNO, a physiological nitric oxide molecule, we show that GSNO treatment inhibited proliferation of chemoresponsive and chemoresistant ovarian cancer cell lines (A2780, C200, SKVO3, ID8, OVCAR3, OVCAR4, OVCAR5, OVCAR7, OVCAR8, OVCAR10, PE01 and PE04 in a dose dependent manner. GSNO treatment abrogated growth factor (HB-EGF induced signal transduction including phosphorylation of Akt, p42/44 and STAT3, which are known to play critical roles in ovarian cancer growth and progression. To examine the therapeutic potential of GSNO in vivo, nude mice bearing intra-peritoneal xenografts of human A2780 ovarian carcinoma cell line (2 × 10(6 were orally administered GSNO at the dose of 1 mg/kg body weight. Daily oral administration of GSNO significantly attenuated tumor mass (p<0.001 in the peritoneal cavity compared to vehicle (phosphate buffered saline treated group at 4 weeks. GSNO also potentiated cisplatin mediated tumor toxicity in an A2780 ovarian carcinoma nude mouse model. GSNO's nitrosylating ability was reflected in the induced nitrosylation of various known proteins including NFκB p65, Akt and EGFR. As a novel finding, we observed that GSNO also induced nitrosylation with inverse relationship at tyrosine 705 phosphorylation of STAT3, an established player in chemoresistance and cell proliferation in ovarian cancer and in cancer in general. Overall, our study underlines the significance of S-nitrosylation of key cancer promoting proteins in modulating ovarian cancer and proposes the therapeutic potential of nitrosylating agents (like GSNO for the treatment of ovarian cancer alone or in combination with chemotherapeutic drugs.

  13. Targeting ferritin receptors for the selective delivery of imaging and therapeutic agents to breast cancer cells

    Science.gov (United States)

    Geninatti Crich, S.; Cadenazzi, M.; Lanzardo, S.; Conti, L.; Ruiu, R.; Alberti, D.; Cavallo, F.; Cutrin, J. C.; Aime, S.

    2015-04-01

    In this work the selective uptake of native horse spleen ferritin and apoferritin loaded with MRI contrast agents has been assessed in human breast cancer cells (MCF-7 and MDA-MB-231). The higher expression of L-ferritin receptors (SCARA5) led to an enhanced uptake in MCF-7 as shown in T2 and T1 weighted MR images, respectively. The high efficiency of ferritin internalization in MCF-7 has been exploited for the simultaneous delivery of curcumin, a natural therapeutic molecule endowed with antineoplastic and anti-inflammatory action, and the MRI contrast agent Gd-HPDO3A. This theranostic system is able to treat selectively breast cancer cells over-expressing ferritin receptors. By entrapping in apoferritin both Gd-HPDO3A and curcumin, it was possible to deliver a therapeutic dose of 167 μg ml-1 (as calculated by MRI) of this natural drug to MCF-7 cells, thus obtaining a significant reduction of cell proliferation.In this work the selective uptake of native horse spleen ferritin and apoferritin loaded with MRI contrast agents has been assessed in human breast cancer cells (MCF-7 and MDA-MB-231). The higher expression of L-ferritin receptors (SCARA5) led to an enhanced uptake in MCF-7 as shown in T2 and T1 weighted MR images, respectively. The high efficiency of ferritin internalization in MCF-7 has been exploited for the simultaneous delivery of curcumin, a natural therapeutic molecule endowed with antineoplastic and anti-inflammatory action, and the MRI contrast agent Gd-HPDO3A. This theranostic system is able to treat selectively breast cancer cells over-expressing ferritin receptors. By entrapping in apoferritin both Gd-HPDO3A and curcumin, it was possible to deliver a therapeutic dose of 167 μg ml-1 (as calculated by MRI) of this natural drug to MCF-7 cells, thus obtaining a significant reduction of cell proliferation. Electronic supplementary information (ESI) available: Competition studies with free apoferritin, Fig. S1; APO-FITC intracellular distribution by

  14. Zinc as a possible preventive and therapeutic agent in pancreatic, prostate, and breast cancer.

    Science.gov (United States)

    Hoang, Ba X; Han, Bo; Shaw, David Graeme; Nimni, Marcel

    2016-09-01

    Zinc is a vital nutrient for human health. Over 300 biological functions in the human body rely on zinc. Even though zinc is incredibly important for our physiology and pathology, our current understanding of zinc, as it relates to tumor cell biology, leaves much to be desired. As with other natural, nonpatentable, and inexpensive agents, zinc remains a subject of explorative research for scientific interest rather than being promoted for practical use. To date, more than 5000 studies with the keywords 'zinc' and 'cancer' have been indexed in the Web of Knowledge portal. Although the numbers of papers have increased 2.5-fold during the last decade, these vast research data have not generated a single recommendation for the incorporation of zinc use in cancer prevention and treatment. In this review, we intend to analyze the current available research data and epidemiological and clinical evidence on the role of zinc in human cancer prevention and treatment. We focus on the cancers - prostate, breast, and pancreatic - for which the most basic and epidemiological studies with zinc have been carried out. The pancreas, and prostate and mammary glands are secretory tissues that have unusual zinc requirements; they tightly regulate zinc metabolism through integration of zinc import, sequestration, and export mechanisms. This suggests to us that zinc could play an important role in the physiology and pathology of these organs. The objective of this review was to stimulate more interest in the research field, focusing on the role of zinc as a possible preventive and therapeutic agent and the accelerated application of this inexpensive and easily accessible nutrient in clinical oncology. PMID:26317381

  15. Natural fatty acid synthase inhibitors as potent therapeutic agents for cancers: A review.

    Science.gov (United States)

    Zhang, Jia-Sui; Lei, Jie-Ping; Wei, Guo-Qing; Chen, Hui; Ma, Chao-Ying; Jiang, He-Zhong

    2016-09-01

    Context Fatty acid synthase (FAS) is the only mammalian enzyme to catalyse the synthesis of fatty acid. The expression level of FAS is related to cancer progression, aggressiveness and metastasis. In recent years, research on natural FAS inhibitors with significant bioactivities and low side effects has increasingly become a new trend. Herein, we present recent research progress on natural fatty acid synthase inhibitors as potent therapeutic agents. Objective This paper is a mini overview of the typical natural FAS inhibitors and their possible mechanism of action in the past 10 years (2004-2014). Method The information was collected and compiled through major databases including Web of Science, PubMed, and CNKI. Results Many natural products induce cancer cells apoptosis by inhibiting FAS expression, with fewer side effects than synthetic inhibitors. Conclusion Natural FAS inhibitors are widely distributed in plants (especially in herbs and foods). Some natural products (mainly phenolics) possessing potent biological activities and stable structures are available as lead compounds to synthesise promising FAS inhibitors.

  16. Natural fatty acid synthase inhibitors as potent therapeutic agents for cancers: A review.

    Science.gov (United States)

    Zhang, Jia-Sui; Lei, Jie-Ping; Wei, Guo-Qing; Chen, Hui; Ma, Chao-Ying; Jiang, He-Zhong

    2016-09-01

    Context Fatty acid synthase (FAS) is the only mammalian enzyme to catalyse the synthesis of fatty acid. The expression level of FAS is related to cancer progression, aggressiveness and metastasis. In recent years, research on natural FAS inhibitors with significant bioactivities and low side effects has increasingly become a new trend. Herein, we present recent research progress on natural fatty acid synthase inhibitors as potent therapeutic agents. Objective This paper is a mini overview of the typical natural FAS inhibitors and their possible mechanism of action in the past 10 years (2004-2014). Method The information was collected and compiled through major databases including Web of Science, PubMed, and CNKI. Results Many natural products induce cancer cells apoptosis by inhibiting FAS expression, with fewer side effects than synthetic inhibitors. Conclusion Natural FAS inhibitors are widely distributed in plants (especially in herbs and foods). Some natural products (mainly phenolics) possessing potent biological activities and stable structures are available as lead compounds to synthesise promising FAS inhibitors. PMID:26864638

  17. Development of new estrogen receptor-targeting therapeutic agents for tamoxifen-resistant breast cancer

    OpenAIRE

    Jiang, Quan; Zheng, Shilong; Wang, Guangdi

    2013-01-01

    Despite our deepening understanding of the mechanisms of resistance and intensive efforts to develop therapeutic solutions to combat resistance, de novo and acquired tamoxifen resistance remains a clinical challenge, and few effective regimens exist to treat tamoxifen-resistant breast cancer. The complexity of tamoxifen resistance calls for diverse therapeutic approaches. This review presents several therapeutic strategies and lead compounds targeting the estrogen receptor signaling pathways ...

  18. Novel compounds in the treatment of lung cancer: current and developing therapeutic agents

    OpenAIRE

    Bao, Rudi

    2011-01-01

    Rudi Bao, Pokman ChanOncology, Curis Inc, Lexington, MA, USAAbstract: Lung cancer is the leading cause of cancer-related death in the United States. Though incremental advances have been made in the treatment of this devastating disease during the past decade, new therapies are urgently needed. Traditional cytotoxic agents have been combined with other modalities with improved survival for early-stage patients. Newer cytotoxic agents targeting the same or different mechanisms have been develo...

  19. Human recombinant truncated RNASET2, devoid of RNase activity; A potential cancer therapeutic agent

    Science.gov (United States)

    Nesiel-Nuttman, Liron; Schwartz, Betty; Shoseyov, Oded

    2014-01-01

    Human RNASET2 has been implicated in antitumorigenic and antiangiogenic activities, independent of its ribonuclease capacities. We constructed a truncated version of human RNASET2, starting at E50 (trT2-50) and devoid of ribonuclease activity. trT2-50 maintained its ability to bind actin and to inhibit angiogenesis and tumorigenesis. trT2-50 binds to cell surface actin and formed a complex with actin in vitro. The antiangiogenic effect of this protein was demonstrated in human umbilical vein endothelial cells (HUVECs) by its ability to arrest tube formation on Matrigel, induced by angiogenic factors. Immunofluorescence staining of HUVECs showed nuclear and cytosolic RNASET2 protein that was no longer detectable inside the cell following trT2-50 treatment. This effect was associated with disruption of the intracellular actin network. trT2-50 co-localized with angiogenin, suggesting that both molecules bind (or compete) for similar cellular epitopes. Moreover, trT2-50 led to a significant inhibition of tumor development. Histological analysis demonstrated abundant necrotic tissue and a substantial loss of endothelial structure in trT2-50-treated tumors. Collectively, the present results indicate that trT2-50, a molecule engineered to be deficient of its catalytic activity, still maintained its actin binding and anticancer-related biological activities. We therefore suggest that trT2-50 may serve as a potential cancer therapeutic agent. PMID:25426551

  20. Nanoceria: a rare-earth nanoparticle as a novel anti-angiogenic therapeutic agent in ovarian cancer.

    Directory of Open Access Journals (Sweden)

    Shailendra Giri

    Full Text Available Ovarian cancer (OvCa is the fifth most common cause of death from all cancers among women in United Sates and the leading cause of death from gynecological malignancies. While most OvCa patients initially respond to surgical debulking and chemotherapy, 75% of patients later succumb to the disease. Thus, there is an urgent need to test novel therapeutic agents to counteract the high mortality rate associated with OvCa. In this context, we have developed and engineered Nanoceria (NCe, nanoparticles of cerium oxide, possessing anti-oxidant properties, to be used as a therapeutic agent in OvCa. We show for the first time that NCe significantly inhibited production of reactive oxygen species (ROS in A2780 cells, attenuated growth factor (SDF1, HB-EGF, VEGF(165 and HGF mediated cell migration and invasion of SKOV3 cells, without affecting the cell proliferation. NCe treatment also inhibited VEGF(165 induced proliferation, capillary tube formation, activation of VEGFR2 and MMP2 in human umbilical vascular endothelial cells (HUVEC. NCe (0.1 mg/kg body weigh treatment of A2780 ovarian cancer cells injected intra-peritoneally in nude mice showed significant reduction (p<0.002 in tumor growth accompanied by decreased tumor cell proliferation as evident from reduced tumor size and Ki67 staining. Accumulation of NCe was found in tumors isolated from treated group using transmission electron microscopy (TEM and inductively coupled plasma mass spectroscopy (ICP-MS. Reduction of the tumor mass was accompanied by attenuation of angiogenesis, as observed by reduced CD31 staining and specific apoptosis of vascular endothelial cells. Collectively, these results indicate that cerium oxide based NCe is a novel nanoparticle that can potentially be used as an anti-angiogenic therapeutic agent in ovarian cancer.

  1. Plasmids encoding therapeutic agents

    Science.gov (United States)

    Keener, William K.

    2007-08-07

    Plasmids encoding anti-HIV and anti-anthrax therapeutic agents are disclosed. Plasmid pWKK-500 encodes a fusion protein containing DP178 as a targeting moiety, the ricin A chain, an HIV protease cleavable linker, and a truncated ricin B chain. N-terminal extensions of the fusion protein include the maltose binding protein and a Factor Xa protease site. C-terminal extensions include a hydrophobic linker, an L domain motif peptide, a KDEL ER retention signal, another Factor Xa protease site, an out-of-frame buforin II coding sequence, the lacZ.alpha. peptide, and a polyhistidine tag. More than twenty derivatives of plasmid pWKK-500 are described. Plasmids pWKK-700 and pWKK-800 are similar to pWKK-500 wherein the DP178-encoding sequence is substituted by RANTES- and SDF-1-encoding sequences, respectively. Plasmid pWKK-900 is similar to pWKK-500 wherein the HIV protease cleavable linker is substituted by a lethal factor (LF) peptide-cleavable linker.

  2. Copper complexes as therapeutic agents.

    Science.gov (United States)

    Duncan, Clare; White, Anthony R

    2012-02-01

    The importance of transition metals in biological processes has been well established. Copper (Cu) is a transition metal that can exist in oxidised and reduced states. This allows it to participate in redox and catalytic chemistry, making it a suitable cofactor for a diverse range of enzymes and molecules. Cu deficiency or toxicity is implicated in a variety of pathological conditions; therefore inorganic complexes of Cu have been investigated for their therapeutic and diagnostic potential. These Cu complexes have been shown to be effective in cancer treatment due to their cytotoxic action on tumour cells. Alternatively, Cu complexes can also modulate Cu homeostasis in the brain, resulting in protective effects in several models of neurodegeneration. In other diseases such as coronary heart disease and skin disease, the success of Cu complexes as potential therapeutics will most likely be due to their ability to increase SOD activity, leading to relief of oxidative stress. This review seeks to provide a broad insight into some of the diverse actions of Cu complexes and demonstrate the strong future for these compounds as potential therapeutic agents.

  3. Cabazitaxel-loaded human serum albumin nanoparticles as a therapeutic agent against prostate cancer

    Science.gov (United States)

    Qu, Na; Lee, Robert J; Sun, Yating; Cai, Guangsheng; Wang, Junyang; Wang, Mengqiao; Lu, Jiahui; Meng, Qingfan; Teng, Lirong; Wang, Di; Teng, Lesheng

    2016-01-01

    Cabazitaxel-loaded human serum albumin nanoparticles (Cbz-NPs) were synthesized to overcome vehicle-related toxicity of current clinical formulation of the drug based on Tween-80 (Cbz-Tween). A salting-out method was used for NP synthesis that avoids the use of chlorinated organic solvent and is simpler compared to the methods based on emulsion-solvent evaporation. Cbz-NPs had a narrow particle size distribution, suitable drug loading content (4.9%), and superior blood biocompatibility based on in vitro hemolysis assay. Blood circulation, tumor uptake, and antitumor activity of Cbz-NPs were assessed in prostatic cancer xenograft-bearing nude mice. Cbz-NPs exhibited prolonged blood circulation and greater accumulation of Cbz in tumors along with reduced toxicity compared to Cbz-Tween. Moreover, hematoxylin and eosin histopathological staining of organs revealed consistent results. The levels of blood urea nitrogen and serum creatinine in drug-treated mice showed that Cbz-NPs were less toxic than Cbz-Tween to the kidneys. In conclusion, Cbz-NPs provide a promising therapeutic for prostate cancer. PMID:27555767

  4. Cabazitaxel-loaded human serum albumin nanoparticles as a therapeutic agent against prostate cancer

    Directory of Open Access Journals (Sweden)

    Qu N

    2016-07-01

    Full Text Available Na Qu,1 Robert J Lee,1,2 Yating Sun,1 Guangsheng Cai,1 Junyang Wang,1 Mengqiao Wang,1 Jiahui Lu,1 Qingfan Meng,1 Lirong Teng,1 Di Wang,1 Lesheng Teng1,3 1School of Life Sciences, Jilin University, Changchun, People’s Republic of China; 2Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, OH, USA; 3State Key Laboratory of Long-acting and Targeting Drug Delivery System, Yantai, People’s Republic of China Abstract: Cabazitaxel-loaded human serum albumin nanoparticles (Cbz-NPs were synthesized to overcome vehicle-related toxicity of current clinical formulation of the drug based on Tween-80 (Cbz-Tween. A salting-out method was used for NP synthesis that avoids the use of chlorinated organic solvent and is simpler compared to the methods based on emulsion-solvent evaporation. Cbz-NPs had a narrow particle size distribution, suitable drug loading content (4.9%, and superior blood biocompatibility based on in vitro hemolysis assay. Blood circulation, tumor uptake, and antitumor activity of Cbz-NPs were assessed in prostatic cancer xenograft-bearing nude mice. Cbz-NPs exhibited prolonged blood circulation and greater accumulation of Cbz in tumors along with reduced toxicity compared to Cbz-Tween. Moreover, hematoxylin and eosin histopathological staining of organs revealed consistent results. The levels of blood urea nitrogen and serum creatinine in drug-treated mice showed that Cbz-NPs were less toxic than Cbz-Tween to the kidneys. In conclusion, Cbz-NPs provide a promising therapeutic for prostate cancer. Keywords: cabazitaxel, human serum albumin, nanoparticle, drug delivery, toxicity, pros­tate cancer

  5. Barnase as a new therapeutic agent triggering apoptosis in human cancer cells.

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    Evelina Edelweiss

    Full Text Available BACKGROUND: RNases are currently studied as non-mutagenic alternatives to the harmful DNA-damaging anticancer drugs commonly used in clinical practice. Many mammalian RNases are not potent toxins due to the strong inhibition by ribonuclease inhibitor (RI presented in the cytoplasm of mammalian cells. METHODOLOGY/PRINCIPAL FINDINGS: In search of new effective anticancer RNases we studied the effects of barnase, a ribonuclease from Bacillus amyloliquefaciens, on human cancer cells. We found that barnase is resistant to RI. In MTT cell viability assay, barnase was cytotoxic to human carcinoma cell lines with half-inhibitory concentrations (IC(50 ranging from 0.2 to 13 microM and to leukemia cell lines with IC(50 values ranging from 2.4 to 82 microM. Also, we characterized the cytotoxic effects of barnase-based immunoRNase scFv 4D5-dibarnase, which consists of two barnase molecules serially fused to the single-chain variable fragment (scFv of humanized antibody 4D5 that recognizes the extracellular domain of cancer marker HER2. The scFv 4D5-dibarnase specifically bound to HER2-positive cells and was internalized via receptor-mediated endocytosis. The intracellular localization of internalized scFv 4D5-dibarnase was determined by electronic microscopy. The cytotoxic effect of scFv 4D5-dibarnase on HER2-positive human ovarian carcinoma SKOV-3 cells (IC(50 = 1.8 nM was three orders of magnitude greater than that of barnase alone. Both barnase and scFv 4D5-dibarnase induced apoptosis in SKOV-3 cells accompanied by internucleosomal chromatin fragmentation, membrane blebbing, the appearance of phosphatidylserine on the outer leaflet of the plasma membrane, and the activation of caspase-3. CONCLUSIONS/SIGNIFICANCE: These results demonstrate that barnase is a potent toxic agent for targeting to cancer cells.

  6. Concanavalin A: A potential anti-neoplastic agent targeting apoptosis, autophagy and anti-angiogenesis for cancer therapeutics

    Energy Technology Data Exchange (ETDEWEB)

    Li, Wen-wen; Yu, Jia-ying; Xu, Huai-long [School of Life Sciences and State Key Laboratory of Oral Diseases, Sichuan University, Chengdu 610064 (China); Bao, Jin-ku, E-mail: jinkubao@yahoo.com [School of Life Sciences and State Key Laboratory of Oral Diseases, Sichuan University, Chengdu 610064 (China)

    2011-10-22

    Highlights: {yields} ConA induces cancer cell death targeting apoptosis and autophagy. {yields} ConA inhibits cancer cell angiogenesis. {yields} ConA is utilized in pre-clinical and clinical trials. -- Abstract: Concanavalin A (ConA), a Ca{sup 2+}/Mn{sup 2+}-dependent and mannose/glucose-binding legume lectin, has drawn a rising attention for its remarkable anti-proliferative and anti-tumor activities to a variety of cancer cells. ConA induces programmed cell death via mitochondria-mediated, P73-Foxo1a-Bim apoptosis and BNIP3-mediated mitochondrial autophagy. Through IKK-NF-{kappa}B-COX-2, SHP-2-MEK-1-ERK, and SHP-2-Ras-ERK anti-angiogenic pathways, ConA would inhibit cancer cell survival. In addition, ConA stimulates cell immunity and generates an immune memory, resisting to the same genotypic tumor. These biological findings shed light on new perspectives of ConA as a potential anti-neoplastic agent targeting apoptosis, autophagy and anti-angiogenesis in pre-clinical or clinical trials for cancer therapeutics.

  7. Mushrooms as therapeutic agents

    Directory of Open Access Journals (Sweden)

    Sushila Rathee

    2012-04-01

    Full Text Available Mushrooms have been known for their nutritional and culinary values and used as medicines and tonics by humans for ages. In modern terms, they can be considered as functional foods which can provide health benefits beyond the traditional nutrients. There are monographs that cover the medicinal and healing properties of some individual traditional mushrooms. There has been a recent upsurge of interest in mushrooms not only as a health food which is rich in protein but also as a source of biologically active compounds of medicinal value which include complementary medicine/dietary supplements for anticancer, antiviral, hepatoprotective, immunopotentiating and hypocholesterolemic agents. However the mechanisms of the various health benefits of mushrooms to humans still require intensive investigation, especially given the emergence of new evidence of their health benefits. In the present paper the medicinal potential of mushrooms is being discussed.

  8. Dietary Pterostilbene is a novel MTA1-targeted chemopreventive and therapeutic agent in prostate cancer

    Science.gov (United States)

    Dietary nutrients with ability to reverse adverse epigenetic events have great potential for cancer chemoprevention. Overexpression of the epigenetic modifier metastasis-associated protein 1 (MTA1) is associated with aggressive human prostate cancer. The purpose of this study was to determine MTA1-d...

  9. Redox-directed cancer therapeutics: Taurolidine and Piperlongumine as broadly effective antineoplastic agents (Review)

    OpenAIRE

    MÖHLER, HANS; PFIRMAN, ROLF W.; Frei, Karl

    2014-01-01

    Targeting the oxygen stress response pathway is considered a promising strategy to exert antineoplastic activity in a broad spectrum of tumor types. Supporting this view, we summarize the mechanism of action of Taurolidine and Piperlongumine, two antineoplastic agents with strikingly broad tumor selectivity. Taurolidine enhances the oxidative stress (ROS) selectively in tumor cells. Its cytotoxicity for various tumor cells in vitro and in vivo, which includes tumor stem cells, is based on the...

  10. Redox-directed cancer therapeutics: Taurolidine and Piperlongumine as broadly effective antineoplastic agents (review).

    Science.gov (United States)

    Möhler, Hanns; Pfirrmann, Rolf W; Frei, Karl

    2014-10-01

    Targeting the oxygen stress response pathway is considered a promising strategy to exert antineoplastic activity in a broad spectrum of tumor types. Supporting this view, we summarize the mechanism of action of Taurolidine and Piperlongumine, two antineoplastic agents with strikingly broad tumor selectivity. Taurolidine enhances the oxidative stress (ROS) selectively in tumor cells. Its cytotoxicity for various tumor cells in vitro and in vivo, which includes tumor stem cells, is based on the induction of programmed cell death, largely via apoptosis but also necroptosis and autophagy. The redox-directed mechanism of action of Taurolidine is apparent from the finding that reducing agents e.g., N-acetylcysteine or glutathione impair its cytotoxicity, while its effectiveness is enhanced by agents which inhibit the cellular anti‑oxidant capacity. A similar redox-directed antineoplastic action is shown by Piperlongumine, a recently described experimental drug of plant origin. Taurolidine is particularly advantageous in surgical oncology as this taurine-derivative can be applied perioperatively or systemically with good tolerability as shown in initial clinical applications. PMID:25175943

  11. Therapeutic effects of cytoprotective agent on breast reconstruction after breast cancer surgery

    OpenAIRE

    He, Xinjia; Wang, Lihua; Li, Wei; Yu, Zhuang; Wang, Xingang

    2015-01-01

    Most patients will choose breast reconstruction after breast cancer surgery, while radiotherapy will damage skin and soft tissue so that will have adverse effect on reconstruction. In this study, we assume that the usage of Amifostine can reduce the incidence of complications after breast reconstruction so that provides more choices of reconstruction operation. Dividing SD rats into surgical placement expansion material group (include 15 ml normal saline) and simple operation group. Then furt...

  12. First In Vivo Evaluation of Liposome-encapsulated 223Ra as a Potential Alpha-particle-emitting Cancer Therapeutic Agent

    Energy Technology Data Exchange (ETDEWEB)

    Jonasdottir, Thora J.; Fisher, Darrell R.; Borrebaek, Jorgen; Bruland, Oyvind S.; Larsen, Roy H.

    2006-09-13

    Liposomes carrying chemotherapeutics have had some success in cancer treatment and may be suitable carriers for therapeutic radionuclides. This study was designed to evaluate the biodistribution of and to estimate the radiation doses from the alpha emitter 223Ra loaded into pegylated liposomes in selected tissues. 223Ra was encapsulated in pegylated liposomal doxorubicin by ionophore-mediated loading. The biodistribution of liposomal 223Ra was compared to free cationic 223Ra in Balb/C mice. We showed that liposomal 223 Ra circulated in the blood with an initial half-time in excess of 24 hours, which agreed well with that reported for liposomal doxorubicin in rodents, while the blood half-time of cationic 223Ra was considerably less than one hour. When liposomal 223 Ra was catabolized, the released 223Ra was either excreted or taken up in the skeleton. This skeletal uptake increased up to 14 days after treatment, but did not reach the level seen with free 223Ra. Pre-treatment with non-radioactive liposomal doxorubicin 4 days in advance lessened the liver uptake of liposomal 223 Ra. Dose estimates showed that the spleen, followed by bone surfaces, received the highest absorbed doses. Liposomal 223 Ra was relatively stable in vivo and may have potential for radionuclide therapy and combination therapy with chemotherapeutic agents.

  13. Coumarin hybrids as novel therapeutic agents.

    Science.gov (United States)

    Sandhu, Sonali; Bansal, Yogita; Silakari, Om; Bansal, Gulshan

    2014-08-01

    Naturally occurring coumarins, having wide spectrum of activities such as antioxidant, anti-inflammatory, anticancer, MAO-B inhibitory and antimicrobial, are frequently used by the researchers to develop novel synthetic and semisynthetic coumarin based therapeutic agents. Many of these agents are hybrid molecules, which are designed through concept of molecular hybridization and have shown multiple pharmacological activities. This multifunctional attribute of these hybrid compounds makes them potential drug candidates for the treatment of multifactorial diseases such as cancer, Alzheimer's disease, metabolic syndromes, AIDS, malaria, and cardiovascular diseases. The present review compiles research reports on development of different coumarin hybrids, classify these on the basis of their therapeutic uses and propose structure-activity relationships. It is intended to help medicinal chemist in designing and synthesizing novel and potent hybrid compounds for the treatment of different disorders. PMID:24934993

  14. Current Status of Poly(ADP-ribose Polymerase Inhibitors as Novel Therapeutic Agents for Triple-Negative Breast Cancer

    Directory of Open Access Journals (Sweden)

    David J. Hiller

    2012-01-01

    Full Text Available Triple-negative breast cancer (TNBC is an aggressive type of breast cancer that is clinically defined as lacking estrogen and progesterone receptors, as well as being ERBB2 (HER-2 negative. Without specific therapeutic targets, TNBC carries a worse prognosis than other types of breast cancer in the absence of therapy. Research has now further differentiated breast cancer into subtypes based on genetic expression patterns. One of these subtypes, basal-like, frequently overlaps with the clinical picture of TNBC. Additionally, both TNBC and basal-like breast cancer link to BRCA mutations. Recent pharmaceutical advances have created a class of drugs, poly(ADP-ribose polymerase (PARP inhibitors, which are showing potential to effectively treat these patients. The aim of this paper is to summarize the basis behind PARP inhibitors and update the current status of their development in clinical trials for the treatment of TNBC.

  15. Applications of inorganic nanoparticles as therapeutic agents

    Science.gov (United States)

    Kim, Taeho; Hyeon, Taeghwan

    2014-01-01

    During the last decade, various functional nanostructured materials with interesting optical, magnetic, mechanical and chemical properties have been extensively applied to biomedical areas including imaging, diagnosis and therapy. In therapeutics, most research has focused on the application of nanoparticles as potential delivery vehicles for drugs and genes, because nanoparticles in the size range of 2-100 nm can interact with biological systems at the molecular level, and allow targeted delivery and passage through biological barriers. Recent investigations have even revealed that several kinds of nanomaterials are intrinsically therapeutic. Not only can they passively interact with cells, but they can also actively mediate molecular processes to regulate cell functions. This can be seen in the treatment of cancer via anti-angiogenic mechanisms as well as the treatment of neurodegenerative diseases by effectively controlling oxidative stress. This review will present recent applications of inorganic nanoparticles as therapeutic agents in the treatment of disease.

  16. Host modulation by therapeutic agents

    Directory of Open Access Journals (Sweden)

    Sugumari Elavarasu

    2012-01-01

    Full Text Available Periodontal disease susceptible group present advanced periodontal breakdown even though they achieve a high standard of oral hygiene. Various destructive enzymes and inflammatory mediators are involved in destruction. These are elevated in case of periodontal destruction. Host modulation aims at bringing these enzymes and mediators to normal level. Doxycycline, nonsteroidal anti-inflammatory drugs (NSAIDs, bisphosphonates, nitrous oxide (NO synthase inhibitors, recombinant human interleukin-11 (rhIL-11, omega-3 fatty acid, mouse anti-human interleukin-6 receptor antibody (MRA, mitogen-activated protein kinase (MAPK inhibitors, nuclear factor-kappa B (NF-kb inhibitors, osteoprotegerin, and tumor necrosis factor antagonist (TNF-α are some of the therapeutic agents that have host modulation properties.

  17. Potential therapeutic implications of IL-6/IL-6R/gp130-targeting agents in breast cancer

    Science.gov (United States)

    Heo, Tae-Hwe; Wahler, Joseph; Suh, Nanjoo

    2016-01-01

    Interleukin-6 (IL-6) is a pleiotropic cytokine with known multiple functions in immune regulation, inflammation, and oncogenesis. Binding of IL-6 to the IL-6 receptor (IL-6R) induces homodimerization and recruitment of glycoprotein 130 (gp130), which leads to activation of downstream signaling. Emerging evidence suggests that high levels of IL-6 are correlated with poor prognosis in breast cancer patients. IL-6 appears to play a critical role in the growth and metastasis of breast cancer cells, renewal of breast cancer stem cells (BCSCs), and drug resistance of BCSCs, making anti–IL-6/IL-6R/gp130 therapies promising options for the treatment and prevention of breast cancers. However, preclinical and clinical studies of the applications of anti–IL-6/IL-6R/gp130 therapy in breast cancers are limited. In this review, we summarize the structures, preclinical and clinical studies, mechanisms of action of chemical and biological blockers that directly bind to IL-6, IL-6R, or gp130, and the potential clinical applications of these pharmacological agents as breast cancer therapies. PMID:26840088

  18. MCM-41 mesoporous silica nanoparticles functionalized with aptamer and radiolabelled with 90Y and 159Gd as a potential therapeutic agent against colorectal cancer

    International Nuclear Information System (INIS)

    Colorectal cancer (CRC) is a malignancy that affects large intestine and rectum, and it is the most common malignancy of the gastrointestinal tract, the third most commonly diagnosed type of cancer in the world and the second leading cause of cancer-related death in the United States. Nowadays, available therapeutic procedures for this type of cancer are limited and ineffective. Conventional radiotherapy is not an often used approach in the treatment of CRC due to the fact that peristaltic movements hamper the targeting of ionizing radiation and this type of treatment is used as adjuvant and palliative to control symptoms. Therefore, surgical intervention is the primary therapeutic choice against this disease. Researches based on the combination of radioisotopes and nanostructured carriers systems have demonstrated significant results in improving the selectivity action as well as reducing the radiation dose into healthy tissues. MCM-41 mesoporous silica nanoparticles have unique characteristics such as high surface area and well-defined pore diameters making these nanoparticles an ideal candidate of therapeutic agent carrier. Thus, the objective of this work is to synthesize and characterize MCM-41 mesoporous silica nanoparticles conjugated with yttrium-90 and gadolinium-159 and evaluate this system as a potential therapeutic agent. The nanoparticles were synthesized via sol-gel method. The sample was characterized using FTIR, SAXS, PCS, Zeta Potential analysis, Thermal analysis, CHN elemental analysis, nitrogen adsorption, scanning and transmission electron microscopy. The ability to incorporate Y+3 and Gd+3 ion was determined in vitro using different ratios (1:1, 1:3, 1:5 v/v) of YCL3 and Gd2O3 and silica nanoparticles dispersed in saline, pH 7.4. The non-incorporated Y+3 and Gd+3 ions were removed by ultracentrifugation procedure and the concentration of ions in the supernatant was determined by ICP-AES. Cell viability was assessed by colorimetric MTT assay in

  19. Therapeutic Tools in Pancreatic Cancer

    Directory of Open Access Journals (Sweden)

    Christopher J Hoimes

    2009-03-01

    Full Text Available Pancreatic cancer is the fourth leading cause of cancer death in the United States and has a lower survival rate than other digestive tract tumors. It remains a therapeutic challenge with limited active agents. Honing our current understanding of markers of toxicity and response, and individualizing treatment with the prognostic and therapeutic tools available are important to make a worthy impact on a patient’s course. The authors summarize selected abstracts from the ASCO Gastrointestinal Cancers Symposium, San Francisco, CA, USA, January 15-17, 2009. The Symposium featured pancreatic cancer in 84 research abstracts, of which, seven are reviewed that focus on markers of toxicity: cytidine deaminase (Abstract #151 and haptogloin (Abstract #167 as markers of gemcitabine toxicity; markers of response: use of PET scan for prognosis (Abstract #157, and correlations with CA 19-9 to postchemo-radiation resectability (Abstract #215 and time to progression (Abstract #160; and individualized applications: characterizing the phenotypic similarities between a patient tumor and the direct xenograft (Abstract #154 and a report about the poor outcome of patients with ascites (Abstract #220. Validated clinical tools that can assist in managing patients through the narrow therapeutic window are needed.

  20. Phase Ⅲ Clinical Trials of the Cell Differentiation Agent-2 (CDA-2): Therapeutic Efficacy on Breast Cancer, Non-Small Cell Lung Cancer and Primary Hepatoma

    Institute of Scientific and Technical Information of China (English)

    Fengyi Feng; Mingzhong Li; Yunzhong Zhu; Meizhen Zhou; Jun Ren; Yetao Gao; Jingpo Zhao; Rongsheng Zheng; Wenhua Zhao; Zhiqiang Meng; Fang Li; Qing Li; Qizhong Zhang; Dongli Zhao; Liyan Xu; Yongqiang Zhang; Yanjun Zhang; Zhenjiu Wang; Shuanqi Liu; Ming C. Liau; Changquan Ling; Yang Zhang; Fengzhan Qin; Huaqing Wang; Wenxia Huang; Shunchang Jiao; Qiang Chen

    2005-01-01

    OBJECTIVE The objective of this study was to explore the effect of CDA-2, a selective inhibitor of abnormal methylation enzymes in cancer cells, on the therapeutic efficacy of cytotoxic chemotherapy.METHODS Advanced cancer patients, all of whom had previously undergone chemotherapy, were randomly divided into 2 groups, one receiving chemotherapy only as the control group, and the other receiving CDA-2 in addition to chemotherapy as the combination group. The therapeutic efficacies and the toxic manifestations of the 2 groups were compared based on the WHO criteria.RESULTS Of 454 cancer patients enrolled in phase Ⅲ clinical trials of CDA-2, 80, 188, and 186 were breast cancer,NSCLC, and primary hepatoma patients, respectively.Among them 378 patients completed treatments according to the protocols. The results showed that the overall effective rate of the combination group was 2.6 fold that of the control group, 4.8 fold in the case of breast cancer, 2.3 fold in the case of primary hepatoma, and 2.2 fold in the case of NSCLC. Surprisingly, the combination therapy appeared to work better for stage Ⅳ than stage Ⅲ patients. CDA-2 did not contribute additional toxicity. On the contrary, it reduced toxic manifestations of chemotherapy, particularly regarding white blood cells, nausea and vomiting.CONCLUSION Modulation of abnormal methylation enzymes by CDA-2 is definitely helpful to supplement chemotherapy. It significantly increased the therapeutic efficacy and reduced the toxic manifestation of cytotoxic chemotherapy on breast cancer and NSCLC.

  1. The potential therapeutic targets for cervical cancer

    Directory of Open Access Journals (Sweden)

    L Priyanka Dwarampudi

    2013-01-01

    Full Text Available In case of invasive cervical carcinoma several molecular events were reported and these molecular events resulting in multiple genetic abnormalities. In order to control these tumors multiple molecular therapeutic targets are needed with different molecular mechanisms. Unfortunately, these molecular targets were in early stages of development. Because of less degree of success of conventional therapeutics for late stages of cervical cancer and lowering of prognosis of patients there is an increase in interest for the development of potential therapeutic targets for cervical cancer. This review article emphasizes the current molecular targeted agents; with special attention to estrogen receptors for human papilloma virus infected cervical cancer.

  2. Therapeutic strategies targeting cancer stem cells.

    Science.gov (United States)

    Ning, Xiaoyan; Shu, Jianchang; Du, Yiqi; Ben, Qiwen; Li, Zhaoshen

    2013-04-01

    Increasing studies have demonstrated a small proportion of cancer stem cells (CSCs) exist in the cancer cell population. CSCs have powerful self-renewal capacity and tumor-initiating ability and are resistant to chemotherapy and radiation. Conventional anticancer therapies kill the rapidly proliferating bulk cancer cells but spare the relatively quiescent CSCs, which cause cancer recurrence. So it is necessary to develop therapeutic strategies acting specifically on CSCs. In recent years, studies have shown that therapeutic agents such as metformin, salinomycin, DECA-14, rapamycin, oncostatin M (OSM), some natural compounds, oncolytic viruses, microRNAs, cell signaling pathway inhibitors, TNF-related apoptosis inducing ligand (TRAIL), interferon (IFN), telomerase inhibitors, all-trans retinoic acid (ATRA) and monoclonal antibodies can suppress the self-renewal of CSCs in vitro and in vivo. A combination of these agents and conventional chemotherapy drugs can significantly inhibit tumor growth, metastasis and recurrence. These strategies targeting CSCs may bring new hopes to cancer therapy. PMID:23358473

  3. Therapeutic potential of the anti-diabetic agent metformin in targeting the skin cancer stem cell diaspora.

    Science.gov (United States)

    Reddi, Anand; Powers, Matthew A; Dellavalle, Robert P

    2014-05-01

    Type II diabetes is associated with increased prevalence of cancer including both melanoma and squamous cell carcinoma (SCC) of the skin. Emerging evidence from epidemiological studies suggest that diabetic patients on metformin have a lower risk of cancer incidence and mortality in a broad range of neoplasms. In both melanoma and SCC, populations of cancer stem cells (CSC) contribute to tumor initiation and metastasis. We propose that metformin constitutes a new class of targeted therapy that acts on the skin CSC diaspora. We posit that metformin selectively and simultaneously targets CSCs of the primary tumor as well as in metastatic niches thereby disrupting the dynamic dispersal of circulating CSCs between the primary tumor and metastatic site. This hypothesis suggests a new concept in dermato-oncology that treatment of type II diabetes and prevention of skin cancer are two sides of the same coin. PMID:24521225

  4. 78 FR 77471 - Prospective Grant of Exclusive License for: Convection Enhanced Delivery of a Therapeutic Agent...

    Science.gov (United States)

    2013-12-23

    ... macromolecular MRI contrast agents such as chelated Gd(III). These macromolecular imaging agents have clearance... Enhanced Delivery of a Therapeutic Agent With a Surrogate Tracer for Treating Cancer and Urological... Agents'', U.S. Provisional Patent Application 60/413,673 (filed September 24, 2002;...

  5. Therapeutic Vaccination for HPV Induced Cervical Cancers

    Directory of Open Access Journals (Sweden)

    Joeli A. Brinkman

    2007-01-01

    Full Text Available Cervical Cancer is the second leading cause of cancer–related deaths in women worldwide and is associated with Human Papillomavirus (HPV infection, creating a unique opportunity to treat cervical cancer through anti-viral vaccination. Although a prophylactic vaccine may be available within a year, millions of women, already infected, will continue to suffer from HPV-related disease, emphasizing the need to develop therapeutic vaccination strategies. A majority of clinical trials examining therapeutic vaccination have shown limited efficacy due to examining patients with more advanced-stage cancer who tend to have decreased immune function. Current trends in clinical trials with therapeutic agents examine patients with pre-invasive lesions in order to prevent invasive cervical cancer. However, longer follow-up is necessary to correlate immune responses to lesion regression. Meanwhile, preclinical studies in this field include further exploration of peptide or protein vaccination, and the delivery of HPV antigens in DNA-based vaccines or in viral vectors. As long as pre-clinical studies continue to advance, the prospect of therapeutic vaccination to treat existing lesions seem good in the near future. Positive consequences of therapeutic vaccination would include less disfiguring treatment options and fewer instances of recurrent or progressive lesions leading to a reduction in cervical cancer incidence.

  6. Cancer stem cells: therapeutic implications and perspectives in cancer therapy

    Directory of Open Access Journals (Sweden)

    Lu Han

    2013-04-01

    Full Text Available The cancer stem cell (CSC theory is gaining increasing attention from researchers and has become an important focus of cancer research. According to the theory, a minority population of cancer cells is capable of self-renewal and generation of differentiated progeny, termed cancer stem cells (CSCs. Understanding the properties and characteristics of CSCs is key to future study on cancer research, such as the isolation and identification of CSCs, the cancer diagnosis, and the cancer therapy. Standard oncology treatments, such as chemotherapy, radiotherapy and surgical resection, can only shrink the bulk tumor and the tumor tends to relapse. Thus, therapeutic strategies that focus on targeting CSCs and their microenvironmental niche address the ineffectiveness of traditional cancer therapies to eradicate the CSCs that otherwise result in therapy resistance. The combined use of traditional therapies with targeted CSC-specific agents may target the whole cancer and offer a promising strategy for lasting treatment and even cure.

  7. Interleukin-1 and cancer progression: the emerging role of interleukin-1 receptor antagonist as a novel therapeutic agent in cancer treatment

    Directory of Open Access Journals (Sweden)

    Varghese Sheelu

    2006-11-01

    Full Text Available Abstract The tumor microenvironment consists of tumor, immune, stromal, and inflammatory cells which produce cytokines, growth factors, and adhesion molecules that promote tumor progression and metastasis. Of particular interest in this setting is interleukin-1 (IL-1, a pleiotropic cytokine with numerous roles in both physiological and pathological states. It is known to be up regulated in many tumor types and has been implicated as a factor in tumor progression via the expression of metastatic and angiogenic genes and growth factors. A number of studies have reported that high IL-1 concentrations within the tumor microenvironment are associated with a more virulent tumor phenotype. Solid tumors in which IL-1 has been shown to be up regulated include breast, colon, lung, head and neck cancers, and melanomas, and patients with IL-1 producing tumors have generally bad prognoses. The exact mechanisms by which IL-1 promotes tumor growth remain unclear, though the protein is believed to act via induction of pro-metastatic genes such as matrix metalloproteinases and through the stimulation of adjacent cells to produce angiogenic proteins and growth factors such as VEGF, IL-8, IL-6, TNFα, and TGFβ. The IL-1 receptor antagonist (IL-1ra is a naturally occurring inhibitor to IL-1 and acts by binding to the IL-1 receptor without activating it. The protein has been shown to decrease tumor growth, angiogenesis, and metastases in murine xenograft models. Our focus in this review is to summarize the known data on the role of IL-1 in tumor progression and metastasis and the use of IL-1 inhibition as a novel therapeutic approach in the treatment of solid organ malignancies.

  8. Cancer stem cells, metabolism, and therapeutic significance.

    Science.gov (United States)

    Yang, Mengqi; Liu, Panpan; Huang, Peng

    2016-05-01

    Cancer stem cells (CSCs) have attracted much attention of the research community in the recent years. Due to their highly tumorigenic and drug-resistant properties, CSCs represent important targets for developing novel anticancer agents and therapeutic strategies. CSCs were first described in hematopoietic malignancies and subsequently identified in various types of solid tumors including brain, breast, lung, colon, melanoma, and ovarian cancer. CSCs possess special biological properties including long-term self-renewal capacity, multi-lineage differentiation, and resistance to conventional chemotherapy and radiotherapy. As such, CSCs are considered as a major source of residual disease after therapy leading to disease occurrence. Thus, it is very important to understand the cellular survival mechanisms specific to CSCs and accordingly develop effective therapeutic approaches to eliminate this subpopulation of cancer cells in order to improve the treatment outcome of cancer patients. Possible therapeutic strategies against CSCs include targeting the self-renewal pathways of CSCs, interrupting the interaction between CSCs and their microenvironment, and exploiting the unique metabolic properties of CSCs. In this review article, we will provide an overview of the biological characteristics of CSCs, with a particular focus on their metabolic properties and potential therapeutic strategies to eliminate CSCs. PMID:26864589

  9. 77 FR 62521 - Prospective Grant of Exclusive License: The Development of Therapeutic Agents for the Treatment...

    Science.gov (United States)

    2012-10-15

    ... Therapeutic Agents for the Treatment of Metastatic Breast Cancer and T- cell Lymphoma AGENCY: National... metastatic breast cancer, or ii) incorporating a p53 isoform antisense oligonucleotide as a single biologic... of a p53 Isoform in Regenerative Medicine, Aging and Cancer'' . The patent rights in these...

  10. Therapeutic Management of Colon Cancer

    Directory of Open Access Journals (Sweden)

    Ana-Maria Todosi

    2014-09-01

    Full Text Available Colorectal cancer is a major public health problem worldwide, and a major cause of mortality and morbidity. Correct pretherapeutic staging has the role of guiding the management of colon cancer patients. The diagnosis is guided by the clinical symptoms. Chemotherapy is an important part of colon cancer treatment. Chemotherapy regimens are adapted to tumor stage and patient status and have various side effects and variable survival outcomes. International guidelines recommend different treatments depending on the presence or absence of metastases. The primary goal of treatment in nonmetastatic colon cancer is surgical removal of the tumor which could be the first step of the complex therapy or preceded by neoadjuvant therapy, depending on pretherapeutic staging. In resectable nonmetastatic tumors the preferred surgical procedure is colectomy with en bloc removal of regional lymph nodes. The extent of colectomy should be based on tumor location. The management of metastatic colon cancer also targets the therapeutic approach of the metastatic disease. Therapy is standardized and applied according to tumor stage. Surveillance has a major role in therapeutic success, reason why a time schedule and a protocol adapted to the primary lesion are essential. The goal of implementing the recommendations of international guidelines for the treatment of colon cancer is to provide a uniform treatment for this disease in view of improving overall survival of patients.

  11. Therapeutic Potential of HDPs as Immunomodulatory Agents

    DEFF Research Database (Denmark)

    Jenssen, Håvard; Hancock, Robert E.W.

    2010-01-01

    strategies for intervention tailored around the appropriate (selective) stimulation of the host’s immune system, and particularly rapid acting innate immunity, as an alternative to direct targeting of microbial pathogens. One recent player in such an immunomodulatory strategy is the naturally occurring host...... defence peptides (HDP) and their synthetic innate defence regulator (IDR) analogues. In this chapter, we will discuss the potential therapeutic use of HDPs and IDRs as immunomodulatory agents....... decline in the rate of discovery of new antimicrobial intervention strategies in parallel with an increasing incidence of multidrug-resistant pathogens; if these circumstances do not change we will continue to approach the end of the antibiotic era. Facing this dark future, scientists are considering new...

  12. A Current Review of Targeted Therapeutics for Ovarian Cancer

    Directory of Open Access Journals (Sweden)

    Susana M. Campos

    2010-01-01

    Full Text Available Difficult to detect, ovarian cancer typically presents at an advanced stage. Significant progress has been achieved in the treatment of ovarian cancer with therapeutics focused on DNA replication or cell division. However, despite sensitivity to induction chemotherapy the majority of patients will develop recurrent disease. Conventional agents for recurrent disease offer little in terms of long-term responses. Various targeted therapeutics have been explored in the management of ovarian cancer. These include monoclonal antibodies to epidermal growth factor receptors, small molecule tyrosine kinase inhibitors, monoclonal antibodies directed at the vascular endothelial growth factor (bevacizumab, and the small tyrosine kinase inhibitors that target the vascular endothelial growth factor receptor. Recently, several other agents have come forth as potential therapeutic agents in the management of ovarian cancer. These include monoclonal antibodies to the folate receptor, triple angiokinase inhibitors, PARP inhibitors, aurora kinase inhibitors, inhibitors of the Hedgehog pathway, folate receptor antagonists, and MTOR inhibitors.

  13. MCM-41 mesoporous silica nanoparticles functionalized with aptamer and radiolabelled with {sup 90}Y and {sup 159}Gd as a potential therapeutic agent against colorectal cancer; Nanoparticulas de silica mesoporosa MCM-41 funcionalizadas com aptamero e radiomarcadas com {sup 90}Y e {sup 159}Gd como um potencial agente terapeutico contra cancer colorretal

    Energy Technology Data Exchange (ETDEWEB)

    Ferreira, Carolina de Aguiar

    2014-06-01

    Colorectal cancer (CRC) is a malignancy that affects large intestine and rectum, and it is the most common malignancy of the gastrointestinal tract, the third most commonly diagnosed type of cancer in the world and the second leading cause of cancer-related death in the United States. Nowadays, available therapeutic procedures for this type of cancer are limited and ineffective. Conventional radiotherapy is not an often used approach in the treatment of CRC due to the fact that peristaltic movements hamper the targeting of ionizing radiation and this type of treatment is used as adjuvant and palliative to control symptoms. Therefore, surgical intervention is the primary therapeutic choice against this disease. Researches based on the combination of radioisotopes and nanostructured carriers systems have demonstrated significant results in improving the selectivity action as well as reducing the radiation dose into healthy tissues. MCM-41 mesoporous silica nanoparticles have unique characteristics such as high surface area and well-defined pore diameters making these nanoparticles an ideal candidate of therapeutic agent carrier. Thus, the objective of this work is to synthesize and characterize MCM-41 mesoporous silica nanoparticles conjugated with yttrium-90 and gadolinium-159 and evaluate this system as a potential therapeutic agent. The nanoparticles were synthesized via sol-gel method. The sample was characterized using FTIR, SAXS, PCS, Zeta Potential analysis, Thermal analysis, CHN elemental analysis, nitrogen adsorption, scanning and transmission electron microscopy. The ability to incorporate Y{sup +3} and Gd{sup +3} ion was determined in vitro using different ratios (1:1, 1:3, 1:5 v/v) of YCL{sub 3} and Gd{sub 2}O{sub 3} and silica nanoparticles dispersed in saline, pH 7.4. The non-incorporated Y{sup +3} and Gd{sup +3} ions were removed by ultracentrifugation procedure and the concentration of ions in the supernatant was determined by ICP-AES. Cell viability

  14. Cooperative Therapeutic Effects of Herpes Simplex Virus Thymidine Kinase Gene/Ganciclovir System and Chemotherapeutic Agents on Prostate Cancer in vitro

    Institute of Scientific and Technical Information of China (English)

    XING Yifei; XIAO Yajun; LU Gongcheng; ZENG Fuqing; ZHAO Jun; XIONG Ping; FENG Wei

    2006-01-01

    The killing effects of herpes simplex virus thymidine kinase gene/ganciclovir (HSV-tk/GCV) approach by the addition of several commonly clinical chemotherapeutic agents on hormone refractory prostate cancer (HRPC) cells PC-3m were investigated. After transferring of the HSV-tk gene into PC-3m cells, mRNA and protein expression of HSV-tk was detected by reverse-transcript polymerase chain reaction (RT-PCR) and strept avidin-biotin complex (SABC) immunohistochemical method. The killing effect of GCV, cisplatin (CDDP), etoposide (VP-16), vincristine (VCR), methotrexate (MTX), 5-fluorouracil (5-Fu), and suramin on PC-3m cells was evaluated by morphological assessment analysis, trypan blue exclusion assay and MTT assay respectively. Additionally, the cooperative effect of HSV-tk/GCV system combined with the above agents on the target cancer cells was determined by MTT. Furthermore, apoptosis and necrosis induced by GCV plus 5-Fu or suramin was analyzed by flow cytometry (FCM). The results showed that that there was HSV-tk mRNA and protein expression in pDR2-tk plasmid transduced PC-3m cell. Combination of GCV with VP-16, VCR, 5-Fu or suramin led to an enhanced cellular killing effect, but with CDDP resulted in a reduced one and with MTX in an approximate one. FCM revealed that synergistic use of GCV and 5-fu or suramin resulted in a rather large proportion of apoptosis and necrosis with the apoptosis index being 36.38 % and 35.51%, and the proportion of necrosis being 33.05 % and 28.87 %, respectively. In conclusion, HSV-tk/CGV approach by addition of certain clinical available chemotherapeutic drugs brings on statistically significant enhanced cell killing over single-agent treatment.Our results highlight the potential for such new combination therapies for future treatments of HRPC.

  15. Positron emission tomography agent 2-deoxy-2-[18F]fluoro-D-glucose has a therapeutic potential in breast cancer

    International Nuclear Information System (INIS)

    Novel approaches are needed for breast cancer patients in whom standard therapy is not effective. 2-Deoxy-2-[18F]fluoro-D-glucose (18F-FDG) was evaluated as a potential radiomolecular therapy agent in breast cancer animal models and, retrospectively, in patients with metastatic breast cancer. Polyoma middle T antigen (PyMT) and mouse mammary tumor virus-NeuT transgenic mice with tumors 0.5–1 cm in diameter were imaged with 18F-FDG, and tumor to liver ratios (TLRs) were calculated. The radiotoxicity of 18F-FDG administration was determined in healthy mice. PyMT mice with small (0.15–0.17 cm) and large (more than 1 cm) tumors were treated with 2–4 mCi of 18F-FDG, and control C3H/B6 mice with 3 mCi of 18F-FDG. At 10 days after treatment the tumors and control mammary glands were analyzed for the presence of apoptotic and necrotic cells. Five patients with breast cancer and metastatic disease were evaluated and standardized uptake values (SUVs) in tumors, maximum tolerated dose, and the doses to the tumor were calculated. Doses up to 5 mCi proved to be non-radiotoxic to normal organs. The 18F-FDG uptake in mouse tumors showed an average TLR of 1.6. The treatment of mice resulted in apoptotic cell death in the small tumors. Cell death through the necrotic pathway was seen in large tumors, and was accompanied by tumor fragmentation and infiltration with leukocytes. Normal mammary tissues were not damaged. A human 18F-FDG dose delivering 200 rad to the red marrow (less than 5% damage) was calculated to be 4.76 Ci for a 70 kg woman, and the dose to the tumors was calculated to be 220, 1100 and 2200 rad for SUVs of 1, 5 and 10, respectively. We have shown that positrons delivered by 18F-FDG to mammary tumors have a tumoricidal effect on cancer cells. The study of breast cancer patients suggests that the tumor and normal organ dosimetry of 18F-FDG makes it suitable for therapy of this malignancy

  16. Hepatic drug transporters and nuclear receptors: Regulation by therapeutic agents

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    The canalicular membrane represents the excretory pole of hepatocytes. Bile is an important route of elimina-tion of potentially toxic endo- and xenobiotics (including drugs and toxins), mediated by the major canalicular transporters: multidrug resistance protein 1 (MDR1, ABCB1), also known as P-glycoprotein, multidrug re-sistance-associated protein 2 (MRP2, ABCC2), and the breast cancer resistance protein (BCRP, ABCG2). Their activities depend on regulation of expression and proper localization at the canalicular membrane, as regulated by transcriptional and post-transcriptional events, re-spectively. At transcriptional level, specific nuclear re-ceptors (NR)s modulated by ligands, co-activators and co-repressors, mediate the physiological requirements of these transporters. This complex system is also re-sponsible for alterations occurring in specific liver pa-thologies. We briefly describe the major Class Ⅱ NRs, pregnane X receptor (PXR) and constitutive androstane receptor (CAR), and their role in regulating expression of multidrug resistance proteins. Several therapeutic agents regulate the expression of relevant drug trans-porters through activation/inactivation of these NRs. We provide some representative examples of the action of therapeutic agents modulating liver drug transporters, which in addition, involve CAR or PXR as mediators.

  17. Metabolic alterations in cancer cells and therapeutic implications

    Institute of Scientific and Technical Information of China (English)

    Naima Hammoudi; Kausar Begam Riaz Ahmed; Celia Garcia-Prieto; Peng Huang

    2011-01-01

    Cancer metabolism has emerged as an important area of research in recent years. Elucidation of the metabolic differences between cancer and normal cells and the underlying mechanisms will not only advance our understanding of fundamental cancer cell biology but also provide an important basis for the development of new therapeutic strategies and novel compounds to selectively eliminate cancer cells by targeting their unique metabolism. This article reviews several important metabolic alterations in cancer cells, with an emphasis on increased aerobic glycolysis (the Warburg effect) and glutamine addiction, and discusses the mechanisms that may contribute to such metabolic changes. In addition, metabolic alterations in cancer stem cells, mitochondrial metabolism and its influence on drug sensitivity, and potential therapeutic strategies and agents that target cancer metabolism are also discussed.

  18. Direct therapeutic intervention for advanced pancreatic cancer.

    Science.gov (United States)

    Takakura, Kazuki; Koido, Shigeo

    2015-12-10

    Currently, chemotherapy is an accredited, standard treatment for unresectable, advanced pancreatic cancer (PC). However, it has been still showed treatment-resistance and followed dismal prognosis in many cases. Therefore, some sort of new, additional treatments are needed for the better therapeutic results for advanced PC. According to the previous reports, it is obvious that interventional endoscopic ultrasonography (EUS) is a well-established, helpful and low-risky procedure in general. As the additional treatments of the conventional therapy for advanced PC, many therapeutic strategies, such as immunotherapies, molecular biological therapies, physiochemical therapies, radioactive therapies, using siRNA, using autophagy have been developing in recent years. Moreover, the efficacy of the other potential therapeutic targets for PC using EUS-fine needle injection, for example, intra-tumoral chemotherapeutic agents (paclitaxel, irinotecan), several ablative energies (radiofrequency ablation and cryothermal treatment, neodymium-doped yttrium aluminum garnet laser, high-intensity focused ultrasound), etc., has already been showed in animal models. Delivering these promising treatments reliably inside tumor, interventional EUS may probably be indispensable existence for the treatment of locally advanced PC in near future. PMID:26677434

  19. Mitochondria as therapeutic targets for cancer stem cells

    Institute of Scientific and Technical Information of China (English)

    In Sung Song; Jeong Yu Jeong; Seung Hun Jeong; Hyoung Kyu Kim; Kyung Soo Ko; Byoung Doo Rhee; Nari Kim; Jin Han

    2015-01-01

    Cancer stem cells (CSCs) are maintained by theirsomatic stem cells and are responsible for tumorinitiation, chemoresistance, and metastasis. Evidencefor the CSCs existence has been reported for a numberof human cancers. The CSC mitochondria have beenshown recently to be an important target for cancertreatment, but clinical significance of CSCs and theirmitochondria properties remain unclear. Mitochondriatargetedagents are considerably more effectivecompared to other agents in triggering apoptosis ofCSCs, as well as general cancer cells, via mitochondrialdysfunction. Mitochondrial metabolism is altered incancer cells because of their reliance on glycolyticintermediates, which are normally destined for oxidativephosphorylation. Therefore, inhibiting cancer-specificmodifications in mitochondrial metabolism, increasingreactive oxygen species production, or stimulatingmitochondrial permeabilization transition could bepromising new therapeutic strategies to activate celldeath in CSCs as well, as in general cancer cells. Thisreview analyzed mitochondrial function and its potentialas a therapeutic target to induce cell death in CSCs.Furthermore, combined treatment with mitochondriatargeteddrugs will be a promising strategy for thetreatment of relapsed and refractory cancer.

  20. Chelating agents in pharmacology, toxicology and therapeutics

    International Nuclear Information System (INIS)

    The proceedings contain 71 abstracts of papers. Fourteen abstracts were inputted in INIS. The topics covered include: the effects of chelating agents on the retention of 63Ni, 109Cd, 203Hg, 144Ce, 95Nb and the excretion of 210Po, 63Ni, 48V, 239Pu, 241Am, 54Mn; the applications of tracer techniques for studies of the efficacy of chelation therapy in patients with heart and brain disorders; and the treatment of metal poisoning with chelating agents. (J.P.)

  1. Molecular therapeutics in pancreas cancer.

    Science.gov (United States)

    Narayanan, Vignesh; Weekes, Colin D

    2016-04-15

    The emergence of the "precision-medicine" paradigm in oncology has ushered in tremendous improvements in patient outcomes in a wide variety of malignancies. However, pancreas ductal adenocarcinoma (PDAC) has remained an obstinate challenge to the oncology community and continues to be associated with a dismal prognosis with 5-year survival rates consistently less than 5%. Cytotoxic chemotherapy with gemcitabine-based regimens has been the cornerstone of treatment in PDAC especially because most patients present with inoperable disease. But in recent years remarkable basic science research has improved our understanding of the molecular and genetic basis of PDAC. Whole genomic analysis has exemplified the genetic heterogeneity of pancreas cancer and has led to ingenious efforts to target oncogenes and their downstream signaling cascades. Novel stromal depletion strategies have been devised based on our enhanced recognition of the complex architecture of the tumor stroma and the various mechanisms in the tumor microenvironment that sustain tumorigenesis. Immunotherapy using vaccines and immune checkpoint inhibitors has also risen to the forefront of therapeutic strategies against PDAC. Furthermore, adoptive T cell transfer and strategies to target epigenetic regulators are being explored with enthusiasm. This review will focus on the recent advances in molecularly targeted therapies in PDAC and offer future perspectives to tackle this lethal disease. PMID:27096032

  2. Predictive and therapeutic markers in ovarian cancer

    Science.gov (United States)

    Gray, Joe W.; Guan, Yinghui; Kuo, Wen-Lin; Fridlyand, Jane; Mills, Gordon B.

    2013-03-26

    Cancer markers may be developed to detect diseases characterized by increased expression of apoptosis-suppressing genes, such as aggressive cancers. Genes in the human chromosomal regions, 8q24, 11q13, 20q11-q13, were found to be amplified indicating in vivo drug resistance in diseases such as ovarian cancer. Diagnosis and assessment of amplification levels certain genes shown to be amplified, including PVT1, can be useful in prediction of poor outcome of patient's response and drug resistance in ovarian cancer patients with low survival rates. Certain genes were found to be high priority therapeutic targets by the identification of recurrent aberrations involving genome sequence, copy number and/or gene expression are associated with reduced survival duration in certain diseases and cancers, specifically ovarian cancer. Therapeutics to inhibit amplification and inhibitors of one of these genes, PVT1, target drug resistance in ovarian cancer patients with low survival rates is described.

  3. Tackling obesity: new therapeutic agents for assisted weight loss

    Directory of Open Access Journals (Sweden)

    JG Karam

    2010-04-01

    Full Text Available JG Karam1, SI McFarlane21SUNY-Downstate-Kings County Hospital, Brooklyn, NY, USA, Maimonides Medical Center, Brooklyn, NY, USA; 2Division of Endocrinology, College of Medicine, State University of New York-Downstate Medical Center, New York, USAAbstract: The pandemic of overweight and obesity continues to rise in an alarming rate in western countries and around the globe representing a major public health challenge in desperate need for new strategies tackling obesity. In the United States nearly two thirds of the population is overweight or obese. Worldwide the number of persons who are overweight or obese exceeded 1.6 billion. These rising figures have been clearly associated with increased morbidity and mortality. For example, in the Framingham study, the risk of death increases with each additional pound of weight gain even in the relatively younger population between 30 and 42 years of age. Overweight and obesity are also associated with increased co-morbid conditions such as diabetes, hypertension and cardiovascular disease as well as certain types of cancer. In this review we discuss the epidemic of obesity, highlighting the pathophysiologic mechanisms of weight gain. We also provide an overview of the assessment of overweight and obese individuals discussing possible secondary causes of obesity. In a detailed section we discuss the currently approved therapeutic interventions for obesity highlighting their mechanisms of action and evidence of their efficacy and safety as provided in clinical trials. Finally, we discuss novel therapeutic interventions that are in various stages of development with a special section on the weight loss effects of anti-diabetic medications. These agents are particularly attractive options for our growing population of obese diabetic individuals.Keywords: obesity, assisted weight loss, therapy

  4. Research progress on target therapeutic agents of HER-2 extracellular ligand-binding domain in breast cancer%乳腺癌HER-2胞外配体结合区靶点治疗的研究进展*

    Institute of Scientific and Technical Information of China (English)

    钟锦绣; 李亚梅(综述); 关晏星(审校)

    2013-01-01

    The target therapeutic agents of HER-2 extracellular ligand-binding domain have become the core of breast cancer research. A small peptide molecule and an anti-HER2 extracellular domain monoclonal antibody conjugated with protein toxins, radioisotopes, and chemotherapeutic drugs (immunoconjugate) can improve efficacy and reduce systemic toxicity. Vaccines based on HER-2 extracellular region should protect patients from HER-2-overexpressing breast cancer growth. In this review, studies on targeted-block therapies of the HER-2 extracellular ligand-binding domain in breast cancer were discussed to provide references for clinical applications.%针对乳腺癌HER-2受体胞外结合区的靶点治疗成为当今研究的热点。小分子多肽、HER-2胞外结合区的单抗药物及其与蛋白毒素、放射性核素,化疗药物的偶联物即免疫偶联物既能增强药物的有效性,又可减少对正常组织的毒害。HER-2胞外区肽疫苗可有效预防HER-2高表达乳腺癌的生长。本文将对乳腺癌HER-2胞外区靶向阻断治疗的研究进行综述,为相应的临床应用提供参考。

  5. THERAPEUTIC OPTIONS FOR BREAST CANCER

    Directory of Open Access Journals (Sweden)

    Milena Georgescu

    2011-12-01

    Full Text Available Breast cancer remains a major public health problem, being the second cause of cancer death in women. There is a marked tendency to restrict the extension of surgical gesture, which directly leads to two different attitudes: radical surgery and conservative surgery, to which, at least in our country, there are still some delays. Prospective and retrospective studies have shown that, in 20 years, conservative and radical therapy had about the same rate of survival and disease-free interval, at least for stage I and II breast cancer, the only real counterargument against conservative surgery being that, in principle, the higher rate of recurrence local constraint can be solved by postoperative radiotherapy. Finally, the survival rate is the main parameter of evaluation, assessing the effectiveness of the treatment in breast cancer, and in all its other forms.

  6. DNA damage responses in cancer stem cells: Implications for cancer therapeutic strategies

    Institute of Scientific and Technical Information of China (English)

    Qi-En; Wang

    2015-01-01

    The identification of cancer stem cells(CSCs) that are responsible for tumor initiation, growth, metastasis, and therapeutic resistance might lead to a new thinking on cancer treatments. Similar to stem cells,CSCs also display high resistance to radiotherapy and chemotherapy with genotoxic agents. Thus, conventional therapy may shrink the tumor volume but cannot eliminate cancer. Eradiation of CSCs represents a novel therapeutic strategy. CSCs possess a highly efficient DNA damage response(DDR) system, which is considered as a contributor to the resistance of these cells from exposures to DNA damaging agents. Targeting of enhanced DDR in CSCs is thus proposed to facilitate the eradication of CSCs by conventional therapeutics. To achieve this aim, a better understanding of the cellular responses to DNA damage in CSCs is needed. In addition to the protein kinases and enzymes that are involved in DDR, other processes that affect the DDR including chromatin remodeling should also be explored.

  7. Therapeutic effect of intratumoral injection of 188Re labeled stannic sulfur suspension in liver cancer. A comparative study with chemical agents in nude mice

    International Nuclear Information System (INIS)

    Objectives: Hepatoma is a common disease in some countries. The intervention therapy was used often for non-resectable tumor. The aim of our study was to compare the therapeutic effect of 188Re labeled stannic sulfur suspension to ethanol, acetic acid and the mixture of mitomycin and lipiodol for hepatoma in an animal model by intermittently injection. Methods: Forty-nine nude mice bearing hepatic cell carcinoma were divided into six groups. Group 1 (n=14) was intratumoral y injected with 0.1 ml saline. There were 5 experimental groups (group 2 to 6). Each group consisted of 7 mice. The mice in group 2 was intratumoral y injected with 18.5 MBq/0.1 ml 188Re labeled stannic sulfur suspension each, the mice in group 3 was injected intratumorally with 9.25 MBq/0.1 ml 188Re labeled stannic sulfur suspension each, group 4 was injected intratumorally with 0.1 ml ethanol, the mice in group 5 was injected with 0.1 ml 30% acetic acid and group 6 was injected intratumorally with 30 μg mitomycin in 0.1 ml lipiodol respectively. The mice were sacrificed 7 days post injection and the specimen were collected for pathological analysis. Results: The average tumor weight were 1.75±0.29 g (mean±S.D.), 0.26±0.03 g, 0.44±0.17 g, 1.38±0.25 g, 0.91±0.28 g, 1.38±0.28 g for group 1 to 6 respectively. Tumors in all experimental groups were significantly smaller than group 1 (control group, P88Re labeled stannic sulfur suspension injection had the smallest tumor weight among all the experimental groups (P188Re labeled stannic sulfur suspension shows better therapeutic effect. (authors)

  8. The potential therapeutic targets for cervical cancer

    OpenAIRE

    L Priyanka Dwarampudi; Gowthamarajan, K.; Shanmugam, R; Madhuri, K.; Nilani, P.; M N Satish Kumar

    2013-01-01

    In case of invasive cervical carcinoma several molecular events were reported and these molecular events resulting in multiple genetic abnormalities. In order to control these tumors multiple molecular therapeutic targets are needed with different molecular mechanisms. Unfortunately, these molecular targets were in early stages of development. Because of less degree of success of conventional therapeutics for late stages of cervical cancer and lowering of prognosis of patients there is an inc...

  9. Cancer stem cell markers in common cancers - therapeutic implications

    DEFF Research Database (Denmark)

    Klonisch, Thomas; Wiechec, Emilia; Hombach-Klonisch, Sabine;

    2008-01-01

    Rapid advance in the cancer stem cell field warrants optimism for the development of more reliable cancer therapies within the next 2-3 decades. Below, we characterize and compare the specific markers that are present on stem cells, cancer cells and cancer stem cells (CSC) in selected tissues......, the last part of the review discusses future directions of this intriguing new research field in the context of new diagnostic and therapeutic opportunities....

  10. Securinine, a myeloid differentiation agent with therapeutic potential for AML.

    Directory of Open Access Journals (Sweden)

    Kalpana Gupta

    Full Text Available As the defining feature of Acute Myeloid Leukemia (AML is a maturation arrest, a highly desirable therapeutic strategy is to induce leukemic cell maturation. This therapeutic strategy has the potential of avoiding the significant side effects that occur with the traditional AML therapeutics. We identified a natural compound securinine, as a leukemia differentiation-inducing agent. Securinine is a plant-derived alkaloid that has previously been used clinically as a therapeutic for primarily neurological related diseases. Securinine induces monocytic differentiation of a wide range of myeloid leukemia cell lines as well as primary leukemic patient samples. Securinine's clinical potential for AML can be seen from its ability to induce significant growth arrest in cell lines and patient samples as well as its activity in significantly impairing the growth of AML tumors in nude mice. In addition, securinine can synergize with currently employed agents such as ATRA and decitabine to induce differentiation. This study has revealed securinine induces differentiation through the activation of DNA damage signaling. Securinine is a promising new monocytic differentiation inducing agent for AML that has seen previous clinical use for non-related disorders.

  11. Therapeutic cancer vaccines: are we there yet?

    OpenAIRE

    Klebanoff, Christopher A.; Acquavella, Nicholas; Yu, Zhiya; Restifo, Nicholas P

    2011-01-01

    Enthusiasm for therapeutic cancer vaccines has been rejuvenated with the recent completion of several large, randomized phase III clinical trials that in some cases have reported an improvement in progression free or overall survival. However, an honest appraisal of their efficacy reveals modest clinical benefit and a frequent requirement for patients with relatively indolent cancers and minimal or no measurable disease. Experience with adoptive cell transfer-based immunotherapies unequivocal...

  12. Apoptosis in cancer: therapeutic implications

    OpenAIRE

    Negoescu, A.

    2000-01-01

    This review outlines the principal limitations of the mechanisms of active cell death (ACD, apoptosis) as the basis of tumorigenesis and the rationale of almost all therapies of malignancy. The concentration of cancer therapy in the directon of ACD induction is presented as both the result of progressive understanding of the mechanisms of apoptosis and that of the favourable tumor environment for ACD signal transmission. The latter property induces the by-stand...

  13. Cisplatin encapsulated nanoparticle as a therapeutic agent for anticancer treatment

    Science.gov (United States)

    Eka Putra, Gusti Ngurah Putu; Huang, Leaf; Hsu, Yih-Chih

    2016-03-01

    The knowledge of manipulating size of biomaterials encapsulated drug into nano-scale particles has been researched and developed in treating cancer. Cancer is the second worldwide cause of death, therefore it is critical to treat cancers challenging with therapeutic modality of various mechanisms. Our preliminary investigation has studied cisplatin encapsulated into lipid-based nanoparticle and examined the therapeutic effect on xenografted animal model. We used mice with tumor volume ranging from 195 to 214 mm3 and then few mice were grouped into three groups including: control (PBS), lipid platinum chloride (LPC) nanoparticles and CDDP (cis-diamminedichloroplatinum(II) at dose of 3mg cisplatin /kg body weight. The effect of the treatment was observed for 12 days post-injection. It showed that LPC NPs demonstrated a better therapeutic effect compared to CDDP at same 3mg cisplatin/kg drug dose of tumor size reduction, 96.6% and 11.1% respectively. In addition, mouse body weight loss of LPC, CDDP and PBS treated group are 12.1%, 24.3% and 1.4%. It means that by compared to CDDP group, LPC group demonstrated less side effect as not much reduction of body weight have found. Our findings have shown to be a potential modality to further investigate as a feasible cancer therapy modality.

  14. Immunocytes as a Biocarrier to Delivery Therapeutic and Imaging Contrast Agents to Tumors

    Directory of Open Access Journals (Sweden)

    Jinhyang Choi

    2012-01-01

    Full Text Available Radiotherapy for cancer treatment has been used for primary or adjuvant treatment in many types of cancer, and approximately half of all cancer patients are undergoing radiation. However, ionizing radiation exposure induces genetic alterations in cancer cells and results in recruitment of monocytes/macrophages by triggering signals released from these cells. Using this characteristic of monocytes/macrophages, we have attempted to develop a biocarrier loading radiosensitizing anticancer agents that can lead to enhance the therapeutic effect of radiation in cancer treatment. The aim of this study is to demonstrate the proof of this concept. THP-1 labeled with Qdot 800 or iron oxide (IO effectively migrated into tumors of subcutaneous mouse model and increased recruitment after ionizing radiation. Functionalized liposomes carrying a radiosensitizing anticancer agent, doxorubicin, are successfully loaded in THP-1 (THP-1-LP-Dox with reduced cytotoxicity, and THP-1-LP-Dox also was observed in tumors after intravenous administration. Here, we report that monocytes/macrophages as a biocarrier can be used as a selective tool for amplification of the therapeutic effects on radiotherapy for human cancer treatment.

  15. Natural Compounds as Therapeutic Agents in the Treatment Cystic Fibrosis

    OpenAIRE

    Dey, Isha; Shah, Kalpit; Bradbury, Neil A.

    2016-01-01

    The recent FDA approval of two drugs to treat the basic defect in cystic fibrosis has given hope to patients and their families battling this devastating disease. Over many years, with heavy financial investment from Vertex Pharmaceuticals and the Cystic Fibrosis Foundation, pre-clinical evaluation of thousands of synthetic drugs resulted in the production of Kalydeco and Orkambi. Yet, despite the success of this endeavor, many other compounds have been proposed as therapeutic agents in the t...

  16. Promises and Challenges of Smac Mimetics as Cancer Therapeutics.

    Science.gov (United States)

    Fulda, Simone

    2015-11-15

    Inhibitor of Apoptosis (IAP) proteins block programmed cell death and are expressed at high levels in various human cancers, thus making them attractive targets for cancer drug development. Second mitochondrial activator of caspases (Smac) mimetics are small-molecule inhibitors that mimic Smac, an endogenous antagonist of IAP proteins. Preclinical studies have shown that Smac mimetics can directly trigger cancer cell death or, even more importantly, sensitize tumor cells for various cytotoxic therapies, including conventional chemotherapy, radiotherapy, or novel agents. Currently, several Smac mimetics are under evaluation in early clinical trials as monotherapy or in rational combinations (i.e., GDC-0917/CUDC-427, LCL161, AT-406/Debio1143, HGS1029, and TL32711/birinapant). This review discusses the promise as well as some challenges at the translational interface of exploiting Smac mimetics as cancer therapeutics.

  17. Epigenetic modulators as therapeutic targets in prostate cancer.

    Science.gov (United States)

    Graça, Inês; Pereira-Silva, Eva; Henrique, Rui; Packham, Graham; Crabb, Simon J; Jerónimo, Carmen

    2016-01-01

    Prostate cancer is one of the most common non-cutaneous malignancies among men worldwide. Epigenetic aberrations, including changes in DNA methylation patterns and/or histone modifications, are key drivers of prostate carcinogenesis. These epigenetic defects might be due to deregulated function and/or expression of the epigenetic machinery, affecting the expression of several important genes. Remarkably, epigenetic modifications are reversible and numerous compounds that target the epigenetic enzymes and regulatory proteins were reported to be effective in cancer growth control. In fact, some of these drugs are already being tested in clinical trials. This review discusses the most important epigenetic alterations in prostate cancer, highlighting the role of epigenetic modulating compounds in pre-clinical and clinical trials as potential therapeutic agents for prostate cancer management. PMID:27651838

  18. {sup 188}Re-HTDD-lipiodol solution as a new therapeutic agent for transhepatic arterial administration in liver cancer: a preclinical study using liver-cancer model in rabbit

    Energy Technology Data Exchange (ETDEWEB)

    Paeng, J. C.; Jeong, J. M.; Lee, Y. S. [College of Medicine, Seoul National Univ., Seoul (Korea, Republic of)] [and others

    2001-07-01

    {sup 188}Re-HTDD-lipiodol solution was developed and reported to be a new therapeutic material for transhepatic arterial embolization (TAE) of liver cancer. In this study we compared the tissue retention of {sup 188}Re-HTDD-lipiodol with that of {sup 188}Re-TDD-lipiodol using liver-cancer model in rabbit. Cancer cell line VX2 was inoculated into 7 rabbits and grown up to larger than 3 cm. TAE was performed with {sup 188}Re-TDD-lipiodol in 3 rabbits and with {sup 188}Re-HTDD-lipiodol in 4 rabbits. Conjugated planar scans were performed at 1, 2, 6, 24, 48 hours after TAE. From these images, the mean life of radioactivity retention in tumor was calculated, and the required dose for human application as also calculated from the mean life and MIRDOSE3 software. The mean lifes of radioactivity in liver were 10.2{+-}1.0 hr in TDD group and 17.6{+-}0.8 hr in HTDD group (p<0.001). The required dose for the tumor to be irradiated 50 Gy of radiation was calculated to be 18 mCi of {sup 188}Re-HTDD-lipiodol for 5.7 cm-sized tumor and 88 mCi for 9,7 cm-sized tumor. By the introduction of long chain alkyl group, {sup 188}Re-HTDD-lipiodol showed significantly better tumor retention than that of {sup 188}Re-TDD-lipiodol. And the required dose of radiation for human application was calculated to be 18 {approx} 88 mCi when using {sup 188}Re-HTDD-lipiodol.

  19. Therapeutic application of anti-angiogenic nanomaterials in cancers

    Science.gov (United States)

    Mukherjee, Sudip; Patra, Chitta Ranjan

    2016-06-01

    Angiogenesis, the formation of new blood vessels from pre-existing vasculature, plays a vital role in physiological and pathological processes (embryonic development, wound healing, tumor growth and metastasis). The overall balance of angiogenesis inside the human body is maintained by pro- and anti-angiogenic signals. The processes by which drugs inhibit angiogenesis as well as tumor growth are called the anti-angiogenesis technique, a most promising cancer treatment strategy. Over the last couple of decades, scientists have been developing angiogenesis inhibitors for the treatment of cancers. However, conventional anti-angiogenic therapy has several limitations including drug resistance that can create problems for a successful therapeutic strategy. Therefore, a new comprehensive treatment strategy using antiangiogenic agents for the treatment of cancer is urgently needed. Recently researchers have been developing and designing several nanoparticles that show anti-angiogenic properties. These nanomedicines could be useful as an alternative strategy for the treatment of various cancers using anti-angiogenic therapy. In this review article, we critically focus on the potential application of anti-angiogenic nanomaterial and nanoparticle based drug/siRNA/peptide delivery systems in cancer therapeutics. We also discuss the basic and clinical perspectives of anti-angiogenesis therapy, highlighting its importance in tumor angiogenesis, current status and future prospects and challenges.Angiogenesis, the formation of new blood vessels from pre-existing vasculature, plays a vital role in physiological and pathological processes (embryonic development, wound healing, tumor growth and metastasis). The overall balance of angiogenesis inside the human body is maintained by pro- and anti-angiogenic signals. The processes by which drugs inhibit angiogenesis as well as tumor growth are called the anti-angiogenesis technique, a most promising cancer treatment strategy. Over the

  20. Exploiting epigenetic vulnerabilities for cancer therapeutics.

    Science.gov (United States)

    Mair, Barbara; Kubicek, Stefan; Nijman, Sebastian M B

    2014-03-01

    Epigenetic deregulation is a hallmark of cancer, and there has been increasing interest in therapeutics that target chromatin-modifying enzymes and other epigenetic regulators. The rationale for applying epigenetic drugs to treat cancer is twofold. First, epigenetic changes are reversible, and drugs could therefore be used to restore the normal (healthy) epigenetic landscape. However, it is unclear whether drugs can faithfully restore the precancerous epigenetic state. Second, chromatin regulators are often mutated in cancer, making them attractive drug targets. However, in most instances it is unknown whether cancer cells are addicted to these mutated chromatin proteins, or whether their mutation merely results in epigenetic instability conducive to the selection of secondary aberrations. An alternative incentive for targeting chromatin regulators is the exploitation of cancer-specific vulnerabilities, including synthetic lethality, caused by epigenetic deregulation. We review evidence for the hypothesis that mechanisms other than oncogene addiction are a basis for the application of epigenetic drugs, and propose future research directions.

  1. Magnetic nanoparticles as both imaging probes and therapeutic agents.

    Science.gov (United States)

    Lacroix, Lise-Marie; Ho, Don; Sun, Shouheng

    2010-01-01

    Magnetic nanoparticles (MNPs) have been explored extensively as contrast agents for magnetic resonance imaging (MRI) or as heating agents for magnetic fluid hyperthermia (MFH) [1]. To achieve optimum operation conditions in MRI and MFH, these NPs should have well-controlled magnetic properties and biological functionalities. Although numerous efforts have been dedicated to the investigations on MNPs for biomedical applications [2-5], the NP optimizations for early diagnostics and efficient therapeutics are still far from reached. Recent efforts in NP syntheses have led to some promising MNP systems for sensitive MRI and efficient MFH applications. This review summarizes these advances in the synthesis of monodisperse MNPs as both contrast probes in MRI and as therapeutic agents via MFH. It will first introduce the nanomagnetism and elucidate the critical parameters to optimize the superparamagnetic NPs for MRI and ferromagnetic NPs for MFH. It will further outline the new chemistry developed for making monodisperse MNPs with controlled magnetic properties. The review will finally highlight the NP functionalization with biocompatible molecules and biological targeting agents for tumor diagnosis and therapy. PMID:20388109

  2. Hedgehog signaling and therapeutics in pancreatic cancer.

    LENUS (Irish Health Repository)

    Kelleher, Fergal C

    2012-02-01

    OBJECTIVE: To conduct a systematic review of the role that the hedgehog signaling pathway has in pancreatic cancer tumorigenesis. METHOD: PubMed search (2000-2010) and literature based references. RESULTS: Firstly, in 2009 a genetic analysis of pancreatic cancers found that a core set of 12 cellular signaling pathways including hedgehog were genetically altered in 67-100% of cases. Secondly, in vitro and in vivo studies of treatment with cyclopamine (a naturally occurring antagonist of the hedgehog signaling pathway component; Smoothened) has shown that inhibition of hedgehog can abrogate pancreatic cancer metastasis. Thirdly, experimental evidence has demonstrated that sonic hedgehog (Shh) is correlated with desmoplasia in pancreatic cancer. This is important because targeting the Shh pathway potentially may facilitate chemotherapeutic drug delivery as pancreatic cancers tend to have a dense fibrotic stroma that extrinsically compresses the tumor vasculature leading to a hypoperfusing intratumoral circulation. It is probable that patients with locally advanced pancreatic cancer will derive the greatest benefit from treatment with Smoothened antagonists. Fourthly, it has been found that ligand dependent activation by hedgehog occurs in the tumor stromal microenvironment in pancreatic cancer, a paracrine effect on tumorigenesis. Finally, in pancreatic cancer, cells with the CD44+CD24+ESA+ immunophenotype select a population enriched for cancer initiating stem cells. Shh is increased 46-fold in CD44+CD24+ESA+ cells compared with normal pancreatic epithelial cells. Medications that destruct pancreatic cancer initiating stem cells are a potentially novel strategy in cancer treatment. CONCLUSIONS: Aberrant hedgehog signaling occurs in pancreatic cancer tumorigenesis and therapeutics that target the transmembrane receptor Smoothened abrogate hedgehog signaling and may improve the outcomes of patients with pancreatic cancer.

  3. Digitoxin and its analogs as novel cancer therapeutics

    Directory of Open Access Journals (Sweden)

    Elbaz Hosam A

    2012-04-01

    Full Text Available Abstract A growing body of evidence indicates that digitoxin cardiac glycoside is a promising anticancer agent when used at therapeutic concentrations. Digitoxin has a prolonged half-life and a well-established clinical profile. New scientific avenues have shown that manipulating the chemical structure of the saccharide moiety of digitoxin leads to synthetic analogs with increased cytotoxic activity. However, the anticancer mechanism of digitoxin or synthetic analogs is still subject to study while concerns about digitoxin's cardiotoxicity preclude its clinical application in cancer therapeutics. This review focuses on digitoxin and its analogs, and their cytotoxicity against cancer cells. Moreover, a new perspective on the pharmacological aspects of digitoxin and its analogs is provided to emphasize new research directions for developing potent chemotherapeutic drugs.

  4. Gynecologic cancer treatment: risk factors for therapeutically induced neoplasia

    International Nuclear Information System (INIS)

    Therapeutic intervention in a course of illness, while producing the desired result, also may have some adverse long-term effects on the patient. Second malignancies are one of the known complications of therapy. The treatments of gynecologic cancers by surgery, irradiation and chemotherapy have been associated with subsequent neoplasms. The use of normal skin from the thigh to fabricate an artificial vagina has resulted in more squamous cell carcinomas than expected. Alkylating agents used in the treatment of ovarian cancer and other diseases have been shown to lead to an increased risk of leukemia. The incidence of lymphoma and uterine, urinary bladder and colon carcinomas has been associated with prior irradiation for gynecologic disease. The literature regarding the therapeutically induced risk factors in gynecologic therapy is reviewed and areas of our knowledge that require more investigation are identified

  5. Cancer genetics and the cardiotoxicity of the therapeutics.

    Science.gov (United States)

    Lal, Hind; Kolaja, Kyle L; Force, Thomas

    2013-01-22

    Cancer genomics has focused on the discovery of mutations and chromosomal structural rearrangements that either increase susceptibility to cancer or support the cancer phenotype. Protein kinases are the most frequently mutated genes in the cancer genome, making them attractive therapeutic targets for drug design. However, the use of some of the kinase inhibitors (KIs) has been associated with toxicities to the heart and vasculature, including acute coronary syndromes and heart failure. Herein we discuss the genetic basis of cancer, focusing on mutations in the kinase genome (kinome) that lead to tumorigenesis. This will allow an understanding of the real and potential power of modern cancer therapeutics. The underlying mechanisms that drive the cardiotoxicity of the KIs are also examined. The preclinical models for predicting cardiotoxicity, including induced pluripotent stem cells and zebrafish, are reviewed, with the hope of eventually being able to identify problematic agents before their use in patients. Finally, the use of biomarkers in the clinic is discussed, and newer strategies (i.e., metabolomics and enhanced imaging strategies) that may allow earlier and more accurate detection of cardiotoxicity are reviewed.

  6. Organometallic iron complexes as potential cancer therapeutics.

    Science.gov (United States)

    Mojžišová, Gabriela; Mojžiš, Ján; Vašková, Janka

    2014-01-01

    Metal-containing drugs have long been used for medicinal purposes in more or less empirical way. The potential of these anticancer agents has only been fully realised and explored since the discovery of the biological activity of cisplatin. Cisplatin and carboplatin have been two of the most successful anti-cancer agents ever developed, and are currently used to treat ovarian, lung and testicular cancers. They share certain side effects, so their clinical use is severely limited by dose-limiting toxicity. Inherent or acquired resistance is a second problem often associated with platinum-based drugs, with further limits of their clinical use. These problems have prompted chemists to employ different strategies in development of the new metal-based anticancer agents with different mechanisms of action. There are various metal complexes still under development and investigation for the future cancer treatment use. In the search for novel bio-organometallic molecules, iron containing anti-tumoral agents are enjoying an increasing interest and appear very promising as the potential drug candidates. Iron, as an essential cofactor in a number of enzymes and physiological processes, may be less toxic than non essential metals, such as platinum. Up to now, some of iron complexes have been tested as cytotoxic agents and found to be endowed with an antitumor activity in several in vitro tests (on cultured cancer cell lines) and few in vivo experiments (e. g. on Ehrlich's ascites carcinoma). Although the precise molecular mechanism is yet to be defined, a number of observations suggest that the reactive oxygen species can play important role in iron-induced cytotoxicty. This review covers some relevant examples of research on the novel iron complexes.

  7. Molecular subtyping of breast cancer: opportunities for new therapeutic approaches.

    Science.gov (United States)

    Mullan, P B; Millikan, R C

    2007-12-01

    Evidence is accumulating that breast cancer is not one disease but many separate diseases. DNA microarray-based gene expression profiling has demonstrated subtypes with distinct phenotypic features and clinical responses. Prominent among the new subtypes is 'basal-like' breast cancer, one of the 'intrinsic' subtypes defined by negativity for the estrogen, progesterone, and HER2/neu receptors and positivity for cytokeratins-5/6. Focusing on basal-like breast cancer, we discuss how molecular technologies provide new chemotherapy targets, optimising treatment whilst sparing patients from unnecessary toxicity. Clinical trials are needed that incorporate long-term follow-up of patients with well-characterised tumour markers. Whilst the absence of an obvious dominant oncogene driving basal-like breast cancer and the lack of specific therapeutic agents are serious stumbling blocks, this review will highlight several promising therapeutic candidates currently under evaluation. Thus, new molecular technologies should provide a fundamental foundation for better understanding breast and other cancers which may be exploited to save lives. (Part of a Multi-author Review). PMID:17957336

  8. Radiopharmaceuticals as therapeutic agents in medical care and treatment

    International Nuclear Information System (INIS)

    Radiation applications in medical research, care, and treatment today are being used to help millions of patients throughout the world. In recent years, the medical community has seen a renaissance of therapeutic radiation applications, particularly of strontium-89 for metastatic bone pain. Radiopharmaceuticals used as therapeutic agents (frequently known as RPTs) are designed to deliver high doses of radiation to selected malignant sites in target organs or tissues, while minimizing the radiation doses to surrounding healthy cells. Over the past several years, several type of RPTs with special properties, including compounds for labelling monoclonal antibodies, have been used in animal and human clinical trials with promising results. The modern trend in radiopharmaceutical research for oncology is the development of RPTs that may be said to be tumour-seeking and tumour-specific. Among the promising RPTs being reported in the medical literature are rhenium-186 and samarium-153. Both can be produced in research reactors available in many countries. 2 tabs

  9. Metathesis access to monocyclic iminocyclitol-based therapeutic agents

    Directory of Open Access Journals (Sweden)

    Albert Demonceau

    2011-05-01

    Full Text Available By focusing on recent developments on natural and non-natural azasugars (iminocyclitols, this review bolsters the case for the role of olefin metathesis reactions (RCM, CM as key transformations in the multistep syntheses of pyrrolidine-, piperidine- and azepane-based iminocyclitols, as important therapeutic agents against a range of common diseases and as tools for studying metabolic disorders. Considerable improvements brought about by introduction of one or more metathesis steps are outlined, with emphasis on the exquisite steric control and atom-economical outcome of the overall process. The comparative performance of several established metathesis catalysts is also highlighted.

  10. Dronedarone for atrial fibrillation: a new therapeutic agent

    Directory of Open Access Journals (Sweden)

    Pawan D Patel

    2009-08-01

    Full Text Available Pawan D Patel, Rohit Bhuriya, Dipal D Patel, Bhaskar L Arora, Param P Singh, Rohit R AroraDepartment of Cardiology, Chicago Medical School, Chicago, IL, USAAbstract: Atrial fibrillation is the most common of the serious cardiac rhythm disturbances and is responsible for substantial morbidity and mortality. Amiodarone is currently one of the most widely used and most effective antiarrhythmic agents for atrial fibrillation. But during chronic usage amiodarone can cause some serious extra cardiac adverse effects, including effects on the thyroid. Dronedarone is a newer therapeutic agent with a structural resemblance to amiodarone, with two molecular changes, and with a better side effect profile. Dronedarone is a multichannel blocker and, like amiodarone, possesses both a rhythm and a rate control property in atrial fibrillation. The US Food and Drug Administration approved dronedarone for atrial fibrillation on July 2, 2009. In this review, we discuss the role of dronedarone in atrial fibrillation.Keywords: dronedarone, amiodarone, atrial fibrillation

  11. Immune evasion in cancer: Mechanistic basis and therapeutic strategies.

    Science.gov (United States)

    Vinay, Dass S; Ryan, Elizabeth P; Pawelec, Graham; Talib, Wamidh H; Stagg, John; Elkord, Eyad; Lichtor, Terry; Decker, William K; Whelan, Richard L; Kumara, H M C Shantha; Signori, Emanuela; Honoki, Kanya; Georgakilas, Alexandros G; Amin, Amr; Helferich, William G; Boosani, Chandra S; Guha, Gunjan; Ciriolo, Maria Rosa; Chen, Sophie; Mohammed, Sulma I; Azmi, Asfar S; Keith, W Nicol; Bilsland, Alan; Bhakta, Dipita; Halicka, Dorota; Fujii, Hiromasa; Aquilano, Katia; Ashraf, S Salman; Nowsheen, Somaira; Yang, Xujuan; Choi, Beom K; Kwon, Byoung S

    2015-12-01

    Cancer immune evasion is a major stumbling block in designing effective anticancer therapeutic strategies. Although considerable progress has been made in understanding how cancers evade destructive immunity, measures to counteract tumor escape have not kept pace. There are a number of factors that contribute to tumor persistence despite having a normal host immune system. Immune editing is one of the key aspects why tumors evade surveillance causing the tumors to lie dormant in patients for years through "equilibrium" and "senescence" before re-emerging. In addition, tumors exploit several immunological processes such as targeting the regulatory T cell function or their secretions, antigen presentation, modifying the production of immune suppressive mediators, tolerance and immune deviation. Besides these, tumor heterogeneity and metastasis also play a critical role in tumor growth. A number of potential targets like promoting Th1, NK cell, γδ T cell responses, inhibiting Treg functionality, induction of IL-12, use of drugs including phytochemicals have been designed to counter tumor progression with much success. Some natural agents and phytochemicals merit further study. For example, use of certain key polysaccharide components from mushrooms and plants have shown to possess therapeutic impact on tumor-imposed genetic instability, anti-growth signaling, replicative immortality, dysregulated metabolism etc. In this review, we will discuss the advances made toward understanding the basis of cancer immune evasion and summarize the efficacy of various therapeutic measures and targets that have been developed or are being investigated to enhance tumor rejection. PMID:25818339

  12. Importins and exportins as therapeutic targets in cancer.

    Science.gov (United States)

    Mahipal, Amit; Malafa, Mokenge

    2016-08-01

    The nuclear transport proteins, importins and exportins (karyopherin-β proteins), may play an important role in cancer by transporting key mediators of oncogenesis across the nuclear membrane in cancer cells. During nucleocytoplasmic transport of tumor suppressor proteins and cell cycle regulators during the processing of these proteins, aberrant cellular growth signaling and inactivation of apoptosis can occur, both critical to growth and development of tumors. Karyopherin-β proteins bind to these cargo proteins and RanGTP for active transport across the nuclear membrane through the nuclear pore complex. Importins and exportins are overexpressed in multiple tumors including melanoma, pancreatic, breast, colon, gastric, prostate, esophageal, lung cancer, and lymphomas. Furthermore, some of the karyopherin-β proteins such as exportin-1 have been implicated in drug resistance in cancer. Importin and exportin inhibitors are being considered as therapeutic targets against cancer and have shown preclinical anticancer activity. Moreover, synergistic activity has been observed with various chemotherapeutic and targeted agents. However, clinical development of the exportin-1 inhibitor leptomycin B was stopped due to adverse events, including vomiting, anorexia, and dehydration. Selinexor, a selective nuclear export inhibitor, is being tested in multiple clinical trials both as a single agent and in combination with chemotherapy. Selinexor has demonstrated clinical activity in multiple cancers, especially acute myelogenous leukemia and multiple myeloma. The roles of other importin and exportin inhibitors still need to be investigated clinically. Targeting the key mediators of nucleocytoplasmic transport in cancer cells represents a novel strategy in cancer intervention with the potential to significantly affect outcomes. PMID:27113410

  13. Therapeutic treatment of Alzheimer's disease using metal complexing agents.

    Science.gov (United States)

    Price, Katherine A; Crouch, Peter J; White, Anthony R

    2007-11-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by deposition of extracellular amyloid plaques, formation of intracellular neurofibrillary tangles and neuronal dysfunction in the brain. A growing body of evidence indicates a central role for biometals such as copper in many critical aspects of AD. The amyloid beta (Abeta) peptide and its parental molecule, the amyloid precursor protein (APP) both modulate Cu and Zn metabolism in the brain. Therefore, aberrant changes to APP or Abeta metabolism could potentially alter biometal homoestasis in AD, leading to increased free radical production and neuronal oxidative stress. Modulation of metal bioavailability in the brain has been proposed as a potential therapeutic strategy for treatment of AD patients. The lipid permeable metal complexing agent, clioquinol (CQ), has shown promising results in animal models of AD and in small clinical trials involving AD patients. Moreover, a new generation of metal-ligand based therapeutics is currently under development. Patents now cover the generation of novel metal ligand structures designed to modulate metal binding to Abeta and quench metal-mediated free radical generation. However, the mechanism by which CQ and other metal complexing agents slows cognitive decline in AD animal models and patients is unknown. Increasing evidence suggests that ligand-mediated redistribution of metals at a cellular level in the brain may be important. Further research will be necessary to fully understand the complex pathways associated with efficacious metal-based pharmaceuticals for treatment of AD.

  14. Curcumin nanomedicine: a road to cancer therapeutics.

    Science.gov (United States)

    Yallapu, Murali M; Jaggi, Meena; Chauhan, Subhash C

    2013-01-01

    Cancer is the second leading cause of death in the United States. Conventional therapies cause widespread systemic toxicity and lead to serious side effects which prohibit their long term use. Additionally, in many circumstances tumor resistance and recurrence is commonly observed. Therefore, there is an urgent need to identify suitable anticancer therapies that are highly precise with minimal side effects. Curcumin is a natural polyphenol molecule derived from the Curcuma longa plant which exhibits anticancer, chemopreventive, chemo- and radio-sensitization properties. Curcumin's widespread availability, safety, low cost and multiple cancer fighting functions justify its development as a drug for cancer treatment. However, various basic and clinical studies elucidate curcumin's limited efficacy due to its low solubility, high rate of metabolism, poor bioavailability and pharmacokinetics. A growing list of nanomedicine(s) using first line therapeutic drugs have been approved or are under consideration by the Food and Drug Administration (FDA) to improve human health. These nanotechnology strategies may help to overcome challenges and ease the translation of curcumin from bench to clinical application. Prominent research is reviewed which shows that advanced drug delivery of curcumin (curcumin nanoformulations or curcumin nanomedicine) is able to leverage therapeutic benefits by improving bioavailability and pharmacokinetics which in turn improves binding, internalization and targeting of tumor(s). Outcomes using these novel drug delivery systems have been discussed in detail. This review also describes the tumor-specific drug delivery system(s) that can be highly effective in destroying tumors. Such new approaches are expected to lead to clinical trials and to improve cancer therapeutics. PMID:23116309

  15. Gynecologic cancer treatment: risk factors for therapeutically induced neoplasia

    International Nuclear Information System (INIS)

    Therapeutic intervention in a course of illness, while producing the desired result, also may have some adverse long-term effects on the patient. Second malignancies are one of the known complications of therapy. The treatments of gynecologic cancers by surgery, irradiation and chemotherapy have been associated with subsequent neoplasms. Care must be exercised in associating previous therapy and a subsequent malignancy. Naturally occurring second cancers must be separated from those which are iatrogenic. Associations in the literature have been made involving malignancies as a sequelae of prior gynecologic therapy. The use of normal skin from the thigh to fabricate an artificial vagina has resulted in more squamous cell carcinomas than expected. Alkylating agents used in the treatment of ovarian cancer and other diseases have been shown to lead to an increased risk of leukemia. Irradiation therapy, however, has not yet been shown to be related to leukemia in cervical cancer patients. The incidence of lymphoma and uterine, urinary bladder and colon carcinomas has been associated with prior irradiation for gynecologic disease. The literature regarding the therapeutically induced risk factors in gynecologic therapy is reviewed and areas of our knowledge that require more investigation are identified

  16. Infectious Agents and Cancer Epidemiology Research Webinar Series

    Science.gov (United States)

    Infectious Agents and Cancer Epidemiology Research Webinar Series highlights emerging and cutting-edge research related to infection-associated cancers, shares scientific knowledge about technologies and methods, and fosters cross-disciplinary discussions on infectious agents and cancer epidemiology.

  17. Exosome removal as a therapeutic adjuvant in cancer.

    Science.gov (United States)

    Marleau, Annette M; Chen, Chien-Shing; Joyce, James A; Tullis, Richard H

    2012-01-01

    Exosome secretion is a notable feature of malignancy owing to the roles of these nanoparticles in cancer growth, immune suppression, tumor angiogenesis and therapeutic resistance. Exosomes are 30-100 nm membrane vesicles released by many cells types during normal physiological processes. Tumors aberrantly secrete large quantities of exosomes that transport oncoproteins and immune suppressive molecules to support tumor growth and metastasis. The role of exosomes in intercellular signaling is exemplified by human epidermal growth factor receptor type 2 (HER2) over-expressing breast cancer, where exosomes with the HER2 oncoprotein stimulate tumor growth and interfere with the activity of the therapeutic antibody Herceptin®. Since numerous observations from experimental model systems point toward an important clinical impact of exosomes in cancer, several pharmacological strategies have been proposed for targeting their malignant activities. We also propose a novel device strategy involving extracorporeal hemofiltration of exosomes from the entire circulatory system using an affinity plasmapheresis platform known as the Aethlon ADAPT™ (adaptive dialysis-like affinity platform technology) system, which would overcome the risks of toxicity and drug interactions posed by pharmacological approaches. This technology allows affinity agents, including exosome-binding lectins and antibodies, to be immobilized in the outer-capillary space of plasma filtration membranes that integrate into existing kidney dialysis systems. Device therapies that evolve from this platform allow rapid extracorporeal capture and selective retention of target particles circulatory system. This strategy is supported by clinical experience in hepatitis C virus-infected patients using an ADAPT™ device, the Hemopurifier®, to reduce the systemic load of virions having similar sizes and glycosylated surfaces as cancer exosomes. This review discusses the possible therapeutic approaches for

  18. Production of Anti-Cancer Agent Using Microbial Biotransformation

    Directory of Open Access Journals (Sweden)

    Changhyun Roh

    2014-10-01

    Full Text Available Microbial biotransformation is a great model system to produce drugs and biologically active compounds. In this study, we elucidated the fermentation and production of an anti-cancer agent from a microbial process for regiospecific hydroxylation of resveratrol. Among the strains examined, a potent strain showed high regiospecific hydroxylation activity to produce piceatannol. In a 5 L (w/v 3 L jar fermentation, this wild type Streptomyces sp. in the batch system produced 205 mg of piceatannol (i.e., 60% yields from 342 mg of resveratrol in 20 h. Using the product, an in vitro anti-cancer study was performed against a human cancer cell line (HeLa. It showed that the biotransformed piceatannol possessed a significant anticancer activity. This result demonstrates that a biotransformation screening method might be of therapeutic interest with respect to the identification of anti-cancer drugs.

  19. Therapeutic strategies for targeting cancer stem cells

    Institute of Scientific and Technical Information of China (English)

    Yu Jeong Kim; Elizabeth L Siegler; Natnaree Siriwon; Pin Wang

    2016-01-01

    The therapeutic limitations of conventional chemotherapeutic drugs present a challenge for cancer therapy; these shortcomings are largely attributed to the ability of cancer cells to repopulate and metastasize after initial therapies. Compelling evidence suggests that cancer stem cells (CSCs) have a crucial impact in current shortcomings of cancer therapy because they are largely responsible for tumor initiation, relapse, metastasis, and chemo-resistance. Thus, a better understanding of the properties and mechanisms underlying CSC resistance to treatments is necessary to improve patient outcomes and survival rates. In this review, the authors characterize and compare different CSC-speciifc biomarkers that are present in various types of tumors. We further discuss multiple targeting approaches currently in preclinical or clinical testing that show great potential for targeting CSCs. This review discusses numerous strategies to eliminate CSCs by targeting surface biomarkers, regulating CSC-associated oncogenes and signaling pathways, inhibiting drug-eflfux pumps involved in drug resistance, modulating the tumor microenvironment and immune system, and applying drug combination therapy using nanomedicine.

  20. Emerging Therapeutic Biomarkers in Endometrial Cancer

    Directory of Open Access Journals (Sweden)

    Peixin Dong

    2013-01-01

    Full Text Available Although clinical trials of molecular therapies targeting critical biomarkers (mTOR, epidermal growth factor receptor/epidermal growth factor receptor 2, and vascular endothelial growth factor in endometrial cancer show modest effects, there are still challenges that might remain regarding primary/acquired drug resistance and unexpected side effects on normal tissues. New studies that aim to target both genetic and epigenetic alterations (noncoding microRNA underlying malignant properties of tumor cells and to specifically attack tumor cells using cell surface markers overexpressed in tumor tissue are emerging. More importantly, strategies that disrupt the cancer stem cell/epithelial-mesenchymal transition-dependent signals and reactivate antitumor immune responses would bring new hope for complete elimination of all cell compartments in endometrial cancer. We briefly review the current status of molecular therapies tested in clinical trials and mainly discuss the potential therapeutic candidates that are possibly used to develop more effective and specific therapies against endometrial cancer progression and metastasis.

  1. Deubiquitinase inhibition as a cancer therapeutic strategy.

    Science.gov (United States)

    D'Arcy, Padraig; Wang, Xin; Linder, Stig

    2015-03-01

    The ubiquitin proteasome system (UPS) is the main system for controlled protein degradation and a key regulator of fundamental cellular processes. The dependency of cancer cells on a functioning UPS has made this an attractive target for development of drugs that show selectivity for tumor cells. Deubiquitinases (DUBs, ubiquitin isopeptidases) are components of the UPS that catalyze the removal of ubiquitin moieties from target proteins or polyubiquitin chains, resulting in altered signaling or changes in protein stability. A number of DUBs regulate processes associated with cell proliferation and apoptosis, and as such represent candidate targets for cancer therapeutics. The majority of DUBs are cysteine proteases and are likely to be more "druggable" than E3 ligases. Cysteine residues in the active sites of DUBs are expected to be reactive to various electrophiles. Various compounds containing α,β-unsaturated ketones have indeed been demonstrated to inhibit cellular DUB activity. Inhibition of proteasomal cysteine DUB enzymes (i.e. USP14 and UCHL5) can be predicted to be particularly cytotoxic to cancer cells as it leads to blocking of proteasome function and accumulation of proteasomal substrates. We here provide an overall review of DUBs relevant to cancer and of various small molecules which have been demonstrated to inhibit DUB activity.

  2. Telomere and Telomerase Therapeutics in Cancer

    Directory of Open Access Journals (Sweden)

    Yucheng Xu

    2016-05-01

    Full Text Available Telomerase is a reverse transcriptase capable of utilizing an integrated RNA component as a template to add protective tandem telomeric single strand DNA repeats, TTAGGG, to the ends of chromosomes. Telomere dysfunction and telomerase reactivation are observed in approximately 90% of human cancers; hence, telomerase activation plays a unique role as a nearly universal step on the path to malignancy. In the past two decades, multiple telomerase targeting therapeutic strategies have been pursued, including direct telomerase inhibition, telomerase interference, hTERT or hTERC promoter driven therapy, telomere-based approaches, and telomerase vaccines. Many of these strategies have entered clinical development, and some have now advanced to phase III clinical trials. In the coming years, one or more of these new telomerase-targeting drugs may be expected to enter the pharmacopeia of standard care. Here, we briefly review the molecular functions of telomerase in cancer and provide an update about the preclinical and clinical development of telomerase targeting therapeutics.

  3. Telomere and Telomerase Therapeutics in Cancer

    Science.gov (United States)

    Xu, Yucheng; Goldkorn, Amir

    2016-01-01

    Telomerase is a reverse transcriptase capable of utilizing an integrated RNA component as a template to add protective tandem telomeric single strand DNA repeats, TTAGGG, to the ends of chromosomes. Telomere dysfunction and telomerase reactivation are observed in approximately 90% of human cancers; hence, telomerase activation plays a unique role as a nearly universal step on the path to malignancy. In the past two decades, multiple telomerase targeting therapeutic strategies have been pursued, including direct telomerase inhibition, telomerase interference, hTERT or hTERC promoter driven therapy, telomere-based approaches, and telomerase vaccines. Many of these strategies have entered clinical development, and some have now advanced to phase III clinical trials. In the coming years, one or more of these new telomerase-targeting drugs may be expected to enter the pharmacopeia of standard care. Here, we briefly review the molecular functions of telomerase in cancer and provide an update about the preclinical and clinical development of telomerase targeting therapeutics. PMID:27240403

  4. Telomere and Telomerase Therapeutics in Cancer.

    Science.gov (United States)

    Xu, Yucheng; Goldkorn, Amir

    2016-01-01

    Telomerase is a reverse transcriptase capable of utilizing an integrated RNA component as a template to add protective tandem telomeric single strand DNA repeats, TTAGGG, to the ends of chromosomes. Telomere dysfunction and telomerase reactivation are observed in approximately 90% of human cancers; hence, telomerase activation plays a unique role as a nearly universal step on the path to malignancy. In the past two decades, multiple telomerase targeting therapeutic strategies have been pursued, including direct telomerase inhibition, telomerase interference, hTERT or hTERC promoter driven therapy, telomere-based approaches, and telomerase vaccines. Many of these strategies have entered clinical development, and some have now advanced to phase III clinical trials. In the coming years, one or more of these new telomerase-targeting drugs may be expected to enter the pharmacopeia of standard care. Here, we briefly review the molecular functions of telomerase in cancer and provide an update about the preclinical and clinical development of telomerase targeting therapeutics. PMID:27240403

  5. Exosome removal as a therapeutic adjuvant in cancer

    Directory of Open Access Journals (Sweden)

    Marleau Annette M

    2012-06-01

    Full Text Available Abstract Exosome secretion is a notable feature of malignancy owing to the roles of these nanoparticles in cancer growth, immune suppression, tumor angiogenesis and therapeutic resistance. Exosomes are 30–100 nm membrane vesicles released by many cells types during normal physiological processes. Tumors aberrantly secrete large quantities of exosomes that transport oncoproteins and immune suppressive molecules to support tumor growth and metastasis. The role of exosomes in intercellular signaling is exemplified by human epidermal growth factor receptor type 2 (HER2 over-expressing breast cancer, where exosomes with the HER2 oncoprotein stimulate tumor growth and interfere with the activity of the therapeutic antibody Herceptin®. Since numerous observations from experimental model systems point toward an important clinical impact of exosomes in cancer, several pharmacological strategies have been proposed for targeting their malignant activities. We also propose a novel device strategy involving extracorporeal hemofiltration of exosomes from the entire circulatory system using an affinity plasmapheresis platform known as the Aethlon ADAPT™ (adaptive dialysis-like affinity platform technology system, which would overcome the risks of toxicity and drug interactions posed by pharmacological approaches. This technology allows affinity agents, including exosome-binding lectins and antibodies, to be immobilized in the outer-capillary space of plasma filtration membranes that integrate into existing kidney dialysis systems. Device therapies that evolve from this platform allow rapid extracorporeal capture and selective retention of target particles 

  6. Multiple roles and therapeutic implications of Akt signaling in cancer

    Directory of Open Access Journals (Sweden)

    Emiliano Calvo

    2009-06-01

    Full Text Available Emiliano Calvo1, Victoria Bolós2, Enrique Grande21Centro Integral Oncológico Clara Campal (CiOCC, Madrid. Spain; 2Pfizer Oncology, Alcobendas-Madrid, SpainAbstract: The prominence of the PI3K-Akt signaling pathway in several tumors indicates a relationship with tumor grade and proliferation. Critical cellular processes are driven through this pathway. More detailed knowledge of the pathogenesis of tumors would enable us to design targeted drugs to block both membrane tyrosine kinase receptors and the intracellular kinases involved in the transmission of the signal. The newly approved molecular inhibitors sunitinib (an inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and other tyrosine kinase receptors, sorafenib (a serine–threonine kinase inhibitor that acts against B-Raf and temsirolimus (an mTOR inhibitor shown clinical activity in advanced kidney cancer. Chronic myeloid leukemia has changed its natural history thanks to imatinib and dasatinib, both of which inhibit the intracellular bcr/abl protein derived from the alteration in the Philadelphia chromosome. Intracellular pathways are still important in cancer development and their blockade directly affects outcome. Cross-talk has been observed but is not well understood. Vertical and horizontal pathway blockade are promising anticancer strategies. Indeed, preclinical and early clinical data suggest that combining superficial and intracellular blocking agents can synergize and leverage single-agent activity. The implication of the Akt signaling pathway in cancer is well established and has led to the development of new anticancer agents that block its activation.Keywords: Akt, cancer, therapeutic target, Akt inhibitors

  7. Cyclic AMP efflux inhibitors as potential therapeutic agents for leukemia

    Science.gov (United States)

    Perez, Dominique R.; Smagley, Yelena; Garcia, Matthew; Carter, Mark B.; Evangelisti, Annette; Matlawska-Wasowska, Ksenia; Winter, Stuart S.; Sklar, Larry A.; Chigaev, Alexandre

    2016-01-01

    Apoptotic evasion is a hallmark of cancer. We propose that some cancers may evade cell death by regulating 3′-5′-cyclic adenosine monophosphate (cAMP), which is associated with pro-apoptotic signaling. We hypothesize that leukemic cells possess mechanisms that efflux cAMP from the cytoplasm, thus protecting them from apoptosis. Accordingly, cAMP efflux inhibition should result in: cAMP accumulation, activation of cAMP-dependent downstream signaling, viability loss, and apoptosis. We developed a novel assay to assess cAMP efflux and performed screens to identify inhibitors. In an acute myeloid leukemia (AML) model, several identified compounds reduced cAMP efflux, appropriately modulated pathways that are responsive to cAMP elevation (cAMP-responsive element-binding protein phosphorylation, and deactivation of Very Late Antigen-4 integrin), and induced mitochondrial depolarization and caspase activation. Blocking adenylyl cyclase activity was sufficient to reduce effects of the most potent compounds. These compounds also decreased cAMP efflux and viability of B-lineage acute lymphoblastic leukemia (B-ALL) cell lines and primary patient samples, but not of normal primary peripheral blood mononuclear cells. Our data suggest that cAMP efflux is a functional feature that could be therapeutically targeted in leukemia. Furthermore, because some of the identified drugs are currently used for treating other illnesses, this work creates an opportunity for repurposing. PMID:27129155

  8. Development of new therapeutic methods of lung cancer through team approach study

    Energy Technology Data Exchange (ETDEWEB)

    Park, Jong Ho; Zo, Jae Ill; Baek, Hee Jong; Jung, Jin Haeng; Lee, Jae Cheol; Ryoo, Baek Yeol; Kim, Mi Sook; Choi, Du Hwan; Park, Sun Young; Lee, Hae Young

    2000-12-01

    The aims of this study were to make the lung cancer clinics in Korea Cancer Center Hospital, and to establish new therapeutic methods of lung cancer for increasing the cure rate and survival rate of patients. Also another purpose of this study was to establish a common treatment method in our hospital. All patients who were operated in Korea Cancer Center Hospital from 1987 due to lung cancer were followed up and evaluated. And we have been studied the effect of postoperative adjuvant therapy in stage I, II, IIIA non-small cell lung cancer patients from 1989 with the phase three study form. Follow-up examinations were scheduled in these patients and interim analysis was made. Also we have been studied the effect of chemo-therapeutic agents in small cell lung cancer patients from 1997 with the phase two study form. We evaluated the results of this study. Some important results of this study were as follows. 1. The new therapeutic method (surgery + MVP chemotherapy) was superior to the standard therapeutic one in stage I Non-small cell lung cancer patients. So, we have to change the standard method of treatment in stage I NSCLC. 2. Also, this new therapeutic method made a good result in stage II NSCLC patients. And this result was reported in The Annals of Thoracic Surgery. 3. However, this new therapeutic method was not superior to the standard treatment method (surgery only) in stage IIIA NSCLC patients. So, we must develop new chemo-therapeutic agents in the future for advanced NSCLC patients. 4. In the results of the randomized phase II studies about small cell lung cancer, there was no difference in survival between Etoposide + Carboplatin + Ifosfamide + Cisplatin group and Etoposide + Carboplatin + Ifosfamide + Cisplatin + Tamoxifen group in both the limited and extended types of small cell lung cancer patients.

  9. Development of new therapeutic methods of lung cancer through team approach study

    International Nuclear Information System (INIS)

    The aims of this study were to make the lung cancer clinics in Korea Cancer Center Hospital, and to establish new therapeutic methods of lung cancer for increasing the cure rate and survival rate of patients. Also another purpose of this study was to establish a common treatment method in our hospital. All patients who were operated in Korea Cancer Center Hospital from 1987 due to lung cancer were followed up and evaluated. And we have been studied the effect of postoperative adjuvant therapy in stage I, II, IIIA non-small cell lung cancer patients from 1989 with the phase three study form. Follow-up examinations were scheduled in these patients and interim analysis was made. Also we have been studied the effect of chemo-therapeutic agents in small cell lung cancer patients from 1997 with the phase two study form. We evaluated the results of this study. Some important results of this study were as follows. 1. The new therapeutic method (surgery + MVP chemotherapy) was superior to the standard therapeutic one in stage I Non-small cell lung cancer patients. So, we have to change the standard method of treatment in stage I NSCLC. 2. Also, this new therapeutic method made a good result in stage II NSCLC patients. And this result was reported in The Annals of Thoracic Surgery. 3. However, this new therapeutic method was not superior to the standard treatment method (surgery only) in stage IIIA NSCLC patients. So, we must develop new chemo-therapeutic agents in the future for advanced NSCLC patients. 4. In the results of the randomized phase II studies about small cell lung cancer, there was no difference in survival between Etoposide + Carboplatin + Ifosfamide + Cisplatin group and Etoposide + Carboplatin + Ifosfamide + Cisplatin + Tamoxifen group in both the limited and extended types of small cell lung cancer patients

  10. Development of Holmium 166-chitosan complex as a radiopharmaceutical agent for liver cancer therapy

    Energy Technology Data Exchange (ETDEWEB)

    Ryu, Jei Man; Nam, Soon Chul; Park, Sun Joo; Moon, Eun Yi; Lee, Won Yong; Shin, Dong Hyuk; Cho, Eun Hee [Korea Atomic Energy Research Instisute, Taejon (Korea, Republic of)

    1997-09-01

    Effective therapeutic methods for cancer disease should be developed because the frequency of cancer disease is being increased rapidly. But there is no effective therapeutic method for treating these disease until now. The purpose of this research is to gain the clinical approval of Holmium{sup 166}-Chitosan complex as a radiopharmaceutical agent for liver cancer. We finished the preclinical test of Holmium{sup 166}-Chitosan complex and got the approval for clinical trial of this agent. 12 refs., 11 tabs., 9 figs. (author)

  11. Key cancer cell signal transduction pathways as therapeutic targets.

    Science.gov (United States)

    Bianco, Roberto; Melisi, Davide; Ciardiello, Fortunato; Tortora, Giampaolo

    2006-02-01

    Growth factor signals are propagated from the cell surface, through the action of transmembrane receptors, to intracellular effectors that control critical functions in human cancer cells, such as differentiation, growth, angiogenesis, and inhibition of cell death and apoptosis. Several kinases are involved in transduction pathways via sequential signalling activation. These kinases include transmembrane receptor kinases (e.g., epidermal growth factor receptor EGFR); or cytoplasmic kinases (e.g., PI3 kinase). In cancer cells, these signalling pathways are often altered and results in a phenotype characterized by uncontrolled growth and increased capability to invade surrounding tissue. Therefore, these crucial transduction molecules represent attractive targets for cancer therapy. This review will summarize current knowledge of key signal transduction pathways, that are altered in cancer cells, as therapeutic targets for novel selective inhibitors. The most advanced targeted agents currently under development interfere with function and expression of several signalling molecules, including the EGFR family; the vascular endothelial growth factor and its receptors; and cytoplasmic kinases such as Ras, PI3K and mTOR.

  12. Tetrodotoxin (TTX as a Therapeutic Agent for Pain

    Directory of Open Access Journals (Sweden)

    Cruz Miguel Cendán

    2012-01-01

    Full Text Available Tetrodotoxin (TTX is a potent neurotoxin that blocks voltage-gated sodium channels (VGSCs. VGSCs play a critical role in neuronal function under both physiological and pathological conditions. TTX has been extensively used to functionally characterize VGSCs, which can be classified as TTX-sensitive or TTX-resistant channels according to their sensitivity to this toxin. Alterations in the expression and/or function of some specific TTX-sensitive VGSCs have been implicated in a number of chronic pain conditions. The administration of TTX at doses below those that interfere with the generation and conduction of action potentials in normal (non-injured nerves has been used in humans and experimental animals under different pain conditions. These data indicate a role for TTX as a potential therapeutic agent for pain. This review focuses on the preclinical and clinical evidence supporting a potential analgesic role for TTX. In addition, the contribution of specific TTX-sensitive VGSCs to pain is reviewed.

  13. Vascular-targeted photodynamic therapy with BF2-chelated Tetraaryl-Azadipyrromethene agents: a multi-modality molecular imaging approach to therapeutic assessment.

    LENUS (Irish Health Repository)

    Byrne, A T

    2009-11-03

    Photodynamic therapy (PDT) is a treatment modality for a range of diseases including cancer. The BF(2)-chelated tetraaryl-azadipyrromethenes (ADPMs) are an emerging class of non-porphyrin PDT agent, which have previously shown excellent photochemical and photophysical properties for therapeutic application. Herein, in vivo efficacy and mechanism of action studies have been completed for the lead agent, ADMP06.

  14. Novel targeted agents for gastric cancer

    Directory of Open Access Journals (Sweden)

    Liu Lian

    2012-06-01

    Full Text Available Abstract Contemporary advancements have had little impact on the treatment of gastric cancer (GC, the world’s second highest cause of cancer death. Agents targeting human epidermal growth factor receptor mediated pathways have been a common topic of contemporary cancer research, including monoclonal antibodies (mAbs and receptor tyrosine kinase inhibitors (TKIs. Trastuzumab is the first target agent evidencing improvements in overall survival in HER2-positive (human epidermal growth factor receptor 2 gastric cancer patients. Agents targeting vascular epithelial growth factor (VEGF, mammalian target of rapamycin (mTOR, and other biological pathways are also undergoing clinical trials, with some marginally positive results. Effective targeted therapy requires patient selection based on predictive molecular biomarkers. Most phase III clinical trials are carried out without patient selection; therefore, it is hard to achieve personalized treatment and to monitor patient outcome individually. The trend for future clinical trials requires patient selection methods based on current understanding of GC biology with the application of biomarkers.

  15. Transcription Inhibition as a Therapeutic Target for Cancer

    International Nuclear Information System (INIS)

    During tumorigenesis the transformed cells lose their normal growth control mechanisms and become dependent on oncogenes' products and pathways for survival. Treatments tailored to block the expression or function of transforming genes have shown efficacy in eliminating neoplastic cells. The mRNAs of many oncogenes, as well as regulators of other key processes such as cell proliferation, angiogenesis, and apoptosis, typically have shorter half-lives. Agents that impede mRNA synthesis are expected to selectively hinder the expression of these genes and, therefore, be detrimental to neoplastic cells that are physiologically dependent on them. In addition to exploiting the tumor cells' dependency on short-lived transcripts, RNA-directed agents also take advantage of the differential sensitivity between transformed and non-transformed cells, as the cytotoxic effects of inhibiting RNA synthesis have not been seen in non-transformed cells. The abrogation of the formation of oncotranscripts provides a new concept in cancer therapeutics and numerous agents have been developed which are able to target transcription. The focus of this review is to give an overview of transcription and the different inhibitory strategies that target various aspects of the transcriptional process

  16. Inferences of drug responses in cancer cells from cancer genomic features and compound chemical and therapeutic properties

    Science.gov (United States)

    Wang, Yongcui; Fang, Jianwen; Chen, Shilong

    2016-01-01

    Accurately predicting the response of a cancer patient to a therapeutic agent is a core goal of precision medicine. Existing approaches were mainly relied primarily on genomic alterations in cancer cells that have been treated with different drugs. Here we focus on predicting drug response based on integration of the heterogeneously pharmacogenomics data from both cell and drug sides. Through a systematical approach, named as PDRCC (Predict Drug Response in Cancer Cells), the cancer genomic alterations and compound chemical and therapeutic properties were incorporated to determine the chemotherapeutic response in cancer patients. Using the Cancer Cell Line Encyclopedia (CCLE) study as the benchmark dataset, all pharmacogenomics data exhibited their roles in inferring the relationships between cancer cells and drugs. When integrating both genomic resources and compound information, the prediction coverage was significantly increased. The validity of PDRCC was also supported by its effective in uncovering the unknown cell-drug associations with database and literature evidences. It set the stage for clinical testing of novel therapeutic strategies, such as the sensitive association between cancer cell ‘A549_LUNG’ and compound ‘Topotecan’. In conclusion, PDRCC offers the possibility for faster, safer, and cheaper the development of novel anti-cancer therapeutics in the early-stage clinical trails. PMID:27645580

  17. Glioblastoma cancer stem cells: Biomarker and therapeutic advances.

    Science.gov (United States)

    Pointer, Kelli B; Clark, Paul A; Zorniak, Michael; Alrfaei, Bahauddeen M; Kuo, John S

    2014-05-01

    Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor in humans. It accounts for fifty-two percent of primary brain malignancies in the United States and twenty percent of all primary intracranial tumors. Despite the current standard therapies of maximal safe surgical resection followed by temozolomide and radiotherapy, the median patient survival is still less than 2 years due to inevitable tumor recurrence. Glioblastoma cancer stem cells (GSCs) are a subgroup of tumor cells that are radiation and chemotherapy resistant and likely contribute to rapid tumor recurrence. In order to gain a better understanding of the many GBM-associated mutations, analysis of the GBM cancer genome is on-going; however, innovative strategies to target GSCs and overcome tumor resistance are needed to improve patient survival. Cancer stem cell biology studies reveal basic understandings of GSC resistance patterns and therapeutic responses. Membrane proteomics using phage and yeast display libraries provides a method to identify novel antibodies and surface antigens to better recognize, isolate, and target GSCs. Altogether, basic GBM and GSC genetics and proteomics studies combined with strategies to discover GSC-targeting agents could lead to novel treatments that significantly improve patient survival and quality of life.

  18. Crocetin: an agent derived from saffron for prevention and therapy for cancer

    OpenAIRE

    Gutheil, William G.; Reed, Gregory; RAY, AMITABHA; Dhar, Animesh

    2012-01-01

    Cancer is one of the leading causes of death in the United States and accounts for approximately 8 million deaths per year worldwide. Although there is an increasing number of therapeutic options available for patients with cancer, their efficacy is time-limited and non-curative. Approximately 50-60% of cancer patients in the United States utilize agents derived from different parts of plants or nutrients (complementary and alternative medicine), exclusively or concurrently with traditional t...

  19. Annotating Cancer Variants and Anti-Cancer Therapeutics in Reactome

    Energy Technology Data Exchange (ETDEWEB)

    Milacic, Marija; Haw, Robin, E-mail: robin.haw@oicr.on.ca; Rothfels, Karen; Wu, Guanming [Informatics and Bio-computing Platform, Ontario Institute for Cancer Research, Toronto, ON, M5G0A3 (Canada); Croft, David; Hermjakob, Henning [European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD (United Kingdom); D’Eustachio, Peter [Department of Biochemistry, NYU School of Medicine, New York, NY 10016 (United States); Stein, Lincoln [Informatics and Bio-computing Platform, Ontario Institute for Cancer Research, Toronto, ON, M5G0A3 (Canada)

    2012-11-08

    Reactome describes biological pathways as chemical reactions that closely mirror the actual physical interactions that occur in the cell. Recent extensions of our data model accommodate the annotation of cancer and other disease processes. First, we have extended our class of protein modifications to accommodate annotation of changes in amino acid sequence and the formation of fusion proteins to describe the proteins involved in disease processes. Second, we have added a disease attribute to reaction, pathway, and physical entity classes that uses disease ontology terms. To support the graphical representation of “cancer” pathways, we have adapted our Pathway Browser to display disease variants and events in a way that allows comparison with the wild type pathway, and shows connections between perturbations in cancer and other biological pathways. The curation of pathways associated with cancer, coupled with our efforts to create other disease-specific pathways, will interoperate with our existing pathway and network analysis tools. Using the Epidermal Growth Factor Receptor (EGFR) signaling pathway as an example, we show how Reactome annotates and presents the altered biological behavior of EGFR variants due to their altered kinase and ligand-binding properties, and the mode of action and specificity of anti-cancer therapeutics.

  20. Reengineered tricyclic anti-cancer agents.

    Science.gov (United States)

    Kastrinsky, David B; Sangodkar, Jaya; Zaware, Nilesh; Izadmehr, Sudeh; Dhawan, Neil S; Narla, Goutham; Ohlmeyer, Michael

    2015-10-01

    The phenothiazine and dibenzazepine tricyclics are potent neurotropic drugs with a documented but underutilized anti-cancer side effect. Reengineering these agents (TFP, CPZ, CIP) by replacing the basic amine with a neutral polar functional group (e.g., RTC-1, RTC-2) abrogated their CNS effects as demonstrated by in vitro pharmacological assays and in vivo behavioral models. Further optimization generated several phenothiazines and dibenzazepines with improved anti-cancer potency, exemplified by RTC-5. This new lead demonstrated efficacy against a xenograft model of an EGFR driven cancer without the neurotropic effects exhibited by the parent molecules. Its effects were attributed to concomitant negative regulation of PI3K-AKT and RAS-ERK signaling. PMID:26372073

  1. Targeting multiple signal pathways by chemopreventive agents for cancer prevention and therapy

    Institute of Scientific and Technical Information of China (English)

    Fazlul H SARKAR; Yi-wei LI

    2007-01-01

    In recent years, growing interest has been focused on the field of cancer prevention.Cancer prevention by chemopreventive agents offers significant promise for re-ducing the incidence and mortality of cancer. Chemopreventive agents may exert their effects either by blocking or metabolizing carcinogens or by inhibiting tumor cell growth. Another important benefit of chemopreventive agents is their non-toxic nature. Therefore, chemopreventive agents have recently been used for cancer treatment in combination with chemotherapeutics or radiotherapy, uncov-ering a novel strategy for cancer therapy. This strategy opens a new avenue fromcancer prevention to cancer treatment. In vitro and in vivo studies have demon-strated that chemopreventive agents could enhance the antitumor activity of chemotherapeutics, improving the treatment outcome. Growing evidence has shown that chemopreventive agents potentiate the efficacy of chemotherapy and radiotherapy through the regulation of multiple signaling pathways, including Akt, NF-κB, c-Myc, cyclooxygenase-2, apoptosis, and others, suggesting a multitargeted nature of chemopreventive agents. However, further in-depth mecha-nistic studies, in vivo animal experiments, and clinical trials are needed to investi-gate the effects of chemopreventive agents in combination treatment of cancer with conventional cancer therapies. More potent natural and synthetic chemo-preventive agents are also needed to improve the efficacy of mechanism-based and targeted therapeutic strategies against cancer, which are likely to make a significant impact on saving lives. Here, we have briefly reviewed the role of chemopreventive agents in cancer prevention, but most importantly, we have reviewed how they could be useful for cancer therapy in combination with con-ventional therapies.

  2. Spherical Nucleic Acids as Intracellular Agents for Nucleic Acid Based Therapeutics

    Science.gov (United States)

    Hao, Liangliang

    Recent functional discoveries on the noncoding sequences of human genome and transcriptome could lead to revolutionary treatment modalities because the noncoding RNAs (ncRNAs) can be applied as therapeutic agents to manipulate disease-causing genes. To date few nucleic acid-based therapeutics have been translated into the clinic due to challenges in the delivery of the oligonucleotide agents in an effective, cell specific, and non-toxic fashion. Unmodified oligonucleotide agents are destroyed rapidly in biological fluids by enzymatic degradation and have difficulty crossing the plasma membrane without the aid of transfection reagents, which often cause inflammatory, cytotoxic, or immunogenic side effects. Spherical nucleic acids (SNAs), nanoparticles consisting of densely organized and highly oriented oligonucleotides, pose one possible solution to circumventing these problems in both the antisense and RNA interference (RNAi) pathways. The unique three dimensional architecture of SNAs protects the bioactive oligonucleotides from unspecific degradation during delivery and supports their targeting of class A scavenger receptors and endocytosis via a lipid-raft-dependent, caveolae-mediated pathway. Owing to their unique structure, SNAs are able to cross cell membranes and regulate target genes expression as a single entity, without triggering the cellular innate immune response. Herein, my thesis has focused on understanding the interactions between SNAs and cellular components and developing SNA-based nanostructures to improve therapeutic capabilities. Specifically, I developed a novel SNA-based, nanoscale agent for delivery of therapeutic oligonucleotides to manipulate microRNAs (miRNAs), the endogenous post-transcriptional gene regulators. I investigated the role of SNAs involving miRNAs in anti-cancer or anti-inflammation responses in cells and in in vivo murine disease models via systemic injection. Furthermore, I explored using different strategies to construct

  3. Liver cancer stem cell markers: Progression and therapeutic implications

    Science.gov (United States)

    Sun, Jing-Hui; Luo, Qing; Liu, Ling-Ling; Song, Guan-Bin

    2016-01-01

    Cancer stem cells (CSCs) are a small subpopulation in cancer, have been proposed to be cancer-initiating cells, and have been shown to be responsible for chemotherapy resistance and cancer recurrence. The identification of CSC subpopulations inside a tumor presents a new understanding of cancer development because it implies that tumors can only be eradicated by targeting CSCs. Although advances in liver cancer detection and treatment have increased the possibility of curing the disease at early stages, unfortunately, most patients will relapse and succumb to their disease. Strategies aimed at efficiently targeting liver CSCs are becoming important for monitoring the progress of liver cancer therapy and for evaluating new therapeutic approaches. Herein, we provide a critical discussion of biological markers described in the literature regarding liver cancer stem cells and the potential of these markers to serve as therapeutic targets. PMID:27053846

  4. Gold Nanostructures as a Platform for Combinational Therapy in Future Cancer Therapeutics

    Energy Technology Data Exchange (ETDEWEB)

    Jelveh, Salomeh [Ontario Cancer Institute, Princess Margaret Hospital, University Health Network, Toronto, ON (Canada); Department of Radiation Physics, Princess Margaret Hospital, Toronto, ON (Canada); Chithrani, Devika B., E-mail: devika.chithrani@rmp.uhn.on.ca [Department of Radiation Physics, Princess Margaret Hospital, Toronto, ON (Canada); STTARR Innovation Centre, Toronto Medical Discovery Tower, Toronto, ON (Canada)

    2011-03-04

    The field of nanotechnology is currently undergoing explosive development on many fronts. The technology is expected to generate innovations and play a critical role in cancer therapeutics. Among other nanoparticle (NP) systems, there has been tremendous progress made in the use of spherical gold NPs (GNPs), gold nanorods (GNRs), gold nanoshells (GNSs) and gold nanocages (GNCs) in cancer therapeutics. In treating cancer, radiation therapy and chemotherapy remain the most widely used treatment options and recent developments in cancer research show that the incorporation of gold nanostructures into these protocols has enhanced tumor cell killing. These nanostructures further provide strategies for better loading, targeting, and controlling the release of drugs to minimize the side effects of highly toxic anticancer drugs used in chemotherapy and photodynamic therapy. In addition, the heat generation capability of gold nanostructures upon exposure to UV or near infrared light is being used to damage tumor cells locally in photothermal therapy. Hence, gold nanostructures provide a versatile platform to integrate many therapeutic options leading to effective combinational therapy in the fight against cancer. In this review article, the recent progress in the development of gold-based NPs towards improved therapeutics will be discussed. A multifunctional platform based on gold nanostructures with targeting ligands, therapeutic molecules, and imaging contrast agents, holds an array of promising directions for cancer research.

  5. Gold Nanostructures as a Platform for Combinational Therapy in Future Cancer Therapeutics

    Directory of Open Access Journals (Sweden)

    Salomeh Jelveh

    2011-03-01

    Full Text Available The field of nanotechnology is currently undergoing explosive development on many fronts. The technology is expected to generate innovations and play a critical role in cancer therapeutics. Among other nanoparticle (NP systems, there has been tremendous progress made in the use of spherical gold NPs (GNPs, gold nanorods (GNRs, gold nanoshells (GNSs and gold nanocages (GNCs in cancer therapeutics. In treating cancer, radiation therapy and chemotherapy remain the most widely used treatment options and recent developments in cancer research show that the incorporation of gold nanostructures into these protocols has enhanced tumor cell killing. These nanostructures further provide strategies for better loading, targeting, and controlling the release of drugs to minimize the side effects of highly toxic anticancer drugs used in chemotherapy and photodynamic therapy. In addition, the heat generation capability of gold nanostructures upon exposure to UV or near infrared light is being used to damage tumor cells locally in photothermal therapy. Hence, gold nanostructures provide a versatile platform to integrate many therapeutic options leading to effective combinational therapy in the fight against cancer. In this review article, the recent progress in the development of gold-based NPs towards improved therapeutics will be discussed. A multifunctional platform based on gold nanostructures with targeting ligands, therapeutic molecules, and imaging contrast agents, holds an array of promising directions for cancer research.

  6. Development of new therapeutic methods of lung cancer through team approach study (II)

    International Nuclear Information System (INIS)

    The aims of this study were to make the lung cancer clinics in Korea Cancer Center Hospital, and to establish new therapeutic methods of lung cancer for increasing the cure rate and survival rate of patients. Also another purpose of this study was to establish a common treatment method in our hospital. All patients who were operated in Korea Cancer Center Hospital from 1987 due to lung cancer were followed up and evaluated. And we have been studied the effect of postoperative adjuvant therapy in stage 1, 2, 3A non-small cell lung cancer patients from 1989 with the phase three study form. Follow-up examinations were scheduled in these patients and interim analysis was made. Also we have been studied the effect of chemotherapeutic agents in small cell lung cancer patients from 1997 with the phase two study form. We evaluated the results of this study

  7. Demethylating Agents in the Treatment of Cancer

    Directory of Open Access Journals (Sweden)

    Paul M. Howell, Jr.

    2010-07-01

    Full Text Available Gene silencing resulting from aberrant DNA methylation can lead to tumorigenesis. Therefore, drugs that inhibit or interfere with DNA methylation have been used to reactivate and induce silenced gene re-expression in malignancies. Two demethylating agents, azacitidine and decitabine, are approved for the treatment of myelodysplastic syndromes (MDS by the U.S. Food and Drug Administration (FDA, and are now considered the standard of care in MDS. In this review, we discuss clinical data, including clinical benefits and toxicities, which led to the approval of azacitidine and decitabine. We also summarize findings from clinical trials that used these two demethylating agents in the treatment of solid tumors. Lastly, we discuss some limitations in the use of azacitidine and decitabine in cancer therapy.

  8. Using a stem cell-based signature to guide therapeutic selection in cancer.

    Science.gov (United States)

    Shats, Igor; Gatza, Michael L; Chang, Jeffrey T; Mori, Seiichi; Wang, Jialiang; Rich, Jeremy; Nevins, Joseph R

    2011-03-01

    Given the very substantial heterogeneity of most human cancers, it is likely that most cancer therapeutics will be active in only a small fraction of any population of patients. As such, the development of new therapeutics, coupled with methods to match a therapy with the individual patient, will be critical to achieving significant gains in disease outcome. One such opportunity is the use of expression signatures to identify key oncogenic phenotypes that can serve not only as biomarkers but also as a means of identifying therapeutic compounds that might specifically target these phenotypes. Given the potential importance of targeting tumors exhibiting a stem-like phenotype, we have developed an expression signature that reflects common biological aspects of various stem-like characteristics. The consensus stemness ranking (CSR) signature is upregulated in cancer stem cell-enriched samples at advanced tumor stages and is associated with poor prognosis in multiple cancer types. Using two independent computational approaches we utilized the CSR signature to identify clinically useful compounds that could target the CSR phenotype. In vitro assays confirmed selectivity of several predicted compounds including topoisomerase inhibitors and resveratrol towards breast cancer cell lines that exhibit a high-CSR phenotype. Importantly, the CSR signature could predict clinical response of breast cancer patients to a neoadjuvant regimen that included a CSR-specific agent. Collectively, these results suggest therapeutic opportunities to target the CSR phenotype in a relevant cohort of cancer patients. PMID:21169407

  9. Combination therapy of potential gene to enhance oral cancer therapeutic effect

    Science.gov (United States)

    Yeh, Chia-Hsien; Hsu, Yih-Chih

    2015-03-01

    The epidermal growth factor receptor (EGFR) over-regulation related to uncontrolled cell division and promotes progression in tumor. Over-expression of human epidermal growth factor receptor (EGFR) has been detected in oral cancer cells. EGFR-targeting agents are potential therapeutic modalities for treating oral cancer based on our in vitro study. Liposome nanotechnology is used to encapsulate siRNA and were modified with target ligand to receptors on the surface of tumor cells. We used EGFR siRNA to treat oral cancer in vitro.

  10. Approaches to improve development methods for therapeutic cancer vaccines.

    Science.gov (United States)

    Ogi, Chizuru; Aruga, Atsushi

    2015-04-01

    Therapeutic cancer vaccines are an immunotherapy that amplify or induce an active immune response against tumors. Notably, limitations in the methodology for existing anti-cancer drugs may subsist while applying them to cancer vaccine therapy. A retrospective analysis was performed using information obtained from ClinicalTrials.gov, PubMed, and published articles. Our research evaluated the optimal methodologies for therapeutic cancer vaccines based on (1) patient populations, (2) immune monitoring, (3) tumor response evaluation, and (4) supplementary therapies. Failure to optimize these methodologies at an early phase may impact development at later stages; thus, we have proposed some points to be considered during the early phase. Moreover, we compared our proposal with the guidance for industry issued by the US Food and Drug Administration in October 2011 entitled "Clinical Considerations for Therapeutic Cancer Vaccines". Consequently, while our research was aligned with the guidance, we hope it provides further insights in order to predict the risks and benefits and facilitate decisions for a new technology. We identified the following points for consideration: (1) include in the selection criteria the immunological stage with a prognostic value, which is as important as the tumor stage; (2) select immunological assays such as phenotype analysis of lymphocytes, based on their features and standardize assay methods; (3) utilize optimal response criteria for immunotherapy in therapeutic cancer vaccine trials; and (4) consider supplementary therapies, including immune checkpoint inhibitors, for future therapeutic cancer vaccines. PMID:25746315

  11. Expression of Cancer Testis Antigens in Colorectal Cancer: New Prognostic and Therapeutic Implications.

    Science.gov (United States)

    Tarnowski, Maciej; Czerewaty, Michał; Deskur, Anna; Safranow, Krzysztof; Marlicz, Wojciech; Urasińska, Elżbieta; Ratajczak, Mariusz Z; Starzyńska, Teresa

    2016-01-01

    Background. While cancer/testis antigens (CTAs) are restricted in postnatal tissues to testes and germ line-derived cells, their role in cancer development and the clinical significance of their expression still remain to be better defined. Objective. The aim of this study was to investigate the level of CTA expression in colon samples from patients with colorectal cancer (CRC) in relation to patient clinical status. Methods. Forty-five patients with newly diagnosed colorectal cancer were included in the study. We selected a panel of 18 CTAs that were previously detected in CRC as well as some new gene candidates, and their expression was detected at the mRNA level by employing RQ-PCR. Additionally, we evaluated CTA expression in three colon cancer cell lines (CL-188, HTB-39, and HTB-37) after exposure to the DNA methylation-modifying drug 5-azacytidine. Results. We report that 6 out of 18 (33%) CTAs tested (MAGEA3, OIP5, TTK, PLU1, DKKL1, and FBXO39) were significantly (p colon samples isolated from the same patients. Conclusions. Moreover, we found that MAGEA3, PLU-1, and DKKL expression positively correlated with disease progression, evaluated according to the Dukes staging system. Finally, 5-azacytidine exposure significantly upregulated expression of CTAs on CRC cells, which indicates that this demethylation agent could be employed therapeutically to enhance the immune response against tumor cells. PMID:27635108

  12. Host-guest supramolecular nanosystems for cancer diagnostics and therapeutics.

    Science.gov (United States)

    Wang, Lei; Li, Li-li; Fan, Yun-shan; Wang, Hao

    2013-07-26

    Extensive efforts have been devoted to the construction of functional supramolecular nanosystems for applications in catalysis, energy conversion, sensing and biomedicine. The applications of supramolecular nanosystems such as liposomes, micelles, inorganic nanoparticles, carbon materials for cancer diagnostics and therapeutics have been reviewed by other groups. Here, we will focus on the recent momentous advances in the implementation of typical supramolecular hosts (i.e., cyclodextrins, calixarenes, cucurbiturils and metallo-hosts) and their nanosystems in cancer diagnostics and therapeutics. We discuss the evolutive process of supramolecular nanosystems from the structural control and characterization to their diagnostic and therapeutic function exploitation and even the future potentials for clinical translation.

  13. Animal models and therapeutic molecular targets of cancer: utility and limitations

    Directory of Open Access Journals (Sweden)

    Cekanova M

    2014-10-01

    Full Text Available Maria Cekanova, Kusum Rathore Department of Small Animal Clinical Sciences, College of Veterinary Medicine, The University of Tennessee, Knoxville, TN, USA Abstract: Cancer is the term used to describe over 100 diseases that share several common hallmarks. Despite prevention, early detection, and novel therapies, cancer is still the second leading cause of death in the USA. Successful bench-to-bedside translation of basic scientific findings about cancer into therapeutic interventions for patients depends on the selection of appropriate animal experimental models. Cancer research uses animal and human cancer cell lines in vitro to study biochemical pathways in these cancer cells. In this review, we summarize the important animal models of cancer with focus on their advantages and limitations. Mouse cancer models are well known, and are frequently used for cancer research. Rodent models have revolutionized our ability to study gene and protein functions in vivo and to better understand their molecular pathways and mechanisms. Xenograft and chemically or genetically induced mouse cancers are the most commonly used rodent cancer models. Companion animals with spontaneous neoplasms are still an underexploited tool for making rapid advances in human and veterinary cancer therapies by testing new drugs and delivery systems that have shown promise in vitro and in vivo in mouse models. Companion animals have a relatively high incidence of cancers, with biological behavior, response to therapy, and response to cytotoxic agents similar to those in humans. Shorter overall lifespan and more rapid disease progression are factors contributing to the advantages of a companion animal model. In addition, the current focus is on discovering molecular targets for new therapeutic drugs to improve survival and quality of life in cancer patients. Keywords: mouse cancer model, companion animal cancer model, dogs, cats, molecular targets

  14. Stratification and therapeutic potential of PML in metastatic breast cancer.

    Science.gov (United States)

    Martín-Martín, Natalia; Piva, Marco; Urosevic, Jelena; Aldaz, Paula; Sutherland, James D; Fernández-Ruiz, Sonia; Arreal, Leire; Torrano, Verónica; Cortazar, Ana R; Planet, Evarist; Guiu, Marc; Radosevic-Robin, Nina; Garcia, Stephane; Macías, Iratxe; Salvador, Fernando; Domenici, Giacomo; Rueda, Oscar M; Zabala-Letona, Amaia; Arruabarrena-Aristorena, Amaia; Zúñiga-García, Patricia; Caro-Maldonado, Alfredo; Valcárcel-Jiménez, Lorea; Sánchez-Mosquera, Pilar; Varela-Rey, Marta; Martínez-Chantar, Maria Luz; Anguita, Juan; Ibrahim, Yasir H; Scaltriti, Maurizio; Lawrie, Charles H; Aransay, Ana M; Iovanna, Juan L; Baselga, Jose; Caldas, Carlos; Barrio, Rosa; Serra, Violeta; Vivanco, Maria dM; Matheu, Ander; Gomis, Roger R; Carracedo, Arkaitz

    2016-01-01

    Patient stratification has been instrumental for the success of targeted therapies in breast cancer. However, the molecular basis of metastatic breast cancer and its therapeutic vulnerabilities remain poorly understood. Here we show that PML is a novel target in aggressive breast cancer. The acquisition of aggressiveness and metastatic features in breast tumours is accompanied by the elevated PML expression and enhanced sensitivity to its inhibition. Interestingly, we find that STAT3 is responsible, at least in part, for the transcriptional upregulation of PML in breast cancer. Moreover, PML targeting hampers breast cancer initiation and metastatic seeding. Mechanistically, this biological activity relies on the regulation of the stem cell gene SOX9 through interaction of PML with its promoter region. Altogether, we identify a novel pathway sustaining breast cancer aggressiveness that can be therapeutically exploited in combination with PML-based stratification. PMID:27553708

  15. Imaging Therapeutic PARP Inhibition In Vivo through Bioorthogonally Developed Companion Imaging Agents

    Directory of Open Access Journals (Sweden)

    Thomas Reiner

    2012-03-01

    Full Text Available A number of small-molecule poly (ADP-ribose polymerase (PARP inhibitors are currently undergoing advanced clinical trials. Determining the distribution and target inhibitory activity of these drugs in individual subjects, however, has proven problematic. Here, we used a PARP agent for positron emission tomography-computed tomography (PET-CT imaging (18F-BO, which we developed based on the Olaparib scaffold using rapid bioorthogonal conjugation chemistries. We show that the bioorthogonal 18F modification of the parent molecule is simple, highly efficient, and well tolerated, resulting in a half maximal inhibitory concentration (IC50 of 17.9 ± 1.1 nM. Intravital imaging showed ubiquitous distribution of the drug and uptake into cancer cells, with ultimate localization within the nucleus, all of which were inhibitable. Whole-body PET-CT imaging showed tumoral uptake of the drug, which decreased significantly, after a daily dose of Olaparib. Standard 18F-fludeoxyglucose imaging, however, failed to detect such therapy-induced changes. This research represents a step toward developing a more generic approach for the rapid codevelopment of companion imaging agents based on small-molecule therapeutic inhibitors.

  16. Alpharetroviral Vectors: From a Cancer-Causing Agent to a Useful Tool for Human Gene Therapy

    OpenAIRE

    Suerth, Julia D.; Verena Labenski; Axel Schambach

    2014-01-01

    Gene therapy using integrating retroviral vectors has proven its effectiveness in several clinical trials for the treatment of inherited diseases and cancer. However, vector-mediated adverse events related to insertional mutagenesis were also observed, emphasizing the need for safer therapeutic vectors. Paradoxically, alpharetroviruses, originally discovered as cancer-causing agents, have a more random and potentially safer integration pattern compared to gammaretro- and lentiviruses. In thi...

  17. Therapeutic cancer vaccines in combination with conventional therapy

    DEFF Research Database (Denmark)

    Junker, Niels; Ellebaek, Eva; Svane, Inge Marie;

    2010-01-01

    The clinical efficacy of most therapeutic vaccines against cancer has not yet met its promise. Data are emerging that strongly support the notion that combining immunotherapy with conventional therapies, for example, radiation and chemotherapy may improve efficacy. In particular combination...... of proteins coupled to intrinsic properties of cancer cells. For example, proteins associated with drug resistance can be targeted, and form ideal target structures for use in combination with chemotherapy for killing of surviving drug resistant cancer cells. Proteins associated with the malignant phenotype...... can be targeted to specifically target cancer cells, but proteins targeted by immunotherapy may also simultaneously target cancer cells as well as suppressive cells in the tumor stroma....

  18. Nanomedicines as cancer therapeutics: Current status

    NARCIS (Netherlands)

    Akhter, S.; Ahmad, M; Ramzani, F.; Singh, A..; Ahmad, I.; Rahman, Z.; Ahmad, F.J.; Storm, G.; Kok, R.J.

    2013-01-01

    As of 21st century, cancer is arguably the most complex and challenging disease known to mankind and an inevitable public health concern of this millennium. Nanotechnology, suitably amalgamated with cancer research, has ushered an era of highly personalized and safer medicines which can improve canc

  19. Identifying therapeutic chemical agents for osteoarthritis by high throughput screening

    OpenAIRE

    Tsui, YK; Masuda, K.; Cheung, KM; Leung, VY; Kao, RY; CHAN, D

    2009-01-01

    INTRODUCTION: An articular cartilage lesion, notably generated by osteoarthritis (OA), is initiated partly by the loss of proteoglycan content from the extracellular matrix and manifests as pain or disturbed joint function [1]. Strategies that restore the proteoglycan content would be of therapeutic benefit to prevent, delay, or even reverse the progression of the lesion. Numerous clinical and experimental approaches have been widely applied [2-4] to relieve the pain or induce healing of the ...

  20. ABCG2 Inhibition as a Therapeutic Approach for Overcoming Multidrug Resistance in Cancer

    Indian Academy of Sciences (India)

    Maryam Hosseini Hasanabady; Fatemeh Kalalinia

    2016-06-01

    Breast cancer resistance protein (BCRP, ABCP or MXR) / ATP-binding cassette subfamily G member 2 (ABCG2) was characterized as a multidrug resistance efflux transporter in 1998. ABCG2 physiologically acts as a part of a self-defense mechanism for the organism; it enhances eliminating of toxic xenobiotic substances and harmful agents in the intestine, as well as through the blood-brain barrier and placental. ABCG2 recognizes and transports numerous anticancer drugs including conventional chemotherapeutic and new targeted small therapeutic molecules in clinical usage. Development of ABCG2 inhibitors for clinical usage may allow increased penetration of therapeutic agents into sanctuary sites and increased their intestinal absorption. In this report, we review the mechanisms that modulate MDR mediated by the ABC transporter ABCG2 in normal and cancer cells by different levels including, epigenetic modifications, transcriptional, posttranscriptional, translation and posttranslational regulation. Some clinical applications of ABCG2 inhibitors, also is explained.

  1. Clinical Delivery of Therapeutic Agents Based on Metals

    OpenAIRE

    Fox, John

    1997-01-01

    Metals have been used in clinical practice for hundreds of years and for a variety of indications. Although potent agents whose activity may be adapted by manipulation of their chemistry and that of associated ligands, their use has been limited by toxic effects. There is now a burgeoning series of delivery technologies available which may be adapted to the administration of metal based drugs. Together with greater understanding of metal chemistry and their mechanisms of action in disease pro...

  2. The therapeutic value of targeting inflammation in gastrointestinal cancers

    OpenAIRE

    Sun, Beicheng; Karin, Michael

    2014-01-01

    Inflammation has been implicated in the initiation and progression of gastrointestinal (GI) cancers. Inflammation also plays important roles in subverting immune tolerance, escape from immune surveillance, and conferring resistance to chemotherapeutic agents. Targeting key regulators and mediators of inflammation represents an attractive strategy for GI cancer prevention and treatment. However, the targeting of inflammation in GI cancer is not straight-forward and sometimes inflammation may c...

  3. Therapeutic potential of bryophytes and derived compounds against cancer

    Institute of Scientific and Technical Information of China (English)

    Abhijit Dey; Anuradha Mukherjee

    2015-01-01

    Bryophytes, taxonomically placed between the algae and the pteridophytes, are divided into three classes such as Liverworts, Hornworts and Mosses. Indigenous use involves this small group of plants to treat various diseases. Bryophytes have been investigated pharmacologically for active biomolecules. Several constituents with therapeutic potential have been isolated, characterized and investigated for antibacterial, antifungal, antiviral, antioxidative, antiinflamatory and anticancerous efficacy. The present review deals with the literature covering the anticancerous potential of bryophytes. Apart from the examples of the compounds and the containing bryophyte genera, the authors have tried to include the examples of cancer cell lines on which the efficacy have been tested and the mode of action of certain cytotoxic agents. Crude extracts and isolated compounds from bryophytes were found to possess potent cytotoxic properties. Different types of terpenoids and bibenzyls have been reported among the most potent cytotoxic compounds. Most of these compounds were found to induce apoptosis by activating a number of genes and enzymes. Biochemical markers such as DNA fragmentation, nuclear condensation, proteolysis of poly (ADP-ribose) polymerase, activation of caspases, inhibition of antiapoptotic nuclear transcriptional factor-kappaB, activation of p38 mitogen-activated protein kinase etc. have been found to be associated with apoptotic and necrotic response. This review summarizes recent scientific findings and suggests further investigations to evaluate the cytotoxic efficacy of bryophytes.

  4. An insight on genistein as potential pharmacological and therapeutic agent

    Institute of Scientific and Technical Information of China (English)

    Shahedur Rahman; Rezuanul Islam; AM Swaraz; Anesa Ansari; Anowar Khasru Parvez; Depak Kumar Paul

    2012-01-01

    Genistein recognized as phytoestrogens is one of the most extensively studied isoflavones. It comprises of significant portion of Asian diet including Japanese and Chinese cuisine in the form of Soy food products. Evidence showed that geinstein increases osteoblasts formation as well as decreases osteoclast production. It plays an important role in immunity; such as suppression of delayed hypersensitivity and increases host resistance to B16F10 tumor by proliferating cytotoxic T and NK cells. It also decreases the activity of lipoprotein lipase which in turn inhibits lipogenesis and prevents the uptake of glucose in type 2 diabetic in rats. Geinstein play important role in reproductive system where it regulates the productive of oestrogen and progesterone. Moreover Geinstein has the ability to inhibit the tumor and cancer cell proliferation. Numerous beneficial effect of Geinstein including cancer treatment and function in immunity, obesity, diabetes and reproductivity Geinstein proves the potentiality of phytoestrogens as a source of bioactive substance.

  5. APPLICATION OF STEM CELL THERAPEUTIC AGENTS TO CONTROL CRITICAL DISEASE

    OpenAIRE

    Sonam Sharma

    2012-01-01

    Stem cell research has been hailed for the potential to revolutionize the future of medicine with the ability to regenerate damaged and diseased organs. On the other hand, stem cell research has been highly controversial due to the ethical issues concerned with the culture and use of stem cells derived from human embryos. This article presents an overview of what stem cells are, what roles they play in normal processes such as development and cancer, and how stem cells could have the potentia...

  6. The protective and therapeutic effects of alpha-solanine on mice breast cancer.

    Science.gov (United States)

    Mohsenikia, Maryam; Alizadeh, Ali Mohammad; Khodayari, Saeed; Khodayari, Hamid; Kouhpayeh, Seyed Amin; Karimi, Aliasghar; Zamani, Mina; Azizian, Saleh; Mohagheghi, Mohammad Ali

    2013-10-15

    Alpha-solanine, a naturally steroidal glycoalkaloid, is found in leaves and fruits of plants as a defensive agent against fungi, bacteria and insects. Herein, we investigated solanine toxicity in vitro and in vivo, and assessed its protective and the therapeutic effects on a typical animal model of breast cancer. The study conducted in three series of experiments to obtain (i) solanine effects on cell viability of mammary carcinoma cells, (ii) in vivo toxicity of solanine, and (iv) the protective and therapeutic effects of solanine on animal model of breast cancer. Alpha-solanine significantly suppressed proliferation of mouse mammary carcinoma cells both in vitro and in vivo (Psolanine has been chosen for assessing its protective and therapeutic effects in mice breast cancer. Tumor take rate in the solanine-treated group was zero compared with a 75% rate in its respective control group (Psolanine-treated animals than its respective control ones (Psolanine compared with its respective control group (Psolanine-treated animals (Psolanine-treated mice (Psolanine exerts a significant chemoprotective and chemotherapeutic effects on an animal model of breast cancer through apoptosis induction, cell proliferation and angiogenesis inhibition. These findings reveal a new therapeutic potential for solanine in cancer.

  7. Honey: A Therapeutic Agent for Disorders of the Skin

    Directory of Open Access Journals (Sweden)

    Pauline McLoone

    2016-08-01

    Full Text Available Problems with conventional treatments for a range of dermatological disorders have led scientists to search for new compounds of therapeutic value. Efforts have included the evaluation of natural products such as honey. Manuka honey, for example, has been scientifically recognised for its anti-microbial and wound healing properties and is now used clinically as a topical treatment for wound infections. In this review, scientific evidence for the effectiveness of honey in the treatment of wounds and other skin conditions is evaluated. A plethora of in vitro studies have revealed that honeys from all over the world have potent anti-microbial activity against skin relevant microbes. Moreover, a number of in vitro studies suggest that honey is able to modulate the skin immune system. Clinical research has shown honey to be efficacious in promoting the healing of partial thickness burn wounds while its effectiveness in the treatment of non-burn acute wounds and chronic wounds is conflicted. Published research investigating the efficacy of honey in the treatment of other types of skin disorders is limited. Nevertheless, positive effects have been reported, for example, kanuka honey from New Zealand was shown to have therapeutic value in the treatment of rosacea. Anti-carcinogenic effects of honey have also been observed in vitro and in a murine model of melanoma.  It can be concluded that honey is a biologically active and clinically interesting substance but more research is necessary for a comprehensive understanding of its medicinal value in dermatology.

  8. Metformin and prostate cancer stem cells: a novel therapeutic target.

    Science.gov (United States)

    Mayer, M J; Klotz, L H; Venkateswaran, V

    2015-12-01

    Prostate cancer is the second most frequently diagnosed cancer in the world. Localized disease can be effectively treated with radiation therapy or radical prostatectomy. However, advanced prostate cancer is more difficult to treat and if metastatic, is incurable. There is a need for more effective therapy for advanced prostate cancer. One potential target is the cancer stem cell (CSC). CSCs have been described in several solid tumors, including prostate cancer, and contribute to therapeutic resistance and tumor recurrence. Metformin, a common oral biguanide used to treat type 2 diabetes, has been demonstrated to have anti-neoplastic effects. Specifically, metformin targets CSCs in breast cancer, pancreatic cancer, glioblastoma and colon cancer. Metformin acts directly on the mitochondria to inhibit oxidative phosphorylation and reduce mitochondrial ATP production. This forces tumor cells to compensate by increasing the rate of glycolysis. CSCs rely heavily on mitochondrial oxidative phosphorylation for energy production. The glycolytic switch results in an energy crisis in these cells. Metformin could be used to exploit this metabolic weakness in CSCs. This would increase CSC sensitivity to conventional cancer therapies, circumventing treatment resistance and enhancing treatment efficacy. This review will explore the characteristics of prostate CSCs, their role in tumor propagation and therapeutic resistance and the role of metformin as a potential prostate CSC sensitizer to current anticancer therapies. PMID:26215782

  9. Orexin receptor antagonists as therapeutic agents for insomnia

    Directory of Open Access Journals (Sweden)

    Ana Clementina Equihua

    2013-12-01

    Full Text Available Insomnia is a common clinical condition characterized by difficulty initiating or maintaining sleep, or non-restorative sleep with impairment of daytime functioning.Currently, treatment for insomnia involves a combination of cognitive behavioral therapy and pharmacological therapy. Among pharmacological interventions, the most evidence exists for benzodiazepine receptor agonist drugs (GABAA receptor, although concerns persist regarding their safety and their limited efficacy. The use of these hypnotic medications must be carefully monitored for adverse effects.Orexin (hypocretin neuropeptides have been shown to regulate transitions between wakefulness and sleep by promoting cholinergic/monoaminergic neural pathways. This has led to the development of a new class of pharmacological agents that antagonize the physiological effects of orexin. The development of these agents may lead to novel therapies for insomnia without the side effect profile of hypnotics (e.g. impaired cognition, disturbed arousal, and motor balance difficulties. However, antagonizing a system that regulates the sleep-wake cycle may create an entirely different side effect profile. In this review, we discuss the role of orexin and its receptors on the sleep-wake cycle and that of orexin antagonists in the treatment of insomnia.

  10. Resveratrol as a Therapeutic Agent for Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    Teng Ma

    2014-01-01

    Full Text Available Alzheimer’s disease (AD is the most common cause of dementia, but there is no effective therapy till now. The pathogenic mechanisms of AD are considerably complex, including Aβ accumulation, tau protein phosphorylation, oxidative stress, and inflammation. Exactly, resveratrol, a polyphenol in red wine and many plants, is indicated to show the neuroprotective effect on mechanisms mostly above. Recent years, there are numerous researches about resveratrol acting on AD in many models, both in vitro and in vivo. However, the effects of resveratrol are limited by its pool bioavailability; therefore researchers have been trying a variety of methods to improve the efficiency. This review summarizes the recent studies in cell cultures and animal models, mainly discusses the molecular mechanisms of the neuroprotective effects of resveratrol, and thus investigates the therapeutic potential in AD.

  11. ATM Mutations in Cancer: Therapeutic Implications.

    Science.gov (United States)

    Choi, Michael; Kipps, Thomas; Kurzrock, Razelle

    2016-08-01

    Activation of checkpoint arrest and homologous DNA repair are necessary for maintenance of genomic integrity during DNA replication. Germ-line mutations of the ataxia telangiectasia mutated (ATM) gene result in the well-characterized ataxia telangiectasia syndrome, which manifests with an increased cancer predisposition, including a 20% to 30% lifetime risk of lymphoid, gastric, breast, central nervous system, skin, and other cancers. Somatic ATM mutations or deletions are commonly found in lymphoid malignancies, as well as a variety of solid tumors. Such mutations may result in chemotherapy resistance and adverse prognosis, but may also be exploited by existing or emerging targeted therapies that produce synthetic lethal states. Mol Cancer Ther; 15(8); 1781-91. ©2016 AACR. PMID:27413114

  12. The therapeutic potential of MicroRNAs in cancer

    DEFF Research Database (Denmark)

    Thorsen, Susanne; Obad, S.; Jensen, N.F.;

    2012-01-01

    MicroRNAs (miRNAs) have been uncovered as important posttranscriptional regulators of nearly every biological process in the cell. Furthermore, mounting evidence implies that miRNAs play key roles in the pathogenesis of cancer and that many miRNAs can function either as oncogenes or tumor...... suppressors. Thus, miRNAs have rapidly emerged as promising targets for the development of novel anticancer therapeutics. The development of miRNA-based cancer therapeutics relies on restoring the activity of tumor suppressor miRNAs using double-stranded miRNA mimics or inhibition of oncogenic miRNAs using...... single-stranded antisense oligonucleotides, termed antimiRs. In the present review, we focus on recent advancements in the discovery and development of miRNA-based cancer therapeutics using these 2 approaches. In addition, we summarize selected studies, in which modulation of miRNA activity in...

  13. APPLICATION OF STEM CELL THERAPEUTIC AGENTS TO CONTROL CRITICAL DISEASE

    Directory of Open Access Journals (Sweden)

    Sonam Sharma

    2012-01-01

    Full Text Available Stem cell research has been hailed for the potential to revolutionize the future of medicine with the ability to regenerate damaged and diseased organs. On the other hand, stem cell research has been highly controversial due to the ethical issues concerned with the culture and use of stem cells derived from human embryos. This article presents an overview of what stem cells are, what roles they play in normal processes such as development and cancer, and how stem cells could have the potential to treat incurable diseases. Ethical issues are not the subject of this review. In addition to offering unprecedented hope in treating many debilitating diseases, stem cells have advanced our understanding of basic biological processes. This review looks at two major aspects of stem cells. Three processes in which stem cells play a central role in an organism, development, repair of damaged tissue, and cancer resulting from stem cell division going awry. II. Research and clinical applications of cultured stem cells: this includes the types of stem cells used, their characteristics, and the uses of stem cells in studying biological processes, drug development and stem cell therapy; heart disease, diabetes and Parkinson's disease are used as examples.

  14. Therapeutic resistance and cancer recurrence mechanisms: Unfolding the story of tumour coming back

    Indian Academy of Sciences (India)

    MOHAMMAD JAVAD DEHGHAN ESMATABADI; BABAK BAKHSHINEJAD; FATEMEH MOVAHEDI MOTLAGH; SADEGH BABASHAH; MAJID SADEGHIZADEH

    2016-09-01

    Cancer recurrence is believed to be one of the major reasons for the failure of cancer treatment strategies. Thisbiological phenomenon could arise from the incomplete eradication of tumour cells after chemo- and radiotherapy.Recent developments in the design of models reflecting cancer recurrence and in vivo imaging techniques have ledresearchers to gain a deeper and more detailed insight into the mechanisms underlying tumour relapse. Here, weprovide an overview of three important drivers of recurrence including cancer stem cells (CSCs), neosis, and phoenixrising. The survival of cancer stem cells is well recognized as one of the primary causes of therapeutic resistance inmalignant cells. CSCs have a relatively latent metabolism and show resistance to therapeutic agents through a varietyof routes. Neosis has proven to be as an important mechanism behind tumour self-proliferation after treatment whichgives rise to the expansion of tumour cells in the injured site via production of Raju cells. Phoenix rising is a prorecurrencepathway through which apoptotic cancer cells send strong signals to the neighbouring diseased cellsleading to their multiplication. The mechanisms involved in therapeutic resistance and tumour recurrence have not yetbeen fully understood and mostly remain unexplained. Without doubt, an improved understanding of the cellularmachinery contributing to recurrence will pave the way for the development of novel, sophisticated and effective antitumourtherapeutic strategies which can eradicate tumour without the threat of relapse.

  15. Metformin induces microRNA-34a to downregulate the Sirt1/Pgc-1α/Nrf2 pathway, leading to increased susceptibility of wild-type p53 cancer cells to oxidative stress and therapeutic agents.

    Science.gov (United States)

    Do, Minh Truong; Kim, Hyung Gyun; Choi, Jae Ho; Jeong, Hye Gwang

    2014-09-01

    Sirtuin 1 (Sirt1) plays an important role in cellular redox balance and resistance to oxidative stress. Sirt1 exhibits oncogenic properties in wild-type p53 cancer cells, whereas it acts as a tumor suppressor in p53-mutated cancer cells. Here, we investigated the effects of metformin on Sirt1 expression in several cancer cell lines. Using human cancer cell lines that exhibit differential expression of p53, we found that metformin reduced Sirt1 protein levels in cancer cells bearing wild-type p53, but did not affect Sirt1 protein levels in cancer cell lines harboring mutant forms of p53. Metformin-induced p53 protein levels in wild-type p53 cancer cells resulted in upregulation of microRNA (miR)-34a. The use of a miR-34a inhibitor confirmed that metformin-induced miR-34a was required for Sirt1 downregulation. Metformin suppressed peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1α (Pgc-1α) expression and its downstream target Nrf2 in MCF-7 cells. Genetic tools demonstrated that the reduction of Sirt1 and Pgc-1α by metformin caused Nrf2 downregulation via suppression of PPARγ transcriptional activity. Metformin reduced heme oxygenase-1 and superoxide dismutase 2 but upregulated catalase expression in MCF-7 cells. Metformin-treated MCF-7 cells had no increase in basal levels of reactive oxygen species but were more susceptible to oxidative stress. Furthermore, upregulation of death receptor 5 by metformin-mediated Sirt1 downregulation enhanced the sensitivity of wild-type p53 cancer cells to TRAIL-induced apoptosis. Our results demonstrated that metformin induces miR-34a to suppress the Sirt1/Pgc-1α/Nrf2 pathway and increases susceptibility of wild-type p53 cancer cells to oxidative stress and TRAIL-induced apoptosis. PMID:24970682

  16. Plasma Proteins Interaction with Curcumin Nanoparticles: Implications in Cancer Therapeutics

    OpenAIRE

    Yallapu, Murali M.; Ebeling, Mara C.; Jaggi, Meena; Chauhan, Subhash C.

    2013-01-01

    Curcumin, a natural bioactive polyphenol, has been widely investigated as a conventional medicine for centuries. Over the past two decades, major pre-clinical and clinical trials have demonstrated its safe therapeutic profile but clinical translation has been hampered due to rapid degradation, poor water solubility, bioavailability and pharmaco-kinetics. To overcome such translational issues, many laboratories have focused on developing curcumin nanoformulations for cancer therapeutics. In th...

  17. Skp2 is a promising therapeutic target in breast cancer

    Directory of Open Access Journals (Sweden)

    Zhiwei eWang

    2012-01-01

    Full Text Available Breast cancer is the most common type of cancer among American women, and remains the second leading cause of cancer-related death for female in the United States. It has been known that several signaling pathways and various factors play critical roles in the development and progression of breast cancer, such as estrogen receptor, Notch, PTEN, Her2, PI3K/Akt, BRCA1 and BRCA2. Emerging evidence has shown that the F-box protein Skp2 (S-phase kinase associated protein 2 also plays an important role in the pathogenesis of breast cancer. Therefore, in this brief review, we summarize the novel functions of Skp2 in the pathogenesis of breast cancer. Moreover, we provide further evidence regarding the state of our knowledge toward the development of novel Skp2 inhibitors especially natural chemopreventive agents as targeted approach for the prevention and/or treatment of breast cancer.

  18. Ethnobotany and the identification of therapeutic agents from the rainforest.

    Science.gov (United States)

    Balick, M J

    1990-01-01

    Many rainforest plant species, including trees and herbaceous plants, are employed as medicines by indigenous people. In much of the American tropics, locally harvested herbal medicines are used for a significant portion of the primary health care, in both rural and urban areas. An experienced curandero or herbal healer is familiar with those species with marked biological activity, which are often classified as 'powerful plants'. Examples are given from studies in progress since 1987 in Belize, Central America. The Institute of Economic Botany of The New York Botanical Garden is collaborating with the National Cancer Institute in Bethesda, Maryland (USA) in the search for higher plants with anti-AIDS and anticancer activity. Several strategies are cited for identification of promising leads from among the circa 110,000 species of higher plants that are present in the neotropics, the focus of this search. Recommendations are offered for the design of future efforts to identify plant leads for pharmaceutical testing. PMID:2086039

  19. Honey: A Potential Therapeutic Agent for Managing Diabetic Wounds

    Directory of Open Access Journals (Sweden)

    Fahmida Alam

    2014-01-01

    Full Text Available Diabetic wounds are unlike typical wounds in that they are slower to heal, making treatment with conventional topical medications an uphill process. Among several different alternative therapies, honey is an effective choice because it provides comparatively rapid wound healing. Although honey has been used as an alternative medicine for wound healing since ancient times, the application of honey to diabetic wounds has only recently been revived. Because honey has some unique natural features as a wound healer, it works even more effectively on diabetic wounds than on normal wounds. In addition, honey is known as an “all in one” remedy for diabetic wound healing because it can combat many microorganisms that are involved in the wound process and because it possesses antioxidant activity and controls inflammation. In this review, the potential role of honey’s antibacterial activity on diabetic wound-related microorganisms and honey’s clinical effectiveness in treating diabetic wounds based on the most recent studies is described. Additionally, ways in which honey can be used as a safer, faster, and effective healing agent for diabetic wounds in comparison with other synthetic medications in terms of microbial resistance and treatment costs are also described to support its traditional claims.

  20. Therapeutic Approaches to Target Cancer Stem Cells

    Energy Technology Data Exchange (ETDEWEB)

    Diaz, Arlhee, E-mail: arlhee@cim.sld.cu; Leon, Kalet [Department of Systems Biology, Center of Molecular Immunology, 216 Street, PO Box 16040, Atabey, Havana 11600 (Cuba)

    2011-08-15

    The clinical relevance of cancer stem cells (CSC) remains a major challenge for current cancer therapies, but preliminary findings indicate that specific targeting may be possible. Recent studies have shown that these tumor subpopulations promote tumor angiogenesis through the increased production of VEGF, whereas the VEGF neutralizing antibody bevacizumab specifically inhibits CSC growth. Moreover, nimotuzumab, a monoclonal antibody against the epidermal growth factor receptor (EGFR) with a potent antiangiogenic activity, has been shown by our group to reduce the frequency of CSC-like subpopulations in mouse models of brain tumors when combined with ionizing radiation. These studies and subsequent reports from other groups support the relevance of approaches based on molecular-targeted therapies to selectively attack CSC. This review discusses the relevance of targeting both the EGFR and angiogenic pathways as valid approaches to this aim. We discuss the relevance of identifying better molecular markers to develop drug screening strategies that selectively target CSC.

  1. Therapeutic Applications of Herbal Medicines for Cancer Patients

    OpenAIRE

    Ning-Sun Yang; Wen-Chi Wei; Feng-Yin Jian; Shu-Yi Yin

    2013-01-01

    Medicinal herbs and their derivative phytocompounds are being increasingly recognized as useful complementary treatments for cancer. A large volume of clinical studies have reported the beneficial effects of herbal medicines on the survival, immune modulation, and quality of life (QOL) of cancer patients, when these herbal medicines are used in combination with conventional therapeutics. Here, we briefly review some examples of clinical studies that investigated the use of herbal medicines fo...

  2. Curcumin Nanomedicine: A Road to Cancer Therapeutics

    OpenAIRE

    Yallapu, Murali M.; Jaggi, Meena; Chauhan, Subhash C.

    2013-01-01

    Cancer is the second leading cause of death in the United States. Conventional therapies cause widespread systemic toxicity and lead to serious side effects which prohibit their long term use. Additionally, in many circumstances tumor resistance and recurrence is commonly observed. Therefore, there is an urgent need to identify suitable anticancer therapies that are highly precise with minimal side effects. Curcumin is a natural polyphenol molecule derived from the Curcuma longa plant which e...

  3. Exosomes for Immunoregulation and Therapeutic Intervention in Cancer.

    Science.gov (United States)

    Zhang, Xuan; Pei, Zenglin; Chen, Jinyun; Ji, Chunxia; Xu, Jianqing; Zhang, Xiaoyan; Wang, Jin

    2016-01-01

    Exosomes, as a subset of extracellular vesicles, function as a mode of intercellular communication and molecular transfer, and facilitate the direct extracellular transfer of proteins, lipids, and miRNAs/mRNAs/DNAs between cells. Cancers have adapted exosomes and related microvesicles as a pathway that can suppress the immune system and establish a fertile local and distant environment to support neoplastic growth, invasion, and metastasis; these tumor-derived exosomes affect immunoregulation mechanisms, including immune activation and immune suppression. Immune cell-derived exosomes can modulate the immune response in cancer, which supports the belief that these membranous vesicles are immunotherapeutic reagents. In this review, we discuss the recent advances in the cancer immunotherapy, roles of exosomes in cancer, immunoregulation of tumor-derived exosomes, and immunomodulation by immune cell-derived exosomes. The topics covered here highlight novel insights into the development of efficient exosome-based cancer vaccines for cancer therapeutic intervention. PMID:27326251

  4. Exosomes for Immunoregulation and Therapeutic Intervention in Cancer

    Science.gov (United States)

    Zhang, Xuan; Pei, Zenglin; Chen, Jinyun; Ji, Chunxia; Xu, Jianqing; Zhang, Xiaoyan; Wang, Jin

    2016-01-01

    Exosomes, as a subset of extracellular vesicles, function as a mode of intercellular communication and molecular transfer, and facilitate the direct extracellular transfer of proteins, lipids, and miRNAs/mRNAs/DNAs between cells. Cancers have adapted exosomes and related microvesicles as a pathway that can suppress the immune system and establish a fertile local and distant environment to support neoplastic growth, invasion, and metastasis; these tumor-derived exosomes affect immunoregulation mechanisms, including immune activation and immune suppression. Immune cell-derived exosomes can modulate the immune response in cancer, which supports the belief that these membranous vesicles are immunotherapeutic reagents. In this review, we discuss the recent advances in the cancer immunotherapy, roles of exosomes in cancer, immunoregulation of tumor-derived exosomes, and immunomodulation by immune cell-derived exosomes. The topics covered here highlight novel insights into the development of efficient exosome-based cancer vaccines for cancer therapeutic intervention. PMID:27326251

  5. Nanoparticles as conjugated delivery agents for therapeutic applications

    Science.gov (United States)

    Muroski, Megan Elizabeth

    This dissertation explores the use of nanoparticles as conjugated delivery agents. Chapter 1 is a general introduction. Chapter 2 discusses the delivery by a nanoparticle platform provides a method to manipulate gene activation, by taking advantage of the high surface area of a nanoparticle and the ability to selectively couple a desired biological moiety to the NP surface. The nanoparticle based transfection approach functions by controlled release of gene regulatory elements from a 6 nm AuNP (gold nanoparticle) surface. The endosomal release of the regulatory elements from the nanoparticle surface results in endogenous protein knockdown simultaneously with exogenous protein expression for the first 48 h. The use of fluorescent proteins as the endogenous and exogenous signals for protein expression enables the efficiency of co-delivery of siRNA (small interfering RNA) for GFP (green fluorescent protein) knockdown and a dsRed-express linearized plasmid for induction to be optically analyzed in CRL-2794, a human kidney cell line expressing an unstable green fluorescent protein. Delivery of the bimodal nanoparticle in cationic liposomes results in 20% GFP knockdown within 24 h of delivery and continues exhibiting knockdown for up to 48 h for the bimodal agent. Simultaneous dsRed expression is observed to initiate within the same time frame with expression levels reaching 34% after 25 days although cells have divided approximately 20 times, implying daughter cell transfection has occurred. Fluorescence cell sorting results in a stable colony, as demonstrated by Western blot analysis. The simultaneous delivery of siRNA and linearized plasmid DNA on the surface of a single nanocrystal provides a unique method for definitive genetic control within a single cell and leads to a very efficient cell transfection protocol. In Chapter 3, we wanted to understand the NP complex within the cell, and to look at the dynamics of release utilizing nanometal surface energy transfer as

  6. Rituximab: An emerging therapeutic agent for kidney transplantation

    Directory of Open Access Journals (Sweden)

    Joseph Kahwaji

    2009-10-01

    Full Text Available Joseph Kahwaji, Chris Tong, Stanley C Jordan, Ashley A VoComprehensive Transplant Center, Transplant immunology Laboratory, HLA Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA, USAAbstract: Rituximab (anti-CD20, anti-B-cell is now emerging as an important drug for modification of B-cell and antibody responses in solid-organ transplant recipients. Its uses are varied and range from facilitating desensitization and ABO blood group-incompatible transplantation to the treatment of antibody-mediated rejection (AMR, post-transplant lymphoproliferative disorder (PTLD, and recurrent glomerular diseases in the renal allograft. Despite these uses, prospective randomized trials are lacking. Only case reports exist in regards to its use in de novo and recurrent diseases in the renal allograft. Recent reports suggests that the addition of rituximab to intravenous immunoglobulin (IVIG may have significant benefits for desensitization and treatment of AMR and chronic rejection. Current dosing recommendations are based on data from United States Food and Drug Administration-approved indications for treatment of B-cell lymphomas and rheumatoid arthritis. From the initial reported experience in solid organ transplant recipients, the drug is well tolerated and not associated with increased infectious risks. However, close monitoring for viral infections is recommended with rituximab use. The occurrence of progressive multifocal leukoencephalopathy (PML has been reported with rituximab use. However, this is rare and not reported in the renal transplant population. Here we will review current information regarding the effectiveness of rituximab as an agent for desensitization of highly human leukocyte antigen-sensitized and ABO-incompatible transplant recipients and its use in treatment of AMR. In addition, the post-transplant use of rituximab for treatment of PTLD and for recurrent and de novo glomerulonephritis in the allograft will be discussed. In

  7. RGD-Binding Integrins in Prostate Cancer: Expression Patterns and Therapeutic Prospects against Bone Metastasis

    International Nuclear Information System (INIS)

    Prostate cancer is the third leading cause of male cancer deaths in the developed world. The current lack of highly specific detection methods and efficient therapeutic agents for advanced disease have been identified as problems requiring further research. The integrins play a vital role in the cross-talk between the cell and extracellular matrix, enhancing the growth, migration, invasion and metastasis of cancer cells. Progression and metastasis of prostate adenocarcinoma is strongly associated with changes in integrin expression, notably abnormal expression and activation of the β3 integrins in tumour cells, which promotes haematogenous spread and tumour growth in bone. As such, influencing integrin cell expression and function using targeted therapeutics represents a potential treatment for bone metastasis, the most common and debilitating complication of advanced prostate cancer. In this review, we highlight the multiple ways in which RGD-binding integrins contribute to prostate cancer progression and metastasis, and identify the rationale for development of multi-integrin antagonists targeting the RGD-binding subfamily as molecularly targeted agents for its treatment

  8. 75 FR 76460 - Lymphohematopoietic Cancers Induced by Chemicals and Other Agents: Overview and Implications for...

    Science.gov (United States)

    2010-12-08

    ... AGENCY Lymphohematopoietic Cancers Induced by Chemicals and Other Agents: Overview and Implications for..., ``Lymphohematopoietic Cancers Induced by Chemicals and Other Agents: Overview and Implications for Risk Assessment.... ADDRESSES: The draft ``Lymphohematopoietic Cancers Induced by Chemicals and Other Agents: Overview...

  9. Coordination of platinum therapeutic agents to met-rich motifs of human copper transport protein1.

    Science.gov (United States)

    Crider, Sarah E; Holbrook, Robert J; Franz, Katherine J

    2010-01-01

    Platinum therapeutic agents are widely used in the treatment of several forms of cancer. Various mechanisms for the transport of the drugs have been proposed including passive diffusion across the cellular membrane and active transport via proteins. The copper transport protein Ctr1 is responsible for high affinity copper uptake but has also been implicated in the transport of cisplatin into cells. Human hCtr1 contains two methionine-rich Mets motifs on its extracellular N-terminus that are potential platinum-binding sites: the first one encompasses residues 7-14 with amino acid sequence Met-Gly-Met-Ser-Tyr-Met-Asp-Ser and the second one spans residues 39-46 with sequence Met-Met-Met-Met-Pro-Met-Thr-Phe. In these studies, we use liquid chromatography and mass spectrometry to compare the binding interactions between cisplatin, carboplatin and oxaliplatin with synthetic peptides corresponding to hCtr1 Mets motifs. The interactions of cisplatin and carboplatin with Met-rich motifs that contain three or more methionines result in removal of the carrier ligands of both platinum complexes. In contrast, oxaliplatin retains its cyclohexyldiamine ligand upon platinum coordination to the peptide.

  10. Epigenetic Modifications: Therapeutic Potential in Cancer

    Directory of Open Access Journals (Sweden)

    Manisha Sachan

    2015-08-01

    Full Text Available Epigenetic modifications and alterations in chromatin structure and function contribute to the cumulative changes observed as normal cells undergo malignant transformation. These modifications and enzymes (DNA methyltransferases, histone deacetylases, histone methyltransferases, and demethylases related to them have been deeply studied to develop new drugs, epigenome-targeted therapies and new diagnostic tools. Epigenetic modifiers aim to restore normal epigenetic modification patterns through the inhibition of epigenetic modifier enzymes. Four of them (azacitidine, decitabine, vorinostat and romidepsin are approved by the U.S. Food and Drug Administration. This article provides an overview about the known functional roles of epigenetic enzymes in cancer development.

  11. Nanoparticles as conjugated delivery agents for therapeutic applications

    Science.gov (United States)

    Muroski, Megan Elizabeth

    This dissertation explores the use of nanoparticles as conjugated delivery agents. Chapter 1 is a general introduction. Chapter 2 discusses the delivery by a nanoparticle platform provides a method to manipulate gene activation, by taking advantage of the high surface area of a nanoparticle and the ability to selectively couple a desired biological moiety to the NP surface. The nanoparticle based transfection approach functions by controlled release of gene regulatory elements from a 6 nm AuNP (gold nanoparticle) surface. The endosomal release of the regulatory elements from the nanoparticle surface results in endogenous protein knockdown simultaneously with exogenous protein expression for the first 48 h. The use of fluorescent proteins as the endogenous and exogenous signals for protein expression enables the efficiency of co-delivery of siRNA (small interfering RNA) for GFP (green fluorescent protein) knockdown and a dsRed-express linearized plasmid for induction to be optically analyzed in CRL-2794, a human kidney cell line expressing an unstable green fluorescent protein. Delivery of the bimodal nanoparticle in cationic liposomes results in 20% GFP knockdown within 24 h of delivery and continues exhibiting knockdown for up to 48 h for the bimodal agent. Simultaneous dsRed expression is observed to initiate within the same time frame with expression levels reaching 34% after 25 days although cells have divided approximately 20 times, implying daughter cell transfection has occurred. Fluorescence cell sorting results in a stable colony, as demonstrated by Western blot analysis. The simultaneous delivery of siRNA and linearized plasmid DNA on the surface of a single nanocrystal provides a unique method for definitive genetic control within a single cell and leads to a very efficient cell transfection protocol. In Chapter 3, we wanted to understand the NP complex within the cell, and to look at the dynamics of release utilizing nanometal surface energy transfer as

  12. Real-time, aptamer-based tracking of circulating therapeutic agents in living animals

    OpenAIRE

    Ferguson, B. Scott; Hoggarth, David A.; Maliniak, Dan; Ploense, Kyle; White, Ryan J.; Woodward, Nick; Hsieh, Kuangwen; Bonham, Andrew J.; Eisenstein, Michael; Kippin, Tod; Plaxco, Kevin W.; Soh, H. Tom

    2013-01-01

    A sensor capable of continuously measuring specific molecules in the bloodstream in vivo would give clinicians a valuable window into patients’ health and their response to therapeutics. Such technology would enable truly personalized medicine, wherein therapeutic agents could be tailored with optimal doses for each patient to maximize efficacy and minimize side effects. Unfortunately, continuous, real-time measurement is currently only possible for a handful of targets, such as glucose, lact...

  13. Multirate delivery of multiple therapeutic agents from metal-organic frameworks

    Directory of Open Access Journals (Sweden)

    Alistair C. McKinlay

    2014-12-01

    Full Text Available The highly porous nature of metal-organic frameworks (MOFs offers great potential for the delivery of therapeutic agents. Here, we show that highly porous metal-organic frameworks can be used to deliver multiple therapeutic agents—a biologically active gas, an antibiotic drug molecule, and an active metal ion—simultaneously but at different rates. The possibilities offered by delivery of multiple agents with different mechanisms of action and, in particular, variable timescales may allow new therapy approaches. Here, we show that the loaded MOFs are highly active against various strains of bacteria.

  14. Exosomal miRNAs as cancer biomarkers and therapeutic targets

    OpenAIRE

    Arron Thind; Clive Wilson

    2016-01-01

    Intercommunication between cancer cells and with their surrounding and distant environments is key to the survival, progression and metastasis of the tumour. Exosomes play a role in this communication process. MicroRNA (miRNA) expression is frequently dysregulated in tumour cells and can be reflected by distinct exosomal miRNA (ex-miRNA) profiles isolated from the bodily fluids of cancer patients. Here, the potential of ex-miRNA as a cancer biomarker and therapeutic target is critically analy...

  15. Computational systems biology approaches to anti-angiogenic cancer therapeutics.

    Science.gov (United States)

    Finley, Stacey D; Chu, Liang-Hui; Popel, Aleksander S

    2015-02-01

    Angiogenesis is an exquisitely regulated process that is required for physiological processes and is also important in numerous diseases. Tumors utilize angiogenesis to generate the vascular network needed to supply the cancer cells with nutrients and oxygen, and many cancer drugs aim to inhibit tumor angiogenesis. Anti-angiogenic therapy involves inhibiting multiple cell types, molecular targets, and intracellular signaling pathways. Computational tools are useful in guiding treatment strategies, predicting the response to treatment, and identifying new targets of interest. Here, we describe progress that has been made in applying mathematical modeling and bioinformatics approaches to study anti-angiogenic therapeutics in cancer.

  16. T-oligo as an anticancer agent in colorectal cancer

    Energy Technology Data Exchange (ETDEWEB)

    Wojdyla, Luke; Stone, Amanda L. [Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, Rockford, IL (United States); Sethakorn, Nan [Department of Medicine, University of Chicago, Chicago, IL (United States); Uppada, Srijayaprakash B.; Devito, Joseph T. [Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, Rockford, IL (United States); Bissonnette, Marc [Department of Medicine, University of Chicago, Chicago, IL (United States); Puri, Neelu, E-mail: neelupur@uic.edu [Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, Rockford, IL (United States)

    2014-04-04

    Highlights: • T-oligo induces cell cycle arrest, senescence, apoptosis, and differentiation in CRC. • Treatment with T-oligo downregulates telomere-associated proteins. • T-oligo combined with an EGFR-TKI additively inhibits cellular proliferation. • T-oligo has potential as an effective therapeutic agent for CRC. - Abstract: In the United States, there will be an estimated 96,830 new cases of colorectal cancer (CRC) and 50,310 deaths in 2014. CRC is often detected at late stages of the disease, at which point there is no effective chemotherapy. Thus, there is an urgent need for effective novel therapies that have minimal effects on normal cells. T-oligo, an oligonucleotide homologous to the 3′-telomere overhang, induces potent DNA damage responses in multiple malignant cell types, however, its efficacy in CRC has not been studied. This is the first investigation demonstrating T-oligo-induced anticancer effects in two CRC cell lines, HT-29 and LoVo, which are highly resistant to conventional chemotherapies. In this investigation, we show that T-oligo may mediate its DNA damage responses through the p53/p73 pathway, thereby inhibiting cellular proliferation and inducing apoptosis or senescence. Additionally, upregulation of downstream DNA damage response proteins, including E2F1, p53 or p73, was observed. In LoVo cells, T-oligo induced senescence, decreased clonogenicity, and increased expression of senescence associated proteins p21, p27, and p53. In addition, downregulation of POT1 and TRF2, two components of the shelterin protein complex which protects telomeric ends, was observed. Moreover, we studied the antiproliferative effects of T-oligo in combination with an EGFR tyrosine kinase inhibitor, Gefitinib, which resulted in an additive inhibitory effect on cellular proliferation. Collectively, these data provide evidence that T-oligo alone, or in combination with other molecularly targeted therapies, has potential as an anti-cancer agent in CRC.

  17. Therapeutic Applications of Herbal Medicines for Cancer Patients

    Directory of Open Access Journals (Sweden)

    Shu-Yi Yin

    2013-01-01

    Full Text Available Medicinal herbs and their derivative phytocompounds are being increasingly recognized as useful complementary treatments for cancer. A large volume of clinical studies have reported the beneficial effects of herbal medicines on the survival, immune modulation, and quality of life (QOL of cancer patients, when these herbal medicines are used in combination with conventional therapeutics. Here, we briefly review some examples of clinical studies that investigated the use of herbal medicines for various cancers and the development of randomized controlled trials (RCTs in this emerging research area. In addition, we also report recent studies on the biochemical and cellular mechanisms of herbal medicines in specific tumor microenvironments and the potential application of specific phytochemicals in cell-based cancer vaccine systems. This review should provide useful technological support for evidence-based application of herbal medicines in cancer therapy.

  18. Molecular markers as therapeutic targets in lung cancer

    Institute of Scientific and Technical Information of China (English)

    Hsin-Hui Tseng; Biao He

    2013-01-01

    Lung cancer is responsible for 29% of cancer deaths in the United States and has very low 5-year survival rates of approximately 11% in men and 15% in women.Although the early diagnosis of lung cancer may increase the survival rate with adequate treatment,advanced lung cancers are often metastasized and receive limited benefit from therapeutic regimens.As conventional treatments for lung cancer reach their limitations,researchers have attempted to discover novel drug therapies aimed at specific targets contributing to the progression of tumorigenesis.Recent advances in systems biology have enabled the molecular biology of lung carcinogenesis to be elucidated.Our understanding of the physiologic processes of tumor development provide a means to design more effective and specific drugs with less toxicity,thereby accelerating the delivery of new drug therapies to the patient's bedside.

  19. c-Met in pancreatic cancer stem cells: Therapeutic implications

    Institute of Scientific and Technical Information of China (English)

    Marta Herreros-Villanueva; Aizpea Zubia-Olascoaga; Luis Bujanda

    2012-01-01

    Pancreatic cancer is the deadliest solid cancer and currently the fourth most frequent cause of cancer-related deaths.Emerging evidence suggests that cancer stem cells (CSCs) play a crucial role in the development and progression of this disease.The identification of CSC markers could lead to the development of new therapeutic targets.In this study,the authors explore the functional role of c-Met in pancreatic CSCs,by analyzing self-renewal with sphere assays and tumorigenicity capacity in NOD SCID mice.They concluded that c-Met is a novel marker for identifying pancreatic CSCs and c-Methigh in a higher tumorigenic cancer cell population.Inhibition of c-Met with XL184 blocks self-renewal capacity in pancreatic CSCs.In pancreatic tumors established in NOD SCID mice,c-Met inhibition slowed tumor growth and reduced the population of CSCs,along with preventing the development of metastases.

  20. Cancer Stem Cells: Biological Functions and Therapeutically Targeting

    Directory of Open Access Journals (Sweden)

    Marius Eugen Ciurea

    2014-05-01

    Full Text Available Almost all tumors are composed of a heterogeneous cell population, making them difficult to treat. A small cancer stem cell population with a low proliferation rate and a high tumorigenic potential is thought to be responsible for cancer development, metastasis and resistance to therapy. Stem cells were reported to be involved in both normal development and carcinogenesis, some molecular mechanisms being common in both processes. No less controversial, stem cells are considered to be important in treatment of malignant diseases both as targets and drug carriers. The efforts to understand the role of different signalling in cancer stem cells requires in depth knowledge about the mechanisms that control their self-renewal, differentiation and malignant potential. The aim of this paper is to discuss insights into cancer stem cells historical background and to provide a brief review of the new therapeutic strategies for targeting cancer stem cells.

  1. Bombarding Cancer: Biolistic Delivery of therapeutics using Porous Si Carriers

    Science.gov (United States)

    Zilony, Neta; Tzur-Balter, Adi; Segal, Ester; Shefi, Orit

    2013-08-01

    A new paradigm for an effective delivery of therapeutics into cancer cells is presented. Degradable porous silicon carriers, which are tailored to carry and release a model anti-cancer drug, are biolistically bombarded into in-vitro cancerous targets. We demonstrate the ability to launch these highly porous microparticles by a pneumatic capillary gene gun, which is conventionally used to deliver cargos by heavy metal carriers. By optimizing the gun parameters e.g., the accelerating gas pressure, we have successfully delivered the porous carriers, to reach deep targets and to cross a skin barrier in a highly spatial resolution. Our study reveals significant cytotoxicity towards the target human breast carcinoma cells following the delivery of drug-loaded carriers, while administrating empty particles results in no effect on cell viability. The unique combination of biolistics with the temporal control of payload release from porous carriers presents a powerful and non-conventional platform for designing new therapeutic strategies.

  2. Biocompatible PEGylated Fe3O4 Nanoparticles as Photothermal Agents for Near-Infrared Light Modulated Cancer Therapy

    OpenAIRE

    Gang Yuan; Yongjie Yuan; Kan Xu; Qi Luo

    2014-01-01

    In accordance with the World Cancer Report, cancer has become the leading cause of mortality worldwide, and various therapeutic strategies have been developed at the same time. In the present study, biocompatible magnetic nanoparticles were designed and synthesized as high-performance photothermal agents for near-infrared light mediated cancer therapy in vitro. Via a facile one-pot solvothermal method, well-defined PEGylated magnetic nanoparticles (PEG–Fe3O4) were prepared with cheap inhesion...

  3. Design of clinical trials for therapeutic cancer vaccines development.

    Science.gov (United States)

    Mackiewicz, Jacek; Mackiewicz, Andrzej

    2009-12-25

    Advances in molecular and cellular biology as well as biotechnology led to definition of a group of drugs referred to as medicinal products of advanced technologies. It includes gene therapy products, somatic cell therapeutics and tissue engineering. Therapeutic cancer vaccines including whole cell tumor cells vaccines or gene modified whole cells belong to somatic therapeutics and/or gene therapy products category. The drug development is a multistep complex process. It comprises of two phases: preclinical and clinical. Guidelines on preclinical testing of cell based immunotherapy medicinal products have been defined by regulatory agencies and are available. However, clinical testing of therapeutic cancer vaccines is still under debate. It presents a serious problem since recently clinical efficacy of the number of cancer vaccines has been demonstrated that focused a lot of public attention. In general clinical testing in the current form is very expensive, time consuming and poorly designed what may lead to overlooking of products clinically beneficial for patients. Accordingly regulatory authorities and researches including Cancer Vaccine Clinical Trial Working Group proposed three regulatory solutions to facilitate clinical development of cancer vaccines: cost-recovery program, conditional marketing authorization, and a new development paradigm. Paradigm includes a model in which cancer vaccines are investigated in two types of clinical trials: proof-of-principle and efficacy. The proof-of-principle trial objectives are: safety; dose selection and schedule of vaccination; and demonstration of proof-of-principle. Efficacy trials are randomized clinical trials with objectives of demonstrating clinical benefit either directly or through a surrogate. The clinical end points are still under debate. PMID:19835869

  4. Preparation and Preliminary Biological Evaluation of {sup 177}Lu-DOTA folate as Potential Folate Receptor Targeting Therapeutic Agent

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Kang-Hyuk; Hong, Young-Don; Pyun, Mi-Sun; Lee, So-Young; Felipe, Fenelope; Yoon, Sun-Ha; Choi, Sun-Ju [Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of)

    2008-10-15

    Folic Acid (FA) and FA derivatives are overexpressed on several tumor cells. The cell-membrane folic acid receptors are known to be responsible for the cellular accumulation of FA and FA analogs, such as methotrexate and folic acid. Folate has been characterized to have high affinity for the folate-receptor positive cells and tissues and considered to be useful as diagnostic imaging and therapeutic agent. In 1940s, Folate analogue, aminopterin, was first used for treatment of leukemia and recently, many folate derivatives were tried for cancer-treatment agent as well as visualization of folate receptor. Many researchers tried to conjugate folic acid with macromolecules or low molecular weight chelators through its alpha or gamma carboxylate. However, despite the reduced binding affinity, FAs are still recognized by the folate receptor. Therefore, we focused to develop folate-based radiopharmaceutical that has the potential to be used as a therapeutic agent. We report here the synthesis and the radiolabeling of {sup 177}Lu-DOTA as well as the biodistribution data of our developed compound.

  5. Therapeutic Implications for Overcoming Radiation Resistance in Cancer Therapy.

    Science.gov (United States)

    Kim, Byeong Mo; Hong, Yunkyung; Lee, Seunghoon; Liu, Pengda; Lim, Ji Hong; Lee, Yong Heon; Lee, Tae Ho; Chang, Kyu Tae; Hong, Yonggeun

    2015-11-10

    Ionizing radiation (IR), such as X-rays and gamma (γ)-rays, mediates various forms of cancer cell death such as apoptosis, necrosis, autophagy, mitotic catastrophe, and senescence. Among them, apoptosis and mitotic catastrophe are the main mechanisms of IR action. DNA damage and genomic instability contribute to IR-induced cancer cell death. Although IR therapy may be curative in a number of cancer types, the resistance of cancer cells to radiation remains a major therapeutic problem. In this review, we describe the morphological and molecular aspects of various IR-induced types of cell death. We also discuss cytogenetic variations representative of IR-induced DNA damage and genomic instability. Most importantly, we focus on several pathways and their associated marker proteins responsible for cancer resistance and its therapeutic implications in terms of cancer cell death of various types and characteristics. Finally, we propose radiation-sensitization strategies, such as the modification of fractionation, inflammation, and hypoxia and the combined treatment, that can counteract the resistance of tumors to IR.

  6. Therapeutic Implications for Overcoming Radiation Resistance in Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Byeong Mo Kim

    2015-11-01

    Full Text Available Ionizing radiation (IR, such as X-rays and gamma (γ-rays, mediates various forms of cancer cell death such as apoptosis, necrosis, autophagy, mitotic catastrophe, and senescence. Among them, apoptosis and mitotic catastrophe are the main mechanisms of IR action. DNA damage and genomic instability contribute to IR-induced cancer cell death. Although IR therapy may be curative in a number of cancer types, the resistance of cancer cells to radiation remains a major therapeutic problem. In this review, we describe the morphological and molecular aspects of various IR-induced types of cell death. We also discuss cytogenetic variations representative of IR-induced DNA damage and genomic instability. Most importantly, we focus on several pathways and their associated marker proteins responsible for cancer resistance and its therapeutic implications in terms of cancer cell death of various types and characteristics. Finally, we propose radiation-sensitization strategies, such as the modification of fractionation, inflammation, and hypoxia and the combined treatment, that can counteract the resistance of tumors to IR.

  7. The Microenvironment of Lung Cancer and Therapeutic Implications.

    Science.gov (United States)

    Mittal, Vivek; El Rayes, Tina; Narula, Navneet; McGraw, Timothy E; Altorki, Nasser K; Barcellos-Hoff, Mary Helen

    2016-01-01

    The tumor microenvironment (TME) represents a milieu that enables tumor cells to acquire the hallmarks of cancer. The TME is heterogeneous in composition and consists of cellular components, growth factors, proteases, and extracellular matrix. Concerted interactions between genetically altered tumor cells and genetically stable intratumoral stromal cells result in an "activated/reprogramed" stroma that promotes carcinogenesis by contributing to inflammation, immune suppression, therapeutic resistance, and generating premetastatic niches that support the initiation and establishment of distant metastasis. The lungs present a unique milieu in which tumors progress in collusion with the TME, as evidenced by regions of aberrant angiogenesis, acidosis and hypoxia. Inflammation plays an important role in the pathogenesis of lung cancer, and pulmonary disorders in lung cancer patients such as chronic obstructive pulmonary disease (COPD) and emphysema, constitute comorbid conditions and are independent risk factors for lung cancer. The TME also contributes to immune suppression, induces epithelial-to-mesenchymal transition (EMT) and diminishes efficacy of chemotherapies. Thus, the TME has begun to emerge as the "Achilles heel" of the disease, and constitutes an attractive target for anti-cancer therapy. Drugs targeting the components of the TME are making their way into clinical trials. Here, we will focus on recent advances and emerging concepts regarding the intriguing role of the TME in lung cancer progression, and discuss future directions in the context of novel diagnostic and therapeutic opportunities. PMID:26703800

  8. Drugs as causative agents and therapeutic agents in inflammatory bowel disease

    Directory of Open Access Journals (Sweden)

    Phani Krishna Kondamudi

    2013-09-01

    Full Text Available Ulcerative colitis and Crohn's disease are collectively known as inflammatory bowel diseases (IBD which are chronic inflammatory disorders of gastrointestinal tract. The etiopathogenesis of IBD has been extensively studied but not fully revealed. Recent advances in physiology, molecular biology and pharmacology have provided some insight into the basic etiopathogenetic causes such as genetic, immunologic, etc. This review focuses on drugs involved in the cause of the disease and the investigational new drugs, current therapeutic strategies and their clinical benefits.

  9. Glycoprotein non-metastatic b (GPNMB: A metastatic mediator and emerging therapeutic target in cancer

    Directory of Open Access Journals (Sweden)

    Maric G

    2013-07-01

    Full Text Available Gordana Maric,1,2 April AN Rose,3 Matthew G Annis,1,2 Peter M Siegel1,2,4,5 1Goodman Cancer Research Centre, 2Department of Medicine, 3Faculty of Medicine, 4Department of Biochemistry, 5Department of Anatomy and Cell Biology, McGill University, Montréal, Québec, Canada Abstract: Molecularly targeted therapies are rapidly growing with respect to their clinical development and impact on cancer treatment due to their highly selective anti-tumor action. However, many aggressive cancers such as triple-negative breast cancer (TNBC currently lack well-defined therapeutic targets against which such agents can be developed. The identification of tumor-associated antigens and the generation of antibody drug-conjugates represent an emerging area of intense interest and growth in the field of cancer therapeutics. Glycoprotein non-metastatic b (GPNMB has recently been identified as a gene that is over-expressed in numerous cancers, including TNBC, and often correlates with the metastatic phenotype. In breast cancer, GPNMB expression in the tumor epithelium is associated with a reduction in disease-free and overall survival. Based on these findings, glembatumumab vedotin (CDX-011, an antibody-drug conjugate that selectively targets GPNMB, is currently being investigated in clinical trials for patients with metastatic breast cancer and unresectable melanoma. This review discusses the physiological and potential pathological roles of GPNMB in normal and cancer tissues, respectively, and details the clinical advances and challenges in targeting GPNMB-expressing malignancies. Keywords: GPNMB, osteoactivin, breast cancer, antibody-drug conjugates, CDX-011

  10. Targeted therapy using novel agents in the treatment of non-small-cell lung cancer.

    Science.gov (United States)

    Herbst, Roy S

    2002-03-01

    Patients with advanced non-small-cell lung cancer (NSCLC) have a poor prognosis and high mortality. The therapeutic improvement caused by the new generation of cytotoxic agents seems to have reached a plateau. The main categories of targeted therapeutics applicable for NSCLC include receptor-targeted therapy, signal transduction or cell-cycle inhibition, angiogenesis inhibitors, gene therapy, and vaccines. Several major classes of agents directed at specific cellular mechanisms exist for the treatment of NSCLC. The anti-epidermal growth factor receptor (EGFR) group contains trastuzumab and IMC-C225, monoclonal antibodies against EGFRs that are overexpressed in many cancers. OSI-774 and ZD1839 are inhibitors of EGFR tyrosine kinase, a key enzyme of the signaling pathway. Farnesyl transferase inhibitors, such as SCH66336, and protein kinase C inhibitors, such as ISIS 3521, have also shown antitumor activity. Antiangiogenesis agents that have shown promise include TNP-470, recombinant endostatin, and angiostatin. Antibodies to vascular endothelial growth factor (VEGF) also seem to control tumor progression and may prolong survival. LY317615, an inhibitor of protein kinase Cb, augmented the tumor growth delay produced by cytotoxic drugs. All of these agents are in different phases of clinical testing and have shown encouraging activity as single agents or in combination with chemotherapy drugs. These new agents are more target specific, less toxic, easier to administer, and may lead to enhanced safety and survival for patients with advanced NSCLC. PMID:14720353

  11. POLYLACTIDE-CO-GLYCOLIDE NANOPARTICLES THERAPEUTIC BENEFITS IN CANCER

    Directory of Open Access Journals (Sweden)

    Pramod V. Burakle

    2013-02-01

    Full Text Available Anticancer therapy majorly hindered by drug low water solubility, poor drug permeability, and high efflux of drug from cells. Nanotechnology is severing as an important tool to overcome these problems of cancer drug therapy. Nanomaterials have been used to enhance drug delivery at targeted site with less toxicity to healthy cells. Biodegradable polyester, polylactide-co-glycolide is approved for use for humans. Review is focusing on recent developments concerning polylactide-co-glycolide nanoparticles prepared for cancer treatment. We have reviewed, methods used for the preparation and characterization of polylactide-co-glycolide nanoparticles and their applications in the delivery of a number of active agents. Polylactide-co-glycolide nanoparticles have provided the necessary momentum for promising future use of these agents in cancer treatment, with higher efficacy and fewer side effects.

  12. Therapeutic Antisense Oligonucleotides against Cancer: Hurdling to the Clinic

    Science.gov (United States)

    Moreno, Pedro; Pêgo, Ana

    2014-10-01

    Under clinical development since the early 90’s and with two successfully approved drugs (Fomivirsen and Mipomersen), oligonucleotide-based therapeutics have not yet delivered a clinical drug to the market in the cancer field. Whilst many pre-clinical data has been generated, a lack of understanding still exists on how to efficiently tackle all the different challenges presented for cancer targeting in a clinical setting. Namely, effective drug vectorization, careful choice of target gene or synergistic multi-gene targeting are surely decisive, while caution must be exerted to avoid potential toxic, often misleading off-target-effects. Here a brief overview will be given on the nucleic acid chemistry advances that established oligonucleotide technologies as a promising therapeutic alternative and ongoing cancer related clinical trials. Special attention will be given towards a perspective on the hurdles encountered specifically in the cancer field by this class of therapeutic oligonucleotides and a view on possible avenues for success is presented, with particular focus on the contribution from nanotechnology to the field.

  13. A Recent Perspective on Discovery and Development of Diverse Therapeutic Agents Inspired from Isatin Alkaloids.

    Science.gov (United States)

    Rane, Rajesh A; Karunanidhi, Sivanandhan; Jain, Kavita; Shaikh, Mahamadhanif; Hampannavar, Girish; Karpoormath, Rajshekhar

    2016-01-01

    Isatin as an alkaloidal framework have consistently attracted attention of medicinal chemist towards development of wide range of novel therapeutic agents. This review report has discussed significant isatin lead molecules and their derivatives which have shown promising biological potential in recent times. The substituted isatins showing a potent pharmacological activities such as antimicrobial, antitubercular, anticancer, antioxidant, anti-histaminic, anti-HIV, antiviral, anti-inflammatory, anti-Parkinson's and antidiabetic have been described in this review. The mechanism of action leading to therapeutic activity of the respective isatin derivation has also been recorded. This review reveals that the systematic and rational modifications on isatin motif exhibited significant bio-activities which can be exploited for the development of potent novel therapeutic agents in the future studies. Hence the quest to investigate more structural alterations on isatin scaffold should be continued. PMID:26369813

  14. Expanding antitumor therapeutic windows by targeting cancer-specific nicotinamide adenine dinucleotide phosphate-biogenesis pathways

    Directory of Open Access Journals (Sweden)

    Chakrabarti G

    2015-03-01

    Full Text Available Gaurab Chakrabarti,1,2,4 David E Gerber,3,4 David A Boothman1,2,4 1Department of Pharmacology, 2Department of Radiation Oncology, 3Division of Hematology and Oncology, 4Harold C Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX, USA Abstract: Nicotinamide adenine dinucleotide phosphate (NADPH biogenesis is an essential mechanism by which both normal and cancer cells maintain redox balance. While antitumor approaches to treat cancers through elevated reactive oxygen species (ROS are not new ideas, depleting specific NADPH-biogenesis pathways that control recovery and repair pathways are novel, viable approaches to enhance cancer therapy. However, to elicit efficacious therapies exploiting NADPH-biogenic pathways, it is crucial to understand and specifically define the roles of NADPH-biogenesis pathways used by cancer cells for survival or recovery from cell stress. It is equally important to select NADPH-biogenic pathways that are expendable or not utilized in normal tissue to avoid unwanted toxicity. Here, we address recent literature that demonstrates specific tumor-selective NADPH-biogenesis pathways that can be exploited using agents that target specific cancer cell pathways normally not utilized in normal cells. Defining NADPH-biogenesis profiles of specific cancer-types should enable novel strategies to exploit these therapeutic windows for increased efficacy against recalcitrant neoplastic disease, such as pancreatic cancers. Accomplishing the goal of using ROS as a weapon against cancer cells will also require agents, such as NQO1 bioactivatable drugs, that selectively induce elevated ROS levels in cancer cells, while normal cells are protected. Keywords: reactive oxygen species (ROS, NQO1-bioactivatable drugs, nicotinamide adenine dinucleotide phosphate (NADPH, glutathione (GSH, biogenic pathways, antioxidant

  15. Expression and therapeutic targeting of dopamine receptor-1 (D1R) in breast cancer.

    Science.gov (United States)

    Borcherding, D C; Tong, W; Hugo, E R; Barnard, D F; Fox, S; LaSance, K; Shaughnessy, E; Ben-Jonathan, N

    2016-06-16

    Patients with advanced breast cancer often fail to respond to treatment, creating a need to develop novel biomarkers and effective therapeutics. Dopamine (DA) is a catecholamine that binds to five G protein-coupled receptors. We discovered expression of DA type-1 receptors (D1Rs) in breast cancer, thereby identifying these receptors as novel therapeutic targets in this disease. Strong to moderate immunoreactive D1R expression was found in 30% of 751 primary breast carcinomas, and was associated with larger tumors, higher tumor grades, node metastasis and shorter patient survival. DA and D1R agonists, signaling through the cGMP/protein kinase G (PKG) pathway, suppressed cell viability, inhibited invasion and induced apoptosis in multiple breast cancer cell lines. Fenoldopam, a peripheral D1R agonist that does not penetrate the brain, dramatically suppressed tumor growth in two mouse models with D1R-expressing xenografts by increasing both necrosis and apoptosis. D1R-expressing primary tumors and metastases in mice were detected by fluorescence imaging. In conclusion, D1R overexpression is associated with advanced breast cancer and poor prognosis. Activation of the D1R/cGMP/PKG pathway induces apoptosis in vitro and causes tumor shrinkage in vivo. Fenoldopam, which is FDA (Food and Drug Administration) approved to treat renal hypertension, could be repurposed as a novel therapeutic agent for patients with D1R-expressing tumors.

  16. Breast cancer stem cells, EMT and therapeutic targets

    Energy Technology Data Exchange (ETDEWEB)

    Kotiyal, Srishti; Bhattacharya, Susinjan, E-mail: s.bhattacharya@jiit.ac.in

    2014-10-10

    Highlights: • Therapeutic targeting or inhibition of the key molecules of signaling pathways can control growth of breast cancer stem cells (BCSCs). • Development of BCSCs also involves miRNA interactions. • Therapeutic achievement can be done by targeting identified targets in the BCSC pathways. - Abstract: A small heterogeneous population of breast cancer cells acts as seeds to induce new tumor growth. These seeds or breast cancer stem cells (BCSCs) exhibit great phenotypical plasticity which allows them to undergo “epithelial to mesenchymal transition” (EMT) at the site of primary tumor and a future reverse transition. Apart from metastasis they are also responsible for maintaining the tumor and conferring it with drug and radiation resistance and a tendency for post-treatment relapse. Many of the signaling pathways involved in induction of EMT are involved in CSC generation and regulation. Here we are briefly reviewing the mechanism of TGF-β, Wnt, Notch, TNF-α, NF-κB, RTK signalling pathways which are involved in EMT as well as BCSCs maintenance. Therapeutic targeting or inhibition of the key/accessory players of these pathways could control growth of BCSCs and hence malignant cancer. Additionally several miRNAs are dysregulated in cancer stem cells indicating their roles as oncogenes or tumor suppressors. This review also lists the miRNA interactions identified in BCSCs and discusses on some newly identified targets in the BCSC regulatory pathways like SHIP2, nicastrin, Pin 1, IGF-1R, pro-inflammatory cytokines and syndecan which can be targeted for therapeutic achievements.

  17. Therapeutic vaccines for cancer: an overview of clinical trials.

    Science.gov (United States)

    Melero, Ignacio; Gaudernack, Gustav; Gerritsen, Winald; Huber, Christoph; Parmiani, Giorgio; Scholl, Suzy; Thatcher, Nicholas; Wagstaff, John; Zielinski, Christoph; Faulkner, Ian; Mellstedt, Håkan

    2014-09-01

    The therapeutic potential of host-specific and tumour-specific immune responses is well recognized and, after many years, active immunotherapies directed at inducing or augmenting these responses are entering clinical practice. Antitumour immunization is a complex, multi-component task, and the optimal combinations of antigens, adjuvants, delivery vehicles and routes of administration are not yet identified. Active immunotherapy must also address the immunosuppressive and tolerogenic mechanisms deployed by tumours. This Review provides an overview of new results from clinical studies of therapeutic cancer vaccines directed against tumour-associated antigens and discusses their implications for the use of active immunotherapy.

  18. Therapeutic Implications of Targeting Energy Metabolism in Breast Cancer

    Directory of Open Access Journals (Sweden)

    Meena K. Sakharkar

    2013-01-01

    Full Text Available PPARs are ligand activated transcription factors. PPARγ agonists have been reported as a new and potentially efficacious treatment of inflammation, diabetes, obesity, cancer, AD, and schizophrenia. Since cancer cells show dysregulation of glycolysis they are potentially manageable through changes in metabolic environment. Interestingly, several of the genes involved in maintaining the metabolic environment and the central energy generation pathway are regulated or predicted to be regulated by PPARγ. The use of synthetic PPARγ ligands as drugs and their recent withdrawal/restricted usage highlight the lack of understanding of the molecular basis of these drugs, their off-target effects, and their network. These data further underscores the complexity of nuclear receptor signalling mechanisms. This paper will discuss the function and role of PPARγ in energy metabolism and cancer biology in general and its emergence as a promising therapeutic target in breast cancer.

  19. Targeting Notch degradation system provides promise for breast cancer therapeutics.

    Science.gov (United States)

    Liu, Jing; Shen, Jia-Xin; Wen, Xiao-Fen; Guo, Yu-Xian; Zhang, Guo-Jun

    2016-08-01

    Notch receptor signaling pathways play an important role, not only in normal breast development but also in breast cancer development and progression. As a group of ligand-induced proteins, different subtypes of mammalian Notch (Notch1-4) are sensitive to subtle changes in protein levels. Thus, a clear understanding of mechanisms of Notch protein turnover is essential for understanding normal and pathological mechanisms of Notch functions. It has been suggested that there is a close relationship between the carcinogenesis and the dysregulation of Notch degradation. However, this relationship remains mostly undefined in the context of breast cancer, as protein degradation is mediated by numerous signaling pathways as well as certain molecule modulators (activators/inhibitors). In this review, we summarize the published data regarding the regulation of Notch family member degradation in breast cancer, while emphasizing areas that are likely to provide new therapeutic modalities for mechanism-based anti-cancer drugs. PMID:27263934

  20. Factors affecting the sensitivity and detection limits of MRI, CT, and SPECT for multimodal diagnostic and therapeutic agents.

    Science.gov (United States)

    Seevinck, Peter R; Seppenwoolde, Jan-Henry; de Wit, Tim C; Nijsen, Johannes F W; Beekman, Freek J; van Het Schip, Alfred D; Bakker, Chris J G

    2007-05-01

    Noninvasive imaging techniques like magnetic resonance imaging (MRI), computed tomography (CT) and single photon emission computed tomography (SPECT) play an increasingly important role in the diagnostic workup and treatment of cancerous disease. In this context, a distinct trend can be observed towards the development of contrast agents and radiopharmaceuticals that open up perspectives on a multimodality imaging approach, involving all three aforementioned techniques. To promote insight into the potentialities of such an approach, we prepared an overview of the strengths and limitations of the various imaging techniques, in particular with regard to their capability to quantify the spatial distribution of a multimodal diagnostic agent. To accomplish this task, we used a two-step approach. In the first step, we examined the situation for a particular therapeutic anti-cancer agent with multimodal imaging opportunities, viz. holmium-loaded microspheres (HoMS). Physical phantom experiments were performed to enable a comparative evaluation of the three modalities assuming the use of standard equipment, standard clinical scan protocols, and signal-known-exactly conditions. These phantom data were then analyzed so as to obtain first order estimates of the sensitivity and detection limits of MRI, CT and SPECT for HoMS. In the second step, the results for HoMS were taken as a starting point for a discussion of the factors affecting the sensitivity and detection limits of MRI, CT and SPECT for multimodal agents in general. In this, emphasis was put on the factors that must be taken into account when extrapolating the findings for HoMS to other diagnostic tasks, other contrast agents, other experimental conditions, and other scan protocols.

  1. Exosomal miRNAs as cancer biomarkers and therapeutic targets.

    Science.gov (United States)

    Thind, Arron; Wilson, Clive

    2016-01-01

    Intercommunication between cancer cells and with their surrounding and distant environments is key to the survival, progression and metastasis of the tumour. Exosomes play a role in this communication process. MicroRNA (miRNA) expression is frequently dysregulated in tumour cells and can be reflected by distinct exosomal miRNA (ex-miRNA) profiles isolated from the bodily fluids of cancer patients. Here, the potential of ex-miRNA as a cancer biomarker and therapeutic target is critically analysed. Exosomes are a stable source of miRNA in bodily fluids but, despite a number of methods for exosome extraction and miRNA quantification, their suitability for diagnostics in a clinical setting is questionable. Furthermore, exosomally transferred miRNAs can alter the behaviour of recipient tumour and stromal cells to promote oncogenesis, highlighting a role in cell communication in cancer. However, our incomplete understanding of exosome biogenesis and miRNA loading mechanisms means that strategies to target exosomes or their transferred miRNAs are limited and not specific to tumour cells. Therefore, if ex-miRNA is to be employed in novel non-invasive diagnostic approaches and as a therapeutic target in cancer, two further advances are necessary: in methods to isolate and detect ex-miRNA, and a better understanding of their biogenesis and functions in tumour-cell communication. PMID:27440105

  2. Cell mediated therapeutics for cancer treatment: Tumor homing cells as therapeutic delivery vehicles

    Science.gov (United States)

    Balivada, Sivasai

    Many cell types were known to have migratory properties towards tumors and different research groups have shown reliable results regarding cells as delivery vehicles of therapeutics for targeted cancer treatment. Present report discusses proof of concept for 1. Cell mediated delivery of Magnetic nanoparticles (MNPs) and targeted Magnetic hyperthermia (MHT) as a cancer treatment by using in vivo mouse cancer models, 2. Cells surface engineering with chimeric proteins for targeted cancer treatment by using in vitro models. 1. Tumor homing cells can carry MNPs specifically to the tumor site and tumor burden will decrease after alternating magnetic field (AMF) exposure. To test this hypothesis, first we loaded Fe/Fe3O4 bi-magnetic NPs into neural progenitor cells (NPCs), which were previously shown to migrate towards melanoma tumors. We observed that NPCs loaded with MNPs travel to subcutaneous melanoma tumors. After alternating magnetic field (AMF) exposure, the targeted delivery of MNPs by the NPCs resulted in a mild decrease in tumor size (Chapter-2). Monocytes/macrophages (Mo/Ma) are known to infiltrate tumor sites, and also have phagocytic activity which can increase their uptake of MNPs. To test Mo/Ma-mediated MHT we transplanted Mo/Ma loaded with MNPs into a mouse model of pancreatic peritoneal carcinomatosis. We observed that MNP-loaded Mo/Ma infiltrated pancreatic tumors and, after AMF treatment, significantly prolonged the lives of mice bearing disseminated intraperitoneal pancreatic tumors (Chapter-3). 2. Targeted cancer treatment could be achieved by engineering tumor homing cell surfaces with tumor proteases cleavable, cancer cell specific recombinant therapeutic proteins. To test this, Urokinase and Calpain (tumor specific proteases) cleavable; prostate cancer cell (CaP) specific (CaP1 targeting peptide); apoptosis inducible (Caspase3 V266ED3)- rCasp3V266ED3 chimeric protein was designed in silico. Hypothesized membrane anchored chimeric protein (rCasp3V

  3. Cell Survival and Apoptosis Signaling as Therapeutic Target for Cancer: Marine Bioactive Compounds

    Directory of Open Access Journals (Sweden)

    Kim Se-Kwon

    2013-01-01

    Full Text Available Inhibition of apoptosis leads to activation of cell survival factors (e.g., AKT causes continuous cell proliferation in cancer. Apoptosis, the major form of cellular suicide, is central to various physiological processes and the maintenance of homeostasis in multicellular organisms. A number of discoveries have clarified the molecular mechanism of apoptosis, thus clarifying the link between apoptosis and cell survival factors, which has a therapeutic outcome. Induction of apoptosis and inhibition of cell survival by anticancer agents has been shown to correlate with tumor response. Cellular damage induces growth arrest and tumor suppression by inducing apoptosis, necrosis and senescence; the mechanism of cell death depends on the magnitude of DNA damage following exposure to various anticancer agents. Apoptosis is mainly regulated by cell survival and proliferating signaling molecules. As a new therapeutic strategy, alternative types of cell death might be exploited to control and eradicate cancer cells. This review discusses the signaling of apoptosis and cell survival, as well as the potential contribution of marine bioactive compounds, suggesting that new therapeutic strategies might follow.

  4. Therapeutic resistance in cancer:microRNA regulation of EGFR signaling networks

    Institute of Scientific and Technical Information of China (English)

    German G. Gomez; Jill Wykosky; Ciro Zanca; Frank B. Furnari; Webster K. Cavenee

    2013-01-01

    Receptor tyrosine kinases (RTKs) such as the epidermal growth factor receptor (EGFR) regulate cellular homeostatic processes. EGFR activates downstream signaling cascades that promote tumor cell survival, proliferation and migration. Dysregulation of EGFR signaling as a consequence of overexpression, amplification and mutation of the EGFR gene occurs frequently in several types of cancers and many become dependent on EGFR signaling to maintain their malignant phenotypes. Consequently, concerted efforts have been mounted to develop therapeutic agents and strategies to effectively inhibit EGFR. However, limited therapeutic beneifts to cancer patients have been derived from EGFR-targeted therapies. A well-documented obstacle to improved patient survival is the presence of EGFR-inhibitor resistant tumor cell variants within heterogeneous tumor cell masses. Here, we summarize the mechanisms by which tumors resist EGFR-targeted therapies and highlight the emerging role of microRNAs (miRs) as downstream effector molecules utilized by EGFR to promote tumor initiation, progression and that play a role in resistance to EGFR inhibitors. We also examine evidence supporting the utility of miRs as predictors of response to targeted therapies and novel therapeutic agents to circumvent EGFR-inhibitor resistance mechanisms.

  5. Bioengineered Colorectal Cancer Drugs: Orally Delivered Anti-Inflammatory Agents.

    Science.gov (United States)

    Urbanska, Aleksandra Malgorzata; Zhang, Xiaoying; Prakash, Satya

    2015-07-01

    Intestinal inflammation is one of the major factors that increase colorectal cancer (CRC) incidence worldwide. Inflammation in the gastrointestinal tract is directly linked to tumor development at the early stages of the disease, thus a key issue toward the prevention and the treatment of colonic neoplasia. Thus, the use of anti-inflammatory drugs has emerged first as a strategy to reduce chronic inflammation in case of many inflammatory bowel diseases (IBD), but it has proven its efficacy by reducing the risk of colonic neoplasia. This comprehensive review highlights the role of chronic inflammation, mainly in IBD, in the development of CRC including molecular and immune mechanisms that have tumorigenic effects. Multiple lines of evidence indicate that several bioactive and phytochemical compounds used as anti-inflammatory drugs have also antitumoral attributes. The uses of orally delivered cytokines and small molecules, as well as key dietary supplementation as anti-inflammatory therapeutics are discussed. In addition, comprehensive knowledge about CRC and intestinal inflammation, and the importance of the intestinal mucosal wall as a mucosal immunological barrier that comes into play during interactions with gut microbiota (pathogens and commensal), luminal secretions (bile acids, and bacterial and epithelial metabolites), and ingested chemicals (food components, high fat content, heterocyclic amines, and low intake of dietary fiber) are underscored. The multifunctionality of several anti-inflammatory drugs opens a line for their application in the treatment and prevention not only in IBD but also in CRC. Current bioengineering approaches for oral delivery of anti-inflammatory agents including cytokines, genetically modified bacteria, or small molecule inhibitors of inflammation directly contribute to the early management of CRC. Limitations of the current therapeutics, which stem from the lack of complete understanding of the complex molecular interactions

  6. New Therapeutics to Treat Castrate-Resistant Prostate Cancer

    OpenAIRE

    Ömer Acar; Tarık Esen; Lack, Nathan A.

    2013-01-01

    Hindawi Publishing Corporation The ScientificWorld Journal Volume 2013, Article ID 379641, 8 pages http://dx.doi.org/10.1155/2013/379641 Review Article New Therapeutics to Treat Castrate-Resistant Prostate Cancer Ömer Acar,1 TarJk Esen,1,2 and Nathan A. Lack1 1 VKF American Hospital, Guzelbahce sokak, Nisantasi, Istanbul 34365, Turkey 2 School of Medicine, Koc¸ University, Rumelifeneri Yolu, Sariyer, Istanbul 34450, Turkey Correspondence should be addressed to Natha...

  7. THERAPEUTIC APPROACH TO CANCER BY VEGETABLES WITH ANTIOXIDANT ACTIVITY

    Directory of Open Access Journals (Sweden)

    Pandey Govind

    2011-01-01

    Full Text Available Cancer is the second leading cause of human deaths in the world. However, the potential treatment of cancer is still under investigation. In fact, the plants may occupy a good place in the treatment of cancer with no ill effect. The medicinal plants and their products, particularly vegetables have antioxidant activity leading to anticancer effect. Thus, more than 80% people in developing countries depend on traditional medicine or plants for their primary health needs. Plants used as vegetables prevent human from several diseases, including cancer. Many doctors recommend that people wish to reduce the risk of cancer must eat several portions of vegetables every day. The vegetables contain many phytochemicals having antioxidant activity. The antioxidants protect the cells from damage caused by ‘free oxygen radicals’. The main phytochemicals which show antioxidant activity are vitamins, carotenoids, terpenoids, flavonoids, polyphenols, saponins, enzymes and minerals. Hence, the present article gives a better therapeutic approach to cancer by the maximum use of antioxidant vegetables against different cancers.

  8. Evaluating the Cancer Therapeutic Potential of Cardiac Glycosides

    Directory of Open Access Journals (Sweden)

    José Manuel Calderón-Montaño

    2014-01-01

    Full Text Available Cardiac glycosides, also known as cardiotonic steroids, are a group of natural products that share a steroid-like structure with an unsaturated lactone ring and the ability to induce cardiotonic effects mediated by a selective inhibition of the Na+/K+-ATPase. Cardiac glycosides have been used for many years in the treatment of cardiac congestion and some types of cardiac arrhythmias. Recent data suggest that cardiac glycosides may also be useful in the treatment of cancer. These compounds typically inhibit cancer cell proliferation at nanomolar concentrations, and recent high-throughput screenings of drug libraries have therefore identified cardiac glycosides as potent inhibitors of cancer cell growth. Cardiac glycosides can also block tumor growth in rodent models, which further supports the idea that they have potential for cancer therapy. Evidence also suggests, however, that cardiac glycosides may not inhibit cancer cell proliferation selectively and the potent inhibition of tumor growth induced by cardiac glycosides in mice xenografted with human cancer cells is probably an experimental artifact caused by their ability to selectively kill human cells versus rodent cells. This paper reviews such evidence and discusses experimental approaches that could be used to reveal the cancer therapeutic potential of cardiac glycosides in preclinical studies.

  9. Phytoconstituents as apoptosis inducing agents: strategy to combat cancer.

    Science.gov (United States)

    Kumar, Manish; Kaur, Varinder; Kumar, Subodh; Kaur, Satwinderjeet

    2016-08-01

    Advancement in the field of cancer molecular biology has aided researchers to develop various new chemopreventive agents which can target cancer cells exclusively. Cancer chemopreventive agents have proficiency to inhibit, reverse and delay process of carcinogenesis during its early and later course. Chemopreventive agents can act as antioxidative, antimutagenic/antigenotoxic, anti-inflammatory agents or via aiming various molecular targets in a cell to induce cell death. Apoptosis is a kind of cell death which shows various cellular morphological alterations such as cell shrinkage, blebbing of membrane, chromatin condensation, DNA fragmentation, formation of apoptotic bodies etc. Nowadays, apoptosis is being one of the new approaches for the identification and development of novel anticancer therapies. For centuries, plants are known to play part in daily routine from providing food to management of human health. In the last two decades, diverse phytochemicals and various botanical formulations have been characterized as agents that possess potential to execute cancer cells via inducing apoptosis. Data obtained from the research carried out globally pointed out that natural products are the potential candidates which have capability to combat cancer. In the present review, we surveyed literature on natural products which throws light on the mechanism through which these phytochemicals induce apoptosis in cancer cells. PMID:26239338

  10. The redox biology network in cancer pathophysiology and therapeutics

    Directory of Open Access Journals (Sweden)

    Gina Manda

    2015-08-01

    Full Text Available The review pinpoints operational concepts related to the redox biology network applied to the pathophysiology and therapeutics of solid tumors. A sophisticated network of intrinsic and extrinsic cues, integrated in the tumor niche, drives tumorigenesis and tumor progression. Critical mutations and distorted redox signaling pathways orchestrate pathologic events inside cancer cells, resulting in resistance to stress and death signals, aberrant proliferation and efficient repair mechanisms. Additionally, the complex inter-cellular crosstalk within the tumor niche, mediated by cytokines, redox-sensitive danger signals (HMGB1 and exosomes, under the pressure of multiple stresses (oxidative, inflammatory, metabolic, greatly contributes to the malignant phenotype. The tumor-associated inflammatory stress and its suppressive action on the anti-tumor immune response are highlighted. We further emphasize that ROS may act either as supporter or enemy of cancer cells, depending on the context. Oxidative stress-based therapies, such as radiotherapy and photodynamic therapy, take advantage of the cytotoxic face of ROS for killing tumor cells by a non-physiologically sudden, localized and intense oxidative burst. The type of tumor cell death elicited by these therapies is discussed. Therapy outcome depends on the differential sensitivity to oxidative stress of particular tumor cells, such as cancer stem cells, and therefore co-therapies that transiently down-regulate their intrinsic antioxidant system hold great promise. We draw attention on the consequences of the damage signals delivered by oxidative stress-injured cells to neighboring and distant cells, and emphasize the benefits of therapeutically triggered immunologic cell death in metastatic cancer. An integrative approach should be applied when designing therapeutic strategies in cancer, taking into consideration the mutational, metabolic, inflammatory and oxidative status of tumor cells, cellular

  11. Therapeutic Cancer Vaccines in Combination with Conventional Therapy

    DEFF Research Database (Denmark)

    Andersen, Mads Hald; Junker, N.; Ellebaek, E.;

    2010-01-01

    The clinical efficacy of most therapeutic vaccines against cancer has not yet met its promise. Data are emerging that strongly support the notion that combining immunotherapy with conventional therapies, for example, radiation and chemotherapy may improve efficacy. In particular combination...... with chemotherapy may lead to improved clinical efficacy by clearing suppressor cells, reboot of the immune system, by rendering tumor cells more susceptible to immune mediated killing, or by activation of cells of the immune system. In addition, a range of tumor antigens have been characterized to allow targeting...... of proteins coupled to intrinsic properties of cancer cells. For example, proteins associated with drug resistance can be targeted, and form ideal target structures for use in combination with chemotherapy for killing of surviving drug resistant cancer cells. Proteins associated with the malignant phenotype...

  12. Rectal cancer in pregnancy: A diagnostic and therapeutic challenge

    International Nuclear Information System (INIS)

    Introduction: The occurrence of colorectal cancer during pregnancy is rare and is associated with diagnostic and therapeutic challenges. Herein, we report such a case of rectal cancer in pregnancy and review the literature. Case report: A 31-year-old multiparous, pregnant woman, in the 20th week of gestation, presented with rectal bleeding progressing to spasmodic abdominal pain and right flank vague pain. A flexible recto sigmoidoscopy showed a large ulcerative mass located in the recto sigmoid junction, 15 cm away from anal verge. Imaging studies and biopsy proved it to be rectal adenocarcinoma with single liver metastasis. The patient’s pregnancy was terminated and neoadjuvant therapy followed by curative surgery was performed. She is currently receiving adjuvant systemic therapy to eradicate potential micro metastatic disease. Conclusion: This case suggests that colorectal cancer can mimic the signs and the symptoms of pregnancy and tends to present at an advanced stage in pregnant women.

  13. Glycoengineering in cancer therapeutics: a review with fucose-depleted trastuzumab as the model.

    Science.gov (United States)

    Listinsky, Jay J; Siegal, Gene P; Listinsky, Catherine M

    2013-03-01

    Experimentally modified trastuzumab antibodies show increased cytotoxic potency when used with human effector cells against HER2-overexpressing human breast cancer cells in vitro and ex vivo. Furthermore, the superior efficacy of 'glycoengineered' trastuzumab has been confirmed in vivo utilizing a preclinical xenograft model of human HER2-amplified, trastuzumab-resistant human breast cancer. The increased cytotoxic potency coupled with other improvements are achieved by a seemingly modest change in trastuzumab's structure, that is, depletion of two α-L-fucose residues from trastuzumab's heavy chains. Fucose-free trastuzumab binds with much greater affinity to human natural killer cells. This improved binding induces much greater antibody-dependent cellular cytotoxicity against HER2-overexpressing cells. The pharmaceutical industry has recognized the advantages of fucose-free therapeutic antibodies and has developed technologies that aim to mass produce such antibodies for human use. Here, we summarize data from multiple academic and pharmaceutical laboratories highlighting fucose depletion of antibodies as a key strategy of glycoengineering in cancer therapeutics. We use fucose-depleted trastuzumab as a model to show the advantages of this new class of anticancer agents. We predict that these advantages will translate clinically into improved therapeutics for many patients including those with HER2-overexpressing neoplasms.

  14. TCGA divides gastric cancer into four molecular subtypes:implications for individualized therapeutics

    Institute of Scientific and Technical Information of China (English)

    Wei Zhang

    2014-01-01

    Gastric cancer is a leading cause of cancer deaths in the world. The treatment of gastric cancer is chalenging because of its highly heterogeneous etiology and clinical characteristics. Recent genomic and molecular characterization of gastric cancer, especialy the findings reported by the Cancer Genome Atlas (TCGA), have shed light on the heterogeneity and potential targeted therapeutics for four different subtypes of gastric cancer.

  15. Anti-cancer agents counteracting tumor glycolysis

    OpenAIRE

    Granchi, Carlotta; Minutolo, Filippo

    2012-01-01

    Can we consider cancer as a “metabolic disease”? Tumors are the result of a metabolic selection, forming tissues composed of heterogeneous cells that generally express an overactive metabolism as a common feature. In fact, cancer cells have to deal with increased needs for both energy and biosynthetic intermediates, in order to support their growth and invasiveness. However, their high proliferation rate often generates regions that are not sufficiently oxygenated. Therefore, their carbohydra...

  16. Metal chelators coupled with nanoparticles as potential therapeutic agents for Alzheimer's disease

    OpenAIRE

    Liu, Gang; Men, Ping; Perry, George; Smith, Mark A.

    2009-01-01

    Alzheimer's disease (AD) is a devastating neuro-degenerative disorder characterized by the progressive and irreversible loss of memory followed by complete dementia. Despite the disease's high prevalence and great economic and social burden, an explicative etiology or viable cure is not available. Great effort has been made to better understand the disease's pathogenesis, and to develop more effective therapeutic agents. However, success is greatly hampered by the presence of the blood-brain ...

  17. Therapeutic drug monitoring (TDM) of antifungal agents: guidelines from the British Society for Medical Mycology

    OpenAIRE

    Ashbee, H. Ruth; Barnes, Rosemary A.; Johnson, Elizabeth M.; Richardson, Malcolm D.; Gorton, Rebecca; Hope, William W.

    2013-01-01

    The burden of human disease related to medically important fungal pathogens is substantial. An improved understanding of antifungal pharmacology and antifungal pharmacokinetics–pharmacodynamics has resulted in therapeutic drug monitoring (TDM) becoming a valuable adjunct to the routine administration of some antifungal agents. TDM may increase the probability of a successful outcome, prevent drug-related toxicity and potentially prevent the emergence of antifungal drug resistance. Much of the...

  18. Epigenetic Therapeutics: A New Weapon in the War Against Cancer.

    Science.gov (United States)

    Ahuja, Nita; Sharma, Anup R; Baylin, Stephen B

    2016-01-01

    The past 15 years have seen an explosion of discoveries related to the cellular regulation of phenotypes through epigenetic mechanisms. This regulation provides a software that packages DNA, without changing the primary base sequence, to establish heritable patterns of gene expression. In cancer, many aspects of the epigenome, controlled by DNA methylation, chromatin, and nucleosome positioning, are altered as one means by which tumor cells maintain abnormal states of self-renewal at the expense of normal maturation. Epigenetic and genetic abnormalities thus collaborate in cancer initiation and progression, as exemplified by frequent mutations in genes encoding proteins that control the epigenome. There is growing emphasis on using epigenetic therapies to reprogram neoplastic cells toward a normal state. Many agents targeting epigenetic regulation are under development and entering clinical trials. This review highlights the promise that epigenetic therapy, often in combination with other therapies, will become a potent tool for cancer management over the next decade.

  19. Effect of therapeutic chemical agents in vitro and on experimental meningoencephalitis due to Naegleria fowleri.

    Science.gov (United States)

    Kim, Jong-Hyun; Jung, Suk-Yul; Lee, Yang-Jin; Song, Kyoung-Ju; Kwon, Daeho; Kim, Kyongmin; Park, Sun; Im, Kyung-Il; Shin, Ho-Joon

    2008-11-01

    Naegleria fowleri is a ubiquitous, pathogenic free-living amoeba; it is the most virulent Naegleria species and causes primary amoebic meningoencephalitis (PAME) in laboratory animals and humans. Although amphotericin B is currently the only agent available for the treatment of PAME, it is a very toxic antibiotic and may cause many adverse effects on other organs. In order to find other potentially therapeutic agents for N. fowleri infection, the present study was undertaken to evaluate the in vitro and in vivo efficacies of miltefosine and chlorpromazine against pathogenic N. fowleri. The result showed that the growth of the amoeba was effectively inhibited by treatment with amphotericin B, miltefosine, and chlorpromazine. When N. fowleri trophozoites were treated with amphotericin B, miltefosine, and chlorpromazine, the MICs of the drug were 0.78, 25, and 12.5 microg/ml, respectively, on day 2. In experimental meningoencephalitis of mice that is caused by N. fowleri, the survival rates of mice treated with amphotericin B, miltefosine, and chlorpromazine were 40, 55, and 75%, respectively, during 1 month. The average mean time to death for the amphotericin B, miltefosine, and chlorpromazine treatments was 17.9 days. In this study, the effect of drugs was found to be optimal when 20 mg/kg was administered three times on days 3, 7, and 11. Finally, chlorpromazine had the best therapeutic activity against N. fowleri in vitro and in vivo. Therefore, it may be a more useful therapeutic agent for the treatment of PAME than amphotericin B.

  20. nab-Paclitaxel in combination with biologically targeted agents for early and metastatic breast cancer.

    Science.gov (United States)

    Megerdichian, Christine; Olimpiadi, Yuliya; Hurvitz, Sara A

    2014-06-01

    Taxanes are highly active chemotherapeutic agents used in the treatment of early-stage and metastatic breast cancer. Novel formulations have been developed to improve efficacy and decrease toxicity associated with these cytotoxic agents. nab-Paclitaxel is a biologically interactive, solvent-free, 130-nm-sized albumin-bound paclitaxel, developed to avoid the Cremophor vehicle used in solvent-based paclitaxel. Based on a pivotal phase 3 study, nab-paclitaxel was shown to be safely infused at a significantly higher dose of paclitaxel than the doses used with standard paclitaxel therapy, and had a shorter infusion time, no premedication, and higher response rates. It is now approved in the United States for treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant therapy, and has demonstrated promising efficacy and favorable tolerability. Recently, several phase 2 and 3 studies have suggested a role for nab-paclitaxel in combination with biologically targeted agents for the treatment of early- and late-stage breast cancer. This review will discuss the findings of clinical trials evaluating nab-paclitaxel in combination with biologically targeted therapeutic agents for breast cancer in the neoadjuvant, adjuvant, and metastatic settings. PMID:24560997

  1. The Landscape of Pancreatic Cancer Therapeutic Resistance Mechanisms.

    Science.gov (United States)

    Chand, Saswati; O'Hayer, Kevin; Blanco, Fernando F; Winter, Jordan M; Brody, Jonathan R

    2016-01-01

    Pancreatic cancer (pancreatic ductal adenocarcinoma, PDA) is infamously moving to the top of the list as one of the most lethal cancers with an overall 5 year survival rate of 7%. Multiple genomic-based and molecular characterization studies of PDA specimens and established animal models have provided the field with multiple targets and a progression model of this disease. Still, to date, the best therapeutic options are surgery and combination cytotoxic therapies. In general, even in the best case scenario (i.e., an early stage diagnosis and a response to a specific therapy), most of these fortunate patients' PDA cells acquire or exert resistance mechanisms and eventually kill the patient. Herein, we touch on a growing field of investigation that focuses on PDA cell therapeutic resistance mechanisms. We examine extrinsic elements (i.e., the tumor microenvironment, hypoxia) to the intrinsic processes within the cell (i.e., post-transcriptional gene regulation and somatic mutations) that are important for therapeutic efficacy and resistance. Even as better targeted and personalized approaches move through the clinical trial pipeline the discussed resistance mechanisms will most likely play a role in the management of this deadly disease.

  2. The Tyrosine Kinome Dictates Breast Cancer Heterogeneity and Therapeutic Responsiveness.

    Science.gov (United States)

    Ha, Jacqueline R; Siegel, Peter M; Ursini-Siegel, Josie

    2016-09-01

    Phospho-tyrosine signaling networks control numerous biological processes including cellular differentiation, cell growth and survival, motility, and invasion. Aberrant regulation of the tyrosine kinome is a hallmark of malignancy and influences all stages of breast cancer progression, from initiation to the development of metastatic disease. The success of specific tyrosine kinase inhibitors strongly validates the clinical relevance of tyrosine phosphorylation networks in breast cancer pathology. However, a significant degree of redundancy exists within the tyrosine kinome. Numerous receptor and cytoplasmic tyrosine kinases converge on a core set of signaling regulators, including adaptor proteins and tyrosine phosphatases, to amplify pro-tumorigenic signal transduction pathways. Mutational activation, amplification, or overexpression of one or more components of the tyrosine kinome represents key contributing events responsible for the tumor heterogeneity that is observed in breast cancers. It is this molecular heterogeneity that has become the most significant barrier to durable clinical responses due to the development of therapeutic resistance. This review focuses on recent literature that supports a prominent role for specific components of the tyrosine kinome in the emergence of unique breast cancer subtypes and in shaping breast cancer plasticity, sensitivity to targeted therapies, and the eventual emergence of acquired resistance. J. Cell. Biochem. 117: 1971-1990, 2016. © 2016 Wiley Periodicals, Inc.

  3. The Tyrosine Kinome Dictates Breast Cancer Heterogeneity and Therapeutic Responsiveness.

    Science.gov (United States)

    Ha, Jacqueline R; Siegel, Peter M; Ursini-Siegel, Josie

    2016-09-01

    Phospho-tyrosine signaling networks control numerous biological processes including cellular differentiation, cell growth and survival, motility, and invasion. Aberrant regulation of the tyrosine kinome is a hallmark of malignancy and influences all stages of breast cancer progression, from initiation to the development of metastatic disease. The success of specific tyrosine kinase inhibitors strongly validates the clinical relevance of tyrosine phosphorylation networks in breast cancer pathology. However, a significant degree of redundancy exists within the tyrosine kinome. Numerous receptor and cytoplasmic tyrosine kinases converge on a core set of signaling regulators, including adaptor proteins and tyrosine phosphatases, to amplify pro-tumorigenic signal transduction pathways. Mutational activation, amplification, or overexpression of one or more components of the tyrosine kinome represents key contributing events responsible for the tumor heterogeneity that is observed in breast cancers. It is this molecular heterogeneity that has become the most significant barrier to durable clinical responses due to the development of therapeutic resistance. This review focuses on recent literature that supports a prominent role for specific components of the tyrosine kinome in the emergence of unique breast cancer subtypes and in shaping breast cancer plasticity, sensitivity to targeted therapies, and the eventual emergence of acquired resistance. J. Cell. Biochem. 117: 1971-1990, 2016. © 2016 Wiley Periodicals, Inc. PMID:27392311

  4. PPARγ as a Novel Therapeutic Target in Lung Cancer

    Directory of Open Access Journals (Sweden)

    Aravind T. Reddy

    2016-01-01

    Full Text Available Lung cancer is the leading cause of cancer-related death, with more than half the patients having advanced-stage disease at the time of initial diagnosis and thus facing a poor prognosis. This dire situation poses a need for new approaches in prevention and treatment. Peroxisome proliferator-activated receptor γ (PPARγ is a ligand-activated transcription factor belonging to the nuclear hormone receptor superfamily. Its involvement in adipocyte differentiation and glucose and lipid homeostasis is well-recognized, but accumulating evidence now suggests that PPARγ may also function as a tumor suppressor, inhibiting development of primary tumors and metastases in lung cancer and other malignancies. Besides having prodifferentiation, antiproliferative, and proapoptotic effects, PPARγ agonists have been shown to prevent cancer cells from acquiring the migratory and invasive capabilities essential for successful metastasis. Angiogenesis and secretion of certain matrix metalloproteinases and extracellular matrix proteins within the tumor microenvironment are also regulated by PPARγ. This review of the current literature highlights the potential of PPARγ agonists as novel therapeutic modalities in lung cancer, either as monotherapy or in combination with standard cytotoxic chemotherapy.

  5. RNAi technology: A Revolutionary tool for the colorectal cancer therapeutics

    Institute of Scientific and Technical Information of China (English)

    Wei Lv; Chao Zhang; Jia Hao

    2006-01-01

    With the many changes that have taken place in people's diet and lifestyle, colorectal cancer (CRC) has become a global concern. There were approximately 950000 new cases diagnosed and 500000 deaths recorded worldwide in 2000. It is the second most common type of cancer in the Western world, and it is the third most common type of digestive tumor in China. It is reported that the morbidity of CRC is 4.08/100000 for men and 3.30/100000 for women in China. Despite the rate of improvements in surgery, radiotherapy and chemotherapy, the overall five-year survival is around 50%. Therefore, novel treatment need to be developed in order to add to the therapeutic armamentarium.RNA interference (RNAi) is a sequence-specific posttranscriptional gene silencing mechanism, which is triggered by double-stranded RNA (dsRNA) and causes degradation of mRNA homologous in sequence to the dsRNA.This new approach has been successfully adopted to inhibit virus replication and tumorigenicity. Recent reports have described DNA vector-based strategies for delivery of small interfering RNA (siRNA) into mammalian cells, further expanding the utility of RNAi. With the development of the RNAi technology and deeper understanding of this field, a promising new modality of treatment appeared, which can be used in combination with the existing therapies .We reviewed the proceedings on the actualities and advancement of RNAi technology for colorectal cancer therapeutics.

  6. Therapeutic vaccines against human papillomavirus and cervical cancer.

    Science.gov (United States)

    Cid-Arregui, Angel

    2009-01-01

    Cervical cancer and its precursor intra-epithelial lesions are linked to infection by a subset of so-called "highrisk" human papillomavirus types, which are estimated to infect nearly four hundred million women worldwide. Two prophylactic vaccines have been commercialized recently targeting HPV16 and 18, the most prevalent viral types found in cervical cancer, which operate through induction of capsid-specific neutralizing antibodies. However, in patients with persistent infection these vaccines have not been found to protect against progression to neoplasia. Attempts are being made to develop therapeutic vaccines targeting nonstructural early viral proteins. Among these, E6 and E7 are the preferred targets, since they are essential for induction and maintenance of the malignant phenotype and are constitutively expressed by the transformed epithelial cells. Here are reviewed the most relevant potential vaccines based on HPV early antigens that have shown efficacy in preclinical models and that are being tested in clinical studies, which should determine their therapeutic capacity for eradicating HPV-induced premalignant and malignant lesions and cure cervical cancer. PMID:19915722

  7. Glycosylation of Glycolipids in Cancer: Basis for Development of Novel Therapeutic Approaches

    Directory of Open Access Journals (Sweden)

    Jose Luis Daniotti

    2013-12-01

    Full Text Available Altered networks of gene regulation underlie many pathologies, including cancer. There are several proteins in cancer cells that are turned either on or off, which dramatically alters the metabolism and the overall activity of the cell, with the complex machinery of enzymes involved in the metabolism of glycolipids not being an exception. The aberrant glycosylation of glycolipids on the surface of the majority of cancer cells, associated with increasing evidence about the functional role of these molecules in a number of cellular physiological pathways, has received considerable attention as a convenient immunotherapeutic target for cancer treatment. This has resulted in the development of a substantial number of passive and active immunotherapies, which have shown promising results in clinical trials. More recently, antibodies to glycolipids have also emerged as an attractive tool for the targeted delivery of cytotoxic agents, thereby providing a rationale for future therapeutic interventions in cancer. This review first summarizes the cellular and molecular bases involved in the metabolic pathway and expression of glycolipids, both in normal and tumor cells, paying particular attention to sialosylated glycolipids (gangliosides. The current strategies in the battle against cancer in which glycolipids are key players are then described.

  8. Therapeutic targeting of epidermal growth factor receptor in human cancer: successes and limitations%Therapeutic targeting of epidermal growth factor receptor in humancancer: successes and limitations

    Institute of Scientific and Technical Information of China (English)

    Jill Wykosky; Tim Fenton; Frank Furnari; Webster K. Cavenee

    2011-01-01

    Epidermal growth factor receptor (EGFR) is one of the most commonly altered genes in human cancer by way of over-expression, amplification, and mutation. Targeted inhibition of EGFR activity suppresses signal transduction pathways which control tumor cell growth, proliferation, and resistance to apoptosis. Small molecule tyrosine kinase inhibitors and monoclonal antibodies are among the most common EGFR-targeting agents and have been used clinically for treating various malignancies. This review discusses the successes and challenges of targeting EGFR in human cancer. The genetic alterations of EGFR tend to occur more often in some solid tumors than others, as do the mechanisms of resistance to targeted inhibition. The clinical and basic science experiences with these agents thus far have important implications for the future of therapeutic targeting of EGFR.

  9. Novel therapeutic Strategies for Targeting Liver Cancer Stem Cells

    Directory of Open Access Journals (Sweden)

    Naoki Oishi, Xin Wei Wang

    2011-01-01

    Full Text Available The cancer stem cell (CSC hypothesis was first proposed over 40 years ago. Advances in CSC isolation were first achieved in hematological malignancies, with the first CSC demonstrated in acute myeloid leukemia. However, using similar strategies and technologies, and taking advantage of available surface markers, CSCs have been more recently demonstrated in a growing range of epithelial and other solid organ malignancies, suggesting that the majority of malignancies are dependent on such a compartment.Primary liver cancer consists predominantly of hepatocellular carcinoma (HCC and intrahepatic cholangiocarcinoma (ICC. It is believed that hepatic progenitor cells (HPCs could be the origin of some HCCs and ICCs. Furthermore, stem cell activators such as Wnt/β-catenin, TGF-β, Notch and Hedgehog signaling pathways also expedite tumorigenesis, and these pathways could serve as molecular targets to assist in designing cancer prevention strategies. Recent studies indicate that additional factors such as EpCAM, Lin28 or miR-181 may also contribute to HCC progression by targeting HCC CSCs. Various therapeutic drugs that directly modulate CSCs have been examined in vivo and in vitro. However, CSCs clearly have a complex pathogenesis, with a considerable crosstalk and redundancy in signaling pathways, and hence targeting single molecules or pathways may have a limited benefit for treatment. Many of the key signaling molecules are shared by both CSCs and normal stem cells, which add further challenges for designing molecularly targeted strategies specific to CSCs but sparing normal stem cells to avoid side effects. In addition to the direct control of CSCs, many other factors that are needed for the maintenance of CSCs, such as angiogenesis, vasculogenesis, invasion and migration, hypoxia, immune evasion, multiple drug resistance, and radioresistance, should be taken into consideration when designing therapeutic strategies for HCC.Here we provide a brief

  10. Botanical Agents for the Treatment of Nonmelanoma Skin Cancer

    Directory of Open Access Journals (Sweden)

    Jillian W. Millsop

    2013-01-01

    Full Text Available Nonmelanoma skin cancers, including basal cell carcinoma and squamous cell carcinoma, are common neoplasms worldwide and are the most common cancers in the United States. Standard therapy for cutaneous neoplasms typically involves surgical removal. However, there is increasing interest in the use of topical alternatives for the prevention and treatment of nonmelanoma skin cancer, particularly superficial variants. Botanicals are compounds derived from herbs, spices, stems, roots, and other substances of plant origin and may be used in the form of dried or fresh plants, extracted plant material, or specific plant-derived chemicals. They possess multiple properties including antioxidant, anti-inflammatory, and immunomodulatory properties and are, therefore, believed to be possible chemopreventive agents or substances that may suppress or reverse the process of carcinogenesis. Here, we provide a review of botanical agents studied for the treatment and prevention of nonmelanoma skin cancers.

  11. Investigational Agents in Development for the Treatment of Ovarian Cancer

    OpenAIRE

    Westin, Shannon N.; Herzog, Thomas J.; Coleman, Robert L.

    2012-01-01

    Although significant success has been achieved in the treatment of advanced and recurrent ovarian cancer, there is clearly room for improvement. The use of targeted agents in this patient population has the promise to provide improved survival and quality of life. There are a myriad of relevant pathways under exploration in all settings of ovarian cancer. Clinical trial data are accumulating for antiangiogenic therapy, including vascular endothelial growth factor (VEGF)-specific inhibitors an...

  12. [The development of therapeutics targeting oxidative stress in prostate cancer].

    Science.gov (United States)

    Shiota, Masaki; Yokomizo, Akira; Naito, Seiji

    2014-12-01

    Oxidative stress is caused by increased reactive-oxygen species (ROS) due to augmented ROS production and impaired anti-oxidative capacity. Recently, oxidative stress has been revealed to promote castration resistance via androgen receptor(AR)-dependent pathway such as AR overexpression, AR cofactor, and AR post-translational modification as well as AR-independent pathway, leading to the emergence of castration-resistant prostate cancer (CRPC). Therefore, antioxidants therapy using natural and chemical ROS scavengers and inhibitors of ROS production seems to be a promising therapy for CRPC as well as preventing castration resistance. However, at present, the application to therapeutics is limited. Therefore, further research on oxidative stress in prostate cancer, as well as on the development for clinical application would be needed.

  13. Frizzled-7 as a Potential Therapeutic Target in Colorectal Cancer

    Directory of Open Access Journals (Sweden)

    Koji Ueno

    2008-07-01

    Full Text Available We investigated whether one of the Wnt receptors, frizzled-7 (FZD7, functions in the canonical Wnt signaling pathway of colorectal cancer (CRC cells harboring an APC or CTNNB1 mutation and may be a potential therapeutic target for sporadic CRCs. The expression level of FZD gene family members in colon cancer cells and primary CRC tissues were determined by real-time PCR. Activation of the Wnt signaling pathway was evaluated by TOPflash assay. The expression level of Wnt target genes was determined by real-time polymerase chain reaction and/or Western blot analysis. Cell growth and cell invasion were assessed by MTS and matrigel assays, respectively. Among 10 FZD gene family members, FZD7 mRNA was predominantly expressed in six colon cancer cell lines with APC or CTNNB1 mutation. These six cell lines were transfected with FZD7 cDNA together with a TOPflash reporter plasmid, resulting in a 1.5- to 24.3-fold increase of Tcf transcriptional activity. The mRNA expression levels of seven known Wnt target genes were also increased by 1.5- to 3.4-fold after transfection of FZD7 cDNA into HCT-116 cells. The six cell lines were then cotransfected with FZD7-siRNA and a TOPflash reporter plasmid, which reduced Tcf transcriptional activity to 20% to 80%. FZD7-siRNA was shown to significantly decrease cell viability and in vitro invasion activity after transfection into HCT-116 cells. Our present data demonstrated that FZD7 activates the canonical Wnt pathway in colon cancer cells despite the presence of APC or CTNNB1 mutation and that FZD7-siRNA may be used as a therapeutic reagent for CRCs.

  14. Assessment of antimicrobial (host defense) peptides as anti-cancer agents.

    Science.gov (United States)

    Douglas, Susan; Hoskin, David W; Hilchie, Ashley L

    2014-01-01

    Cationic antimicrobial (host defense) peptides (CAPs) are able to kill microorganisms and cancer cells, leading to their consideration as novel candidate therapeutic agents in human medicine. CAPs can physically associate with anionic membrane structures, such as those found on cancer cells, causing pore formation, intracellular disturbances, and leakage of cell contents. In contrast, normal cells are less negatively-charged and are typically not susceptible to CAP-mediated cell death. Because the interaction of CAPs with cells is based on charge properties rather than cell proliferation, both rapidly dividing and quiescent cancer cells, as well as multidrug-resistant cancer cells, are targeted by CAPs, making CAPS potentially valuable as anti-cancer agents. CAPs often exist as families of peptides with slightly different amino acid sequences. In addition, libraries of synthetic peptide variants based on naturally occurring CAP templates can be generated in order to improve upon their action. High-throughput screens are needed to quickly and efficiently assess the suitability of each CAP variant. Here we present the methods for assessing CAP-mediated cytotoxicity against cancer cells (suspension and adherent) and untransformed cells (measured using the tritiated thymidine-release or MTT assay), and for discriminating between cell death caused by necrosis (measured using lactate dehydrogenase- or (51)Cr-release assays), or apoptosis and necrosis (single-stranded DNA content measured by flow cytometry). In addition the clonogenic assay, which assesses the ability of single transformed cells to multiply and produce colonies, is described.

  15. Epigenetic Modulating Agents as a New Therapeutic Approach in Multiple Myeloma

    Energy Technology Data Exchange (ETDEWEB)

    Maes, Ken, E-mail: kemaes@vub.ac.be; Menu, Eline; Van Valckenborgh, Els [Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussel (Belgium); Van Riet, Ivan [Stem Cell Laboratory, Department Clinical Hematology, Universitair Ziekenhuis Brussel (UZ Brussel), Laarbeeklaan 101, 1090 Brussel (Belgium); Vanderkerken, Karin; De Bruyne, Elke, E-mail: kemaes@vub.ac.be [Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussel (Belgium)

    2013-04-15

    Multiple myeloma (MM) is an incurable B-cell malignancy. Therefore, new targets and drugs are urgently needed to improve patient outcome. Epigenetic aberrations play a crucial role in development and progression in cancer, including MM. To target these aberrations, epigenetic modulating agents, such as DNA methyltransferase inhibitors (DNMTi) and histone deacetylase inhibitors (HDACi), are under intense investigation in solid and hematological cancers. A clinical benefit of the use of these agents as single agents and in combination regimens has been suggested based on numerous studies in pre-clinical tumor models, including MM models. The mechanisms of action are not yet fully understood but appear to involve a combination of true epigenetic changes and cytotoxic actions. In addition, the interactions with the BM niche are also affected by epigenetic modulating agents that will further determine the in vivo efficacy and thus patient outcome. A better understanding of the molecular events underlying the anti-tumor activity of the epigenetic drugs will lead to more rational drug combinations. This review focuses on the involvement of epigenetic changes in MM pathogenesis and how the use of DNMTi and HDACi affect the myeloma tumor itself and its interactions with the microenvironment.

  16. Perspectives on Phytochemicals as Antibacterial Agents: An Outstanding Contribution to Modern Therapeutics.

    Science.gov (United States)

    Khatri, Savita; Kumar, Manish; Phougat, Neetu; Chaudhary, Renu; Chhillar, Anil Kumar

    2016-01-01

    Despite the considerable advancements in the development of antimicrobial agents, incidents of epidemics due to multi drug resistance in microorganisms have created a massive hazard to mankind. Due to increased resistance against conventional antibiotics, researchers and pharmaceutical industries are more concerned about novel therapeutic agents for the prevention of bacterial infections. Enormous wealth of traditional system of medicine gains importance in health therapies over again. With ancient credentials of potent medicinal plants, various herbal remedies came forward for the management of bacterial infections. The Ayurvedic approach facilitates the development of new therapeutic agents due to structural and functional diversity among phytochemicals. The abundance and diversity is responsible for the characterization of new lead structures from medicinal plants. Industrial interest has increased due to recent research advancements viz. synergistic and high-throughput screening approach for the evaluation of vast variety of phytochemicals. The review certainly emphasizes on the traditional medicines as alternatives to conventional chemotherapeutic drugs. The review briefly describes mode of action of various antibiotics and resistance mechanisms. This review focuses on the chemical diversity and various mechanisms of action of phytochemicals against bacterial pathogens. PMID:26873345

  17. A Preclinical Evaluation of Antimycin A as a Potential Antilung Cancer Stem Cell Agent

    Directory of Open Access Journals (Sweden)

    Chi-Tai Yeh

    2013-01-01

    Full Text Available Drug resistance and tumor recurrence are major obstacles in treating lung cancer patients. Accumulating evidence considers lung cancer stem cells (CSCs as the major contributor to these clinical challenges. Agents that can target lung CSCs could potentially provide a more effective treatment than traditional chemotherapy. Here, we utilized the side-population (SP method to isolate lung CSCs from A549 and PC-9 cell lines. Subsequently, a high throughput platform, connectivity maps (CMAPs, was used to identify potential anti-CSC agents. An antibiotic, antimycin A (AMA, was identified as a top candidate. SP A549 cells exhibited an elevated stemness profile, including Nanog, β-catenin, Sox2, and CD133, and increased self-renewal ability. AMA treatment was found to suppress β-catenin signaling components and tumor sphere formation. Furthermore, AMA treatment decreased the proliferation of gefitinib-resistant PC-9/GR cells and percentage of SP population. AMA demonstrated synergistic suppression of PC-9/GR cell viability when combined with gefitinib. Finally, AMA treatment suppressed tumorigenesis in mice inoculated with A549 SP cells. Collectively, we have identified AMA using CMAP as a novel antilung CSC agent, which acts to downregulate β-catenin signaling. The combination of AMA and targeted therapeutic agents could be considered for overcoming drug resistance and relapse in lung cancer patients.

  18. Rational Choice of Antiemetic Agents during Cancer Chemotherapy

    Science.gov (United States)

    Brigden, Malcolm L.; Wilson, Kenneth S.; Barnett, Jeffrey B.

    1983-01-01

    Nausea and vomiting are major limitations in cancer chemotherapy. Individual susceptibility to nausea varies enormously. There is no ideal antiemetic, but some work with some chemotherapeutic agents, and some are more effective in younger patients. This article describes a flexible, stepped approach using the phenothiazines, metoclopramide, cannabinoids, anticholinergics, antihistamines and others. PMID:21283402

  19. Environmental carcinogenic agents and cancer prevention. Risk assessment and management

    International Nuclear Information System (INIS)

    Many agents in our environment have been established as being carcinogenic, and in most cases, the carcinogenic properties of these agents were identified because of high-dose occupational or accidental exposure. Risk characterization, taking into account the dose-response relationship, and exposure assessment are essential for risk assessment and subsequent cancer prevention. Based on scientific risk assessment, risk management should be conducted practically by considering the economic, social, political, and other technical issues and by balancing the risks and benefits. Asbestos and environmental tobacco smoke are typical examples of established carcinogenic agents in the general environment, contributing to low-dose exposure. Further epidemiological studies are required to investigate the carcinogenicity of low-dose exposure to known carcinogenic agents such as arsenic and cadmium through dietary intake, radiation via medical and natural exposure, and air pollution due to diesel exhaust. In contrast, occupational chemical exposure to 1,2-dichloropropane and/or dichloromethane, whose carcinogenicity had not been established, was suggested to cause cholangiocarcinoma among workers involved in offset color proof-printing only after a rare situation of high-dose exposure was unveiled. Continuous monitoring of unusual cancer occurrences in target populations such as workers in occupational and regional settings as well as exposure reduction to suspected carcinogenic agents to levels as low as reasonably achievable is essential for reducing the risk of cancer due to environmental carcinogens. (author)

  20. Cooperative nanomaterials systems for cancer diagnosis and therapeutics

    Science.gov (United States)

    Park, Ji Ho

    The unique electromagnetic and biologic properties of nanomaterials are being harnessed to build powerful new medical technologies. Particularly, there have been recently increasing interests in cancer nanotechnology, wherein nanomaterials play an important role in ultrasensitive imaging, targeting, and therapy of cancer. However, these nanomaterials typically function as individual units and are designed to independently perform their tasks. In this dissertation, new cooperative nanosystems consisting of two distinct nanomaterials that work together to target, identify, or treat tumors in vivo were studied. In the first two chapters, the synthesis of worm-shaped dextran-coated iron oxide nanoparticles (nanoworms, NW) exhibiting substantial in vivo circulation times and significant tumor targeting when coated with tumor-homing peptides were studied. NWs are also found to display a greater magnetic resonance (MR) response than the spherical nanoparticles. Next, two types of multifunctional nanoparticles were fabricated for simultaneous detection and treatment of cancer. Micellar hybrid nanoparticles (MHN) that contain magnetic nanoparticles, quantum dots, and an anti-cancer drug doxorubicin (DOX) within a single PEG-modified phospholipid micelle were first prepared. Simultaneous multimodal imaging (MR and fluorescence) and targeted drug delivery in vitro and in vivo was performed using DOX-incorporated targeted MHN. Secondly, luminescent porous silicon nanoparticles (LPSINP) that were drug-loadable, biodegradable and relatively non-toxic were prepared. In contrast to most inorganic nanomaterials, LPSINP were degraded in vivo in a relatively short time with no noticeable toxicity. The clearance and degradation of intravenously injected LPSINP in the bladder, liver, and spleen were established by whole-body fluorescence imaging. Finally, two types of cooperative nanomaterials systems to amplify targeting and deliver drugs efficiently to regions of tumor invasion were

  1. Production and evaluation of Lutetium-177 maltolate as a possible therapeutic agent

    International Nuclear Information System (INIS)

    Development of oral therapeutic radiopharmaceuticals is a new concept in radiopharmacy. Due to the interesting therapeutic properties of 177Lu and oral bioavailability of maltolate (MAL) metal complexes, 177Lu-maltolate (177Lu-MAL) was developed as a possible therapeutic compound for ultimate oral administration. The specific activity of 2.6-3 GBq/mg was obtained by irradiation of natural Lu2O3 sample with thermal neutron flux of 4x1013 n.cm-2.s-1 for Lu-177. The product was converted into chloride form which was further used for labeling maltol (MAL). At optimized conditions a radiochemical purity of about >99% was obtained for 177Lu-MAL shown by ITLC (specific activity, 970-1000 Mbq/mmole). The stability of the labeled compound as well as the partition coefficient was determined in the final solution up to 24h. Biodistribution studies of Lu-177 chloride and 177Lu-MAL were carried out in wild-type rats for post-oral distribution phase data. Lu-MAL is a possible therapeutic agent in human malignancies for the bone palliation therapy so the efficacy of the compound should be tested in various animal models.

  2. Real-time, aptamer-based tracking of circulating therapeutic agents in living animals.

    Science.gov (United States)

    Ferguson, Brian Scott; Hoggarth, David A; Maliniak, Dan; Ploense, Kyle; White, Ryan J; Woodward, Nick; Hsieh, Kuangwen; Bonham, Andrew J; Eisenstein, Michael; Kippin, Tod E; Plaxco, Kevin W; Soh, Hyongsok Tom

    2013-11-27

    A sensor capable of continuously measuring specific molecules in the bloodstream in vivo would give clinicians a valuable window into patients' health and their response to therapeutics. Such technology would enable truly personalized medicine, wherein therapeutic agents could be tailored with optimal doses for each patient to maximize efficacy and minimize side effects. Unfortunately, continuous, real-time measurement is currently only possible for a handful of targets, such as glucose, lactose, and oxygen, and the few existing platforms for continuous measurement are not generalizable for the monitoring of other analytes, such as small-molecule therapeutics. In response, we have developed a real-time biosensor capable of continuously tracking a wide range of circulating drugs in living subjects. Our microfluidic electrochemical detector for in vivo continuous monitoring (MEDIC) requires no exogenous reagents, operates at room temperature, and can be reconfigured to measure different target molecules by exchanging probes in a modular manner. To demonstrate the system's versatility, we measured therapeutic in vivo concentrations of doxorubicin (a chemotherapeutic) and kanamycin (an antibiotic) in live rats and in human whole blood for several hours with high sensitivity and specificity at subminute temporal resolution. We show that MEDIC can also obtain pharmacokinetic parameters for individual animals in real time. Accordingly, just as continuous glucose monitoring technology is currently revolutionizing diabetes care, we believe that MEDIC could be a powerful enabler for personalized medicine by ensuring delivery of optimal drug doses for individual patients based on direct detection of physiological parameters. PMID:24285484

  3. Synthesis of Multifunctional Nanoparticles for Cancer Diagnostics and Therapeutics

    Science.gov (United States)

    Fang, Chen

    2011-12-01

    Magnetic nanoparticles (MNPs) have attracted enormous research attention due to their unique magnetic properties that enable the detection by the non-invasive medical imaging modality---magnetic resonance imaging (MRI). By incorporating advanced features, such as specific targeting, multimodality, therapeutic delivery, the detectability and applicability of MNPs have been dramatically expanded. Smart and rational design on structure, composition and surface chemistry is essential to achieving desired properties in MNP systems, such as high sensitivity and colloidal stability, target specificity and/or multimodality. The goal of this research is to develop MNP-based platforms for the detection, diagnosis and treatment of cancer. MNPs with high contrast enhancement were coated with poly(ethylene glycol) (PEG)-based polymers to render aqueous stability and confer therapeutic-loading capability. Tumor-specific MNPs were developed by functionalization of nanoparticles with chlorotoxin (CTX) or arginine-glycine-aspartic acid (RGD) that targets, respectively, MMP-2 receptor or alphavbeta3 integrin overexpressed on a variety of cancer cells. The effects of ligands' molecular targets on the temporal and spatial distribution of MNPs within tumors were also investigated both in vitro and in vivo. All MNPs exhibited excellent long-term stability in cell culture media. CTX-labeled MNP exhibited sustained accumulation, penetration and distribution in the tumor mass. These findings revealed the influence of the targeting ligands on the intratumoral distribution of the ligand-enabled nanoprobes. To demonstrate the ability of nanoparticles as drug carrier, anthracyline chemotherapeutic drugs doxorubicin and mitoxantrone were attached to iron oxide nanoparticles. The theragnostic nanoparticles showed sufficient contrast enhancement and comparable anti-neoplastic efficacy in vitro. With flexible surface chemistry, our nanoparticle platform can be used in a modular fashion to

  4. Phytocannabinoids for Cancer Therapeutics: Recent Updates and Future Prospects.

    Science.gov (United States)

    Patil, K R; Goyal, S N; Sharma, C; Patil, C R; Ojha, S

    2015-01-01

    Phytocannabinoids (pCBs) are lipid-soluble phytochemicals present in the plant, Cannabis sativa L. and non-cannabis plants which have a long history in recreation and traditional medicine. The plant and the constituents isolated were central in the discovery of the endocannabinoid system (ECS), the most new target for drug discovery. The ECS includes two G-protein-coupled receptors; the cannabinoid receptors-1 and -2 (CB1 and CB2) for marijuana's psychoactive principle Δ(9)-tetrahydrocannabinol (Δ(9)-THC), their endogenous small lipid ligands; namely anandamide (AEA) and 2-arachidonoylglycerol (2-AG), also known as endocannabinoids and the enzymes for endocannabinoid biosynthesis and degradation such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). The ECS has been suggested as a pro-homeostatic and pleiotropic signaling system activated in a time- and tissue-specific way during pathological conditions including cancer. Targeting the CB1 receptors becomes a concern because of adverse psychotropic reactions. Hence, targeting the CB2 receptors or the endocannabinoid metabolizing enzymes by pCBs obtained from plants lacking psychotropic adverse reactions has garnered interest in drug discovery. These pCBs derived from plants appear safe and effective with a wider access and availability. In the recent years, several pCBs derived other than non-cannabinoid plants have been reported to bind to and functionally interact with cannabinoid receptors and appear promising candidate for drug development including cancer therapeutics. Several of them also targets the endocannabinoid metabolizing enzymes that control endocannabinoid levels. In this article, we summarize and critically discuss the updates and future prospects of the pCBs as novel and promising candidates for cancer therapeutics. PMID:26179998

  5. Anti-angiogenic agents in metastatic colorectal cancer

    Institute of Scientific and Technical Information of China (English)

    2015-01-01

    Colorectal cancer (CRC) is a major public health concernbeing the third leading cause of cancer mortality inthe United States. The availability of better therapeuticoptions has led to a decline in cancer mortality in thesepatients. Surgical resection should be considered in allstages of the disease. The use of conversion therapyhas made surgery a potentially curative option even inpatients with initially unresectable metastatic disease.In this review we discuss the role of various antiangiogenicagents in patients with metastatic CRC(mCRC). We describe the mechanism of action of theseagents, and the rationale for their use in combinationwith chemotherapy. We also review important clinicalstudies that have evaluated the safety and efficacy ofthese agents in mCRC patients. Despite the discoveryof several promising anti-angiogenic agents, mCRCremains an incurable disease with a median overallsurvival of just over 2 years in patients exposed to allavailable treatment regimens. Further insights intotumor biology and tumor microenvironment may helpimprove outcomes in these patients.

  6. Beer constituents as potential cancer chemopreventive agents.

    Science.gov (United States)

    Gerhäuser, Clarissa

    2005-09-01

    Beer is a complex alcoholic beverage made from barley (malt), hop, water and yeast. Phenolic constituents of beer are derived from malt (70-80%) and hop (20-30%). Structural classes include simple phenols, benzoic- and cinnamic acid derivatives, coumarins, catechins, di-, tri- and oligomeric proanthocyanidins, (prenylated) chalcones and flavonoids as well as alpha- and iso-alpha-acids derived from hop. Compounds belonging to different structural classes have distinct profiles of biological activity in in vitro test systems, and in combination might lead to enhanced effects. Scientific evidence has accumulated over the past 10 years pointing to the cancer preventive potential of selected hop-derived beer constituents, i.e., prenylflavonoids including xanthohumol and isoxanthohumol, and hop bitter acids. Chemopreventive activities observed with these compounds relevant to inhibition of carcinogenesis at the initiation, promotion and progression phases, as well as results from in vivo studies on metabolism, bioavailability and efficacy are summarised in this review. PMID:15953717

  7. Liposome Formulation of Fullerene-Based Molecular Diagnostic and Therapeutic Agents

    Directory of Open Access Journals (Sweden)

    Zhiguo Zhou

    2013-10-01

    Full Text Available Fullerene medicine is a new but rapidly growing research subject. Fullerene has a number of desired structural, physical and chemical properties to be adapted for biological use including antioxidants, anti-aging, anti-inflammation, photodynamic therapy, drug delivery, and magnetic resonance imaging contrast agents. Chemical functionalization of fullerenes has led to several interesting compounds with very promising preclinical efficacy, pharmacokinetic and safety data. However, there is no clinical evaluation or human use except in fullerene-based cosmetic products for human skincare. This article summarizes recent advances in liposome formulation of fullerenes for the use in therapeutics and molecular imaging.

  8. Design of a 2D MRI compatible robot for performing prostate cancer treatment using therapeutic ultrasound

    OpenAIRE

    Yiallouras, Christos

    2015-01-01

    Therapeutic ultrasound is a promising treatment method for many common cancers, including prostate cancer. Magnetic resonance image (MRI) guidance of therapeutic ultrasound permits targeting and monitoring of therapy. In this thesis a prototype MRI compatible positioning device for the treatment of prostate cancer using therapeutic ultrasound is presented. The accuracy, MRI compatibility and functionality of the positioning device was evaluated in in vitro experiments (using gel phantoms and ...

  9. Recent Advancement of Chitosan-Based Nanoparticles for Oral Controlled Delivery of Insulin and Other Therapeutic Agents

    OpenAIRE

    Chaudhury, Anumita; Das, Surajit

    2010-01-01

    Nanoparticles composed of naturally occurring biodegradable polymers have emerged as potential carriers of various therapeutic agents for controlled drug delivery through the oral route. Chitosan, a cationic polysaccharide, is one of such biodegradable polymers, which has been extensively exploited for the preparation of nanoparticles for oral controlled delivery of several therapeutic agents. In recent years, the area of focus has shifted from chitosan to chitosan derivatized polymers for th...

  10. RPS2: a novel therapeutic target in prostate cancer

    Directory of Open Access Journals (Sweden)

    Stearns Mark E

    2009-01-01

    Full Text Available Abstract Background A number of studies have previously shown that the over expression of different ribosomal proteins might play an important role in cancer (i.e. S3a, L10, L16. We have previously reported that RPS2, a 33 Kda ribosomal protein was over expressed in malignant prostate cancer cell lines and in archived tumor specimens. Thus, RPS2 or other aberrantly over-expressed ribosomal proteins might promote cancer and be excellent therapeutic targets for treatment of the disease. Methods Western blotting and RT-PCR have been used to measure and compare the levels of expression of RPS2 in a variety of malignant prostate cancer cell lines, plus normal and benign cells lines. We have developed a 'ribozyme-like' DNAZYM-1P '10–23' motif oligonucleotide and examined whether it targets RPS2 in different cell lines by RT-PCR and Western blots. Growth and apoptosis assays were carried out to measure whether DNAZYM-1P 'knock-down' of RPS2 influenced cell proliferation or survival. We have also developed a SCID mouse tumor model with PC-3ML cells to determine whether DNAZYM-1P targeting of RPS2 compromised tumor growth and mouse survival rates in vivo. Results Western blots showed that PC-3ML, LNCaP, CPTX-1532, and pBABE-cmyc stably transfected IBC-10a cells all over-expressed RPS2, whereas IBC-10a parent, NPTX-1532, and BPH-1 cells or mouse NIH-3T3 cells expressed barely detectable levels of RPS2. RT-PCR assays showed that DNAZYM-1P, which targeted RPS2, 'knocked-down' RPS2 expression in the malignant cells (i.e. PC-3ML cells in vitro. The DNAZYM-1P also inhibited cell growth and induced apoptosis in the malignant prostate cells, but had little effect on the normal IBC-10a or NPTX-1532 cell lines. Finally, SCID mouse tumor modeling studies showed that DNAZYM-1P blocked tumor growth and metastasis by PC-3ML cells and eventually eradicated tumors following localized or systemic i.v. delivery. Mouse survival studies revealed that there was a dosage

  11. Silibinin, dexamethasone, and doxycycline as potential therapeutic agents for treating vesicant-inflicted ocular injuries

    International Nuclear Information System (INIS)

    There are no effective and approved therapies against devastating ocular injuries caused by vesicating chemical agents sulfur mustard (SM) and nitrogen mustard (NM). Herein, studies were carried out in rabbit corneal cultures to establish relevant ocular injury biomarkers with NM for screening potential efficacious agents in laboratory settings. NM (100 nmol) exposure of the corneas for 2 h (cultured for 24 h), showed increases in epithelial thickness, ulceration, apoptotic cell death, epithelial detachment microbullae formation, and the levels of VEGF, cyclooxygenase-2 (COX-2) and matrix metalloproteinase-9 (MMP-9). Employing these biomarkers, efficacy studies were performed with agent treatments 2 h and every 4 h thereafter, for 24 h following NM exposure. Three agents were evaluated, including prescription drugs dexamethasone (0.1%; anti-inflammatory steroid) and doxycycline (100 nmol; antibiotic and MMP inhibitor) that have been studied earlier for treating vesicant-induced eye injuries. We also examined silibinin (100 μg), a non-toxic natural flavanone found to be effective in treating SM analog-induced skin injuries in our earlier studies. Treatments of doxycycline + dexamethasone, and silibinin were more effective than doxycycline or dexamethasone alone in reversing NM-induced epithelial thickening, microbullae formation, apoptotic cell death, and MMP-9 elevation. However, dexamethasone and silibinin alone were more effective in reversing NM-induced VEGF levels. Doxycycline, dexamethasone and silibinin were all effective in reversing NM-induced COX-2 levels. Apart from therapeutic efficacy of doxycycline and dexamethasone, these results show strong multifunctional efficacy of silibinin in reversing NM-induced ocular injuries, which could help develop effective and safe therapeutics against ocular injuries by vesicants. -- Highlights: ► Established injury biomarkers in rabbit corneal culture with nitrogen mustard (NM) ► This NM model is a cost effective

  12. Silibinin, dexamethasone, and doxycycline as potential therapeutic agents for treating vesicant-inflicted ocular injuries

    Energy Technology Data Exchange (ETDEWEB)

    Tewari-Singh, Neera, E-mail: Neera.Tewari-Singh@ucdenver.edu [Department of Pharmaceutical Sciences, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO 80045 (United States); Jain, Anil K., E-mail: Anil.Jain@ucdenver.edu [Department of Pharmaceutical Sciences, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO 80045 (United States); Inturi, Swetha, E-mail: Swetha.Inturi@ucdenver.edu [Department of Pharmaceutical Sciences, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO 80045 (United States); Ammar, David A., E-mail: David.Ammar@ucdenver.edu [Department of Ophthalmology, University of Colorado School of Medicine, Aurora, CO 80045 (United States); Agarwal, Chapla, E-mail: Chapla.Agarwal@ucdenver.edu [Department of Pharmaceutical Sciences, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO 80045 (United States); Tyagi, Puneet, E-mail: Puneet.Tyagi@ucdenver.edu [Department of Pharmaceutical Sciences, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO 80045 (United States); Kompella, Uday B., E-mail: Uday.Kompella@ucdenver.edu [Department of Pharmaceutical Sciences, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO 80045 (United States); Enzenauer, Robert W., E-mail: Robert.Enzenauer@ucdenver.edu [Department of Ophthalmology, University of Colorado School of Medicine, Aurora, CO 80045 (United States); Petrash, J. Mark, E-mail: Mark.Petrash@ucdenver.edu [Department of Ophthalmology, University of Colorado School of Medicine, Aurora, CO 80045 (United States); Agarwal, Rajesh, E-mail: Rajesh.Agarwal@ucdenver.edu [Department of Pharmaceutical Sciences, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO 80045 (United States)

    2012-10-01

    There are no effective and approved therapies against devastating ocular injuries caused by vesicating chemical agents sulfur mustard (SM) and nitrogen mustard (NM). Herein, studies were carried out in rabbit corneal cultures to establish relevant ocular injury biomarkers with NM for screening potential efficacious agents in laboratory settings. NM (100 nmol) exposure of the corneas for 2 h (cultured for 24 h), showed increases in epithelial thickness, ulceration, apoptotic cell death, epithelial detachment microbullae formation, and the levels of VEGF, cyclooxygenase-2 (COX-2) and matrix metalloproteinase-9 (MMP-9). Employing these biomarkers, efficacy studies were performed with agent treatments 2 h and every 4 h thereafter, for 24 h following NM exposure. Three agents were evaluated, including prescription drugs dexamethasone (0.1%; anti-inflammatory steroid) and doxycycline (100 nmol; antibiotic and MMP inhibitor) that have been studied earlier for treating vesicant-induced eye injuries. We also examined silibinin (100 μg), a non-toxic natural flavanone found to be effective in treating SM analog-induced skin injuries in our earlier studies. Treatments of doxycycline + dexamethasone, and silibinin were more effective than doxycycline or dexamethasone alone in reversing NM-induced epithelial thickening, microbullae formation, apoptotic cell death, and MMP-9 elevation. However, dexamethasone and silibinin alone were more effective in reversing NM-induced VEGF levels. Doxycycline, dexamethasone and silibinin were all effective in reversing NM-induced COX-2 levels. Apart from therapeutic efficacy of doxycycline and dexamethasone, these results show strong multifunctional efficacy of silibinin in reversing NM-induced ocular injuries, which could help develop effective and safe therapeutics against ocular injuries by vesicants. -- Highlights: ► Established injury biomarkers in rabbit corneal culture with nitrogen mustard (NM) ► This NM model is a cost effective

  13. An injectable nanoparticle generator enhances delivery of cancer therapeutics.

    Science.gov (United States)

    Xu, Rong; Zhang, Guodong; Mai, Junhua; Deng, Xiaoyong; Segura-Ibarra, Victor; Wu, Suhong; Shen, Jianliang; Liu, Haoran; Hu, Zhenhua; Chen, Lingxiao; Huang, Yi; Koay, Eugene; Huang, Yu; Liu, Jun; Ensor, Joe E; Blanco, Elvin; Liu, Xuewu; Ferrari, Mauro; Shen, Haifa

    2016-04-01

    The efficacy of cancer drugs is often limited because only a small fraction of the administered dose accumulates in tumors. Here we report an injectable nanoparticle generator (iNPG) that overcomes multiple biological barriers to cancer drug delivery. The iNPG is a discoidal micrometer-sized particle that can be loaded with chemotherapeutics. We conjugate doxorubicin to poly(L-glutamic acid) by means of a pH-sensitive cleavable linker, and load the polymeric drug (pDox) into iNPG to assemble iNPG-pDox. Once released from iNPG, pDox spontaneously forms nanometer-sized particles in aqueous solution. Intravenously injected iNPG-pDox accumulates at tumors due to natural tropism and enhanced vascular dynamics and releases pDox nanoparticles that are internalized by tumor cells. Intracellularly, pDox nanoparticles are transported to the perinuclear region and cleaved into Dox, thereby avoiding excretion by drug efflux pumps. Compared to its individual components or current therapeutic formulations, iNPG-pDox shows enhanced efficacy in MDA-MB-231 and 4T1 mouse models of metastatic breast cancer, including functional cures in 40-50% of treated mice. PMID:26974511

  14. Epigenetics modifications and therapeutic prospects in human thyroid cancer

    Directory of Open Access Journals (Sweden)

    Maria Graziella eCatalano

    2012-03-01

    Full Text Available At present no successful treatment is available for advanced thyroid cancer, which comprises poorly differentiated, anaplastic, and metastatic or recurrent differentiated thyroid cancer not responding to radioiodine. In the last few years, biologically targeted therapies for advanced thyroid carcinomas have been proposed on the basis of the recognition of key oncogenic mutations. Although the results of several phase II trials look promising, none of the patients treated had a complete response, and only a minority of them had a partial response, suggesting that the treatment is, at best, effective in stabilizing patients with progressive disease. Epigenetic refers to the study of heritable changes in gene expression that occur without any alteration in the primary DNA sequence. The epigenetic processes establish and maintain the global and local chroma¬tin states that determine gene expression. Epigenetic abnormalities are present in almost all cancers and, together with genetic changes, drive tumour progression. Various genes involved in the control of cell proliferation and invasion (p16INK4A, RASSF1A,PTEN, Rap1GAP, TIMP3, DAPK, RARβ2, E-cadherin, and CITED1 as well as genes specific of thyroid differentiation (Na+/I- symport, TSH receptor, pendrin, SL5A8, and TTF-1 present aberrant methylation in thyroid cancer.This review deals with the most frequent epigenetic alterations in thyroid cancer and focuses on epigenetic therapy, whose goal is to target the chromatin in rapidly dividing tumour cells and potentially restore normal cell functions. Experimental data and clinical trials, especially using deacetylase inhibitors and demethylating agents, are discussed.

  15. Phytochemical Modulators of Mitochondria: The Search for Chemopreventive Agents and Supportive Therapeutics

    Directory of Open Access Journals (Sweden)

    Maja M. Grabacka

    2014-09-01

    Full Text Available Mitochondria are crucially important for maintaining not only the energy homeostasis, but the proper cellular functions in a general sense. Impairment of mitochondrial functions is observed in a broad variety of pathological states such as neoplastic transformations and cancer, neurodegenerative diseases, metabolic disorders and chronic inflammation. Currently, in parallel to the classical drug design approaches, there is an increasing interest in the screening for natural bioactive substances, mainly phytochemicals, in order to develop new therapeutic solutions for the mentioned pathologies. Dietary phytochemicals such as resveratrol, curcumin and sulforaphane are very well tolerated and can effectively complement classical pharmacological therapeutic regimens. In this paper we disscuss the effect of the chosen phytochemicals (e.g., resveratrol, curcumin, sulforaphane on various aspects of mitochondrial biology, namely mitochondrial biogenesis, membrane potential and reactive oxygen species production, signaling to and from the nucleus and unfolded protein response.

  16. Colon Cancer Biomarkers To Identify Patients Suitable For Therapeutic Intervention | NCI Technology Transfer Center | TTC

    Science.gov (United States)

    The National Cancer Institute's Laboratory of Human Carcinogenesis is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize cancer biomarkers and therapeutic targets.

  17. Modeling of Cancer Stem Cell State Transitions Predicts Therapeutic Response.

    Directory of Open Access Journals (Sweden)

    Mary E Sehl

    Full Text Available Cancer stem cells (CSCs possess capacity to both self-renew and generate all cells within a tumor, and are thought to drive tumor recurrence. Targeting the stem cell niche to eradicate CSCs represents an important area of therapeutic development. The complex nature of many interacting elements of the stem cell niche, including both intracellular signals and microenvironmental growth factors and cytokines, creates a challenge in choosing which elements to target, alone or in combination. Stochastic stimulation techniques allow for the careful study of complex systems in biology and medicine and are ideal for the investigation of strategies aimed at CSC eradication. We present a mathematical model of the breast cancer stem cell (BCSC niche to predict population dynamics during carcinogenesis and in response to treatment. Using data from cell line and mouse xenograft experiments, we estimate rates of interconversion between mesenchymal and epithelial states in BCSCs and find that EMT/MET transitions occur frequently. We examine bulk tumor growth dynamics in response to alterations in the rate of symmetric self-renewal of BCSCs and find that small changes in BCSC behavior can give rise to the Gompertzian growth pattern observed in breast tumors. Finally, we examine stochastic reaction kinetic simulations in which elements of the breast cancer stem cell niche are inhibited individually and in combination. We find that slowing self-renewal and disrupting the positive feedback loop between IL-6, Stat3 activation, and NF-κB signaling by simultaneous inhibition of IL-6 and HER2 is the most effective combination to eliminate both mesenchymal and epithelial populations of BCSCs. Predictions from our model and simulations show excellent agreement with experimental data showing the efficacy of combined HER2 and Il-6 blockade in reducing BCSC populations. Our findings will be directly examined in a planned clinical trial of combined HER2 and IL-6 targeted

  18. Molecular targeted agents for gastric and gastroesophageal junction cancer.

    Science.gov (United States)

    Oshima, Takashi; Masuda, Munetaka

    2012-04-01

    Despite recent improvements in surgical techniques and chemotherapy, advanced cancers of the stomach and gastroesophageal junction (GEJ) continue to have poor clinical outcomes. However, molecules intimately related to cancer cell proliferation, invasion, and metastasis have been studied as candidates for molecular targeted agents. Target molecules, such as the epidermal growth factor receptor, vascular endothelial growth factor receptor, and P13k/Akt/mTor pathway, as well as the insulin-like growth factor receptor, c-Met pathways, fibroblast growth factor receptor, and other pathways are considered to be promising candidates for molecular targeted therapy for gastric and GEJ cancer. In this review we focus on the recent developments in targeting relevant pathways in these types of cancer.

  19. From Molecular Classification to Targeted Therapeutics: The Changing Face of Systemic Therapy in Metastatic Gastroesophageal Cancer

    Directory of Open Access Journals (Sweden)

    Adrian Murphy

    2015-01-01

    Full Text Available Histological classification of adenocarcinoma or squamous cell carcinoma for esophageal cancer or using the Lauren classification for intestinal and diffuse type gastric cancer has limited clinical utility in the management of advanced disease. Germline mutations in E-cadherin (CDH1 or mismatch repair genes (Lynch syndrome were identified many years ago but given their rarity, the identification of these molecular alterations does not substantially impact treatment in the advanced setting. Recent molecular profiling studies of upper GI tumors have added to our knowledge of the underlying biology but have not led to an alternative classification system which can guide clinician’s therapeutic decisions. Recently the Cancer Genome Atlas Research Network has proposed four subtypes of gastric cancer dividing tumors into those positive for Epstein-Barr virus, microsatellite unstable tumors, genomically stable tumors, and tumors with chromosomal instability. Unfortunately to date, many phase III clinical trials involving molecularly targeted agents have failed to meet their survival endpoints due to their use in unselected populations. Future clinical trials should utilize molecular profiling of individual tumors in order to determine the optimal use of targeted therapies in preselected patients.

  20. From molecular classification to targeted therapeutics: the changing face of systemic therapy in metastatic gastroesophageal cancer.

    Science.gov (United States)

    Murphy, Adrian; Kelly, Ronan J

    2015-01-01

    Histological classification of adenocarcinoma or squamous cell carcinoma for esophageal cancer or using the Lauren classification for intestinal and diffuse type gastric cancer has limited clinical utility in the management of advanced disease. Germline mutations in E-cadherin (CDH1) or mismatch repair genes (Lynch syndrome) were identified many years ago but given their rarity, the identification of these molecular alterations does not substantially impact treatment in the advanced setting. Recent molecular profiling studies of upper GI tumors have added to our knowledge of the underlying biology but have not led to an alternative classification system which can guide clinician's therapeutic decisions. Recently the Cancer Genome Atlas Research Network has proposed four subtypes of gastric cancer dividing tumors into those positive for Epstein-Barr virus, microsatellite unstable tumors, genomically stable tumors, and tumors with chromosomal instability. Unfortunately to date, many phase III clinical trials involving molecularly targeted agents have failed to meet their survival endpoints due to their use in unselected populations. Future clinical trials should utilize molecular profiling of individual tumors in order to determine the optimal use of targeted therapies in preselected patients.

  1. Dendritic cell-based vaccination in cancer: therapeutic implications emerging from murine models

    Directory of Open Access Journals (Sweden)

    Soledad eMac Keon

    2015-05-01

    Full Text Available Dendritic cells (DCs play a pivotal role in the orchestration of immune responses, and are thus key targets in cancer vaccine design. Since the 2010 FDA approval of the first cancer DC-based vaccine (Sipuleucel T there has been a surge of interest in exploiting these cells as a therapeutic option for the treatment of tumors of diverse origin. In spite of the encouraging results obtained in the clinic, many elements of DC-based vaccination strategies need to be optimized. In this context, the use of experimental cancer models can help direct efforts towards an effective vaccine design. This paper reviews recent findings in murine models regarding the antitumoral mechanisms of DC-based vaccination, covering issues related to antigen sources, the use of adjuvants and maturing agents, and the role of DC subsets and their interaction in the initiation of antitumoral immune responses. The summary of such diverse aspects will highlight advantages and drawbacks in the use of murine models, and contribute to the design of successful DC-based translational approaches for cancer treatment.

  2. Bioreductive prodrugs as cancer therapeutics: targeting tumor hypoxia.

    Science.gov (United States)

    Guise, Christopher P; Mowday, Alexandra M; Ashoorzadeh, Amir; Yuan, Ran; Lin, Wan-Hua; Wu, Dong-Hai; Smaill, Jeff B; Patterson, Adam V; Ding, Ke

    2014-02-01

    Hypoxia, a state of low oxygen, is a common feature of solid tumors and is associated with disease progression as well as resistance to radiotherapy and certain chemotherapeutic drugs. Hypoxic regions in tumors, therefore, represent attractive targets for cancer therapy. To date, five distinct classes of bioreactive prodrugs have been developed to target hypoxic cells in solid tumors. These hypoxia-activated prodrugs, including nitro compounds, N-oxides, quinones, and metal complexes, generally share a common mechanism of activation whereby they are reduced by intracellular oxidoreductases in an oxygen-sensitive manner to form cytotoxins. Several examples including PR-104, TH-302, and EO9 are currently undergoing phase II and phase III clinical evaluation. In this review, we discuss the nature of tumor hypoxia as a therapeutic target, focusing on the development of bioreductive prodrugs. We also describe the current knowledge of how each prodrug class is activated and detail the clinical progress of leading examples.

  3. Bioreductive prodrugs as cancer therapeutics:targeting tumor hypoxia

    Institute of Scientific and Technical Information of China (English)

    Christopher P. Guise; Alexandra M. Mowday; Amir Ashoorzadeh; Ran Yuan; Wan-Hua Lin; Dong-Hai Wu; Jeff B. Smaill; Adam V. Patterson; Ke Ding

    2014-01-01

    Hypoxia, a state of low oxygen, is a common feature of solid tumors and is associated with disease progression as well as resistance to radiotherapy and certain chemotherapeutic drugs. Hypoxic regions in tumors, therefore, represent attractive targets for cancer therapy. To date, five distinct classes of bioreactive prodrugs have been developed to target hypoxic cels in solid tumors. These hypoxia-activated prodrugs, including nitro compounds, N-oxides, quinones, and metal complexes, generally share a common mechanism of activation whereby they are reduced by intracelular oxidoreductases in an oxygen-sensitive manner to form cytotoxins. Several examples including PR-104, TH-302, and EO9 are currently undergoing phase II and phase III clinical evaluation. In this review, we discuss the nature of tumor hypoxia as a therapeutic target, focusing on the development of bioreductive prodrugs. We also describe the current knowledge of how each prodrug class is activated and detail the clinical progress of leading examples.

  4. ErbB polymorphisms: insights and implications for response to targeted cancer therapeutics.

    Science.gov (United States)

    Alaoui-Jamali, Moulay A; Morand, Grégoire B; da Silva, Sabrina Daniela

    2015-01-01

    Advances in high-throughput genomic-scanning have expanded the repertory of genetic variations in DNA sequences encoding ErbB tyrosine kinase receptors in humans, including single nucleotide polymorphisms (SNPs), polymorphic repetitive elements, microsatellite variations, small-scale insertions and deletions. The ErbB family members: EGFR, ErbB2, ErbB3, and ErbB4 receptors are established as drivers of many aspects of tumor initiation and progression to metastasis. This knowledge has provided rationales for the development of an arsenal of anti-ErbB therapeutics, ranging from small molecule kinase inhibitors to monoclonal antibodies. Anti-ErbB agents are becoming the cornerstone therapeutics for the management of cancers that overexpress hyperactive variants of ErbB receptors, in particular ErbB2-positive breast cancer and non-small cell lung carcinomas. However, their clinical benefit has been limited to a subset of patients due to a wide heterogeneity in drug response despite the expression of the ErbB targets, attributed to intrinsic (primary) and to acquired (secondary) resistance. Somatic mutations in ErbB tyrosine kinase domains have been extensively investigated in preclinical and clinical setting as determinants for either high sensitivity or resistance to anti-ErbB therapeutics. In contrast, only scant information is available on the impact of SNPs, which are widespread in genes encoding ErbB receptors, on receptor structure and activity, and their predictive values for drug susceptibility. This review aims to briefly update polymorphic variations in genes encoding ErbB receptors based on recent advances in deep sequencing technologies, and to address challenging issues for a better understanding of the functional impact of single versus combined SNPs in ErbB genes to receptor topology, receptor-drug interaction, and drug susceptibility. The potential of exploiting SNPs in the era of stratified targeted therapeutics is discussed. PMID:25699077

  5. ErbB polymorphisms: Insights and implications for response to targeted cancer therapeutics

    Directory of Open Access Journals (Sweden)

    Moulay A Alaoui-Jamali

    2015-02-01

    Full Text Available Advances in high-throughput genomic-scanning have expanded the repertory of genetic variations in DNA sequences encoding ErbB tyrosine kinase receptors in humans, including single nucleotide polymorphisms (SNPs, polymorphic repetitive elements, microsatellite variations, small-scale insertions and deletions. The ErbB family members: EGFR, ErbB2, ErbB3 and ErbB4 receptors are established as drivers of many aspects of tumor initiation and progression to metastasis. This knowledge has provided rationales for the development of an arsenal of anti-ErbB therapeutics, ranging from small molecule kinase inhibitors to monoclonal antibodies. Anti-ErbB agents are becoming the cornerstone therapeutics for the management of cancers that overexpress hyperactive variants of ErbB receptors, in particular ErbB2-positive breast cancer and non-small cell lung carcinomas. However, their clinical benefit has been limited to a subset of patients due to a wide heterogeneity in drug response despite the expression of the ErbB targets, attributed to intrinsic (primary and to acquired (secondary resistance. Somatic mutations in ErbB tyrosine kinase domains have been extensively investigated in preclinical and clinical setting as determinants for either high sensitivity or resistance to anti-ErbB therapeutics. In contrast, only scant information is available on the impact of SNPs, which are widespread in genes encoding ErbB receptors, on receptor structure and activity, and their predictive values for drug susceptibility. This review aims to briefly update polymorphic variations in genes encoding ErbB receptors based on recent advances in deep sequencing technologies, and to address challenging issues for a better understanding of the functional impact of single versus combined SNPs in ErbB genes to receptor topology, receptor-drug interaction, and drug susceptibility. The potential of exploiting SNPs in the era of stratified targeted therapeutics is discussed.

  6. Complete genome sequence analysis of two Pseudomonas plecoglossicida phages, potential therapeutic agents.

    Science.gov (United States)

    Kawato, Yasuhiko; Yasuike, Motoshige; Nakamura, Yoji; Shigenobu, Yuya; Fujiwara, Atushi; Sano, Motohiko; Nakai, Toshihiro

    2015-02-01

    Pseudomonas plecoglossicida is a lethal pathogen of ayu (Plecoglossus altivelis) in Japan and is responsible for substantial economic costs to ayu culture. Previously, we demonstrated the efficacy of phage therapy against P. plecoglossicida infection using two lytic phages (PPpW-3 and PPpW-4) (S. C. Park, I. Shimamura, M. Fukunaga, K. Mori, and T. Nakai, Appl Environ Microbiol 66:1416-1422, 2000, http://dx.doi.org/10.1128/AEM.66.4.1416-1422.2000; S. C. Park and T. Nakai, Dis Aquat Org 53:33-39, 2003, http://dx.doi.org/10.3354/dao053033). In the present study, the complete genome sequences of these therapeutic P. plecoglossicida phages were determined and analyzed for deleterious factors as therapeutic agents. The genome of PPpW-3 (myovirus) consisted of 43,564 bp with a GC content of 61.1% and 66 predicted open reading frames (ORFs). Approximately half of the genes were similar to the genes of the Escherichia coli phage vB_EcoM_ECO1230-10 (myovirus). The genome of PPpW-4 (podovirus) consisted of 41,386 bp with a GC content of 56.8% and 50 predicted ORFs. More than 70% of the genes were similar to the genes of Pseudomonas fluorescens phage ϕIBB-PF7A and Pseudomonas putida phage ϕ15 (podoviruses). The whole-genome analysis revealed that no known virulence genes were present in PPpW-3 and PPpW-4. An integrase gene was found in PPpW-3, but other factors used for lysogeny were not confirmed. The PCR detection of phage genes in phage-resistant variants provided no evidence of lysogenic activity in PPpW-3 and PPpW-4. We conclude that these two lytic phages qualify as therapeutic agents.

  7. The effects of physical therapeutic agents on serum levels of stress hormones in patients with osteoarthritis

    Science.gov (United States)

    Tönük, Şükrü Burak; Serin, Erdinc; Ayhan, Fikriye Figen; Yorgancioglu, Zeynep Rezan

    2016-01-01

    Abstract To investigate the effects of physical agents on the levels of stress hormones in patients with osteoarthritis (OA). Transcutaneous electrical nerve stimulation, hot packs, and therapeutic ultrasound were applied to the lumbar region and knees of patients with OA. Blood samples were taken for the measurement of the serum levels of glucose, insulin (INS), growth hormone (GH), prolactin (PRL), cortisol (COR), and plasma adrenocorticotropic hormone (ACTH) immediately before and after the 1st session, to investigate the acute effects of those physical agents on the endocrine system. The hormone levels were also measured every 5 sessions in a total of 10 sessions. The treatment response was also evaluated by using the visual analogue scale (VAS), Roland Morris Disability Questionnaire (RMDQ), and Western Ontario and McMaster Universities Arthritis Index (WOMAC) throughout the therapy period. After the 1st session, there was a decrease in INS levels and a mild decrease in PRL levels (P = 0.001 and P hormone levels. The decrease in ACTH and COR levels may be attributed to the analgesic effect of agents and may be an indicator of patient comfort through a central action. PMID:27583888

  8. Novel agents in the management of lung cancer.

    LENUS (Irish Health Repository)

    Kennedy, B

    2012-01-31

    Lung cancer is the leading cause of cancer death worldwide. Survival remains poor as approximately 80% of cases present with advanced stage disease. However, new treatments are emerging which offer hope to patients with advanced disease. Insights into cell biology have identified numerous intracellular and extracellular peptides that are pivotal in cancer cell signalling. Disrupting the function of these peptides inhibits intracellular signal transduction and diminishes uncontrolled proliferation, resistance to apoptosis and tumour angiogenesis. The most widely studied signalling pathway is the Epidermal Growth Factor (EGF) pathway. EGF signalling can be disrupted at numerous points. Blockade of the cell surface receptor is achieved by the monoclonal antibody cetuximab; intracellular tyrosine kinase activity is inhibited by erlotinib. Vascular Endothelial Growth Factor (VEGF) regulates another pathway important for tumour growth. Inhibition of VEGF impairs angiogenesis and disrupts metastatic spread. Bevacizumab is a monoclonal antibody that binds to VEGF and blocks interaction with its cell surface receptor. Clinical trials have demonstrated that disruption of these signalling pathways can improve survival in advanced lung cancer. New compounds including folate antimetabolites such as pemetrexed, proteasome inhibitors such as bortezomib, modified glutathione analogues such as TLK286, and other agents such as epothilones and other small molecules are currently being evaluated in patients with lung cancer. As more and more signalling peptides are targeted for manipulation, it is hoped that a new era is dawning in the treatment of advanced stage lung cancer. This review will focus on emerging new therapies in the management of lung cancer.

  9. Cancer targeted therapeutics: From molecules to drug delivery vehicles.

    Science.gov (United States)

    Liu, Daxing; Auguste, Debra T

    2015-12-10

    The pitfall of all chemotherapeutics lies in drug resistance and the severe side effects experienced by patients. One way to reduce the off-target effects of chemotherapy on healthy tissues is to alter the biodistribution of drug. This can be achieved in two ways: Passive targeting utilizes shape, size, and surface chemistry to increase particle circulation and tumor accumulation. Active targeting employs either chemical moieties (e.g. peptides, sugars, aptamers, antibodies) to selectively bind to cell membranes or responsive elements (e.g. ultrasound, magnetism, light) to deliver its cargo within a local region. This article will focus on the systemic administration of anti-cancer agents and their ability to home to tumors and, if relevant, distant metastatic sites.

  10. Therapeutic applications of TRAIL receptor agonists in cancer and beyond.

    Science.gov (United States)

    Amarante-Mendes, Gustavo P; Griffith, Thomas S

    2015-11-01

    TRAIL/Apo-2L is a member of the TNF superfamily first described as an apoptosis-inducing cytokine in 1995. Similar to TNF and Fas ligand, TRAIL induces apoptosis in caspase-dependent manner following TRAIL death receptor trimerization. Because tumor cells were shown to be particularly sensitive to this cytokine while normal cells/tissues proved to be resistant along with being able to synthesize and release TRAIL, it was rapidly appreciated that TRAIL likely served as one of our major physiologic weapons against cancer. In line with this, a number of research laboratories and pharmaceutical companies have attempted to exploit the ability of TRAIL to kill cancer cells by developing recombinant forms of TRAIL or TRAIL receptor agonists (e.g., receptor-specific mAb) for therapeutic purposes. In this review article we will describe the biochemical pathways used by TRAIL to induce different cell death programs. We will also summarize the clinical trials related to this pathway and discuss possible novel uses of TRAIL-related therapies. In recent years, the physiological importance of TRAIL has expanded beyond being a tumoricidal molecule to one critical for a number of clinical settings - ranging from infectious disease and autoimmunity to cardiovascular anomalies. We will also highlight some of these conditions where modulation of the TRAIL/TRAIL receptor system may be targeted in the future. PMID:26343199

  11. Capsaicin: From Plants to a Cancer-Suppressing Agent.

    Science.gov (United States)

    Chapa-Oliver, Angela M; Mejía-Teniente, Laura

    2016-01-01

    Capsaicinoids are plant secondary metabolites, capsaicin being the principal responsible for the pungency of chili peppers. It is biosynthesized through two pathways involved in phenylpropanoid and fatty acid metabolism. Plant capsaicin concentration is mainly affected by genetic, environmental and crop management factors. However, its synthesis can be enhanced by the use of elicitors. Capsaicin is employed as food additive and in pharmaceutical applications. Additionally, it has been found that capsaicin can act as a cancer preventive agent and shows wide applications against various types of cancer. This review is an approach in contextualizing the use of controlled stress on the plant to increase the content of capsaicin, highlighting its synthesis and its potential use as anticancer agent. PMID:27472308

  12. Therapeutic vaccines in non-small cell lung cancer

    Directory of Open Access Journals (Sweden)

    Socola F

    2013-09-01

    Full Text Available Francisco Socola,1 Naomi Scherfenberg,2 Luis E Raez3 1Division of Hematology/Oncology, Sylvester Comprehensive Cancer Center, University of Miami Leonard M Miller School of Medicine, Miami, Florida, USA; 2University of Miami Leonard M Miller School of Medicine, Miami, Florida, USA; 3Thoracic Oncology Program, Memorial Cancer Institute, Memorial Health Care System, Pembroke Pines, Florida, USA Abstract: Non-small cell lung cancer (NSCLC unfortunately carries a very poor prognosis. Patients usually do not become symptomatic, and therefore do not seek treatment, until the cancer is advanced and it is too late to employ curative treatment options. New therapeutic options are urgently needed for NSCLC, because even current targeted therapies cure very few patients. Active immunotherapy is an option that is gaining more attention. A delicate and complex interplay exists between the tumor and the immune system. Solid tumors utilize a variety of mechanisms to evade immune detection. However, if the immune system can be stimulated to recognize the tumor as foreign, tumor cells can be specifically eliminated with little systemic toxicity. A number of vaccines designed to boost immunity against NSCLC are currently undergoing investigation in phase III clinical trials. Belagenpumatucel-L, an allogeneic cell vaccine that decreases transforming growth factor (TGF-β in the tumor microenvironment, releases the immune suppression caused by the tumor and it has shown efficacy in a wide array of patients with advanced NSCLC. Melanoma-associated antigen A3 (MAGE-A3, an antigen-based vaccine, has shown promising results in MAGE-A3+ NSCLC patients who have undergone complete surgical resection. L-BLP25 and TG4010 are both antigenic vaccines that target the Mucin 1 protein (MUC-1, a proto-oncogene that is commonly mutated in solid tumors. CIMAVax is a recombinant human epidermal growth factor (EGF vaccine that induces anti-EGF antibody production and prevents EGF

  13. Regulation of MicroRNAs by Natural Agents: New Strategies in Cancer Therapies

    Directory of Open Access Journals (Sweden)

    Neoh Hun Phuah

    2014-01-01

    Full Text Available MicroRNAs (miRNAs are short noncoding RNA which regulate gene expression by messenger RNA (mRNA degradation or translation repression. The plethora of published reports in recent years demonstrated that they play fundamental roles in many biological processes, such as carcinogenesis, angiogenesis, programmed cell death, cell proliferation, invasion, migration, and differentiation by acting as tumour suppressor or oncogene, and aberrations in their expressions have been linked to onset and progression of various cancers. Furthermore, each miRNA is capable of regulating the expression of many genes, allowing them to simultaneously regulate multiple cellular signalling pathways. Hence, miRNAs have the potential to be used as biomarkers for cancer diagnosis and prognosis as well as therapeutic targets. Recent studies have shown that natural agents such as curcumin, resveratrol, genistein, epigallocatechin-3-gallate, indole-3-carbinol, and 3,3′-diindolylmethane exert their antiproliferative and/or proapoptotic effects through the regulation of one or more miRNAs. Therefore, this review will look at the regulation of miRNAs by natural agents as a means to potentially enhance the efficacy of conventional chemotherapy through combinatorial therapies. It is hoped that this would provide new strategies in cancer therapies to improve overall response and survival outcome in cancer patients.

  14. Bypassing the blood-brain barrier: delivery of therapeutic agents by macrophages

    Science.gov (United States)

    Hirschberg, Henry; Baek, Seung-Kuk; Kwon, Young Jik; Sun, Chung-Ho; Madsen, Steen J.

    2010-02-01

    Introduction: Failure to eradicate infiltrating glioma cells using conventional treatment regimens results in tumor recurrence and is responsible for the dismal prognosis of patients with glioblastoma multiforme (GBM). This is due to the fact that these migratory cells are protected by the blood-brain barrier (BBB) and the blood brain tumor barrier (BBTB) which prevents the delivery of most anti-cancer agents. We have evaluated the ability of monocytes/macrophages (Mo/Ma) to cross the BBB in rats. This will permit access of anti-cancer agents such as nanoparticles to effectively target the infiltrating tumor cells, and potentially improve the treatment effectiveness for malignant gliomas. Materials and Methods: The infiltration of Mo/Ma into brain tumor spheroids in vitro was determined using fluorescent stained Mo/Ma. Tumors were also established in the brains of inbred rats and ALA-PDT was given 18 days following tumor induction. The degredation of the BBTB and quantification of the number of infiltrating Mo/Ma was examined on histological sections from removed brains. Results & Conclusion: PDT was highly effective in locally opening the BBTB and inducing macrophage migration into the irradiated portions of brain tumors.

  15. The effects of physical therapeutic agents on serum levels of stress hormones in patients with osteoarthritis

    Science.gov (United States)

    Tönük, Şükrü Burak; Serin, Erdinc; Ayhan, Fikriye Figen; Yorgancioglu, Zeynep Rezan

    2016-01-01

    Abstract To investigate the effects of physical agents on the levels of stress hormones in patients with osteoarthritis (OA). Transcutaneous electrical nerve stimulation, hot packs, and therapeutic ultrasound were applied to the lumbar region and knees of patients with OA. Blood samples were taken for the measurement of the serum levels of glucose, insulin (INS), growth hormone (GH), prolactin (PRL), cortisol (COR), and plasma adrenocorticotropic hormone (ACTH) immediately before and after the 1st session, to investigate the acute effects of those physical agents on the endocrine system. The hormone levels were also measured every 5 sessions in a total of 10 sessions. The treatment response was also evaluated by using the visual analogue scale (VAS), Roland Morris Disability Questionnaire (RMDQ), and Western Ontario and McMaster Universities Arthritis Index (WOMAC) throughout the therapy period. After the 1st session, there was a decrease in INS levels and a mild decrease in PRL levels (P = 0.001 and P < 0.05, respectively). Throughout the 10-session therapy period, the INS levels increased, whereas the ACTH and COR levels decreased (P < 0.05 for all). The VAS-spine, RMDQ, VAS-knee, and WOMAC scores decreased (P = 0.001 for VAS-spine and P < 0.001 for all others). A positive correlation was detected between the changes in serum COR and WOMAC-pain score (P < 0.05). Although the combination therapy caused changes in INS level accompanied with steady glucose levels, the application of physical agents did not adversely affect the hormone levels. The decrease in ACTH and COR levels may be attributed to the analgesic effect of agents and may be an indicator of patient comfort through a central action. PMID:27583888

  16. Challenges to improved therapeutics for metastatic castrate resistant prostate cancer: from recent successes and failures

    Directory of Open Access Journals (Sweden)

    Huang Xuan

    2012-07-01

    Full Text Available Abstract Men with metastatic castration-resistant prostate cancer (mCRPC carry poor prognosis despite the use of docetaxel-based regimens which has modest survival benefit shown by randomized clinical trials. Significant progress in the discovery of novel therapeutic agents has been made in the past few years. While sipuleucel-T, cabazitaxel, and abiraterone gained regulatory approval in 2010 and 2011, several highly promising candidates/regimens have failed in large scale clinical trials. Challenges remain to optimize the design and interpretation of clinical trial results and develop more effective strategies for mCRPC. In this review, we examined the positive and negative clinical trials in mCRPC in the past and discussed the various aspects of clinical trial design including selection of targets and appropriate outcome measures, biomarker development and implementation, and strategies for combination therapy.

  17. Novel agents in the management of castration resistant prostate cancer

    Directory of Open Access Journals (Sweden)

    Shruti Chaturvedi

    2014-01-01

    Full Text Available Prostate cancer (PCa is a leading cause of cancer mortality in men and despite high cure rates with surgery and/or radiation, 30-40% of patients will eventually develop advanced disease. Androgen deprivation is the first line therapy for standard of care for men with advanced disease. Eventually however all men will progress to castration-resistant prostate cancer (CRPC. Insight into the molecular mechanisms of androgen resistance has led to the development of alternative novel hormonal agents. Newer hormonal agents such as abiraterone, enzalutamide and TOK-001; and the first cancer vaccine, Sipuleucel T have been approved for use in men with CRPC. The recognition of the importance of bone health and morbidity associated with skeletal related events has led to the introduction of the receptor activator of nuclear factor kappa-B-ligand inhibitor denosumab. Other molecularly targeted therapies have shown promise in pre-clinical studies, but this has not consistently translated into clinical efficacy. It is increasingly evident that CRPC is a heterogeneous disease and an individualized approach directed at identifying primary involvement of specific pathways could maximize the benefit from targeted therapies. This review focuses on targeted therapy for PCa with special emphasis on therapies that have been Food and Drug Administration approved for use in men with CRPC.

  18. Neem components as potential agents for cancer prevention and treatment.

    Science.gov (United States)

    Hao, Fang; Kumar, Sandeep; Yadav, Neelu; Chandra, Dhyan

    2014-08-01

    Azadirachta indica, also known as neem, is commonly found in many semi-tropical and tropical countries including India, Pakistan, and Bangladesh. The components extracted from neem plant have been used in traditional medicine for the cure of multiple diseases including cancer for centuries. The extracts of seeds, leaves, flowers, and fruits of neem have consistently shown chemopreventive and antitumor effects in different types of cancer. Azadirachtin and nimbolide are among the few bioactive components in neem that have been studied extensively, but research on a great number of additional bioactive components is warranted. The key anticancer effects of neem components on malignant cells include inhibition of cell proliferation, induction of cell death, suppression of cancer angiogenesis, restoration of cellular reduction/oxidation (redox) balance, and enhancement of the host immune responses against tumor cells. While the underlying mechanisms of these effects are mostly unclear, the suppression of NF-κB signaling pathway is, at least partially, involved in the anticancer functions of neem components. Importantly, the anti-proliferative and apoptosis-inducing effects of neem components are tumor selective as the effects on normal cells are significantly weaker. In addition, neem extracts sensitize cancer cells to immunotherapy and radiotherapy, and enhance the efficacy of certain cancer chemotherapeutic agents. This review summarizes the current updates on the anticancer effects of neem components and their possible impact on managing cancer incidence and treatment. PMID:25016141

  19. Bile acids as endogenous etiologic agents in gastrointestinal cancer

    Institute of Scientific and Technical Information of China (English)

    Harris Bernstein; Carol Bernstein; Claire M Payne; Katerina Dvorak

    2009-01-01

    Bile acids are implicated as etiologic agents in cancer of the gastrointestinal (GI) tract, including cancer of the esophagus, stomach, small intestine, liver, biliary tract, pancreas and colon/rectum. Deleterious effects of bile acid exposure, likely related to carcinogenesis,include: induction of reactive oxygen and reactive nitrogen species; induction of DNA damage; stimulation of mutation; induction of apoptosis in the short term,and selection for apoptosis resistance in the long term.These deleterious effects have, so far, been reported most consistently in relation to esophageal and colorectal cancer, but also to some extent in relation to cancer of other organs. In addition, evidence is reviewed for an association of increased bile acid exposure with cancer risk in human populations, in specific human genetic conditions, and in animal experiments. A model for the role of bile acids in GI carcinogenesis is presented from a Darwinian perspective that offers an explanation for how the observed effects of bile acids on cells contribute to cancer development.

  20. Neem components as potential agents for cancer prevention and treatment.

    Science.gov (United States)

    Hao, Fang; Kumar, Sandeep; Yadav, Neelu; Chandra, Dhyan

    2014-08-01

    Azadirachta indica, also known as neem, is commonly found in many semi-tropical and tropical countries including India, Pakistan, and Bangladesh. The components extracted from neem plant have been used in traditional medicine for the cure of multiple diseases including cancer for centuries. The extracts of seeds, leaves, flowers, and fruits of neem have consistently shown chemopreventive and antitumor effects in different types of cancer. Azadirachtin and nimbolide are among the few bioactive components in neem that have been studied extensively, but research on a great number of additional bioactive components is warranted. The key anticancer effects of neem components on malignant cells include inhibition of cell proliferation, induction of cell death, suppression of cancer angiogenesis, restoration of cellular reduction/oxidation (redox) balance, and enhancement of the host immune responses against tumor cells. While the underlying mechanisms of these effects are mostly unclear, the suppression of NF-κB signaling pathway is, at least partially, involved in the anticancer functions of neem components. Importantly, the anti-proliferative and apoptosis-inducing effects of neem components are tumor selective as the effects on normal cells are significantly weaker. In addition, neem extracts sensitize cancer cells to immunotherapy and radiotherapy, and enhance the efficacy of certain cancer chemotherapeutic agents. This review summarizes the current updates on the anticancer effects of neem components and their possible impact on managing cancer incidence and treatment.

  1. Preclinical Assessment of Vernonia amygdalina Leaf Extracts as DNA Damaging Anti-cancer Agent in the Management of Breast Cancer

    Directory of Open Access Journals (Sweden)

    Ernest Izevbigie

    2008-12-01

    Full Text Available Breast cancer is the leading cause of death among women between 40 and 55 years of age and is the second overall cause of death among women. Fortunately, the mortality rate from breast cancer has decreased in recent years due to an increased emphasis on early detection and more effective treatments. Despite early detection, conventional and chemotherapeutic methods of treatment, about 7% of women still died every year. Hence, the aim of the present study was to assess the therapeutic efficacy of Vernonia amygdalina (VA leaf extracts as anti-cancer agent against human breast cancer in vitro using the MTT [3-(4, 5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide] and alkaline single cell gel electrophoresis (Comet assays, respectively. In this experiment, human breast adenocarcinoma (MCF-7 cells were treated with different doses of VA leaf extracts for 48 hours. Data obtained from the MTT assay showed that VA significantly ((P < 0.05 reduced the viability of MCF-7 cells in a dose-dependent manner upon 48 hours of exposure. Data generated from the comet assay also indicated a slight dose-dependent increase in DNA damage in MCF-7 cells associated with VA treatment. We observed a slight increase in comet tail-length, tail arm and tail moment, as well as in percentages of DNA cleavage at all doses tested, showing an evidence that VA-induced minimal genotoxic damage in MCF-7 cells. Taken together, our findings suggest that VA treatment moderately (P < 0.05 reduces cellular viability and induces minimal DNA damage in MCF-7 cells. These findings provide evidence that VA extracts represent a DNA-damaging anti-cancer agent against breast cancer and its mechanisms of action functions, at least in part, through minimal DNA damage and moderate toxicity in tumors cells.

  2. Review of therapeutic agents for burns pruritus and protocols for management in adult and paediatric patients using the GRADE classification

    Directory of Open Access Journals (Sweden)

    Goutos Ioannis

    2010-10-01

    Full Text Available To review the current evidence on therapeutic agents for burns pruritus and use the Grading of Recommendations, Assessment, Development and Evaluation (GRADE classification to propose therapeutic protocols for adult and paediatric patients. All published interventions for burns pruritus were analysed by a multidisciplinary panel of burns specialists following the GRADE classification to rate individual agents. Following the collation of results and panel discussion, consensus protocols are presented. Twenty-three studies appraising therapeutic agents in the burns literature were identified. The majority of these studies (16 out of 23 are of an observational nature, making an evidence-based approach to defining optimal therapy not feasible. Our multidisciplinary approach employing the GRADE classification recommends the use of antihistamines (cetirizine and cimetidine and gabapentin as the first-line pharmacological agents for both adult and paediatric patients. Ondansetron and loratadine are the second-line medications in our protocols. We additionally recommend a variety of non-pharmacological adjuncts for the perusal of clinicians in order to maximise symptomatic relief in patients troubled with postburn itch. Most studies in the subject area lack sufficient statistical power to dictate a ′gold standard′ treatment agent for burns itch. We encourage clinicians to employ the GRADE system in order to delineate the most appropriate therapeutic approach for burns pruritus until further research elucidates the most efficacious interventions. This widely adopted classification empowers burns clinicians to tailor therapeutic regimens according to current evidence, patient values, risks and resource considerations in different medical environments.

  3. Squalamine as a broad-spectrum systemic antiviral agent with therapeutic potential.

    Science.gov (United States)

    Zasloff, Michael; Adams, A Paige; Beckerman, Bernard; Campbell, Ann; Han, Ziying; Luijten, Erik; Meza, Isaura; Julander, Justin; Mishra, Abhijit; Qu, Wei; Taylor, John M; Weaver, Scott C; Wong, Gerard C L

    2011-09-20

    Antiviral compounds that increase the resistance of host tissues represent an attractive class of therapeutic. Here, we show that squalamine, a compound previously isolated from the tissues of the dogfish shark (Squalus acanthias) and the sea lamprey (Petromyzon marinus), exhibits broad-spectrum antiviral activity against human pathogens, which were studied in vitro as well as in vivo. Both RNA- and DNA-enveloped viruses are shown to be susceptible. The proposed mechanism involves the capacity of squalamine, a cationic amphipathic sterol, to neutralize the negative electrostatic surface charge of intracellular membranes in a way that renders the cell less effective in supporting viral replication. Because squalamine can be readily synthesized and has a known safety profile in man, we believe its potential as a broad-spectrum human antiviral agent should be explored. PMID:21930925

  4. Avena sativa (Oat), a potential neutraceutical and therapeutic agent: an overview.

    Science.gov (United States)

    Singh, Rajinder; De, Subrata; Belkheir, Asma

    2013-01-01

    The aim of the present review article is to summarize the available information related to the availability, production, chemical composition, pharmacological activity, and traditional uses of Avena sativa to highlight its potential to contribute to human health. Oats are now cultivated worldwide and form an important dietary staple for the people in number of countries. Several varieties of oats are available. It is a rich source of protein, contains a number of important minerals, lipids, β-glucan, a mixed-linkage polysaccharide, which forms an important part of oat dietary fiber, and also contains various other phytoconstituents like avenanthramides, an indole alkaloid-gramine, flavonoids, flavonolignans, triterpenoid saponins, sterols, and tocols. Traditionally oats have been in use since long and are considered as stimulant, antispasmodic, antitumor, diuretic, and neurotonic. Oat possesses different pharmacological activities like antioxidant, anti-inflammatory, wound healing, immunomodulatory, antidiabetic, anticholesterolaemic, etc. A wide spectrum of biological activities indicates that oat is a potential therapeutic agent. PMID:23072529

  5. Pentosan polysulfate as a prophylactic and therapeutic agent against prion disease.

    Science.gov (United States)

    Dealler, Stephen; Rainov, Nikolai G

    2003-05-01

    Pentosan polysulfate (PPS) acts by imitating the physiological roles of the heparans. It binds to heparan binding sites on proteins and alters the physiological actions of these proteins. PPS acts as a prophylactic agent against infection with prions both in vivo and in vitro. Low concentrations (10 mg/ml) are needed extracellularly for this effect to be seen but, due to cellular uptake, it is believed that a much higher concentration is found intracellularly. The prophylactic effect of PPS is observed if the drug is administered to mice between 3 months before and approximately 30 days after the inoculation of the disease. After that point it is considered that the infection has entered the nervous system, and that the drug cannot penetrate the blood-brain barrier. The prophylaxis of humans with oral PPS and the current therapeutic activity of the drug when given by intracerebroventricular infusion to symptomatic, prion-infected animals are discussed.

  6. Novel enterobactin analogues as potential therapeutic chelating agents: Synthesis, thermodynamic and antioxidant studies

    Science.gov (United States)

    Zhang, Qingchun; Jin, Bo; Shi, Zhaotao; Wang, Xiaofang; Liu, Qiangqiang; Lei, Shan; Peng, Rufang

    2016-09-01

    A series of novel hexadentate enterobactin analogues, which contain three catechol chelating moieties attached to different molecular scaffolds with flexible alkyl chain lengths, were prepared. The solution thermodynamic stabilities of the complexes with uranyl, ferric(III), and zinc(II) ions were then investigated. The hexadentate ligands demonstrate effective binding ability to uranyl ion, and the average uranyl affinities are two orders of magnitude higher than 2,3-dihydroxy-N1,N4-bis[(1,2-hydroxypyridinone-6-carboxamide)ethyl]terephthalamide [TMA(2Li-1,2-HOPO)2] ligand with similar denticity. The high affinity of hexadentate ligands could be due to the presence of the flexible scaffold, which favors the geometric agreement between the ligand and the uranyl coordination preference. The hexadentate ligands also exhibit higher antiradical efficiency than butylated hydroxyanisole (BHA). These results provide a basis for further studies on the potential applications of hexadentate ligands as therapeutic chelating agents.

  7. Use of Integrated Computational Approaches in the Search for New Therapeutic Agents.

    Science.gov (United States)

    Persico, Marco; Di Dato, Antonio; Orteca, Nausicaa; Cimino, Paola; Novellino, Ettore; Fattorusso, Caterina

    2016-09-01

    Computer-aided drug discovery plays a strategic role in the development of new potential therapeutic agents. Nevertheless, the modeling of biological systems still represents a challenge for computational chemists and at present a single computational method able to face such challenge is not available. This prompted us, as computational medicinal chemists, to develop in-house methodologies by mixing various bioinformatics and computational tools. Importantly, thanks to multi-disciplinary collaborations, our computational studies were integrated and validated by experimental data in an iterative process. In this review, we describe some recent applications of such integrated approaches and how they were successfully applied in i) the search of new allosteric inhibitors of protein-protein interactions and ii) the development of new redox-active antimalarials from natural leads.

  8. Technical cooperation for the wider uses of Ho-166 therapeutic agents in European countries

    CERN Document Server

    Park, K B; Choi, S M; Han, K H; Hong, Y D; Park, W W; Shin, B C

    2002-01-01

    Czech has put their priority in developing the radiopharmaceuticals based on reactor produced Ho-166 and a related fabrication will be extended to other EU conturies including Germany, France, etc after a development of project. The collaboration will be based on the mutual agreement for developing the between research institutes, industries and academic institutes and further researches should be followed by the issue of developing radiopharmaceuticals using Ho-166. To strengthen the collaboration, detailed discussions for the practical collaboration have been made through the visitation to the research institution of each counter part. For implementing the collaboration between NPI and KAERI, an institutional basis technical cooperation agreement(TCA) will be concluded. Furthermore, agreement for the substantial collaboration on Ho-166 related researches will be made after the conclusion of the TCA. It will accelerate the commercialization of KAERI developed Ho-166 therapeutic agents into other European cou...

  9. Avena sativa (Oat), a potential neutraceutical and therapeutic agent: an overview.

    Science.gov (United States)

    Singh, Rajinder; De, Subrata; Belkheir, Asma

    2013-01-01

    The aim of the present review article is to summarize the available information related to the availability, production, chemical composition, pharmacological activity, and traditional uses of Avena sativa to highlight its potential to contribute to human health. Oats are now cultivated worldwide and form an important dietary staple for the people in number of countries. Several varieties of oats are available. It is a rich source of protein, contains a number of important minerals, lipids, β-glucan, a mixed-linkage polysaccharide, which forms an important part of oat dietary fiber, and also contains various other phytoconstituents like avenanthramides, an indole alkaloid-gramine, flavonoids, flavonolignans, triterpenoid saponins, sterols, and tocols. Traditionally oats have been in use since long and are considered as stimulant, antispasmodic, antitumor, diuretic, and neurotonic. Oat possesses different pharmacological activities like antioxidant, anti-inflammatory, wound healing, immunomodulatory, antidiabetic, anticholesterolaemic, etc. A wide spectrum of biological activities indicates that oat is a potential therapeutic agent.

  10. Potential of radiosensitizing agents in cancer chemo-radiotherapy

    Directory of Open Access Journals (Sweden)

    Girdhani S

    2005-01-01

    Full Text Available Potential of herbs and other plant-based formulations have been increasingly recognized in prevention and treatment of human diseases including cancer. There exist enormous prospect for screening and evaluation of herbal/plant products for developing effective radiosensitization and radioprotection relevant to nuclear research program. Investigations in our laboratory have focused on the mechanism of activity of variety of anticancer and antioxidant agents, namely, Eugenol, (EU, Ellagic acid (EA, Triphala (TPL, Tocopherol Succinate (TOS and Arachidonic acid on normal and cancer cells with view to design effective protocols in practical radioprotection and cancer radiotherapy. This paper is mainly focused on studies on cytotoxic effects on cancer cell lines. Results have shown that these agents produced radiosensitizing action involving oxidative damage, membrane alteration and damage to nucleic acid in various human cell lines. Studies were performed employing fluorescence probes and electron spin resonance methods and gel electrophoresis protocols. It has been found that cytotoxic effect was induced by initiating membrane oxidative damage and by triggering intracellular generation of reactive oxygen species (ROS by gamma radiation in combination with phytochemicals like TPL, EA and TOS in tumor cell line Ehrlich Ascites (EAC, Human cervical (HeLa and breast (MCF-7 cells. Membrane damage and ROS generation was measured by DPH and DCF-FDA fluorescent probes respectively after exposure to low to moderate doses of gamma radiation. This talk will present the cytotoxic effects of phytochemicals in combination with ionizing radiation. It is emphasized that modulation of membrane peroxidative damage and intra cellular ROS may help achieve efficient killing of cancer cells which may provide a new approach to developing effective treatment of cancer.

  11. Alpharetroviral Vectors: From a Cancer-Causing Agent to a Useful Tool for Human Gene Therapy

    Directory of Open Access Journals (Sweden)

    Julia D. Suerth

    2014-12-01

    Full Text Available Gene therapy using integrating retroviral vectors has proven its effectiveness in several clinical trials for the treatment of inherited diseases and cancer. However, vector-mediated adverse events related to insertional mutagenesis were also observed, emphasizing the need for safer therapeutic vectors. Paradoxically, alpharetroviruses, originally discovered as cancer-causing agents, have a more random and potentially safer integration pattern compared to gammaretro- and lentiviruses. In this review, we provide a short overview of the history of alpharetroviruses and explain how they can be converted into state-of-the-art gene delivery tools with improved safety features. We discuss development of alpharetroviral vectors in compliance with regulatory requirements for clinical translation, and provide an outlook on possible future gene therapy applications. Taken together, this review is a broad overview of alpharetroviral vectors spanning the bridge from their parental virus discovery to their potential applicability in clinical settings.

  12. CpG oligodeoxynucleotides as TLR9 agonists: therapeutic applications in cancer.

    Science.gov (United States)

    Murad, Yanal M; Clay, Timothy M

    2009-01-01

    Toll-like receptors (TLRs) are part of the innate immune system, and they belong to the pattern recognition receptors (PRR) family. The PRR family is designed to recognize and bind conserved pathogen-associated molecular patterns, which are not generated by the host and are restricted and essential to micro-organisms. TLR9, which recognizes unmethylated CpG (cytosine guanosine dinucleotide), is a very promising target for therapeutic activation. Stimulation of TLR9 activates human plasmacytoid dendritic cells and B cells, and results in potent T helper-1 (T(h)1)-type immune responses and antitumor responses in mouse tumor models and in patients. Several pharmaceutical companies, such as Pfizer, Idera, and Dynavax, are developing CpG oligodeoxynucleotides (ODNs) for the treatment of cancer, along with other conditions, such as infections and allergy. CpG ODNs have shown promising results as vaccine adjuvants and in combination with cancer immunotherapy. Several TLR9 agonists are being developed and have entered clinical trials to evaluate their safety and efficacy for the treatment of several hematopoietic and solid tumors. In this review, we discuss the use of CpG ODNs in several phase I and II clinical trials for the treatment of NHL, renal cell carcinoma, melanoma, and non-small cell lung cancer, either alone or in combination with other agents. PMID:19894778

  13. The biology of cancer testis antigens: putative function, regulation and therapeutic potential.

    Science.gov (United States)

    Fratta, Elisabetta; Coral, Sandra; Covre, Alessia; Parisi, Giulia; Colizzi, Francesca; Danielli, Riccardo; Nicolay, Hugues Jean Marie; Sigalotti, Luca; Maio, Michele

    2011-04-01

    Cancer testis antigens (CTA) are a large family of tumor-associated antigens expressed in human tumors of different histological origin, but not in normal tissues except for testis and placenta. This tumor-restricted pattern of expression, together with their strong in vivo immunogenicity, identified CTA as ideal targets for tumor-specific immunotherapeutic approaches, and prompted the development of several clinical trials of CTA-based vaccine therapy. Driven by this practical clinical interest, a more detailed characterization of CTA biology has been recently undertaken. So far, at least 70 families of CTA, globally accounting for about 140 members, have been identified. Most of these CTA are expressed during spermatogenesis, but their function is still largely unknown. Epigenetic events, particularly DNA methylation, appear to be the primary mechanism regulating CTA expression in both normal and transformed cells, as well as in cancer stem cells. In view of the growing interest in CTA biology, the aim of this review is to provide the most recent information on their expression, regulation and function, together with a brief summary of the major clinical trials involving CTA as therapeutic agents. The pharmacologic modulation of CTA expression profiles on neoplastic cells by DNA hypomethylating drugs will also be discussed as a feasible approach to design new combination therapies potentially able to improve the clinical efficacy of currently adopted CTA-based immunotherapeutic regimens in cancer patients.

  14. Therapeutic effects of lentivirus-mediated shRNA targeting of cyclin D1 in human gastric cancer

    International Nuclear Information System (INIS)

    Gastric cancer is the second most common cause of cancer-related death in males and the fourth in females. Traditional treatment has poor prognosis because of recurrence and systemic side effects. Therefore, the development of new therapeutic strategies is an important issue. Lentivirus-mediated shRNA stably inhibits target genes and can efficiently transduce most cells. Since overexpressed cyclin D1 is closely related to human gastric cancer progression, inhibition of cyclin D1 using specific targeting could be an effective treatment method of human gastric cancer. The therapeutic effect of lentivirus-mediated shRNA targeting of cyclin D1 (ShCCND1) was analyzed both in vitro and in vivo experiments. In vitro, NCI-N87 cells with downregulation of cyclin D1 by ShCCND1 showed significant inhibition of cell proliferation, cell motility, and clonogenicity. Downregulation of cyclin D1 in NCI-N87 cells also resulted in significantly increased G1 arrest and apoptosis. In vivo, stable NCI-N87 cells expressing ShCCND1 were engrafted into nude mice. Then, the cancer-growth inhibition effect of lentivirus was confirmed. To assess lentivirus including ShCCND1 as a therapeutic agent, intratumoral injection was conducted. Tumor growth of the lentivirus-treated group was significantly inhibited compared to growth of the control group. These results are in accordance with the in vitro data and lend support to the mitotic figure count and apoptosis analysis of the tumor mass. The lentivirus-mediated ShCCND1 was constructed, which effectively inhibited growth of NCI-N87-derived cancer both in vitro and in vivo. The efficiency of shRNA knockdown and variation in the degree of inhibition is mediated by different shRNA sequences and cancer cell lines. These experimental results suggest the possibility of developing new gastric cancer therapies using lentivirus-mediated shRNA

  15. ADVANCED MOLECULAR DESIGN OF BIOPOLYMERS FOR TRANSMUCOSAL AND INTRACELLULAR DELIVERY OF CHEMOTHERAPEUTIC AGENTS AND BIOLOGICAL THERAPEUTICS

    Science.gov (United States)

    Liechty, William B.; Caldorera-Moore, Mary; Phillips, Margaret A.; Schoener, Cody; Peppas, Nicholas A.

    2011-01-01

    Hydrogels have been instrumental in the development of polymeric systems for controlled release of therapeutic agents. These materials are attractive for transmucosal and intracellular drug delivery because of their facile synthesis, inherent biocompatibility, tunable physicochemical properties, and capacity to respond to various physiological stimuli. In this contribution, we outline a multifaceted hydrogel-based approach for expanding the range of therapeutics in oral formulations from classical small-molecule drugs to include proteins, chemotherapeutics, and nucleic acids. Through judicious materials selection and careful design of copolymer composition and molecular architecture, we can engineer systems capable of responding to distinct physiological cues, with tunable physicochemical properties that are optimized to load, protect, and deliver valuable macromolecular payloads to their intended site of action. These hydrogel carriers, including complexation hydrogels, tethered hydrogels, interpenetrating networks, nanoscale hydrogels, and hydrogels with decorated structures are investigated for their ability respond to changes in pH, to load and release insulin and fluorescein, and remain non-toxic to Caco-2 cells. Our results suggest these novel hydrogel networks have great potential for controlled delivery of proteins, chemotherapeutics, and nucleic acids. PMID:21699934

  16. pH-Sensitive stimulus-responsive nanocarriers for targeted delivery of therapeutic agents.

    Science.gov (United States)

    Karimi, Mahdi; Eslami, Masoud; Sahandi-Zangabad, Parham; Mirab, Fereshteh; Farajisafiloo, Negar; Shafaei, Zahra; Ghosh, Deepanjan; Bozorgomid, Mahnaz; Dashkhaneh, Fariba; Hamblin, Michael R

    2016-09-01

    In recent years miscellaneous smart micro/nanosystems that respond to various exogenous/endogenous stimuli including temperature, magnetic/electric field, mechanical force, ultrasound/light irradiation, redox potentials, and biomolecule concentration have been developed for targeted delivery and release of encapsulated therapeutic agents such as drugs, genes, proteins, and metal ions specifically at their required site of action. Owing to physiological differences between malignant and normal cells, or between tumors and normal tissues, pH-sensitive nanosystems represent promising smart delivery vehicles for transport and delivery of anticancer agents. Furthermore, pH-sensitive systems possess applications in delivery of metal ions and biomolecules such as proteins, insulin, etc., as well as co-delivery of cargos, dual pH-sensitive nanocarriers, dual/multi stimuli-responsive nanosystems, and even in the search for new solutions for therapy of diseases such as Alzheimer's. In order to design an optimized system, it is necessary to understand the various pH-responsive micro/nanoparticles and the different mechanisms of pH-sensitive drug release. This should be accompanied by an assessment of the theoretical and practical challenges in the design and use of these carriers. WIREs Nanomed Nanobiotechnol 2016, 8:696-716. doi: 10.1002/wnan.1389 For further resources related to this article, please visit the WIREs website. PMID:26762467

  17. Targeting Potassium Channels for Increasing Delivery of Imaging Agents and Therapeutics to Brain Tumors

    Directory of Open Access Journals (Sweden)

    Nagendra Sanyasihally Ningaraj

    2013-05-01

    Full Text Available Every year in the US, 20,000 new primary and nearly 200,000 metastatic brain tumor cases are reported. The cerebral microvessels/ capillaries that form the blood–brain barrier (BBB not only protect the brain from toxic agents in the blood but also pose a significant hindrance to the delivery of small and large therapeutic molecules. Different strategies have been employed to circumvent the physiological barrier posed by blood-brain tumor barrier (BTB. Studies in our laboratory have identified significant differences in the expression levels of certain genes and proteins between normal and brain tumor capillary endothelial cells. In this study, we validated the non-invasive and clinically relevant Dynamic Contrast Enhancing-Magnetic Resonance Imaging (DCE-MRI method with invasive, clinically irrelevant but highly accurate Quantitative Autoradiography (QAR method using rat glioma model. We also showed that DCE-MRI metric of tissue vessel perfusion-permeability is sensitive to changes in blood vessel permeability following administration of calcium-activated potassium (BKCa channel activator NS-1619. Our results show that human gliomas and brain tumor endothelial cells that overexpress BKCa channels can be targeted for increased BTB permeability for MRI enhancing agents to brain tumors. We conclude that monitoring the outcome of increased MRI enhancing agents’ delivery to microsatellites and leading tumor edges in glioma patients would lead to beneficial clinical outcome.

  18. Renal cell carcinoma: review of novel single-agent therapeutics and combination regimens.

    Science.gov (United States)

    Amato, R J

    2005-01-01

    A search of the Medline database and ASCO 2003 conference proceedings was conducted to identify clinical trials currently underway using single-agent therapy for renal cell carcinoma (RCC). Combination trials were identified using the ASCO 2003 conference proceedings. Fourteen single-agent therapies employing different mechanisms of action were identified in the published literature: imatinib mesylate (Gleevec); bevacizumab (Avastin); thalidomide (Thalomid); gefitinib (ZD1839) (Iressa); cetuximab (IMC-C225) (Erbitux); bortezomib (PS-341) (Velcade); HSPPC-96 (Oncophage); BAY 59-8862; ABT-510; G250; CCI-779; SU5416; PTK/ZK; and ABX-EGF. Six distinct fields of clinical research have emerged: monoclonal antibodies, small molecules, vaccines, second-generation taxanes, nonapeptides and immunomodulators. Five combination regimens, primarily biological response modifiers (interleukin-2 or interferon-alpha), chemotherapy- or thalidomide-based, were identified. All therapies demonstrated acceptable toxicity profiles. Clinical benefit was assessed based on each study's reported criteria: antitumor response (regression or stability) ranged from 5% to 71%. In the past several years, significant advances in the underlying biological mechanisms of RCC, particularly the role of tumor angiogenesis, have permitted the design of molecularly targeted therapeutics. Based on preliminary and limited studies, combination therapies offer the greatest clinical benefit in the management of this malignancy, although additional basic research is still warranted.

  19. Therapeutic vaccines in non-small cell lung cancer

    Science.gov (United States)

    Socola, Francisco; Scherfenberg, Naomi; Raez, Luis E

    2013-01-01

    Non-small cell lung cancer (NSCLC) unfortunately carries a very poor prognosis. Patients usually do not become symptomatic, and therefore do not seek treatment, until the cancer is advanced and it is too late to employ curative treatment options. New therapeutic options are urgently needed for NSCLC, because even current targeted therapies cure very few patients. Active immunotherapy is an option that is gaining more attention. A delicate and complex interplay exists between the tumor and the immune system. Solid tumors utilize a variety of mechanisms to evade immune detection. However, if the immune system can be stimulated to recognize the tumor as foreign, tumor cells can be specifically eliminated with little systemic toxicity. A number of vaccines designed to boost immunity against NSCLC are currently undergoing investigation in phase III clinical trials. Belagenpumatucel-L, an allogeneic cell vaccine that decreases transforming growth factor (TGF-β) in the tumor microenvironment, releases the immune suppression caused by the tumor and it has shown efficacy in a wide array of patients with advanced NSCLC. Melanoma-associated antigen A3 (MAGE-A3), an antigen-based vaccine, has shown promising results in MAGE-A3+ NSCLC patients who have undergone complete surgical resection. L-BLP25 and TG4010 are both antigenic vaccines that target the Mucin-1 protein (MUC-1), a proto-oncogene that is commonly mutated in solid tumors. CIMAVax is a recombinant human epidermal growth factor (EGF) vaccine that induces anti-EGF antibody production and prevents EGF from binding to its receptor. These vaccines may significantly improve survival and quality of life for patients with an otherwise dismal NSCLC prognosis. This review is intended to give an overview of the current data and the most promising studies of active immunotherapy for NSCLC.

  20. Therapeutic potential of thalidomide for gemcitabine-resistant bladder cancer.

    Science.gov (United States)

    Huang, Yen Ta; Cheng, Chuan Chu; Chiu, Ted H; Lai, Pei Chun

    2015-11-01

    Controversial effects of thalidomide for solid malignancies have been reported. In the present study, we evaluate the effects of thalidomide for transitional cell carcinoma (TCC), the most common type of bladder cancer. Thalidomide precipitates were observed when its DMSO solution was added to the culture medium. No precipitation was found when thalidomide was dissolved in 45% γ-cyclodextrin, and this concentration of γ-cyclodextrin elicited slight cytotoxicity on TCC BFTC905 and primary human urothelial cells. Thalidomide-γ-cyclodextrin complex exerted a concentration-dependent cytotoxicity in TCC cells, but was relatively less cytotoxic (with IC50 of 200 µM) in BFTC905 cells than the other 3 TCC cell lines, possibly due to upregulation of Bcl-xL and HIF-1α mediated carbonic anhydrase IX, and promotion of quiescence. Gemcitabine-resistant BFTC905 cells were chosen for additional experiments. Thalidomide induced apoptosis through downregulation of survivin and securin. The secretion of VEGF and TNF-α was ameliorated by thalidomide, but they did not affect cell proliferation. Immune-modulating lenalidomide and pomalidomide did not elicit cytotoxicity. In addition, cereblon did not play a role in the thalidomide effect. Oxidative DNA damage was triggered by thalidomide, and anti-oxidants reversed the effect. Thalidomide also inhibited TNF-α induced invasion through inhibition of NF-κB, and downregulation of effectors, ICAM-1 and MMP-9. Thalidomide inhibited the growth of BFTC905 xenograft tumors in SCID mice via induction of DNA damage and suppression of angiogenesis. Higher average body weight, indicating less chachexia, was observed in thalidomide treated group. Sedative effect was observed within one-week of treatment. These pre-clinical results suggest therapeutic potential of thalidomide for gemcitabine-resistant bladder cancer.

  1. Keap1-Nrf2 pathway: A promising target towards lung cancer prevention and therapeutics

    Institute of Scientific and Technical Information of China (English)

    Ying-Hui Tong; Bo Zhang; Yun Fan; Neng-Ming Lin

    2015-01-01

    Objectives: Drugs for targeted therapy have become a new strategy of adjuvant therapy for treatment of lung cancer.The Keapl (kelch-like ECH-associated protein 1)-Nrf2 (nuclear factor erythroid 2-related factor 2) pathway is recognized to be critical in regulating genes related to the cellular protective response and protecting cells from oxidative damages and toxic insult.Methods: Pubmed, Embase, OVID, and the Cochrane Library databases were searched from the beginning of each database without any limitations to the date of publication.Search terms were "Nrf2" or "Keap1" and "Lung cancer".Results: The upregulation of Nrf2 had been closely related to tumor protection and drug resistance.The aberrant state of Keap 1 or Nrf2 that were frequently found in lung cancer conferred a poor prognosis.Nrf2 could prevent cells from undergoing oncogenesis as a tumor suppressor, while it could also promote cancer progression and resistance to chemotherapeutic drugs as an oncogene,depending on the different stages of tumor progression.Target Nrf2 signaling by specific chemicals showed it could prevent tumor growth or combat chemoresistance.Conclusions: Increasing evidence has demonstrated the dual roles of the Keap1-Nrf2 pathway in tumor initiation and progression.In this paper, we provide a comprehensive overview of the potency of the Keap 1-Nrf2 pathway as an antitumor target, and the current status of Nrf2 activators or inhibitors for therapeutic approaches.Further studies are required to clarify the role of Nrf2 in lung cancer at different tumor stages, in order to maximize the efficacy of Keap1-Nrf2 targeting agents.Copyright 2015, Chinese Medical Association Production.Production and hosting by Elsevier B.V.on behalf of KeAi Communications Co., Ltd.This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/ by-nc-nd/4.0/).

  2. The Evolution of Triple-Negative Breast Cancer: From Biology to Novel Therapeutics.

    Science.gov (United States)

    Anders, Carey K; Abramson, Vandana; Tan, Tira; Dent, Rebecca

    2016-01-01

    Triple-negative breast cancer (TNBC) is clinically defined as lacking expression of the estrogen receptor (ER), progesterone receptor (ER), and HER2. Historically, TNBC has been characterized by an aggressive natural history and worse disease-specific outcomes compared with other breast cancer subtypes. The advent of next-generation sequencing (NGS) has allowed for the dissection of TNBC into molecular subtypes (i.e., basal-like, claudin-low). Within TNBC, several subtypes have emerged as "immune-activated," consistently illustrating better disease outcome. In addition, NGS has revealed a host of molecular features characteristic of TNBC, including high rates of TP53 mutations, PI3K and MEK pathway activation, and genetic similarities to serous ovarian cancers, including inactivation of the BRCA pathway. Identified genetic vulnerabilities of TNBC have led to promising therapeutic approaches, including DNA-damaging agents (i.e., platinum salts and PARP inhibitors), as well as immunotherapy. Platinum salts are routinely incorporated into the treatment of metastatic TNBC; however, best outcomes are observed among those with deficiencies in the BRCA pathway. Although the incorporation of platinum in the neoadjuvant care of patients with TNBC yields higher pathologic complete response (pCR) rates, the impact on longer-term outcome is less clear. The presence of immune infiltrate in TNBC has shown both a predictive and prognostic role. Checkpoint inhibitors, including PD-1 and PD-L1 inhibitors, are under investigation in the setting of metastatic TNBC and have shown responses in initial clinical trials. Finally, matching emerging therapeutic strategies to optimal subtype of TNBC is of utmost importance as we design future research strategies to improve patient outcome.

  3. 3H-1,2-dithiole-3-thione as a novel therapeutic agent for the treatment of experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Kuo, Ping-Chang; Brown, Dennis A; Scofield, Barbara A; Yu, I-Chen; Chang, Fen-Lei; Wang, Pei-Yu; Yen, Jui-Hung

    2016-10-01

    3H-1,2-dithiole-3-thione (D3T), the simplest member of the sulfur-containing dithiolethiones, is found in cruciferous vegetables, and has been previously reported to be a potent inducer of antioxidant genes and glutathione biosynthesis by activation of the transcription factor Nrf2. D3T is a cancer chemopreventive agent and possesses anti-inflammatory properties. Although D3T has been shown to protect against neoplasia, the effect of D3T in the autoimmune inflammatory disease multiple sclerosis/experimental autoimmune encephalomyelitis (EAE) is unknown. The present study is the first report of the therapeutic effect of D3T in EAE. Our results show D3T, administered post immunization, not only delays disease onset but also dramatically reduces disease severity in EAE. Strikingly, D3T, administered post disease onset of EAE, effectively prevents disease progression and exacerbation. Mechanistic studies revealed that D3T suppresses dendritic cell activation and cytokine production, inhibits pathogenic Th1 and Th17 differentiation, represses microglia activation and inflammatory cytokine expression, and promotes microglia phase II enzyme induction. In summary, these results indicate that D3T affects both innate and adaptive immune cells, and the protective effect of D3T in EAE might be attributed to its effects on modulating dendritic cell and microglia activation and pathogenic Th1/Th17 cell differentiation. PMID:27013356

  4. Cancer chemopreventive and therapeutic activities of red ginseng.

    Science.gov (United States)

    Xiaoguang, C; Hongyan, L; Xiaohong, L; Zhaodi, F; Yan, L; Lihua, T; Rui, H

    1998-02-01

    Red ginseng extract A and B are the active components of Panax ginseng. Red ginseng is a classical traditional Chinese medicine. Among Chinese herbs, red ginseng has been considered as one of the tonics. Many studies indicated that red ginseng could enhance immune function of the human body. The effects of red ginseng extracts on transplantable tumors, proliferation of lymphocyte, two-stage model and rat liver lipid peroxidation were studied. In a two-stage model, red ginseng extracts had a significant cancer chemoprevention. At 50-400 mg/kg, they could inhibit DMBA/Croton oil-induced skin papilloma in mice, decrease the incidence of papilloma, prolong the latent period of tumor occurrence and reduce tumor number per mouse in a dose-dependent manner. Red ginseng extract B could effectively inhibit the Fe2+/cysteine-induced lipid peroxidation of rat liver microsome, suggesting that red ginseng extract B has a stronger antioxidative effect than that of extract A. The results indicated that red ginseng extracts (50 approximately 400 mg/kg) could significantly inhibit the growth of transplantable mouse sarcoma S180 and melanoma B16. Red ginseng extracts A (0.5 mg/ml) and B (0.1 and 0.25 mg/ml) might effectively promote the transformation of T lymphocyte, but there was no influence on lymphocyte proliferation stimulated by concanavalin A. This suggests that red ginseng extracts have potent tumor therapeutic activity and improve the cell immune system. PMID:9533434

  5. Protein MRI contrast agent with unprecedented metal selectivity and sensitivity for liver cancer imaging.

    Science.gov (United States)

    Xue, Shenghui; Yang, Hua; Qiao, Jingjuan; Pu, Fan; Jiang, Jie; Hubbard, Kendra; Hekmatyar, Khan; Langley, Jason; Salarian, Mani; Long, Robert C; Bryant, Robert G; Hu, Xiaoping Philip; Grossniklaus, Hans E; Liu, Zhi-Ren; Yang, Jenny J

    2015-05-26

    With available MRI techniques, primary and metastatic liver cancers that are associated with high mortality rates and poor treatment responses are only diagnosed at late stages, due to the lack of highly sensitive contrast agents without Gd(3+) toxicity. We have developed a protein contrast agent (ProCA32) that exhibits high stability for Gd(3+) and a 10(11)-fold greater selectivity for Gd(3+) over Zn(2+) compared with existing contrast agents. ProCA32, modified from parvalbumin, possesses high relaxivities (r1/r2: 66.8 mmol(-1)⋅s(-1)/89.2 mmol(-1)⋅s(-1) per particle). Using T1- and T2-weighted, as well as T2/T1 ratio imaging, we have achieved, for the first time (to our knowledge), robust MRI detection of early liver metastases as small as ∼0.24 mm in diameter, much smaller than the current detection limit of 10-20 mm. Furthermore, ProCA32 exhibits appropriate in vivo preference for liver sinusoidal spaces and pharmacokinetics for high-quality imaging. ProCA32 will be invaluable for noninvasive early detection of primary and metastatic liver cancers as well as for monitoring treatment and guiding therapeutic interventions, including drug delivery.

  6. Chain elongation analog of resveratrol as potent cancer chemoprevention agent.

    Science.gov (United States)

    Kang, Yan-Fei; Qiao, Hai-Xia; Xin, Long-Zuo; Ge, Li-Ping

    2016-09-01

    Resveratrol is identified as a natural cancer chemoprevention agent. There has been a lot of interest in designing and developing resveratrol analogs with cancer chemoprevention activity superior to that of parent molecule and exploring their action mechanism in the past several decades. In this study, we have synthesized resveratrol analogs of compounds A-C via conjugated chain elongation based on isoprene unit retention strategy. Remarkably, cytotoxic activity analysis results indicated that compound B possesses the best proliferation inhibition activity for NCI-H460 cells in all the test compounds. Intriguingly, compound B displayed a higher cytotoxicity against human non-small cell lung cancer cells (NCI-H460) compared to normal human embryonic lung fibroblasts (MRC-5). Afterward, flow cytometry analysis showed that compound B would induce cell apoptosis. We further researched the action mechanism. When NCI-H460 cells were incubated by compound B for 6 or 9 h, respectively, the intracellular reactive oxygen species (ROS) level was enhanced obviously. With elevation of intracellular ROS level, flow cytometry measurement verified mitochondrial transmembrane potential collapse, which was accompanied by the up-regulation of Bax and down-regulation of Bcl-2. More interestingly, compound B increased the expression of caspase-9 and caspase-3, which induced cell apoptosis. Moreover, compound B arrested cell cycle in G0/G1 phase. These are all to provide useful information for designing resveratrol-based chemoprevention agent and understanding the action mechanism. PMID:27160168

  7. Programmed death-1 : Therapeutic success after more than 100 years of cancer immunotherapy

    NARCIS (Netherlands)

    Dömling, Alexander; Holak, Tad A

    2014-01-01

    No other cancer therapy target class caused more excitement than the programmed death-1 (PD-1) pathway related. Antibodies against PD-1 and PD-1 ligands represent a therapeutic breakthrough and are the first examples of broadly efficacious and durable cancer immunotherapies. Cancer for the first tim

  8. 76 FR 68768 - Guidance for Industry: Clinical Considerations for Therapeutic Cancer Vaccines; Availability

    Science.gov (United States)

    2011-11-07

    ... Therapeutic Cancer Vaccines; Availability AGENCY: Food and Drug Administration, HHS. ACTION: Notice. SUMMARY... treatment of patients with an existing diagnosis of cancer. The guidance does not apply to vaccines for... patients with an existing diagnosis of cancer. The guidance does not apply to vaccines for preventative...

  9. Insights into orphan nuclear receptors as prognostic markers and novel therapeutic targets for breast cancer

    OpenAIRE

    Reidun eAesoy; Colin D Clyne; Ashwini eChand

    2015-01-01

    The roles of orphan nuclear receptors in breast cancer development and progression are not well understood. In this review, we correlate orphan nuclear receptor expression in breast cancer tumour subtypes with patient outcomes and provide an overview of functional evidence that identifies candidate orphan nuclear receptors as prognostic markers or as therapeutic targets in breast cancer.

  10. A review of experimental studies of hydrogen as a new therapeutic agent in emergency and critical care medicine

    OpenAIRE

    Shen, Meihua; Zhang, Hongying; Yu, Congjun; Wang, Fan; Sun, Xuejun

    2014-01-01

    Hydrogen is the most abundant chemical element in the Universe, but is seldom regarded as a therapeutic agent. Recent evidence has shown that hydrogen is a potent antioxidative, antiapoptotic and anti-inflammatory agent and so may have potential medical applications in cells, tissues and organs. There are several methods to administer hydrogen, such as inhalation of hydrogen gas, aerosol inhalation of a hydrogen-rich solution, drinking hydrogen dissolved in water, injecting hydrogen-rich sali...

  11. Bardoxolone methyl (CDDO-Me as a therapeutic agent: an update on its pharmacokinetic and pharmacodynamic properties

    Directory of Open Access Journals (Sweden)

    Wang YY

    2014-10-01

    Full Text Available Yan-Yang Wang,1,2 Yin-Xue Yang,3 Hong Zhe,1 Zhi-Xu He,4 Shu-Feng Zhou2,4 1Department of Radiation Oncology, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, People’s Republic of China; 2Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA; 3Department of Colon-rectal Surgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, People’s Republic of China; 4Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Center and Sino-US Joint Laboratory for Medical Sciences, Guiyang Medical University, Guiyang, Guizhou, People’s Republic of China Abstract: Triterpenoids have been used for medicinal purposes in many Asian countries because of their anti-inflammatory, antioxidant, antiproliferative, anticancer, and anticarcinogenic properties. Bardoxolone methyl, the C-28 methyl ester of 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO known as CDDO-Me or RTA 402, is one of the derivatives of synthetic triterpenoids. CDDO-Me has been used for the treatment of chronic kidney disease, cancer (including leukemia and solid tumors, and other diseases. In this review, we will update our knowledge of the clinical pharmacokinetics and pharmacodynamics of CDDO-Me, highlighting its clinical benefits and the underlying mechanisms involved. The role of the Kelch-like erythroid cell-derived protein with CNC homology-associated protein 1 (Keap1/the nuclear factor erythroid 2-related factor 2 (Nrf2 pathway in the therapeutic activities of CDDO-Me will be discussed. CDDO-Me contains a,ß-unsaturated carbonyl groups on rings A and C that can generate reversible adducts with the thiol groups of Cys residues in target proteins such as Keap1 and IκB kinase. At low nanomolar concentrations, CDDO-Me protects the cells against oxidative stress via inhibition of reactive oxygen species generation, while CDDO-Me at low micromolar

  12. Natural and genetically engineered viral agents for oncolysis and gene therapy of human cancers.

    Science.gov (United States)

    Sinkovics, Joseph G; Horvath, Joseph C

    2008-12-01

    combination of naturally oncolytic viruses and wild-type viruses rendered oncolytic and harmless by genetic engineering, that will induce complete remissions of human tumors. It may be necessary to co-administer certain chemotherapeutic agents, advanced cancer vaccines, or even immune lymphocytes, and targeted therapeuticals, to ascertain, that remissions induced by the viral agents will remain complete and durable; will co-operate with anti-tumor host immune reactions, and eventually will result in cures of advanced metastatic human cancers. PMID:19104757

  13. Using lithium as a neuroprotective agent in patients with cancer

    Directory of Open Access Journals (Sweden)

    Khasraw Mustafa

    2012-11-01

    Full Text Available Abstract Neurocognitive impairment is being increasingly recognized as an important issue in patients with cancer who develop cognitive difficulties either as part of direct or indirect involvement of the nervous system or as a consequence of either chemotherapy-related or radiotherapy-related complications. Brain radiotherapy in particular can lead to significant cognitive defects. Neurocognitive decline adversely affects quality of life, meaningful employment, and even simple daily activities. Neuroprotection may be a viable and realistic goal in preventing neurocognitive sequelae in these patients, especially in the setting of cranial irradiation. Lithium is an agent that has been in use for psychiatric disorders for decades, but recently there has been emerging evidence that it can have a neuroprotective effect. This review discusses neurocognitive impairment in patients with cancer and the potential for investigating the use of lithium as a neuroprotectant in such patients.

  14. Aspirin as a chemoprevention agent for colorectal cancer.

    LENUS (Irish Health Repository)

    Lee, Chun Seng

    2012-11-01

    Colorectal cancer (CRC) is one of the leading causes of mortality in the western world. It is widely accepted that neoplasms such as colonic polyps are precursors to CRC formation; with the polyp-adenoma-carcinoma sequences well described in medical literature [1, 2]. It has been shown that Aspirin and other non-steroid anti-inflammatory drugs (NSAID) have a negative effect on polyp and cancer formation. This review aims to describe some of the mechanism behind the chemoprotective properties of aspirin; COX 2 inhibition, regulation of proliferation and apoptosis and effects on the immune system and also the current evidence that supports its use as a chemoprevention agent against CRC. We will also aim to explore the side effects with the use of aspirin and the pitfalls of using aspirin routinely for primary prophylaxis against CRC.

  15. Candidate cancer-targeting agents identified by expression-profiling arrays

    Directory of Open Access Journals (Sweden)

    Termglinchan V

    2013-04-01

    Full Text Available Vittavat Termglinchan,1 Wachiraporn Wanichnopparat,1 Kulachanya Suwanwongse,1 Chunhakarn Teeyapant,1 Kanticha Chatpermporn,1 Kanchana Leerunyakul,1 Khwanruthai Chuadpia,1 Onpailin Sirimaneethum,1 Parinya Wijitworawong,1 Wattanakitch Mutirangura,1 Chatchawit Aporntewan,2 Chanida Vinayanuwattikun,3 Apiwat Mutirangura4 1Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; 2Department of Mathematics and Computer Science, Faculty of Science, Chulalongkorn University, Bangkok, Thailand; 3Division of Medical Oncology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and The King Chulalongkorn Memorial Hospital, Bangkok, Thailand; 4Center of Excellence in Molecular Genetics of Cancer and Human Diseases, Department of Anatomy, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand Background: One particularly promising component of personalized medicine in cancer treatment is targeted therapy, which aims to maximize therapeutic efficacy while minimizing toxicity. However, the number of approved targeted agents remains limited. Expression microarray data for different types of cancer are resources to identify genes that were upregulated. The genes are candidate targets for cancer-targeting agents for future anticancer research and targeted treatments. Methods and findings: The gene expression profiles of 48 types of cancer from 2,141 microarrays reported in the Gene Expression Omnibus were analyzed. These data were organized into 78 experimental groups, on which we performed comprehensive analyses using two-tailed Student's t-tests with significance set at P < 0.01 to identify genes that were upregulated compared with normal cells in each cancer type. The resulting list of significantly upregulated genes was cross-referenced with three categories of protein inhibitor targets, categorized by inhibitor type ('Targets of US Food and Drug Administration (FDA-approved anticancer drugs', 'Targets of FDA

  16. Use of incretin agents and risk of pancreatic cancer

    DEFF Research Database (Denmark)

    Knapen, L M; van Dalem, J; Keulemans, Y C;

    2016-01-01

    AIM: To investigate the association between the use of incretin agents and the risk of pancreatic cancer. METHODS: A retrospective population-based cohort study, using data from the Clinical Practice Research Datalink, 2007-2012, was conducted. Patients (n = 182 428) with at least one non......-insulin antidiabetic drug (NIAD) prescription and aged ≥18 years during data collection, were matched one-to-one to control patients without diabetes. Multivariable Cox proportional hazards models and a new user design were used to estimate the hazard ratio (HR) of pancreatic cancer in incretin users (n = 28 370...... of pancreatic cancer [HR 4.28, 95% confidence interval (CI) 3.49-5.24]. This risk was almost doubled among current incretin users as compared with control subjects. Incretin use was not associated with pancreatic cancer when compared with control subjects with diabetes (HR 1.36, 95% CI 0.94-1.96); however...

  17. Glucose-lowering agents and the patterns of risk for cancer

    DEFF Research Database (Denmark)

    van Staa, T P; Patel, D; Gallagher, A M;

    2012-01-01

    INTRODUCTION: Recent studies suggesting an increased cancer risk with glucose-lowering agents have received widespread publicity. The objectives of this study were to evaluate the comparability in underlying cancer risk and patterns of cancer risk over time with different glucose-lowering agents....

  18. [Weighing use and safety of therapeutic agents and feed additives (author's transl)].

    Science.gov (United States)

    van der Wal, P

    1982-02-01

    (1) The pros and cons of using feed additives and therapeutic agents may be successfully weighed in the light of carefully considered consumer requirements. (2) The socio-economic interests of the producer and the welfare of the animal will also determine the response of the production apparatus to consumer requirements. (3) Consumption of the current amounts of products of animal origin and maintenance of price and quality will only be feasible in the event of rational large-scale production in which constituents used in nutrition, prophylaxis and therapeutics are highly important factors. (4) Using these ingredients should be preceded by accurate evaluation of their use and safety. Testing facilities, conduct of studies and reporting should be such as to make the results nationally and internationally acceptable to all those concerned. (5) In deciding whether feed constituents are acceptable in view of the established use and safety, compliance will have to be sought with those standards which are accepted in other fields of society. Measures which result in raising the price of food without actually helping to reduce the risks to the safety of man, animals and environment, are likely to be rejected by any well-informed consumer who is aware of the facts. (6) For accurate weighing of use and safety at a national level, possibilities are hardly adequate in Europe. Decisions reached within the framework of the European Community, also tuned to U.S.A.- conditions are rightly encouraged. A centrally managed professionally staffed and equipped test system in the European Community would appear to be indispensable. PMID:7058519

  19. Hedgehog pathway aberrations and gastric cancer; evaluation of prognostic impact and exploration of therapeutic potentials.

    Science.gov (United States)

    Abdel-Rahman, Omar

    2015-03-01

    Gastric cancer is an important cause for mortality and morbidity worldwide; it lies in the fourt rank as a cause of cancer-related death in males and in the fifth rank of cancer-related death in women. The prognosis of advanced/metastatic gastric cancer cases looks poor with the majority of available therapeutics. Thus, novel therapeutic strategies in this setting have been considered a priority for leading cooperative oncology groups. Hedgehog(Hh) pathway aberrations have sparked particular interest as prognostic markers with data from multiple studies showing consistent evidence of a poor prognostic value of Gli over expression in gastric cancer while on the other hand the prognostic significance of Hh protein over expression (particularly SHH) was not consistent among different studies. This review article revises the prognostic and potential therapeutic opportunities in the targeting of hedgehog pathway in gastric cancer. PMID:25680409

  20. Interactions between radiopharmaceuticals and therapeutic agents: Animal experiments on the influence of therapeutic agents on the pharmacokinetics of 99m-Tc-methylene diphosphonate

    International Nuclear Information System (INIS)

    In this study examined if skeletal uptake, distribution or excretion of 99m-Tc-methylene-diphosphonate (99m-Tc- MDP) will change under the influence of different therapeutic drugs or the state of dehydration. As therapeutic drugs we chose tetracyclines, sympathomimetic drugs, sympatholytic drugs, diuretics, a Ca-antagonist and a corticosteroid. The state of dehydration of the laboratory animals (female Wistar-rats) was achieved by withdrawal of drinking water for 48 hours. The activity was measured in the organs or body compartments blood, kidney, lung, liver, skeletal muscle and femur. The measurements were performed 2 hours after the application of the radiopharmaceutical. (orig./MG)

  1. Discovery of Narrow Spectrum Kinase Inhibitors: New Therapeutic Agents for the Treatment of COPD and Steroid-Resistant Asthma.

    Science.gov (United States)

    Onions, Stuart T; Ito, Kazuhiro; Charron, Catherine E; Brown, Richard J; Colucci, Marie; Frickel, Fritz; Hardy, George; Joly, Kevin; King-Underwood, John; Kizawa, Yasuo; Knowles, Ian; Murray, P John; Novak, Andrew; Rani, Anjna; Rapeport, Garth; Smith, Alun; Strong, Peter; Taddei, David M; Williams, Jonathan G

    2016-03-10

    The discovery of a novel series of therapeutic agents that has been designed and optimized for treating chronic obstructive pulmonary disease is reported. The pharmacological strategy was based on the identification of compounds that inhibit a defined subset of kinase enzymes modulating inflammatory processes that would be effective against steroid refractory disease and exhibit a sustained duration of action after inhaled delivery. PMID:26800309

  2. Use of F-18 FDG PET for therapeutic monitoring in locally advanced head and neck cancers

    International Nuclear Information System (INIS)

    Full text: Locally advanced head and neck cancer has a poor prognosis likely, in part, reflecting radioresistance due to tumour-related hypoxia In 12 patients with bulky head and neck cancer, therapeutic response to a novel chemo-radiotherapy including an agent which specifically targets hypoxic cells was evaluated by serial FDG-PET. Standardised uptake values (SUV) were calculated for the primary lesion and lymph node (LN) metastases at 4 weeks (mid-treatment) and 12 weeks after completion of treatment (20 weeks). All patients had a significant reduction in SUV in the primary (Mean 67±8%, range 54-84%, p<0 05) and LN (Mean 57±13%, Range 23-73%, p<0 05) by 4 weeks which often preceded clinical evidence of response, particularly in nodal masses. In 8/9 patients evaluated thus far at 20 weeks, a further reduction was seen in the primary (Mean 74±9%, Range 67-87%, p < 0 05)and LN (Mean 74±13%, Range 41-83%, p < 0 02) correlating with excellent clinical and CT response. The other pt with an SUV of 23.2 at baseline had an increase in SUV from 5.5 on the 4 week study to 15.5 at week 20, corresponding to clinical and CT relapse. These preliminary results indicate the potential of FDG-PET for early assessment of the efficacy of experimental treatment regimens even in dose escalation (phase I) trials

  3. Therapeutic potential of thiazolidinedione-8 as an antibiofilm agent against Candida albicans.

    Directory of Open Access Journals (Sweden)

    Mark Feldman

    Full Text Available Candida albicans is known as a commensal microorganism but it is also the most common fungal pathogen in humans, causing both mucosal and systemic infections. Biofilm-associated C. albicans infections present clinically important features due to their high levels of resistance to traditional antifungal agents. Quorum sensing is closely associated with biofilm formation and increasing fungal pathogenicity. We investigated the ability of the novel bacterial quorum sensing quencher thiazolidinedione-8 (S-8 to inhibit the formation of, and eradication of mature C. albicans biofilms. In addition, the capability of S-8 to alter fungal adhesion to mammalian cells was checked. S-8 exhibited specific antibiofilm and antiadhesion activities against C. albicans, at four- to eightfold lower concentrations than the minimum inhibitory concentration (MIC. Using fluorescence microscopy, we observed that S-8 dose-dependently reduces C. albicans-GFP binding to RAW macrophages. S-8 at sub-MICs also interfered with fungal morphogenesis by inhibiting the yeast-to-hyphal form transition. In addition, the tested agent strongly affected fungal cell wall characteristics by modulating its hydrophobicity. We evaluated the molecular mode of S-8 antibiofilm and antiadhesion activities using real-time RT-PCR. The expression levels of genes associated with biofilm formation, adhesion and filamentation, HWP1, ALS3 and EAP1, respectively, were dose-dependently downregulated by S-8. Transcript levels of UME6, responsible for long-term hyphal maintenance, were also significantly decreased by the tested agent. Both signaling pathways of hyphal formation-cAMP-PKA and MAPK-were interrupted by S-8. Their upstream general regulator RAS1 was markedly suppressed by S-8. In addition, the expression levels of MAPK cascade components CST20, HST7 and CPH1 were downregulated by S-8. Finally, transcriptional repressors of filament formation, TUP1 and NRG1, were dramatically upregulated by our

  4. CRISPRi and CRISPRa: New Functional Genomics Tools Provide Complementary Insights into Cancer Biology and Therapeutic Strategies | Office of Cancer Genomics

    Science.gov (United States)

    A central goal of research for targeted cancer therapy, or precision oncology, is to reveal the intrinsic vulnerabilities of cancer cells and exploit them as therapeutic targets. Examples of cancer cell vulnerabilities include driver oncogenes that are essential for the initiation and progression of cancer, or non-oncogene addictions resulting from the cancerous state of the cell. To identify vulnerabilities, scientists perform genetic “loss-of-function” and “gain-of-function” studies to better understand the roles of specific genes in cancer cells.

  5. Nanosized tamoxifen-porphyrin-glucose [TPG] conjugate: novel selective anti-breast-cancer agent, synthesis and in vitro evaluations.

    Science.gov (United States)

    Amanlou, Massoud; Heidari, Zahra; Siadat, Seyed Davar; Aghasadeghi, Mohammad Reza; Ghorbani, Masoud; Ebrahimi, Seyed Esmaeil Sadat; Sadat, Seyed Mehdi; Hajmohammadi, Mehdi; Arabzadeh, Ali Jabbari; Hekmat, Soheila; Alaei-Beirami, Mahmood; Saraji, Alireza Azizi; Moghaddam, Hadi Fathi; Alavidjeh, Mohammad Shafiee; Delbaz, Seyed Ali; Dashtbani-Roozbehani, Abolfazl; Ardestani, Mehdi Shafiee

    2013-06-01

    Tumor and especially breast cancer is among the most common causes of death worldwide. Finding novel nanosized therapeutic compounds have important role to decrease the chance of death and increase the survival. Cancer cells are highly attractive to glucose [with a nanosize bimolecular structure 1nm] as an energy source more than normal cell and nanosized therapeutics due to possessing different pharmacokinetic and pharmacodynamic have advantageous over classical dosage forms in cancer therapy. The aim of the study was to synthesize Glucosamin-Porphyrin-Tamoxifen [TPG] nanosized complex as a novel selective biocompatible anti breast cancer agent. After the synthesis procedure, this complex was purified and then tested In Vitro on breast cancer cells [MCF-7] in the absence or presence of the red light and found totally successful. The results showed a good anti breast cancer activity mediated by the activation of TNF-α and necrosis/apoptosis pathways for the nanosized complex with no alteration effects on blood PT/APTT and glucose or hexokinase levels/ activity. TPG nanoconjugate seems to be very good opponents to current anti breast cancer drugs and needs to be further investigated in near future.

  6. Natural therapeutic agents for neurodegenerative diseases from a traditional herbal medicine Pongamia pinnata (L.) Pierre.

    Science.gov (United States)

    Li, Jiayuan; Jiang, Zhe; Li, Xuezheng; Hou, Yue; Liu, Fen; Li, Ning; Liu, Xia; Yang, Lihua

    2015-01-01

    Neurodegenerative diseases are associated with neuroinflammation, manifested by over-production of nitric oxide (NO) by microglial cells. Now there still lack effective treatment and prevention for the neurodegenerative diseases. Concerning neuroinflammation mediated by microglia cell, bioactivity-guided phytochemical research of Pongamia pinnata (L.) Pierre was performed in this study. A new chlorinated flavonoid, 2′,6′-dichlore-3′, 5′-dimethoxy-[2′′,3′′:7,8]-furanoflavone (1) was identified together with 29 known compounds, including flavonoids (compounds 2-17), isoflavonoids (compounds 18-23), chalcones (compounds 24-25), flavonones (compounds 26-27), triterpenes (28-29) and alkaloid (30) from the effective dichloride methane extract of dry stem of P. pinnata (L.) Pierre. Their structures were elucidated by physicochemical and spectral methods. The anti-neuroinflammatory activities were assayed in BV-2 cells by assessing LPS-induced NO production. Then pongaglabol methyl ether (2), lonchocarpin (24) and glabrachromene II (25) were selected as potential therapeutic agents for neurodegenerative diseases because of their significant anti-neuroinflammatory activities. Furthermore, the characteristics of structure type existing in P. pinnata (L.) Pierre and brief SAR were summarized, respectively.

  7. Chemically modified tetracyclines: Novel therapeutic agents in the management of chronic periodontitis

    Directory of Open Access Journals (Sweden)

    Rupali Agnihotri

    2012-01-01

    Full Text Available Chronic periodontitis is a complex infection initiated by gram-negative bacteria which destroy the supporting structures of the tooth. Recently, it has been recognized that it is the host response to bacterial infection which causes greater destruction of the connective tissue elements, periodontal ligament and alveolar bone in periodontitis. This has led to the development of various host modulating approaches to target cells and their destructive mediators involved in tissue degradation. Chemically modified tetracyclines (CMTs are derivatives of tetracycline group of drugs which lack antimicrobial action but have potent host modulating affects. They inhibit pathologically elevated matrix metal loproteinases, pro-inflammtory cytokines and other destructive mediators. Bone resorption is also suppressed due to their combined anti-proteinase and apoptotic affects on osteoblasts and osteoclasts, respectively. Development of resistant bacteria and gastrointestinal toxicity seen with parent tetracyclines is not produced by CMTs. Hence, CMTs are viewed as potential therapeutic agents in the management of chronic diseases like periodontitis that involve destruction of connective tissue and bone.

  8. Efficient refolding of the bifunctional therapeutic fusion protein VAS-TRAIL by a triple agent solution.

    Science.gov (United States)

    Fan, Jiying; Wang, Zhanqing; Huang, Liying; Shen, Yaling

    2016-09-01

    VAS-TRAIL is a bifunctional fusion protein that combines anti-angiogenic activity with tumor-selective apoptotic activity for enhanced anti-tumor efficacy. VAS-TRAIL is expressed as inclusion body in Escherichia coli, but protein refolding is difficult to achieve and results in low yields of bioactive protein. In this study, we describe an efficient method for VAS-TRAIL refolding. The solubilization of aggregated VAS-TRAIL was achieved by a triple agent solution, which consists of an alkaline solution (pH 11.5) containing 0.4M l-arginine and 2M urea. The solubilized protein showed high purity and preserved secondary structure according to fluorescence properties. VAS-TRAIL refolding was performed through stepwise dialysis and resulted in more than 50% recovery of the soluble protein. The function of l-arginine was additive with alkaline pH, as shown by the significant improvement in refolding yield (≈30%) by l-arginine-containing solubilization solutions compared with alkaline solubilization solutions without l-arginine. The refolded VAS-TRAIL also showed β-sheet structures and the propensity for oligomerization. Bioassays showed that the refolded fusion protein exhibited the expected activities, including its apoptotic activities toward tumor and endothelial cells, which proposed its promising therapeutic potential. PMID:26358405

  9. Tumor Progression Locus 2 (Tpl2 Kinase as a Novel Therapeutic Target for Cancer: Double-Sided Effects of Tpl2 on Cancer

    Directory of Open Access Journals (Sweden)

    Hye Won Lee

    2015-02-01

    Full Text Available Tumor progression locus 2 (Tpl2 is a mitogen-activated protein kinase (MAPK kinase kinase (MAP3K that conveys various intra- and extra-cellular stimuli to effector proteins of cells provoking adequate adoptive responses. Recent studies have elucidated that Tpl2 is an indispensable signal transducer as an MAP3K family member in diverse signaling pathways that regulate cell proliferation, survival, and death. Since tumorigenesis results from dysregulation of cellular proliferation, differentiation, and apoptosis, Tpl2 participates in many decisive molecular processes of tumor development and progression. Moreover, Tpl2 is closely associated with cytokine release of inflammatory cells, which has crucial effects on not only tumor cells but also tumor microenvironments. These critical roles of Tpl2 in human cancers make it an attractive anti-cancer therapeutic target. However, Tpl2 contradictorily works as a tumor suppressor in some cancers. The double-sided effects of Tpl2 originate from the specific upstream and downstream signaling environment of each tumor, since Tpl2 interacts with various signaling components. This review summarizes recent studies concerning the possible roles of Tpl2 in human cancers and considers its possibility as a therapeutic target, against which novel anti-cancer agents could be developed.

  10. Crystal structures of Two Potential Tumor Imaging Agents and Therapeutic Agents-Copper(II)Ternary Complexes With Salicylidene-tyrosinato Schiff Base and Nitrogen-donor Chelating Lewis Base

    Institute of Scientific and Technical Information of China (English)

    Ming Zhao WANG; Guan Liang CAI; Ling XIA; Jun Jian YAO; Hong Yan CHEN; Zhao Xing MENG; Bo Li LIU

    2004-01-01

    The crystal structures of two potential tumor imaging agents and therapeutic agents -copper(II) complexes with salicylidene-tyrosinato Schiff base and nitrogen-donor chelating Lewis base,[Cu(sal-tyr)(bipy)] 1 and [Cu(sal-tyr)(phen)]·2CH3OH 2, are presented. Our work is helpful to get deep understanding of novel 64Cu tumor imaging agents and therapeutic agents.

  11. Mesoporous silica nanoparticles with organo-bridged silsesquioxane framework as innovative platforms for bioimaging and therapeutic agent delivery.

    Science.gov (United States)

    Du, Xin; Li, Xiaoyu; Xiong, Lin; Zhang, Xueji; Kleitz, Freddy; Qiao, Shi Zhang

    2016-06-01

    Mesoporous silica material with organo-bridged silsesquioxane frameworks is a kind of synergistic combination of inorganic silica, mesopores and organics, resulting in some novel or enhanced physicochemical and biocompatible properties compared with conventional mesoporous silica materials with pure Si-O composition. With the rapid development of nanotechnology, monodispersed nanoscale periodic mesoporous organosilica nanoparticles (PMO NPs) and organo-bridged mesoporous silica nanoparticles (MSNs) with various organic groups and structures have recently been synthesized from 100%, or less, bridged organosilica precursors, respectively. Since then, these materials have been employed as carrier platforms to construct bioimaging and/or therapeutic agent delivery nanosystems for nano-biomedical application, and they demonstrate some unique and/or enhanced properties and performances. This review article provides a comprehensive overview of the controlled synthesis of PMO NPs and organo-bridged MSNs, physicochemical and biocompatible properties, and their nano-biomedical application as bioimaging agent and/or therapeutic agent delivery system. PMID:27017579

  12. Gastric cancer stem cells: A novel therapeutic target

    OpenAIRE

    Singh, Shree Ram

    2013-01-01

    Gastric cancer remains one of the leading causes of global cancer mortality. Multipotent gastric stem cells have been identified in both mouse and human stomachs, and they play an essential role in the self-renewal and homeostasis of gastric mucosa. There are several environmental and genetic factors known to promote gastric cancer. In recent years, numerous in vitro and in vivo studies suggest that gastric cancer may originate from normal stem cells or bone marrow–derived mesenchymal cells, ...

  13. microRNAs as neuroregulators, biomarkers and therapeutic agents in neurodegenerative diseases.

    Science.gov (United States)

    Basak, Indranil; Patil, Ketan S; Alves, Guido; Larsen, Jan Petter; Møller, Simon Geir

    2016-02-01

    The last decade has experienced the emergence of microRNAs as a key molecular tool for the diagnosis and prognosis of human diseases. Although the focus has mostly been on cancer, neurodegenerative diseases present an exciting, yet less explored, platform for microRNA research. Several studies have highlighted the significance of microRNAs in neurogenesis and neurodegeneration, and pre-clinical studies have shown the potential of microRNAs as biomarkers. Despite this, no bona fide microRNAs have been identified as true diagnostic or prognostic biomarkers for neurodegenerative disease. This is mainly due to the lack of precisely defined patient cohorts and the variability within and between individual cohorts. However, the discovery that microRNAs exist as stable molecules at detectable levels in body fluids has opened up new avenues for microRNAs as potential biomarker candidates. Furthermore, technological developments in microRNA biology have contributed to the possible design of microRNA-mediated disease intervention strategies. The combination of these advancements, with the availability of well-defined longitudinal patient cohort, promises to not only assist in developing invaluable diagnostic tools for clinicians, but also to increase our overall understanding of the underlying heterogeneity of neurodegenerative diseases. In this review, we present a comprehensive overview of the existing knowledge of microRNAs in neurodegeneration and provide a perspective of the applicability of microRNAs as a basis for future therapeutic intervention strategies.

  14. Periostin: a promising target of therapeutical intervention for prostate cancer

    Directory of Open Access Journals (Sweden)

    Ding Weihong

    2011-06-01

    Full Text Available Abstract Background In our recent study, Periostin was up-regulated in prostate cancer(PCa compared with benign prostate hyperplasia (BPH by proteomics analysis of prostate biopsies. We investigated the effect of sliencing Periostin by RNA interference (RNAi on the proliferation and migration of PCa LNCap cell line. Methods All the prostate biopsies from PCa, BPH and BPH with local prostatic intraepithelial neoplasm(PIN were analyzed by iTRAQ(Isobaric tags for relative and absolute quantification technology. Western blotting and immunohistochemical staining were used to verify Periostin expression in the tissues of PCa. Periostin expression in different PCa cell lines was determined by immunofluorescence staining, western blotting and reverse transcription PCR(RT-PCR. The LNCap cells with Periostin expression were used for transfecting shRNA-Periostin lentiviral particles. The efficancy of transfecting shRNA lentiviral particles was evaluated by immunofluorescence, western blotting and Real-time PCR. The effect of silencing Periostin expression by RNAi on proliferation of LNCap cells was determined by MTT assay and tumor xenografts. The tissue slices from theses xenografts were analyzed by hematoxylin and eosin(HE staining. The expression of Periostin in the xenografts was deteminned by Immunohistochemical staining and western blotting. The migration of LNCap cells after silencing Periostin gene expression were analyzed in vitro. Results Periostin as the protein of interest was shown 9.12 fold up-regulation in PCa compared with BPH. The overexpression of Periostin in the stroma of PCa was confirmed by western blotting and immunohistochemical staining. Periostin was only expressed in PCa LNCap cell line. Our results indicated that the transfection ratio was more than 90%. As was expected, both the protein level and mRNA level of Periostin in the stably expressing shRNA-Periostin LNCap cells were significantly reduced. The stably expressing sh

  15. Design and synthesis of an in vivo-efficacious PIM3 kinase inhibitor as a candidate anti-pancreatic cancer agent.

    Science.gov (United States)

    Nakano, Hirofumi; Hasegawa, Tsukasa; Saito, Nae; Furukawa, Kaoru; Mukaida, Naofumi; Kojima, Hirotatsu; Okabe, Takayoshi; Nagano, Tetsuo

    2015-12-15

    Serine/threonine kinase PIM3 is a potential therapeutic target for pancreatic cancer. Here, we describe the evolution of our previous PIM1 inhibitor 1 into PIM3 inhibitor 11 guided by use of the crystal structure of PIM1 as a surrogate to provide a basis for rational modification. Compound 11 potently inhibits PIM3 kinase activity, as well as growth of several pancreatic cancer cell lines. In a mouse xenograft model, 11 inhibited growth of human pancreatic cancer cell line PCI66 with negligible body weight loss. Thus, 11 appears to be a promising lead compound for further optimization to develop new anti-pancreatic cancer agents. PMID:26547690

  16. Combinatorial strategies for cancer eradication by silibinin and cytotoxic agents: efficacy and mechanisms

    Institute of Scientific and Technical Information of China (English)

    Komal RAINA; Rajesh AGARWAL

    2007-01-01

    In an effort to develop effective alternative strategies that increase the therapeu-tic efficacy and minimize the systemic toxicity of chemotherapeutic agents, more efforts are being directed towards the investigation of dietary supplements and other phytotherapeutic agents for their synergistic efficacy in combination with anticancer drugs. One such agent is silibinin, which has shown promising chemopreventive and anticancer effects in various in vitro and in vivo studies.The present review summarizes the effects of the combination of silibinin and chemotherapeutic drugs on the growth inhibition, cell cycle regulation, and apoptosis induction in prostate, breast, and lung cancer systems. Together, the results indicate a synergistic effect of silibinin on growth inhibition, reversal of chemoresistance, apoptosis induction, and a strong increase in G2-M checkpoint arrest when given in combination with these drugs. These results are highly significant with respect to the combined chemotherapy approach, wherein thecriteria for combination is that the response has to be synergistic and that the drugs should not share common mechanisms of resistance and not overlap in their major side-effects.

  17. Breast cancer phenotypes regulated by tissue factor-factor VII pathway: Possible therapeutic targets.

    Science.gov (United States)

    Koizume, Shiro; Miyagi, Yohei

    2014-12-10

    Breast cancer is a leading cause of cancer death in women, worldwide. Fortunately, breast cancer is relatively chemosensitive, with recent advances leading to the development of effective therapeutic strategies, significantly increasing disease cure rate. However, disease recurrence and treatment of cases lacking therapeutic molecular targets, such as epidermal growth factor receptor 2 and hormone receptors, referred to as triple-negative breast cancers, still pose major hurdles in the treatment of breast cancer. Thus, novel therapeutic approaches to treat aggressive breast cancers are essential. Blood coagulation factor VII (fVII) is produced in the liver and secreted into the blood stream. Tissue factor (TF), the cellular receptor for fVII, is an integral membrane protein that plays key roles in the extrinsic coagulation cascade. TF is overexpressed in breast cancer tissues. The TF-fVII complex may be formed in the absence of injury, because fVII potentially exists in the tissue fluid within cancer tissues. The active form of this complex (TF-fVIIa) may stimulate the expression of numerous malignant phenotypes in breast cancer cells. Thus, the TF-fVII pathway is a potentially attractive target for breast cancer treatment. To date, a number of studies investigating the mechanisms by which TF-fVII signaling contributes to breast cancer progression, have been conducted. In this review, we summarize the mechanisms controlling TF and fVII synthesis and regulation in breast cancer cells. Our current understanding of the TF-fVII pathway as a mediator of breast cancer progression will be also described. Finally, we will discuss how this knowledge can be applied to the design of future therapeutic strategies. PMID:25493229

  18. Stem cells and lung cancer: future therapeutic targets?

    Science.gov (United States)

    Alison, Malcolm R; Lebrenne, Arielle C; Islam, Shahriar

    2009-09-01

    In both the UK and USA more people die of lung cancer than any other type of cancer. Lung cancer's high mortality rate is also reflected on a global scale, with lung cancer accounting for more than 1 million deaths per year. In tissues with ordered structure such a lung epithelia, it is likely that the cancers have their origins in normal adult stem cells, and then the tumours themselves are maintained by a population of malignant stem cells - so-called cancer stem cells. This review examines both these postulates in animal models and in the clinical setting, noting that stem cell niches appear to foster tumour development, and that drug resistance can often be attributed to malignant cells with stem cell properties. PMID:19653862

  19. Parenteral anticoagulation in patients with cancer who have no therapeutic or prophylactic indication for anticoagulation

    NARCIS (Netherlands)

    E.A. Akl; S. Gunukula; M. Barba; V.E.D. Yosuico; F.F. van Doormaal; S. Kuipers; S. Middeldorp; H.O. Dickinson; A. Bryant; H. Schuenemann

    2011-01-01

    Background Anticoagulation may improve survival in patients with cancer through an antitumor effect in addition to the perceived antithrombotic effect. Objectives To evaluate the efficacy and safety of parenteral anticoagulants in patients with cancer with no therapeutic or prophylactic indication f

  20. DIAGNOSTIC AND THERAPEUTIC POSSIBILITIES IN THE PROPHYLAXIS OF CERVICAL CANCER

    OpenAIRE

    Marzena Wrześniewska; Olga Adamczyk-Gruszka; Jakub Gruszka; Beata Bąk

    2013-01-01

    Poland is one of the countries with high cervical cancer morbidity and mortality. The main means to change this situation is to manage an active and modern programme of cervical cancer prophylaxis and diagnostics. To a large extent, the effectiveness of a cervical cancer prophylaxis programme is decided by the availability of modern diagnostic research. The conventional Papanicolaou test and modern LBC cytology techniques were discussed in the article, taking into consideration HPV diagno...

  1. THERAPEUTIC APPROACH TO CANCER BY VEGETABLES WITH ANTIOXIDANT ACTIVITY

    OpenAIRE

    Pandey Govind; Madhuri S.

    2011-01-01

    Cancer is the second leading cause of human deaths in the world. However, the potential treatment of cancer is still under investigation. In fact, the plants may occupy a good place in the treatment of cancer with no ill effect. The medicinal plants and their products, particularly vegetables have antioxidant activity leading to anticancer effect. Thus, more than 80% people in developing countries depend on traditional medicine or plants for their primary health needs. Plants used as vegetabl...

  2. Pancreatic cancer cachexia: a review of mechanisms and therapeutics

    OpenAIRE

    Carlyn Rose Tan; Laith eJamil; Patrick eYaffee; Richard eTuli; Nick eNissen; Simon eLo; Stephen J Pandol; Andrew Eugene Hendifar

    2014-01-01

    Over the last decade, we have gained new insight into the pathophysiology of cachexia associated with pancreatic cancer. Unfortunately, its treatment is complex and remains a challenge. Pancreatic cancer cachexia is a multifactorial syndrome characterized by uncompensated adipose tissue and skeletal muscle loss in the setting of anorexia that leads to progressive functional impairment. This paper will review the current concepts of pancreatic cancer cachexia, its assessment and pathophysiolog...

  3. Development of the Fibulin-3 protein therapeutics of non small cell lung cancer stem cells

    International Nuclear Information System (INIS)

    This study focuses on developing an efficient bioprocess for large-scale production of fibulin-3 using Chinese Hamster Ovary cell expression system and evaluating its therapeutic potential for the treatment of cancer. The specific aims are as follows: Isolation and establishment of CSCs using FACS based on cell surface markers and high ALDH1 activity. Identification and characterization of lung cancer stem cells that acquire features of CSC upon exposure to ionizing radiation. Evaluation of the fibulin-3 effects on the stem traits and signaling pathways required for the generation and maintenance of CSCs. In vivo validation of fivulin-3 for tumor prognosis and therapeutic efficacy against lung cancer using animal model

  4. Development of the Fibulin-3 protein therapeutics of non small cell lung cancer stem cells

    Energy Technology Data Exchange (ETDEWEB)

    Kim, In Gyu; Kim, Kugchan; Jung, Il Lae; Kim, Seo Yeon; Choi, Su Im; Lee, Jae Ha

    2013-09-15

    This study focuses on developing an efficient bioprocess for large-scale production of fibulin-3 using Chinese Hamster Ovary cell expression system and evaluating its therapeutic potential for the treatment of cancer. The specific aims are as follows: Isolation and establishment of CSCs using FACS based on cell surface markers and high ALDH1 activity. Identification and characterization of lung cancer stem cells that acquire features of CSC upon exposure to ionizing radiation. Evaluation of the fibulin-3 effects on the stem traits and signaling pathways required for the generation and maintenance of CSCs. In vivo validation of fivulin-3 for tumor prognosis and therapeutic efficacy against lung cancer using animal model.

  5. Biodegradable polymer based theranostic agents for photoacoustic imaging and cancer therapy

    Science.gov (United States)

    Wang, Yan J.; Strohm, Eric M.; Kolios, Michael C.

    2016-03-01

    In this study, multifunctional theranostic agents for photoacoustic (PA), ultrasound (US), fluorescent imaging, and for therapeutic drug delivery were developed and tested. These agents consisted of a shell made from a biodegradable Poly(lactide-co-glycolic acid) (PLGA) polymer, loaded with perfluorohexane (PFH) liquid and gold nanoparticles (GNPs) in the core, and lipophilic carbocyanines fluorescent dye DiD and therapeutic drug Paclitaxel (PAC) in the shell. Their multifunctional capacity was investigated in an in vitro study. The PLGA/PFH/DiD-GNPs particles were synthesized by a double emulsion technique. The average PLGA particle diameter was 560 nm, with 50 nm diameter silica-coated gold nano-spheres in the shell. MCF7 human breast cancer cells were incubated with PLGA/PFH/DiDGNPs for 24 hours. Fluorescent and PA images were recorded using a fluorescent/PA microscope using a 1000 MHz transducer and a 532 nm pulsed laser. For the particle vaporization and drug delivery test, MCF7 cells were incubated with the PLGA/PFH-GNPs-PAC or PLGA/PFH-GNPs particles for 6, 12 and 24 hours. The effects of particle vaporization and drug delivery inside the cells were examined by irradiating the cells with a laser fluence of 100 mJ/cm2, and cell viability quantified using the MTT assay. The PA images of MCF7 cells containing PLGA/PFH/DiD-GNPs were spatially coincident with the fluorescent images, and confirmed particle uptake. After exposure to the PLGA/PFHGNP- PAC for 6, 12 and 24 hours, the cell survival rate was 43%, 38%, and 36% respectively compared with the control group, confirming drug delivery and release inside the cells. Upon vaporization, cell viability decreased to 20%. The particles show potential as imaging agents and drug delivery vehicles.

  6. Animal models and therapeutic molecular targets of cancer: utility and limitations

    OpenAIRE

    Cekanova M; Rathore K

    2014-01-01

    Maria Cekanova, Kusum Rathore Department of Small Animal Clinical Sciences, College of Veterinary Medicine, The University of Tennessee, Knoxville, TN, USA Abstract: Cancer is the term used to describe over 100 diseases that share several common hallmarks. Despite prevention, early detection, and novel therapies, cancer is still the second leading cause of death in the USA. Successful bench-to-bedside translation of basic scientific findings about cancer into therapeutic interventions for pa...

  7. MicroRNA-based Cancer Therapeutics: Big Hope from Small RNAs

    OpenAIRE

    Bhardwaj, Arun; Singh, Seema; Ajay P Singh

    2010-01-01

    Tremendous progress has been made during the last few years in identification of novel tumor-associated microRNAs and experimental validation of their cancer relevant gene targets. Indeed, these small non-coding RNAs are now known to modulate many biological pathways related to cancer progression, metastasis and therapy-resistance. Therefore, modulating miRNA functions may provide novel therapeutic opportunities for cancer treatment. This article reviews recent literature on the role of miRNA...

  8. Cancer as a metabolic disease: implications for novel therapeutics.

    Science.gov (United States)

    Seyfried, Thomas N; Flores, Roberto E; Poff, Angela M; D'Agostino, Dominic P

    2014-03-01

    Emerging evidence indicates that cancer is primarily a metabolic disease involving disturbances in energy production through respiration and fermentation. The genomic instability observed in tumor cells and all other recognized hallmarks of cancer are considered downstream epiphenomena of the initial disturbance of cellular energy metabolism. The disturbances in tumor cell energy metabolism can be linked to abnormalities in the structure and function of the mitochondria. When viewed as a mitochondrial metabolic disease, the evolutionary theory of Lamarck can better explain cancer progression than can the evolutionary theory of Darwin. Cancer growth and progression can be managed following a whole body transition from fermentable metabolites, primarily glucose and glutamine, to respiratory metabolites, primarily ketone bodies. As each individual is a unique metabolic entity, personalization of metabolic therapy as a broad-based cancer treatment strategy will require fine-tuning to match the therapy to an individual's unique physiology. PMID:24343361

  9. Emerging role of cancer stem cells in the biology and treatment of ovarian cancer: basic knowledge and therapeutic possibilities for an innovative approach.

    Science.gov (United States)

    Tomao, Federica; Papa, Anselmo; Rossi, Luigi; Strudel, Martina; Vici, Patrizia; Lo Russo, Giuseppe; Tomao, Silverio

    2013-08-01

    In 2013 there will be an estimated 22,240 new diagnoses and 14,030 deaths from ovarian cancer in the United States. Despite the improved surgical approach and the novel active drugs that are available today in clinical practice, about 80% of women presenting with late-stage disease have a 5-year survival rate of only 30%. In the last years a growing scientific knowledge about the molecular pathways involved in ovarian carcinogenesis has led to the discovery and evaluation of several novel molecular targeted agents, with the aim to test alternative models of treatment in order to overcome the clinical problem of resistance. Cancer stem cells tend to be more resistant to chemotherapeutic agents and radiation than more differentiated cellular subtypes from the same tissue. In this context the study of ovarian cancer stem cells is taking on an increasingly important strategic role, mostly for the potential therapeutic application in the next future. In our review, we focused our attention on the molecular characteristics of epithelial ovarian cancer stem cells, in particular on possible targets to hit with targeted therapies.

  10. The evidence for natural therapeutics as potential anti-scarring agents in burn-related scarring.

    Science.gov (United States)

    Mehta, M; Branford, O A; Rolfe, K J

    2016-01-01

    Though survival rate following severe thermal injuries has improved, the incidence and treatment of scarring have not improved at the same speed. This review discusses the formation of scars and in particular the formation of hypertrophic scars. Further, though there is as yet no gold standard treatment for the prevention or treatment of scarring, a brief overview is included. A number of natural therapeutics have shown beneficial effects both in vivo and in vitro with the potential of becoming clinical therapeutics in the future. These natural therapeutics include both plant-based products such as resveratrol, quercetin and epigallocatechin gallate as examples and includes the non-plant-based therapeutic honey. The review also includes potential mechanism of action for the therapeutics, any recorded adverse events and current administration of the therapeutics used. This review discusses a number of potential 'treatments' that may reduce or even prevent scarring particularly hypertrophic scarring, which is associated with thermal injuries without compromising wound repair. PMID:27574685

  11. Inhibition of human telomerase enhances the effect of chemotherapeutic agents in lung cancer cells.

    Science.gov (United States)

    Misawa, Masafumi; Tauchi, Tetsuzo; Sashida, Goro; Nakajima, Akihiro; Abe, Kenji; Ohyashiki, Junko H; Ohyashiki, Kazuma

    2002-11-01

    Telomerase is a ribonucleoprotein enzyme that maintains protective structures at the ends of eukaryotic chromosomes. Earlier studies have reported that the presence of telomerase activity in tumors of patients with non-small cell lung cancer patients correlates with a high proliferation rate and advanced pathological stage. Thus, the modification of telomerase activity may be a potential therapeutic modality for the treatment of lung and other cancers. We introduced vectors encoding dominant negative (DN)-hTERT, or wild-type (WT)-hTERT, or a control vector expressing only a drug-resistance marker, into the A549 lung cancer cell line, and assessed the biological effect of telomerase inhibition on cellular immortality. Ectopic expression of DN-hTERT resulted in complete inhibition of telomerase activity and reduction of telomere length. The entire population of telomerase-inhibited A549 cells exhibited cytoplasmic blebbling and chromatin condensation, which are features of apoptosis. In contrast, A549 cells expressing wild-type hTERT, which differs from the mutants by only two amino acids, exhibited normal morphology. Evidence for apoptosis in the telomerase-inhibited cells was provided by flow cytometric analysis with APO2.7 monoclonal antibody. We also observed enhanced induction of apoptosis by chemotherapeutic reagents, including cisplatin, docetaxel and etoposide, in DN-hTERT-expressing A549 cells, as compared with WT-hTERT-expressing cells. These results demonstrate that disruption of telomere maintenance limits the cellular lifespan of lung cancer cells, and show that the combined use of chemotherapeutic agents and telomere maintenance inhibition may be effective in the treatment of patients with non-small cell lung cancer.

  12. Going Ape as an Approach to Cancer Therapeutics

    OpenAIRE

    Bapat, Aditi; Fishel, Melissa L.; Kelley, Mark R.

    2009-01-01

    The DNA base excision repair (BER) pathway repairs alkylation and oxidative DNA damage caused by endogenous and exogenous agents, including chemotherapeutic agents. Upon removal of the damaged base AP endonuclease 1 (Ape1), a critical component of the pathway cleaves the abasic site to facilitate repair. Ape1 is a multifunctional protein which plays a role not only in DNA repair but it also functions as a reduction–oxidation factor, known as Ref-1 in the literature, to increase the DNA bindin...

  13. Localized sequence-specific release of a chemopreventive agent and an anticancer drug in a time-controllable manner to enhance therapeutic efficacy.

    Science.gov (United States)

    Pan, Wen-Yu; Lin, Kun-Ju; Huang, Chieh-Cheng; Chiang, Wei-Lun; Lin, Yu-Jung; Lin, Wei-Chih; Chuang, Er-Yuan; Chang, Yen; Sung, Hsing-Wen

    2016-09-01

    Combination chemotherapy with multiple drugs commonly requires several injections on various schedules, and the probability that the drug molecules reach the diseased tissues at the proper time and effective therapeutic concentrations is very low. This work elucidates an injectable co-delivery system that is based on cationic liposomes that are adsorbed on anionic hollow microspheres (Lipos-HMs) via electrostatic interaction, from which the localized sequence-specific release of a chemopreventive agent (1,25(OH)2D3) and an anticancer drug (doxorubicin; DOX) can be thermally driven in a time-controllable manner by an externally applied high-frequency magnetic field (HFMF). Lipos-HMs can greatly promote the accumulation of reactive oxygen species (ROS) in tumor cells by reducing their cytoplasmic expression of an antioxidant enzyme (superoxide dismutase) by 1,25(OH)2D3, increasing the susceptibility of cancer cells to the cytotoxic action of DOX. In nude mice that bear xenograft tumors, treatment with Lipos-HMs under exposure to HFMF effectively inhibits tumor growth and is the most effective therapeutic intervention among all the investigated. These empirical results demonstrate that the synergistic anticancer effects of sequential release of 1,25(OH)2D3 and DOX from the Lipos-HMs may have potential for maximizing DOX cytotoxicity, supporting more effective cancer treatment. PMID:27294541

  14. A new prospect in cancer therapy: targeting cancer stem cells to eradicate cancer

    Institute of Scientific and Technical Information of China (English)

    Li-Sha Chen; An-Xin Wang; Bing Dong; Ke-Feng Pu; Li-Hua Yuan; Yi-Min Zhu

    2012-01-01

    According to the cancer stem cell theory,cancers can be initiated by cancer stem cells.This makes cancer stem cells prime targets for therapeutic intervention.Eradicating cancer stem cells by efficient targeting agents may have the potential to cure cancer.In this review,we summarize recent breakthroughs that have improved our understanding of cancer stem cells,and we discuss the therapeutic strategy of targeting cancer stem cells,a promising future direction for cancer stem cell research.

  15. A new prospect in cancer therapy: targeting cancer stem cells to eradicate cancer

    OpenAIRE

    Yi-Min Zhu; Li-Hua Yuan; Ke-Feng Pu; Bing Dong; An-Xin Wang; Li-Sha Chen

    2012-01-01

    According to the cancer stem cell theory, cancers can be initiated by cancer stem cells. This makes cancer stem cells prime targets for therapeutic intervention. Eradicating cancer stem cells by efficient targeting agents may have the potential to cure cancer. In this review, we summarize recent breakthroughs that have improved our understanding of cancer stem cells, and we discuss the therapeutic strategy of targeting cancer stem cells, a promising future direction for cancer stem cell resea...

  16. Copper signaling axis as a target for prostate cancer therapeutics.

    Science.gov (United States)

    Safi, Rachid; Nelson, Erik R; Chitneni, Satish K; Franz, Katherine J; George, Daniel J; Zalutsky, Michael R; McDonnell, Donald P

    2014-10-15

    Previously published reports indicate that serum copper levels are elevated in patients with prostate cancer and that increased copper uptake can be used as a means to image prostate tumors. It is unclear, however, to what extent copper is required for prostate cancer cell function as we observed only modest effects of chelation strategies on the growth of these cells in vitro. With the goal of exploiting prostate cancer cell proclivity for copper uptake, we developed a "conditional lethal" screen to identify compounds whose cytotoxic actions were manifested in a copper-dependent manner. Emerging from this screen was a series of dithiocarbamates, which, when complexed with copper, induced reactive oxygen species-dependent apoptosis of malignant, but not normal, prostate cells. One of the dithiocarbamates identified, disulfiram (DSF), is an FDA-approved drug that has previously yielded disappointing results in clinical trials in patients with recurrent prostate cancer. Similarly, in our studies, DSF alone had a minimal effect on the growth of prostate cancer tumors when propagated as xenografts. However, when DSF was coadministered with copper, a very dramatic inhibition of tumor growth in models of hormone-sensitive and of castrate-resistant disease was observed. Furthermore, we determined that prostate cancer cells express high levels of CTR1, the primary copper transporter, and additional chaperones that are required to maintain intracellular copper homeostasis. The expression levels of most of these proteins are increased further upon treatment of androgen receptor (AR)-positive prostate cancer cell lines with androgens. Not surprisingly, robust CTR1-dependent uptake of copper into prostate cancer cells was observed, an activity that was accentuated by activation of AR. Given these data linking AR to intracellular copper uptake, we believe that dithiocarbamate/copper complexes are likely to be effective for the treatment of patients with prostate cancer whose

  17. DIAGNOSTIC AND THERAPEUTIC POSSIBILITIES IN THE PROPHYLAXIS OF CERVICAL CANCER

    Directory of Open Access Journals (Sweden)

    Marzena Wrześniewska

    2013-11-01

    Full Text Available Poland is one of the countries with high cervical cancer morbidity and mortality. The main means to change this situation is to manage an active and modern programme of cervical cancer prophylaxis and diagnostics. To a large extent, the effectiveness of a cervical cancer prophylaxis programme is decided by the availability of modern diagnostic research. The conventional Papanicolaou test and modern LBC cytology techniques were discussed in the article, taking into consideration HPV diagnostics in the procedures for carefully selected cytological diagnosis, in the so called in-depth stage of preventive screening tests and the role of the p16 biomarker in predicting the development of a higher degree of epithelial-cell pathologies of the cervix. Colposcopy as a diagnostic method for the verification of cytological and virological abnormalities. The modern LEEP/LLETZ procedure used in diagnosis and treatment of cervical changes is used to realise the in-depth stage of cervical cancer prophylaxis programmes.

  18. Biological studies of samarium-153 bleomycin complex in human breast cancer murine xenografts for therapeutic applications

    International Nuclear Information System (INIS)

    In this work, a potential therapeutic DNA targeting agent, 153Sm-bleomycin complex (153Sm-BLM), was developed and the tumor accumulation studies were performed using single photon emission computed tomography (SPECT) and scarification studies. 153Sm-BLM was prepared at optimized conditions (room temperature, 4-8 h, 0.1 mg bleomycin for 740-3700 MBq 153SmCl3, radiochemical purity over 98%, HPLC, specific activity = 55 TBq/mmol). 153Sm-BLM was administered into human breast cancer murine xenografts and the biodistribution and imaging studies were performed up to 48 h. 153Sm-BLM demonstrated superior tumor accumulation properties in contrast with the other radiolabeled bleomycins with tumor:blood ratios of 41, 72 and 182 at 4, 24 and 48 h, respectively, and tumor:muscle ratios of 23, 33 and > 1490 at 4, 24 and 48 h, respectively, while administered intravenously. The SPECT images also demonstrated the obvious tumor uptake at the chest region of the breast-tumor bearing mice. These initial experiments demonstrate significant accumulation of 153Sm-BLM in tumor tissues. (orig.)

  19. Hypoxia-Inducible Factor-1 as a Therapeutic Target in Endometrial Cancer Management

    Directory of Open Access Journals (Sweden)

    Laura M. S. Seeber

    2010-01-01

    Full Text Available In the Western world, endometrial cancer (EC is the most common malignant tumor of the female genital tract. Solid tumors like EC outgrow their vasculature resulting in hypoxia. Tumor hypoxia is important because it renders an aggressive phenotype and leads to radio- and chemo-therapy resistance. Hypoxia-inducible factor-1 (HIF-1 plays an essential role in the adaptive cellular response to hypoxia and is associated with poor clinical outcome in EC. Therefore, HIF-1 could be an attractive therapeutic target. Selective HIF-1 inhibitors have not been identified. A number of nonselective inhibitors which target signaling pathways upstream or downstream HIF-1 are known to decrease HIF-1 protein levels. In clinical trials for the treatment of advanced and/or recurrent EC are the topoisomerase I inhibitor Topotecan, mTOR-inhibitor Rapamycin, and angiogenesis inhibitor Bevacizumab. Preliminary data shows encouraging results for these agents. Further work is needed to identify selective HIF-1 inhibitors and to translate these into clinical trials.

  20. Curcumin: A review of anti-cancer properties and therapeutic activity in head and neck squamous cell carcinoma

    Directory of Open Access Journals (Sweden)

    Wang Marilene B

    2011-02-01

    Full Text Available Abstract Curcumin (diferuloylmethane is a polyphenol derived from the Curcuma longa plant, commonly known as turmeric. Curcumin has been used extensively in Ayurvedic medicine for centuries, as it is nontoxic and has a variety of therapeutic properties including anti-oxidant, analgesic, anti-inflammatory and antiseptic activity. More recently curcumin has been found to possess anti-cancer activities via its effect on a variety of biological pathways involved in mutagenesis, oncogene expression, cell cycle regulation, apoptosis, tumorigenesis and metastasis. Curcumin has shown anti-proliferative effect in multiple cancers, and is an inhibitor of the transcription factor NF-κB and downstream gene products (including c-myc, Bcl-2, COX-2, NOS, Cyclin D1, TNF-α, interleukins and MMP-9. In addition, curcumin affects a variety of growth factor receptors and cell adhesion molecules involved in tumor growth, angiogenesis and metastasis. Head and neck squamous cell carcinoma (HNSCC is the sixth most common cancer worldwide and treatment protocols include disfiguring surgery, platinum-based chemotherapy and radiation, all of which may result in tremendous patient morbidity. As a result, there is significant interest in developing adjuvant chemotherapies to augment currently available treatment protocols, which may allow decreased side effects and toxicity without compromising therapeutic efficacy. Curcumin is one such potential candidate, and this review presents an overview of the current in vitro and in vivo data supporting its therapeutic activity in head and neck cancer as well as some of the challenges concerning its development as an adjuvant chemotherapeutic agent.

  1. Strategies for optimizing the clinical impact of immunotherapeutic agents such as sipuleucel-T in prostate cancer.

    Science.gov (United States)

    Madan, Ravi A; Schwaab, Thomas; Gulley, James L

    2012-12-01

    Sipuleucel-T is a therapeutic cancer vaccine that has shown improved survival in men with metastatic castration-resistant prostate cancer. As a first-in-class agent, it has been met with both fan-fare and controversy. A broad review of immune-based therapies may reveal the delayed clinical impact of sipuleucel-T to be a class effect. As new strategies of immune-based therapy are developed, their effects can be optimized through better understanding of how they affect disease differently from more standard therapeutics. Furthermore, combination therapy with agents that can either work synergistically with immune-activating therapies or deplete immune-regulating cells may result in more vigorous immune responses and improved clinical outcomes. In addition, therapeutic vaccines may be ideal candidates to safely combine with standard-of-care therapies because of their nonoverlapping toxicity profile. The ultimate role of immunotherapy may not be to supplant standard therapies, but rather to work in concert with them to maximize clinical benefit for patients. PMID:23221788

  2. Contemporary Therapeutic Approaches Targeting Bone Complications in Prostate Cancer

    OpenAIRE

    Lee, Richard J.; Saylor, Philip J.; Smith, Matthew R.

    2010-01-01

    Skeletal complications are major causes of morbidity in patients with prostate cancer. Despite the osteoblastic appearance of prostate cancer bone metastases, elevated serum and urinary markers of bone resorption are indicative of high osteoclast activity. Increased osteoclast activity is independently associated with subsequent skeletal complications, disease progression, and death. Osteoclast-targeted therapies aim to reduce the risk for disease-related skeletal complications, bone metastas...

  3. Inflammatory breast cancer: unique biological and therapeutic considerations.

    Science.gov (United States)

    Woodward, Wendy A

    2015-11-01

    Through the concerted efforts of many patients, health-care providers, legislators, and other supporters, the past decade has seen the development of the first clinics dedicated to the care of patients with inflammatory breast cancer in the USA and other countries. Together with social networking, advocacy, and education, a few specialised centres have had substantial increases in patient numbers (in some cases ten times higher), which has further expanded the community of science and advocacy and increased the understanding of the disease process. Although inflammatory breast cancer is considered rare, constituting only 2-4% of breast cancer cases, poor prognosis means that patients with the disease account for roughly 10% of breast cancer mortality annually in the USA. I propose that the unique presentation of inflammatory breast cancer might require specific, identifiable changes in the breast parenchyma that occur before the tumour-initiating event. This would make the breast tissue itself a tumour-promoting medium that should be treated as a component of the pathology in multidisciplinary treatment and should be further studied for complementary targets to inhibit the pathobiology that is specific to inflammatory breast cancer. PMID:26545845

  4. Regulatory T Cells in the Tumor Microenvironment and Cancer Progression: Role and Therapeutic Targeting

    Science.gov (United States)

    Chaudhary, Belal; Elkord, Eyad

    2016-01-01

    Recent years have seen significant efforts in understanding and modulating the immune response in cancer. In this context, immunosuppressive cells, including regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), have come under intense investigation for their proposed roles in suppressing tumor-specific immune responses and establishing an immunosuppressive tumor microenvironment, thus enabling tumor immune evasion. Additionally, recent evidence indicates that Tregs comprise diverse and heterogeneous subsets; phenotypically and functionally distinct subsets of tumor-infiltrating Tregs could contribute differently to cancer prognosis and clinical outcomes. Understanding Treg biology in the setting of cancer, and specifically the tumor microenvironment, is important for designing effective cancer therapies. In this review, we critically examine the role of Tregs in the tumor microenvironment and in cancer progression focusing on human studies. We also discuss the impact of current therapeutic modalities on Treg biology and the therapeutic opportunities for targeting Tregs to enhance anti-tumor immune responses and clinical benefits. PMID:27509527

  5. Improving DNA double-strand repair inhibitor KU55933 therapeutic index in cancer radiotherapy using nanoparticle drug delivery

    Science.gov (United States)

    Tian, Xi; Lara, Haydee; Wagner, Kyle T.; Saripalli, Srinivas; Hyder, Syed Nabeel; Foote, Michael; Sethi, Manish; Wang, Edina; Caster, Joseph M.; Zhang, Longzhen; Wang, Andrew Z.

    2015-11-01

    Radiotherapy is a key component of cancer treatment. Because of its importance, there has been high interest in developing agents and strategies to further improve the therapeutic index of radiotherapy. DNA double-strand repair inhibitors (DSBRIs) are among the most promising agents to improve radiotherapy. However, their clinical translation has been limited by their potential toxicity to normal tissue. Recent advances in nanomedicine offer an opportunity to overcome this limitation. In this study, we aim to demonstrate the proof of principle by developing and evaluating nanoparticle (NP) formulations of KU55933, a DSBRI. We engineered a NP formulation of KU55933 using nanoprecipitation method with different lipid polymer nanoparticle formulation. NP KU55933 using PLGA formulation has the best loading efficacy as well as prolonged drug release profile. We demonstrated that NP KU55933 is a potent radiosensitizer in vitro using clonogenic assay and is more effective as a radiosensitizer than free KU55933 in vivo using mouse xenograft models of non-small cell lung cancer (NSCLC). Western blots and immunofluorescence showed NP KU55933 exhibited more prolonged inhibition of DNA repair pathway. In addition, NP KU55933 leads to lower skin toxicity than KU55933. Our study supports further investigations using NP to deliver DSBRIs to improve cancer radiotherapy treatment.

  6. Therapeutic Efficacy of Ginger, Cisplatin and Radiation on Chemically-Induced Cancer in Male Albino Rats

    International Nuclear Information System (INIS)

    This study aimed to investigate the in vivo effect of dietary supplementation with ginger to evaluate its therapeutic effect against lung and kidney cancer and in combination with cisplatin as chemotherapy and radiotherapy in male albino rats. 54 male albino rats were divided into nine groups of 6 animals each, all animals were allowed to food and water ad libitum . Group I was treated with 0.5 ml saline, orlly for 12 consecutive weeks serve as con - trol group Group II injected with N-nitrosodimethylamine (NDMA) and carbon tetrachloride (CCl4 ); all groups were injected with NDMA + CCl4 for 6 weeks. Group III were given ginger for 6 consecutive weeks (200 mg/kg, b.wt./day). Group IV animals received cisplatin, group V irradiated with 2 Gy, group VI treated with ginger then irradiated, group VII treated with ginger then injected with cisplatin, group VIII injected with cisplatin then irradiated and group IX treated with ginger and cisplatin then irradiated. Antioxidant status in both kidney and lung tissues were estimated by determining the activity of antioxidant enzyme superoxide dismutase (SOD); as well as the level of reduced glutathione (GSH), Malondialdehyde (MDA) and Nitric oxide (NO). In parallel to histopathological investigations of lung and kidney tissues. In addition, Tumor Necrosis Factor Alpha (TNF-α) level, advanced oxidative protein product (AOPP), urea, creatinine and uric acid. Remarkable disturbances were observed in the levels of all tested parameters in NDMA + CCl4 group. On the other hand, rats injected with the cancer agents then treated with cisplatin+radiation showed moderate improvements in the studied parameters while, treatment with ginger + cisplatin + radiation ameliorated the levels of the disturbed bio

  7. Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia

    OpenAIRE

    Conley, Sarah J.; Gheordunescu, Elizabeth; Kakarala, Pramod; Newman, Bryan; Korkaya, Hasan; Heath, Amber N.; Clouthier, Shawn G.; Wicha, Max S.

    2012-01-01

    Antiangiogenic therapy has been thought to hold significant potential for the treatment of cancer. However, the efficacy of such treatments, especially in breast cancer patients, has been called into question, as recent clinical trials reveal only limited effectiveness of antiangiogenic agents in prolonging patient survival. New research using preclinical models further suggests that antiangiogenic agents actually increase invasive and metastatic properties of breast cancer cells. We demonstr...

  8. Antibody-conjugated gold-gold sulfide nanoparticles as multifunctional agents for imaging and therapy of breast cancer

    Directory of Open Access Journals (Sweden)

    Emily S Day

    2010-06-01

    Full Text Available Emily S Day, Lissett R Bickford, John H Slater, Nicholas S Riggall, Rebekah A Drezek, Jennifer L WestDepartment of Bioengineering, Rice University, Houston, TX, USAAbstract: The goal of this study was to develop near-infrared (NIR resonant gold-gold sulfide nanoparticles (GGS-NPs as dual contrast and therapeutic agents for cancer management via multiphoton microscopy followed by higher intensity photoablation. We demonstrate that GGS-NPs exposed to a pulsed, NIR laser exhibit two-photon induced photoluminescence that can be utilized to visualize cancerous cells in vitro. When conjugated with anti-HER2 antibodies, these nanoparticles specifically bind SK-BR-3 breast carcinoma cells that overexpress the HER2 receptor, enabling the cells to be imaged via multiphoton microscopy with an incident laser power of 1 mW. Higher excitation power (50 mW could be employed to induce thermal damage to the cancerous cells, producing extensive membrane blebbing within seconds leading to cell death. GGS-NPs are ideal multifunctional agents for cancer management because they offer the ability to pinpoint precise treatment sites and perform subsequent thermal ablation in a single setting.Keywords: cancer, nanomedicine, multiphoton microscopy, photoluminescence, photothermal therapy, theranostics

  9. Exploiting Nanotechnology for the Development of MicroRNA-Based Cancer Therapeutics.

    Science.gov (United States)

    Tyagi, Nikhil; Arora, Sumit; Deshmukh, Sachin K; Singh, Seema; Marimuthu, Saravanakumar; Singh, Ajay P

    2016-01-01

    MicroRNAs (miRNAs/miRs) represent a novel class of small non-coding RNAs that post-transcriptionally regulate gene expression by base pairing with complementary sequences in the 3' untranslated region (UTR) of target mRNAs. Functional studies suggest that miRNAs control almost every biological process, and their aberrant expression leads to a disease state, such as cancer. Differential expression of miRNAs in cancerous versus normal cells have generated enormous interest for the development of miRNA-based cancer cell-targeted therapeutics. Depending on the miRNA function and expression in cancer, two types of miRNA-based therapeutic strategies can be utilized that either restore or inhibit miRNA function through exogenous delivery of miRNAs mimics or inhibitors (anti-miRs). However, hydrophilic nature of miRNA mimics/anti-miRs, sensitivity to nuclease degradation in serum, poor penetration and reduced uptake by the tumor cells are chief hurdles in accomplishing their efficient in vivo delivery. To overcome these barriers, several nanotechnology-based systems are being developed and tested for delivery efficacy. This review summarizes the importance of miRNAs-based therapeutics in cancer, associated translational challenges and novel nanotechnology-assisted delivery systems that hold potential for next-generation miRNA-based cancer therapeutics. PMID:27301170

  10. Targeting glucose metabolism in cancer: new class of agents for loco-regional and systemic therapy of liver cancer and beyond?

    Science.gov (United States)

    Savic, Lynn Jeanette; Chapiro, Julius; Duwe, Gregor; Geschwind, Jean-François

    2016-01-01

    Hepatocellular carcinoma (HCC) is one of the most prevalent cancers and the third leading cause of cancer-related deaths worldwide. In patients with unresectable disease, loco-regional catheter-based intra-arterial therapies (IAT) can achieve selective tumor control while minimizing systemic toxicity. As molecular features of tumor growth and microenvironment are better understood, new targets arise for selective anticancer therapy. Particularly, antiglycolytic drugs that exploit the hyperglycolytic cancer cell metabolism – also known as the ‘Warburg effect’ – have emerged as promising therapeutic options. Thus, future developments will combine the selective character of loco-regional drug delivery platforms with highly specific molecular targeted antiglycolytic agents. This review will exemplify literature on antiglycolytic approaches and particularly focus on intra-arterial delivery methods. PMID:26989470

  11. Enhanced in vitro and in vivo therapeutic efficacy of codrug-loaded nanoparticles against liver cancer

    Directory of Open Access Journals (Sweden)

    Li X

    2012-10-01

    Full Text Available Xiaolin Li,1,* Hua’e Xu,2,* Xinzheng Dai,3,4,* Zhenshu Zhu,5 Baorui Liu,6 Xiaowei Lu11Department of Geriatrics, 2Department of Pharmacy, the First Affiliated Hospital to Nanjing Medical University, Nanjing; 3Key Laboratory of Living Donor Liver Transplantation, Ministry of Public Health, 4Liver Transplantation Center, the First Affiliated Hospital to Nanjing Medical University, Nanjing; 5Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing; 6The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University, Nanjing, China*These authors contributed equally to this workAbstract: Paclitaxel (Ptx, one of the most widely used anticancer agents, has demonstrated extraordinary activities against a variety of solid tumors. However, the therapeutic response of Ptx is often associated with severe side effects caused by its nonspecific cytotoxic effects and special solvents (Cremophor EL®. The current study reports the stable controlled release of Ptx/tetrandrine (Tet-coloaded nanoparticles by amphilic methoxy poly(ethylene glycol–poly(caprolactone block copolymers. There were three significant findings. Firstly, Tet could effectively stabilize Ptx-loaded nanoparticles with the coencapsulation of Tet and Ptx. The influence of different Ptx/Tet feeding ratios on the size and loading efficiency of the nanoparticles was also explored. Secondly, the encapsulation of Tet and Ptx into nanoparticles retains the synergistic anticancer efficiency of Tet and Ptx against mice hepatoma H22 cells. Thirdly, in the in vivo evaluation, intratumoral administration was adopted to increase the site-specific delivery. Ptx/Tet nanoparticles, when delivered intratumorally, exhibited significantly improved antitumor efficacy; moreover, they substantially increased the overall survival in an established H22-transplanted mice model. Further investigation into the

  12. Mind-mapping for lung cancer: Towards a personalized therapeutics approach

    OpenAIRE

    Mollberg, N; Surati, M; Demchuk, C; R Fathi; Salama, AK; Husain, AN; Hensing, T; Salgia, R

    2011-01-01

    There will be over 220,000 people diagnosed with lung cancer and over 160,000 dying of lung cancer this year alone in the United States. In order to arrive at better control, prevention, diagnosis, and therapeutics for lung cancer, we must be able to personalize the approach towards lung cancer. Mind-mapping has existed for centuries for physicians to properly think about various “flows” of personalized medicine. We include here the epidemiology, diagnosis, histology, and treatment of lung ca...

  13. Evaluation of carbamate insecticides as chemotherapeutic agents for cancer

    Directory of Open Access Journals (Sweden)

    Mohd. Amanullah

    2011-01-01

    Full Text Available Background: Cancer chemotherapy has already been in practice by the use of toxins and some of the specific poisonous compounds of cyanide derivatives. Carbamate insecticides inhibit cellular metabolism including energy, protein, and nucleic acid metabolism, thereby, causing cell regression and death. Aim: Preliminary evaluation of three carbamate insecticides, namely, baygon, carbaryl, and carbofuran as chemotherapeutic agents for cancer is undertaken in the present study. Materials and Methods: The toxicity of carbamates on squamous cell carcinoma was assessed in-vitro using dye binding tests. Cells were grown in microtitration ELISA plates, as adherent cultures, for six hours, and then exposed to the drugs for 2, 4, 8, and 12 hours, and finally stained with neutral red, to assess the viable cell number, and with methylene blue for the determination of protein in the monolayer. Optical density was read in an ELISA reader. Statistical Analysis: The data obtained during the experiment was subjected to statistical analysis by using the student ′t′ test. Results: The results indicated that the percentage of the viable cell number reduced with an increase in the time of exposure of the drugs. Exposure of the tumor cells to the drugs for 12 hours detached them completely from the wells, and hence, all the cells were washed out. Exposure of the drugs prior to the establishment of the culture in-vitro resulted in the non-formation of the monolayer in the wells. Conclusions: Among the three drugs studied, the survival percent was least with carbaryl treatment followed by baygon, and with carbofuran treatment it was almost near to control group.

  14. Nanomedicine therapeutic approaches to overcome cancer drug resistance.

    Science.gov (United States)

    Markman, Janet L; Rekechenetskiy, Arthur; Holler, Eggehard; Ljubimova, Julia Y

    2013-11-01

    Nanomedicine is an emerging form of therapy that focuses on alternative drug delivery and improvement of the treatment efficacy while reducing detrimental side effects to normal tissues. Cancer drug resistance is a complicated process that involves multiple mechanisms. Here we discuss the major forms of drug resistance and the new possibilities that nanomedicines offer to overcome these treatment obstacles. Novel nanomedicines that have a high ability for flexible, fast drug design and production based on tumor genetic profiles can be created making drug selection for personal patient treatment much more intensive and effective. This review aims to demonstrate the advantage of the young medical science field, nanomedicine, for overcoming cancer drug resistance. With the advanced design and alternative mechanisms of drug delivery known for different nanodrugs including liposomes, polymer conjugates, micelles, dendrimers, carbon-based, and metallic nanoparticles, overcoming various forms of multi-drug resistance looks promising and opens new horizons for cancer treatment. PMID:24120656

  15. MDSCs in cancer: Conceiving new prognostic and therapeutic targets.

    Science.gov (United States)

    De Sanctis, Francesco; Solito, Samantha; Ugel, Stefano; Molon, Barbara; Bronte, Vincenzo; Marigo, Ilaria

    2016-01-01

    The incomplete clinical efficacy of anti-tumor immunotherapy can depend on the presence of an immunosuppressive environment in the host that supports tumor progression. Tumor-derived cytokines and growth factors induce an altered hematopoiesis that modifies the myeloid cell differentiation process, promoting proliferation and expansion of cells with immunosuppressive skills, namely myeloid derived suppressor cells (MDSCs). MDSCs promote tumor growth not only by shaping immune responses towards tumor tolerance, but also by supporting several processes necessary for the neoplastic progression such as tumor angiogenesis, cancer stemness, and metastasis dissemination. Thus, MDSC targeting represents a promising tool to eliminate host immune dysfunctions and increase the efficacy of immune-based cancer therapies.

  16. Standard of Care and Promising New Agents for Triple Negative Metastatic Breast Cancer

    Directory of Open Access Journals (Sweden)

    Patrizia Mancini

    2014-10-01

    Full Text Available Triple negative breast cancer (TNBC is a cluster of heterogeneous diseases, all of them sharing the lack of expression of estrogen and progesterone receptors and HER2 protein. They are characterized by different biological, molecular and clinical features, including a poor prognosis despite the increased sensitivity to the current cytotoxic therapies. Several studies have identified important molecular features which enable further subdivision of this type of tumor. We are drawing from genomics, transcription and translation analysis at different levels, to improve our knowledge of the molecular alterations along the pathways which are activated during carcinogenesis and tumor progression. How this information should be used for the rational selection of therapy is an ongoing challenge and the subject of numerous research studies in progress. Currently, the vascular endothelial growth factor (VEGF, poly (ADP-ribose polymerase (PARP, HSP90 and Aurora inhibitors are most used as targeting agents in metastatic setting clinical trials. In this paper we will review the current knowledge about the genetic subtypes of TNBC and their different responses to conventional therapeutic strategies, as well as to some new promising molecular target agents, aimed to achieve more tailored therapies.

  17. Standard of Care and Promising New Agents for Triple Negative Metastatic Breast Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Mancini, Patrizia, E-mail: patrizia.mancini@uniroma1.it [Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, Rome 00161 (Italy); Angeloni, Antonio [Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 324, Rome 00161 (Italy); Risi, Emanuela [Department of Radiology, Oncology and Human Pathology, Sapienza University of Rome, Viale Regina Elena 324, Rome 00161 (Italy); Orsi, Errico [Department of Surgical Science, Sapienza University of Rome, Viale Regina Elena 324, Rome 00161 (Italy); Mezi, Silvia [Department of Radiology, Oncology and Human Pathology, Sapienza University of Rome, Viale Regina Elena 324, Rome 00161 (Italy)

    2014-10-24

    Triple negative breast cancer (TNBC) is a cluster of heterogeneous diseases, all of them sharing the lack of expression of estrogen and progesterone receptors and HER2 protein. They are characterized by different biological, molecular and clinical features, including a poor prognosis despite the increased sensitivity to the current cytotoxic therapies. Several studies have identified important molecular features which enable further subdivision of this type of tumor. We are drawing from genomics, transcription and translation analysis at different levels, to improve our knowledge of the molecular alterations along the pathways which are activated during carcinogenesis and tumor progression. How this information should be used for the rational selection of therapy is an ongoing challenge and the subject of numerous research studies in progress. Currently, the vascular endothelial growth factor (VEGF), poly (ADP-ribose) polymerase (PARP), HSP90 and Aurora inhibitors are most used as targeting agents in metastatic setting clinical trials. In this paper we will review the current knowledge about the genetic subtypes of TNBC and their different responses to conventional therapeutic strategies, as well as to some new promising molecular target agents, aimed to achieve more tailored therapies.

  18. Therapeutic efficacy of an oncolytic adenovirus containing RGD ligand in minor capsid protein IX and Fiber, Δ24DoubleRGD, in an ovarian cancer model

    Directory of Open Access Journals (Sweden)

    Anton V Borovjagin

    2012-02-01

    Full Text Available Ovarian cancer is the leading cause of gynecological disease death despite advances in medicine. Therefore, novel strategies are required for ovarian cancer therapy. Conditionally replicative adenoviruses (CRAds, genetically modified as anti-cancer therapeutics, are one of the most attractive candidate agents for cancer therapy. However, a paucity of coxsackie B virus and adenovirus receptor (CAR expression on the surface of ovarian cancer cells has impeded treatment of ovarian cancer using this approach.This study sought to engineer a CRAd with enhanced oncolytic ability in ovarian cancer cells, “Δ24DoubleRGD.” Δ24DoubleRGD carries an arginine-glycine-aspartate (RGD motif incorporated into both fiber and capsid protein IX (pIX and its oncolytic efficacy was evaluated in ovarian cancer. In vitro analysis of cell viability showed that infection of ovarian cancer cells with Δ24DoubleRGD leads to increased cell killing relative to the control CRAds. Data from this study suggested that not only an increase in number of RGD motifs on the CRAd capsid, but also a change in the repertoir of targeted integrins could lead to enhanced oncolytic potency of Δ24DoubleRGD in ovarian cancer cells in vitro. In an intraperitoneal model of ovarian cancer, mice injected with Δ24DoubleRGD showed, however, a similar survival rate as mice treated with control CRAds.

  19. Optimal Therapeutic Strategy for Non-small Cell Lung Cancer with Mutated Epidermal Growth Factor Receptor

    Directory of Open Access Journals (Sweden)

    Zhong SHI

    2015-02-01

    Full Text Available Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs have been widely used in non-small cell lung cancer (NSCLC patients, it is still controversial about how to combine EGFR-TKI with chemotherapy and other targeted drugs. We have made a summary on the current therapeutic models of EGFR-TKI combined with chemotherapy/bevacizumab in this review and aimed to find the optimal therapeutic strategy for NSCLC patients with EGFR mutation.

  20. The role of kinin receptors in cancer and therapeutic opportunities.

    Science.gov (United States)

    da Costa, Patrícia L N; Sirois, Pierre; Tannock, Ian F; Chammas, Roger

    2014-04-01

    Kinins are generated within inflammatory tissue microenvironments, where they exert diverse functions, including cell proliferation, leukocyte activation, cell migration, endothelial cell activation and nociception. These pleiotropic functions depend on signaling through two cross talking receptors, the constitutively expressed kinin receptor 2 (B2R) and the inducible kinin receptor 1 (B1R). We have reviewed evidence, which supports the concept that kinin receptors, especially kinin receptor 1, are promising targets for cancer therapy, since (1) many tumor cells express aberrantly high levels of these receptors; (2) some cancers produce kinins and use them as autocrine factors to stimulate their growth; (3) activation of kinin receptors leads to activation of macrophages, dendritic cells and other cells from the tumor microenvironment; (4) kinins have pro-angiogenic properties; (5) kinin receptors have been implicated in cancer migration, invasion and metastasis; and (6) selective antagonists for either B1R or B2R have shown anti-proliferative, anti-inflammatory, anti-angiogenic and anti-migratory properties. The multiple cross talks between kinin receptors and renin-angiotensin system (RAS) as well as its implications for targeting KKS or RAS for the treatment of malignancies are also discussed. It is expected that B1R antagonists would interfere less with housekeeping functions and therefore would be attractive compounds to treat selected types of cancer. Reliable clinical studies are needed to establish the translatability of these data to human settings and the usefulness of kinin receptor antagonists. PMID:24333733

  1. Inhibitor of apoptosis proteins: new therapeutic targets in hematological cancer?

    NARCIS (Netherlands)

    Graaf, A.O. de; Witte, T.J.M. de; Jansen, J.H.

    2004-01-01

    Apoptosis is an essential process for the selection and survival of lymphocytes. Resistance to apoptosis can promote malignant transformation of hematopoietic cells. Proteins that regulate apoptosis may therefore be critically involved in the development of hematological cancer. A delicate balance b

  2. Therapeutic strategy for small-sized lung cancer.

    Science.gov (United States)

    Iwata, Hisashi

    2016-08-01

    Minimizing the volume of lung resection without diminishing curability has recently become an important issue in primary lung cancer. In this review, we will discuss the current state of the feasibility of sublobar resection and specific issues for a segmentectomy procedure. A previous randomized controlled trial showed that lobectomy must still be considered the standard surgical procedure compared with sublobar resection for T1N0 non-small cell lung cancer with a tumor less than 3 cm in size. Since then, supporting studies for segmentectomy of lung cancer with a tumor less than 2 cm in size were reported. In addition, segmentectomy seems to be feasible for clinical stage I adenocarcinoma less than 2 cm in size, in women younger than 70 years old, with a low tumor 18F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) standardized uptake value (SUV) from propensity-matching studies. In a meta-analysis of sublobar resection vs. lobectomy, intentionally performed sublobar resection showed equivalent outcomes to lobectomy. In the near future, two ongoing prospective, randomized trials will report results. As specific issues for the surgical procedure of segmentectomy, achieving a sufficient surgical margin is an important issue for preventing loco-regional recurrence. More studies regarding the regional lymph node dissection area for segmentectomy are needed. Sublobar resection has the potential to become the standard procedure for peripheral small-sized lung cancer less than 2 cm. However, more information is needed about the characteristics of this cancer and the surgical procedure, including nodal dissection. PMID:27300350

  3. Emerging Lung Cancer Therapeutic Targets Based on the Pathogenesis of Bone Metastases

    Directory of Open Access Journals (Sweden)

    Moses O. Oyewumi

    2014-01-01

    Full Text Available Lung cancer is the second most common cancer and the leading cause of cancer related mortality in both men and women. Each year, more people die of lung cancer than of colon, breast, and prostate cancers combined. It is widely accepted that tumor metastasis is a formidable barrier to effective treatment of lung cancer. The bone is one of the frequent metastatic sites for lung cancer occurring in a large number of patients. Bone metastases can cause a wide range of symptoms that could impair quality of life of lung cancer patients and shorten their survival. We strongly believe that molecular targets (tumor-related and bone microenvironment based that have been implicated in lung cancer bone metastases hold great promise in lung cancer therapeutics. Thus, this paper discusses some of the emerging molecular targets that have provided insights into the cascade of metastases in lung cancer with the focus on bone invasion. It is anticipated that the information gathered might be useful in future efforts of optimizing lung cancer treatment strategies.

  4. Annexin A9 (ANXA9) biomarker and therapeutic target in epithelial cancer

    Science.gov (United States)

    Hu, Zhi; Kuo, Wen-Lin; Neve, Richard M.; Gray, Joe W.

    2012-06-12

    Amplification of the ANXA9 gene in human chromosomal region 1q21 in epithelial cancers indicates a likelihood of both in vivo drug resistance and metastasis, and serves as a biomarker indicating these aspects of the disease. ANXA9 can also serve as a therapeutic target. Interfering RNAs (iRNAs) (such as siRNA and miRNA) and shRNA adapted to inhibit ANXA9 expression, when formulated in a therapeutic composition, and delivered to cells of the tumor, function to treat the epithelial cancer.

  5. Aptámeros: agentes diagnósticos y terapéuticos = Aptamers: diagnostic and therapeutic agents

    Directory of Open Access Journals (Sweden)

    Frank J Hernandez

    2012-04-01

    Full Text Available Los aptámeros son ácidos nucleicos de cadena sencilla, ADN o ARN, que reconocen una gran variedad de moléculas. Cada aptámero posee una estructura tridimensional particular que le permite unirse con afinidad y especificidad altas a la molécula diana. Los aptámeros tienen propiedades de reconocimiento equiparables a las de los anticuerpos; sin embargo, por la naturaleza de su composición tienen ventajas significativas en cuanto a su tamaño, producción y modificación. Estas características los hacen excelentes candidatos para el desarrollo de nuevas plataformas biotecnológicas. Se han identificado aptámeros con propiedades terapéuticas que han sido evaluados exitosamente en modelos animales; entre ellos, algunos se encuentran en fase clínica y uno ya fue aprobado para tratamiento por la FDA (Food and Drug Administration. Todos estos avances ocurridos durante las dos últimas décadas permiten anticipar el protagonismo que tendrán los aptámeros como agentes diagnósticos y terapéuticos en un futuro cercano.

  6. Choline and Geranate Deep Eutectic Solvent as a Broad-Spectrum Antiseptic Agent for Preventive and Therapeutic Applications.

    Science.gov (United States)

    Zakrewsky, Michael; Banerjee, Amrita; Apte, Sanjana; Kern, Theresa L; Jones, Mattie R; Sesto, Rico E Del; Koppisch, Andrew T; Fox, David T; Mitragotri, Samir

    2016-06-01

    Antiseptic agents are the primary arsenal to disinfect skin and prevent pathogens spreading within the host as well as into the surroundings; however the Food and Drug Administration published a report in 2015 requiring additional validation of nearly all current antiseptic agents before their continued use can be allowed. This vulnerable position calls for urgent identification of novel antiseptic agents. Recently, the ability of a deep eutectic, Choline And Geranate (CAGE), to treat biofilms of Pseudomonas aeruginosa and Salmonella enterica was demonstrated. Here it is reported that CAGE exhibits broad-spectrum antimicrobial activity against a number of drug-resistant bacteria, fungi, and viruses including clinical isolates of Mycobacterium tuberculosis, Staphylococcus aureus, and Candida albicans as well as laboratory strains of Herpes Simplex Virus. Studies in human keratinocytes and mice show that CAGE affords negligible local or systemic toxicity, and an ≈180-14 000-fold improved efficacy/toxicity ratio over currently used antiseptic agents. Further, CAGE penetrates deep into the dermis and treats pathogens located in deep skin layers as confirmed by the ability of CAGE in vivo to treat Propionibacterium acnes infection. In combination, the results clearly demonstrate CAGE holds promise as a transformative platform antiseptic agent for preventive as well as therapeutic applications. PMID:26959835

  7. Human Papillomavirus: Current and Future RNAi Therapeutic Strategies for Cervical Cancer

    Directory of Open Access Journals (Sweden)

    Hun Soon Jung

    2015-05-01

    Full Text Available Human papillomaviruses (HPVs are small DNA viruses; some oncogenic ones can cause different types of cancer, in particular cervical cancer. HPV-associated carcinogenesis provides a classical model system for RNA interference (RNAi based cancer therapies, because the viral oncogenes E6 and E7 that cause cervical cancer are expressed only in cancerous cells. Previous studies on the development of therapeutic RNAi facilitated the advancement of therapeutic siRNAs and demonstrated its versatility by siRNA-mediated depletion of single or multiple cellular/viral targets. Sequence-specific gene silencing using RNAi shows promise as a novel therapeutic approach for the treatment of a variety of diseases that currently lack effective treatments. However, siRNA-based targeting requires further validation of its efficacy in vitro and in vivo, for its potential off-target effects, and of the design of conventional therapies to be used in combination with siRNAs and their drug delivery vehicles. In this review we discuss what is currently known about HPV-associated carcinogenesis and the potential for combining siRNA with other treatment strategies for the development of future therapies. Finally, we present our assessment of the most promising path to the development of RNAi therapeutic strategies for clinical settings.

  8. The zebrafish embryo as a tool for screening and characterizing pleurocidin host-defense peptides as anti-cancer agents

    OpenAIRE

    Morash, Michael G.; Douglas, Susan E.; Anna Robotham; Ridley, Christina M.; Gallant, Jeffrey W.; Soanes, Kelly H.

    2011-01-01

    SUMMARY The emergence of multidrug-resistant cancers and the lack of targeted therapies for many cancers underscore an unmet need for new therapeutics with novel modes of action towards cancer cells. Host-defense peptides often exhibit selective cytotoxicity towards cancer cells and show potential as anti-cancer therapeutics. Here, we screen 26 naturally occurring variants of the peptide pleurocidin for cytotoxic and anti-cancer activities, and investigate the underlying mechanism of actio...

  9. The zebrafish embryo as a tool for screening and characterizing pleurocidin host-defense peptides as anti-cancer agents

    OpenAIRE

    Michael G. Morash; Douglas, Susan E.; Anna Robotham; Ridley, Christina M.; Gallant, Jeffrey W.; Soanes, Kelly H.

    2011-01-01

    SUMMARY The emergence of multidrug-resistant cancers and the lack of targeted therapies for many cancers underscore an unmet need for new therapeutics with novel modes of action towards cancer cells. Host-defense peptides often exhibit selective cytotoxicity towards cancer cells and show potential as anti-cancer therapeutics. Here, we screen 26 naturally occurring variants of the peptide pleurocidin for cytotoxic and anti-cancer activities, and investigate the underlying mechanism of action. ...

  10. Moringa oleifera as an Anti-Cancer Agent against Breast and Colorectal Cancer Cell Lines.

    Directory of Open Access Journals (Sweden)

    Abdulrahman Khazim Al-Asmari

    Full Text Available In this study we investigated the anti-cancer effect of Moringa oleifera leaves, bark and seed extracts. When tested against MDA-MB-231 and HCT-8 cancer cell lines, the extracts of leaves and bark showed remarkable anti-cancer properties while surprisingly, seed extracts exhibited hardly any such properties. Cell survival was significantly low in both cells lines when treated with leaves and bark extracts. Furthermore, a striking reduction (about 70-90% in colony formation as well as cell motility was observed upon treatment with leaves and bark. Additionally, apoptosis assay performed on these treated breast and colorectal cancer lines showed a remarkable increase in the number of apoptotic cells; with a 7 fold increase in MD-MB-231 to an increase of several fold in colorectal cancer cell lines. However, no significant apoptotic cells were detected upon seeds extract treatment. Moreover, the cell cycle distribution showed a G2/M enrichment (about 2-3 fold indicating that these extracts effectively arrest the cell progression at the G2/M phase. The GC-MS analyses of these extracts revealed numerous known anti-cancer compounds, namely eugenol, isopropyl isothiocynate, D-allose, and hexadeconoic acid ethyl ester, all of which possess long chain hydrocarbons, sugar moiety and an aromatic ring. This suggests that the anti-cancer properties of Moringa oleifera could be attributed to the bioactive compounds present in the extracts from this plant. This is a novel study because no report has yet been cited on the effectiveness of Moringa extracts obtained in the locally grown environment as an anti-cancer agent against breast and colorectal cancers. Our study is the first of its kind to evaluate the anti-malignant properties of Moringa not only in leaves but also in bark. These findings suggest that both the leaf and bark extracts of Moringa collected from the Saudi Arabian region possess anti-cancer activity that can be used to develop new drugs for

  11. Moringa oleifera as an Anti-Cancer Agent against Breast and Colorectal Cancer Cell Lines.

    Science.gov (United States)

    Al-Asmari, Abdulrahman Khazim; Albalawi, Sulaiman Mansour; Athar, Md Tanwir; Khan, Abdul Quaiyoom; Al-Shahrani, Hamoud; Islam, Mozaffarul

    2015-01-01

    In this study we investigated the anti-cancer effect of Moringa oleifera leaves, bark and seed extracts. When tested against MDA-MB-231 and HCT-8 cancer cell lines, the extracts of leaves and bark showed remarkable anti-cancer properties while surprisingly, seed extracts exhibited hardly any such properties. Cell survival was significantly low in both cells lines when treated with leaves and bark extracts. Furthermore, a striking reduction (about 70-90%) in colony formation as well as cell motility was observed upon treatment with leaves and bark. Additionally, apoptosis assay performed on these treated breast and colorectal cancer lines showed a remarkable increase in the number of apoptotic cells; with a 7 fold increase in MD-MB-231 to an increase of several fold in colorectal cancer cell lines. However, no significant apoptotic cells were detected upon seeds extract treatment. Moreover, the cell cycle distribution showed a G2/M enrichment (about 2-3 fold) indicating that these extracts effectively arrest the cell progression at the G2/M phase. The GC-MS analyses of these extracts revealed numerous known anti-cancer compounds, namely eugenol, isopropyl isothiocynate, D-allose, and hexadeconoic acid ethyl ester, all of which possess long chain hydrocarbons, sugar moiety and an aromatic ring. This suggests that the anti-cancer properties of Moringa oleifera could be attributed to the bioactive compounds present in the extracts from this plant. This is a novel study because no report has yet been cited on the effectiveness of Moringa extracts obtained in the locally grown environment as an anti-cancer agent against breast and colorectal cancers. Our study is the first of its kind to evaluate the anti-malignant properties of Moringa not only in leaves but also in bark. These findings suggest that both the leaf and bark extracts of Moringa collected from the Saudi Arabian region possess anti-cancer activity that can be used to develop new drugs for treatment of breast

  12. Copper and conquer: copper complexes of di-2-pyridylketone thiosemicarbazones as novel anti-cancer therapeutics.

    Science.gov (United States)

    Park, Kyung Chan; Fouani, Leyla; Jansson, Patric J; Wooi, Danson; Sahni, Sumit; Lane, Darius J R; Palanimuthu, Duraippandi; Lok, Hiu Chuen; Kovačević, Zaklina; Huang, Michael L H; Kalinowski, Danuta S; Richardson, Des R

    2016-09-01

    Copper is an essential trace metal required by organisms to perform a number of important biological processes. Copper readily cycles between its reduced Cu(i) and oxidised Cu(ii) states, which makes it redox active in biological systems. This redox-cycling propensity is vital for copper to act as a catalytic co-factor in enzymes. While copper is essential for normal physiology, enhanced copper levels in tumours leads to cancer progression. In particular, the stimulatory effect of copper on angiogenesis has been established in the last several decades. Additionally, it has been demonstrated that copper affects tumour growth and promotes metastasis. Based on the effects of copper on cancer progression, chelators that bind copper have been developed as anti-cancer agents. In fact, a novel class of thiosemicarbazone compounds, namely the di-2-pyridylketone thiosemicarbazones that bind copper, have shown great promise in terms of their anti-cancer activity. These agents have a unique mechanism of action, in which they form redox-active complexes with copper in the lysosomes of cancer cells. Furthermore, these agents are able to overcome P-glycoprotein (P-gp) mediated multi-drug resistance (MDR) and act as potent anti-oncogenic agents through their ability to up-regulate the metastasis suppressor protein, N-myc downstream regulated gene-1 (NDRG1). This review provides an overview of the metabolism and regulation of copper in normal physiology, followed by a discussion of the dysregulation of copper homeostasis in cancer and the effects of copper on cancer progression. Finally, recent advances in our understanding of the mechanisms of action of anti-cancer agents targeting copper are discussed.

  13. The Role of Chemokines in Breast Cancer Pathology and Its Possible Use as Therapeutic Targets

    Directory of Open Access Journals (Sweden)

    M. Isabel Palacios-Arreola

    2014-01-01

    Full Text Available Chemokines are small proteins that primarily regulate the traffic of leukocytes under homeostatic conditions and during specific immune responses. The chemokine-chemokine receptor system comprises almost 50 chemokines and approximately 20 chemokine receptors; thus, there is no unique ligand for each receptor and the binding of different chemokines to the same receptor might have disparate effects. Complicating the system further, these effects depend on the cellular milieu. In cancer, although chemokines are associated primarily with the generation of a protumoral microenvironment and organ-directed metastasis, they also mediate other phenomena related to disease progression, such as angiogenesis and even chemoresistance. Therefore, the chemokine system is becoming a target in cancer therapeutics. We review the emerging data and correlations between chemokines/chemokine receptors and breast cancer, their implications in cancer progression, and possible therapeutic strategies that exploit the chemokine system.

  14. Personalized in vitro cancer models to predict therapeutic response: Challenges and a framework for improvement.

    Science.gov (United States)

    Morgan, Molly M; Johnson, Brian P; Livingston, Megan K; Schuler, Linda A; Alarid, Elaine T; Sung, Kyung E; Beebe, David J

    2016-09-01

    Personalized cancer therapy focuses on characterizing the relevant phenotypes of the patient, as well as the patient's tumor, to predict the most effective cancer therapy. Historically, these methods have not proven predictive in regards to predicting therapeutic response. Emerging culture platforms are designed to better recapitulate the in vivo environment, thus, there is renewed interest in integrating patient samples into in vitro cancer models to assess therapeutic response. Successful examples of translating in vitro response to clinical relevance are limited due to issues with patient sample acquisition, variability and culture. We will review traditional and emerging in vitro models for personalized medicine, focusing on the technologies, microenvironmental components, and readouts utilized. We will then offer our perspective on how to apply a framework derived from toxicology and ecology towards designing improved personalized in vitro models of cancer. The framework serves as a tool for identifying optimal readouts and culture conditions, thus maximizing the information gained from each patient sample.

  15. Gene therapy of cancer and development of therapeutic target gene

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Chang Min; Kwon, Hee Chung

    1998-04-01

    We applied HSV-tk/GCV strategy to orthotopic rat hepatoma model and showed anticancer effects of hepatoma. The increased expression of Lac Z gene after adenovirus-mediated gene delivery throughout hepatic artery was thought that is increased the possibility of gene therapy for curing hepatoma. With the construction of kGLP-laboratory, it is possible to produce a good quantity and quality of adenovirus in lage-scale production and purification of adenovirus vector. Also, the analysis of hepatoma related genes by PCR-LOH could be used for the diagnosis of patients and the development of therapeutic gene.

  16. Gene therapy of cancer and development of therapeutic target gene

    International Nuclear Information System (INIS)

    We applied HSV-tk/GCV strategy to orthotopic rat hepatoma model and showed anticancer effects of hepatoma. The increased expression of Lac Z gene after adenovirus-mediated gene delivery throughout hepatic artery was thought that is increased the possibility of gene therapy for curing hepatoma. With the construction of kGLP-laboratory, it is possible to produce a good quantity and quality of adenovirus in lage-scale production and purification of adenovirus vector. Also, the analysis of hepatoma related genes by PCR-LOH could be used for the diagnosis of patients and the development of therapeutic gene

  17. Osteopontin as potential biomarker and therapeutic target in gastric and liver cancers

    Institute of Scientific and Technical Information of China (English)

    Dong-Xing Cao; Zhi-Jie Li; Xiao-Ou Jiang; Yick Liang Lum; Ester Khin; Nikki P Lee; Guo-Hao Wu; John M Luk

    2012-01-01

    Gastric cancer and liver cancer are among the most common malignancies and the leading causes of death worldwide,due to late detection and high recurrence rates.Today,these cancers have a heavy socioeconomic burden,for which a full understanding of their pathophysiological features is warranted to search for promising biomarkers and therapeutic targets.Osteopontin (OPN) is overexpressed in most patients with gastric and liver cancers.Over the past decade,emerging evidence has revealed a correlation of OPN level and clinicopathological features and prognosis in gastric and liver cancers,indicating its potential as an independent prognostic indicator in such patients.Functional studies have verified the potential of OPN knockdown as a therapeutic approach in vitro and in vivo.Furthermore,OPN mediates multifaceted roles in the interaction between cancer cells and the tumor microenvironment,in which many details need further exploration.OPN signaling results in various functions,including prevention of apoptosis,modulation of angiogenesis,malfunction of tumor-associated macrophages,degradation of extracellular matrix,activation of phosphoinositide 3-kinase-Akt and nuclear factor-κB pathways,which lead to tumor formation and progression,particularly in gastric and liver cancers.This editorial aims to review recent findings on alteration in OPN expression and its clinicopathological associations with tumor progression,its potential as a therapeutic target,and putative mechanisms in gastric and liver cancers.Better understanding of the implications of OPN in tumorigenesis might facilitate development of therapeutic regimens to benefit patients with these deadly malignancies.

  18. Potential Diagnostic, Prognostic and Therapeutic Targets of MicroRNAs in Human Gastric Cancer

    OpenAIRE

    Ming-Ming Tsai; Chia-Siu Wang; Chung-Ying Tsai; Hsiang-Wei Huang; Hsiang-Cheng Chi; Yang-Hsiang Lin; Pei-Hsuan Lu; Kwang-Huei Lin

    2016-01-01

    Human gastric cancer (GC) is characterized by a high incidence and mortality rate, largely because it is normally not identified until a relatively advanced stage owing to a lack of early diagnostic biomarkers. Gastroscopy with biopsy is the routine method for screening, and gastrectomy is the major therapeutic strategy for GC. However, in more than 30% of GC surgical patients, cancer has progressed too far for effective medical resection. Thus, useful biomarkers for early screening or detect...

  19. Therapeutic applications of curcumin for patients with pancreatic cancer

    OpenAIRE

    Kanai, Masashi

    2014-01-01

    A number of preclinical studies have demonstrated anticancer effects for curcumin in various types of tumors, including pancreatic cancer. Curcumin has anticancer effects both alone and in combination with other anticancer drugs (e.g., gemcitabine, 5-fluorouracil, and oxaliplatin), and it has been shown to modulate a variety of molecular targets in preclinical models, with more than 30 molecular targets identified to date. Of these various molecules, NF-κB is thought to be one of the primary ...

  20. Therapeutic applications of curcumin for patients with pancreatic cancer.

    OpenAIRE

    Kanai, Masashi

    2014-01-01

    A number of preclinical studies have demonstrated anticancer effects for curcumin in various types of tumors, including pancreatic cancer. Curcumin has anticancer effects both alone and in combination with other anticancer drugs (e.g., gemcitabine, 5-fluorouracil, and oxaliplatin), and it has been shown to modulate a variety of molecular targets in preclinical models, with more than 30 molecular targets identified to date. Of these various molecules, NF-κB is thought to be one of the primary ...

  1. POLYLACTIDE-CO-GLYCOLIDE NANOPARTICLES THERAPEUTIC BENEFITS IN CANCER

    OpenAIRE

    Pramod V. Burakle; Priti S. Tidk; Chandak, Prakash G.; Jamkhande, Prasad G.

    2013-01-01

    Anticancer therapy majorly hindered by drug low water solubility, poor drug permeability, and high efflux of drug from cells. Nanotechnology is severing as an important tool to overcome these problems of cancer drug therapy. Nanomaterials have been used to enhance drug delivery at targeted site with less toxicity to healthy cells. Biodegradable polyester, polylactide-co-glycolide is approved for use for humans. Review is focusing on recent developments concerning polylactide-co-glycolide nano...

  2. Evaluating the Cancer Therapeutic Potential of Cardiac Glycosides

    OpenAIRE

    José Manuel Calderón-Montaño; Estefanía Burgos-Morón; Manuel Luis Orta; Dolores Maldonado-Navas; Irene García-Domínguez; Miguel López-Lázaro

    2014-01-01

    Cardiac glycosides, also known as cardiotonic steroids, are a group of natural products that share a steroid-like structure with an unsaturated lactone ring and the ability to induce cardiotonic effects mediated by a selective inhibition of the Na+/K+-ATPase. Cardiac glycosides have been used for many years in the treatment of cardiac congestion and some types of cardiac arrhythmias. Recent data suggest that cardiac glycosides may also be useful in the treatment of cancer. These compounds typ...

  3. Prevention of Bone Metastases in Breast Cancer Patients. Therapeutic Perspectives

    Directory of Open Access Journals (Sweden)

    Philippe Beuzeboc

    2014-05-01

    Full Text Available One in four breast cancer patients is at risk of developing bone metastases in her life time. The early prevention of bone metastases is a crucial challenge. It has been suggested that the use of zoledronic acid (ZOL in the adjuvant setting may reduce the persistence of disseminated tumor cells and thereby might improve outcome, specifically in a population of patients with a low estrogen microenvironment. More recently, the results of a large meta-analysis from 41 randomized trials comparing a bisphosphonate (BP to placebo or to an open control have been presented at the 2013 San Antonio Breast Cancer Meeting. Data on 17,016 patients confirm that adjuvant BPs, irrespective of the type of treatment or the treatment schedule and formulation (oral or intra-venously (IV, significantly reduced bone recurrences and improved breast cancer survival in postmenopausal women. No advantage was seen in premenopausal women. BPs are soon likely to become integrated into standard practice. Published data on the mechanisms involved in tumor cell seeding from the primary site, in homing to bone tissues and in the reactivation of dormant tumor cells will be reviewed; these might offer new ideas for innovative combination strategies.

  4. Carbon nanotubes as cancer therapeutic carriers and mediators

    Science.gov (United States)

    Son, Kuk Hui; Hong, Jeong Hee; Lee, Jin Woo

    2016-01-01

    Carbon nanotubes (CNTs) have received increasing attention in biomedical fields because of their unique structures and properties, including high aspect ratios, large surface areas, rich surface chemical functionalities, and size stability on the nanoscale. Particularly, they are attractive as carriers and mediators for cancer therapy. Through appropriate functionalization, CNTs have been used as nanocarriers for anticancer drugs including doxorubicin, camptothecin, carboplatin, cisplatin, paclitaxel, Pt(II), and Pt(IV), and genes including plasmid DNA, small-interfering RNA, oligonucleotides, and RNA/DNA aptamers. CNTs can also deliver proteins and immunotherapy components. Using combinations of light energy, they have also been applied as mediators for photothermal therapy and photodynamic therapy to directly destroy cancer cells without severely damaging normal tissue. If limitations such as a long-term cytotoxicity in the body, lack of size uniformity during the synthetic process, loading deviations for drug–CNT complexes, and release controllability at the target point are overcome, CNTs will become one of the strongest tools that are available for various other biomedical fields as well as for cancer therapy. PMID:27785021

  5. Enhancing cancer therapeutics using size-optimized magnetic fluid hyperthermia

    Science.gov (United States)

    Khandhar, Amit P.; Ferguson, R. Matthew; Simon, Julian A.; Krishnan, Kannan M.

    2012-04-01

    Magnetic fluid hyperthermia (MFH) employs heat dissipation from magnetic nanoparticles to elicit a therapeutic outcome in tumor sites, which results in either cell death (>42 °C) or damage (Fe3O4) nanoparticles (MNPs) synthesized in organic solvents and subsequently transferred to aqueous phase using a biocompatible amphiphilic polymer. Monodisperse MNPs, ˜16 nm diameter, show maximum heating efficiency, or specific loss power (watts/g Fe3O4) in a 373 kHz alternating magnetic field. Our in vitro results, for 15 min of heating, show that only 40% of cells survive for a relatively low dose (490 μg Fe/ml) of these size-optimized MNPs, compared to 80% and 90% survival fraction for 12 and 13 nm MNPs at 600 μg Fe/ml. The significant decrease in cell viability due to MNP-induced hyperthermia from only size-optimized nanoparticles demonstrates the central idea of tailoring size for a specific frequency in order to intrinsically improve the therapeutic potency of MFH by optimizing both dose and time of application.

  6. Enhancing cancer therapeutics using size-optimized magnetic fluid hyperthermia.

    Science.gov (United States)

    Khandhar, Amit P; Ferguson, R Matthew; Simon, Julian A; Krishnan, Kannan M

    2012-04-01

    Magnetic fluid hyperthermia (MFH) employs heat dissipation from magnetic nanoparticles to elicit a therapeutic outcome in tumor sites, which results in either cell death (>42 °C) or damage (monodisperse magnetite (Fe(3)O(4)) nanoparticles (MNPs) synthesized in organic solvents and subsequently transferred to aqueous phase using a biocompatible amphiphilic polymer. Monodisperse MNPs, ∼16 nm diameter, show maximum heating efficiency, or specific loss power (watts/g Fe(3)O(4)) in a 373 kHz alternating magnetic field. Our in vitro results, for 15 min of heating, show that only 40% of cells survive for a relatively low dose (490 μg Fe/ml) of these size-optimized MNPs, compared to 80% and 90% survival fraction for 12 and 13 nm MNPs at 600 μg Fe/ml. The significant decrease in cell viability due to MNP-induced hyperthermia from only size-optimized nanoparticles demonstrates the central idea of tailoring size for a specific frequency in order to intrinsically improve the therapeutic potency of MFH by optimizing both dose and time of application. PMID:22393267

  7. Nurses as therapeutic agents in the extreme environment of the desert war, 1940-44

    OpenAIRE

    Jane Brooks

    2015-01-01

    Aims: The purpose of this article is to explore therapeutic nursing with combatants in the extreme environment of the desert in World War II. Background: The notion of nursing as therapy gained credence in the 1990s and is currently experiencing resurgence, as nurses seek to find meaning in their work and improve patient care in the post-Francis environment. Design: This discussion paper will use the hostile space of the desert war zone in World War II to explore nurses’ therapeutic e...

  8. Topical erythropoietin as a novel preventive and therapeutic agent in bisphosphonate-related osteonecrosis of the jaw

    Directory of Open Access Journals (Sweden)

    Pantea Nazeman

    2016-01-01

    Full Text Available Introduction: One of the most common side effects of bisphosphonate intake is osteonecrosis of the jaw (ONJ which may develop following dentoalveolar interventions. Despite the vast available protocols, there is no clear guideline in the management of this condition. In osteonecrosis, the number and proliferation of bone-forming cells as well as vascularity are disturbed. Erythropoietin (EPO is a hematopoietic hormone with angiogenic, osteogenic, and antiapoptotic properties. The Hypothesis: It is suggested to utilize poly lactic-co-glycolic acid hydrogel containing 1500-3000 IU/kg EPO following dentoalveolar surgery in samples receiving bisphosphonates as a preventive or therapeutic agent. Evaluation of the Hypothesis: Considering the pathophysiology of ONJ and therapeutic properties of EPO, it is assumed that EPO may be effective in treatment of ONJ. Furthermore, as a preventive measure, utilizing EPO following dentoalveolar surgery may be beneficial in the patients at risk of ONJ.

  9. Enzyme inhibition as a key target for the development of novel metal-based anti-cancer therapeutics.

    Science.gov (United States)

    Griffith, Darren; Parker, James P; Marmion, Celine J

    2010-06-01

    Historically, DNA has been the target for many metal-based anti-cancer drugs, but drawbacks of prevailing therapies have stimulated the search for new molecular targets which may present unique opportunities for therapeutic exploitation. Enzyme inhibition has recently been identified as an alternative and significant target. The pursuit of novel metallodrug candidates that selectively target enzymes is now the subject of intense investigation in medicinal bioinorganic chemistry and chemical biology. In the field of drug design, it is recognised by many that exploiting the structural and chemical diversity of metal ions for the identification of potential hit and lead candidates can dramatically increase the number of possible drug candidates that may be added to the already abundant armoury of chemotherapeutic agents. This review will focus on recent key advancements in enzyme inhibition as a key target for the development of novel metal-based anti-cancer therapeutics. The enormous clinical success of classical platinum drugs, amongst others, coupled with the wealth of knowledge accumulated in recent years on enzyme structure and function, has undoubtedly been the impetus behind the development of new metallodrug candidates with enzyme inhibitory properties. Recent trends in this field will be reviewed with a particular emphasis on metal complexes that inhibit protein and lipid kinases, matrix metalloproteases, telomerases, topoisomerases, glutathione-S-transferases, and histone deacetylases.

  10. Functional genomics identifies therapeutic targets for MYC-driven cancer

    OpenAIRE

    Toyoshima, Masafumi; Howie, Heather L; Imakura, Maki; Walsh, Ryan M.; Annis, James E.; Chang, Aaron N; Frazier, Jason; Chau, B. Nelson; Loboda, Andrey; Linsley, Peter S; Cleary, Michele A.; Park, Julie R.; Grandori, Carla

    2012-01-01

    MYC oncogene family members are broadly implicated in human cancers, yet are considered “undruggable” as they encode transcription factors. MYC also carries out essential functions in proliferative tissues, suggesting that its inhibition could cause severe side effects. We elected to identify synthetic lethal interactions with c-MYC overexpression (MYC-SL) in a collection of ∼3,300 druggable genes, using high-throughput siRNA screening. Of 49 genes selected for follow-up, 48 were confirmed by...

  11. 77 FR 26772 - Prospective Grant of Exclusive License: Ocular Therapeutics Agent Delivery Devices and Methods...

    Science.gov (United States)

    2012-05-07

    ... compared to drugs applied systemically. Data are available for rodents, rabbits, dogs, and horses. The... HUMAN SERVICES National Institutes of Health Prospective Grant of Exclusive License: Ocular Therapeutics... Health and Human Services, is contemplating the grant of an exclusive patent license to practice...

  12. Use of flubendazole as a therapeutic agent against rotifers (Brachionus plicatilis) in intensive cultures of the harpacticoid copepod Tisbe holothuriae

    DEFF Research Database (Denmark)

    Steenfeldt, Svend Jørgen; Nielsen, Johan W.

    2010-01-01

    holothuria). Flubendazole was lethal to rotifers in concentrations as low as 0.05 mg L−1. There was no significant effect on the concentration of copepods, even at the highest concentration tested, i.e. 5.0 mg L−1 flubendazole. We conclude that flubendazole is an effective drug for control of B. plicatilis...... down production and subsequently use a therapeutic agent to eliminate all zooplankton in the system before restart with a stock culture free of rotifers. We tested flubendazole as a mean of controlling rotifers (Brachionus plicatilis) in intensive laboratory cultures of the harpacticoid copepod (Tisbe...

  13. Pembrolizumab: PD-1 inhibition as a therapeutic strategy in cancer.

    Science.gov (United States)

    McDermott, J; Jimeno, A

    2015-01-01

    Programmed cell death protein 1 (PD-1) and its ligands, programmed cell death 1 ligand 1 (PD-L1) and 2 (PD-L2) play an important role in regulating immune response through various mechanisms. This inhibitory action is thought to assist in immune evasion by cancer cells as PD-1, PD-L1 and PD-L2 have been found to be abnormally expressed by tumor cells and lymphocytes in the tumor microenvironment. Preclinical studies described PD-1 blockade resulting in tumor growth suppression and even decreased metastasis. This has led to the development of pembrolizumab (MK-3475), a highly selective, humanized monoclonal IgG4-kappa isotype antibody against PD-1. Early clinical trials have shown high tumor response rates and long duration of effect in previously treated advanced melanoma resulting in accelerated FDA approval for the drug in this situation. Pembrolizumab has also had success in non-small cell lung cancer and is being tested in multiple other tumor types. This review will discuss the development, preclinical data, pharmacokinetics and clinical efficacy to date of pembrolizumab.

  14. Musashi1 as a potential therapeutic target and diagnostic marker for lung cancer

    OpenAIRE

    Wang, Xiao-Yang; Yu, Huina; Linnoila, R. Ilona; Li, Laodong; Li, Dangyu; Mo, Biwen; Okano, Hideyuki; Luiz O. F. Penalva; Glazer, Robert I.

    2013-01-01

    Lung cancer remains one of the leading causes of cancer-related deaths worldwide with a 5-year survival rate of less than 20%. One approach to improving survival is the identification of biomarkers to detect early stage disease. In this study, we investigated the potential of the stem cell and progenitor cell marker, Musashi1 (Msi1), as a diagnostic marker and potential therapeutic target for lung cancer. Functional studies in A549 bronchioalveolar carcinoma and NCI-H520 squamous cell carcino...

  15. Development of Therapeutic Modality of Esophageal Cancer Using Ho-166 Stent

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Jong Doo; Park, Kwang Kyun; Lee, Min Geol [Yonsei University Medical College, Seoul (Korea, Republic of); Park, Kyung Bae [Korea Atomic Energy Research Institute, Taejon (Korea, Republic of)

    1997-09-01

    The prognosis of esophageal cancer is poor due absence of serosa which prevent local invasion to the surrounding organs such as aorta, mediastinum, trachea, and bronchi. We developed a Ho-166 Coated Radioactive Self-Expandable Metallic Stent which is a new herapeutic device in the treatment of esophageal cancer and underwent an animal experiment in mongrel dogs. We observed mucosal destruction by 4-6 mCi of Ho-166 without serious complications such as perforation of esophageal wall. Therefore, Ho-166 coated self-expandable stent appears to be an effective therapeutic device in the palliative treatment of esophageal cancer. 17 refs., 4 figs. (author)

  16. Effect of Therapeutic Touch in Patients with Cancer: a Literature Review

    Science.gov (United States)

    Tabatabaee, Amir; Tafreshi, Mansoureh Zagheri; Rassouli, Maryam; Aledavood, Seyed Amir; AlaviMajd, Hamid; Farahmand, Seyed Kazem

    2016-01-01

    Background: The use of complementary and alternative medicine (CAM) techniques has been growing. The National Center for Complementary and Alternative Medicine places therapeutic touch (TT) into the category of bio field energy. This literature review is aimed at critically evaluating the data from clinical trials examining the clinical efficacy of therapeutic touch as a supportive care modality in adult patients with cancer. Methods: Electronic databases (PubMed, Scopus, Scholar Google, and Science Direct) were searched from the year 1990 to 2015 to locate potentially relevant peer-reviewed articles using the key words therapeutic touch, touch therapy, neoplasm, cancer, and CAM. Additionally, relevant journals and references of all the located articles were manually searched for other potentially relevant studies. Results: The number of 334 articles was found on the basis of the key words, of which 17 articles related to the clinical trial were examined in accordance with the objectives of the study. A total of 6 articles were in the final dataset in which several examples of the positive effects of healing touch on pain, nausea, anxiety and fatigue, and life quality and also on biochemical parameters were observed. Conclusion: Based on the results of this study, an affirmation can be made regarding the use of TT, as a non-invasive intervention for improving the health status in patients with cancer. Moreover, therapeutic touch was proved to be a useful strategy for adult patients with cancer. PMID:27194823

  17. The Growing Complexity of Cancer Cell Response to DNA-Damaging Agents: Caspase 3 Mediates Cell Death or Survival?

    Science.gov (United States)

    Mirzayans, Razmik; Andrais, Bonnie; Kumar, Piyush; Murray, David

    2016-05-11

    It is widely stated that wild-type p53 either mediates the activation of cell cycle checkpoints to facilitate DNA repair and promote cell survival, or orchestrates apoptotic cell death following exposure to cancer therapeutic agents. This reigning paradigm has been challenged by numerous discoveries with different human cell types, including solid tumor-derived cell lines. Thus, activation of the p53 signaling pathway by ionizing radiation and other DNA-damaging agents hinders apoptosis and triggers growth arrest (e.g., through premature senescence) in some genetic backgrounds; such growth arrested cells remain viable, secrete growth-promoting factors, and give rise to progeny with stem cell-like properties. In addition, caspase 3, which is best known for its role in the execution phase of apoptosis, has been recently reported to facilitate (rather than suppress) DNA damage-induced genomic instability and carcinogenesis. This observation is consistent with an earlier report demonstrating that caspase 3 mediates secretion of the pro-survival factor prostaglandin E₂, which in turn promotes enrichment of tumor repopulating cells. In this article, we review these and related discoveries and point out novel cancer therapeutic strategies. One of our objectives is to demonstrate the growing complexity of the DNA damage response beyond the conventional "repair and survive, or die" hypothesis.

  18. Toward discovering new anti-cancer agents targeting topoisomerase IIα: a facile screening strategy adaptable to high throughput platform.

    Directory of Open Access Journals (Sweden)

    Yu-Shih Lin

    Full Text Available Topoisomerases are a family of vital enzymes capable of resolving topological problems in DNA during various genetic processes. Topoisomerase poisons, blocking reunion of cleaved DNA strands and stabilizing enzyme-mediated DNA cleavage complex, are clinically important antineoplastic and anti-microbial agents. However, the rapid rise of drug resistance that impedes the therapeutic efficacy of these life-saving drugs makes the discovering of new lead compounds ever more urgent. We report here a facile high throughput screening system for agents targeting human topoisomerase IIα (Top2α. The assay is based on the measurement of fluorescence anisotropy of a 29 bp fluorophore-labeled oligonucleotide duplex. Since drug-stabilized Top2α-bound DNA has a higher anisotropy compared with free DNA, this assay can work if one can use a dissociating agent to specifically disrupt the enzyme/DNA binary complexes but not the drug-stabilized ternary complexes. Here we demonstrate that NaClO4, a chaotropic agent, serves a critical role in our screening method to differentiate the drug-stabilized enzyme/DNA complexes from those that are not. With this strategy we screened a chemical library of 100,000 compounds and obtained 54 positive hits. We characterized three of them on this list and demonstrated their effects on the Top2α-mediated reactions. Our results suggest that this new screening strategy can be useful in discovering additional candidates of anti-cancer agents.

  19. Molecular and Cellular Effects of Hydrogen Peroxide on Human Lung Cancer Cells: Potential Therapeutic Implications

    Science.gov (United States)

    2016-01-01

    Lung cancer has a very high mortality-to-incidence ratio, representing one of the main causes of cancer mortality worldwide. Therefore, new treatment strategies are urgently needed. Several diseases including lung cancer have been associated with the action of reactive oxygen species (ROS) from which hydrogen peroxide (H2O2) is one of the most studied. Despite the fact that H2O2 may have opposite effects on cell proliferation depending on the concentration and cell type, it triggers several antiproliferative responses. H2O2 produces both nuclear and mitochondrial DNA lesions, increases the expression of cell adhesion molecules, and increases p53 activity and other transcription factors orchestrating cancer cell death. In addition, H2O2 facilitates the endocytosis of oligonucleotides, affects membrane proteins, induces calcium release, and decreases cancer cell migration and invasion. Furthermore, the MAPK pathway and the expression of genes related to inflammation including interleukins, TNF-α, and NF-κB are also affected by H2O2. Herein, we will summarize the main effects of hydrogen peroxide on human lung cancer leading to suggesting it as a potential therapeutic tool to fight this disease. Because of the multimechanistic nature of this molecule, novel therapeutic approaches for lung cancer based on the use of H2O2 may help to decrease the mortality from this malignancy. PMID:27375834

  20. Therapeutic modulation of endogenous gene function by agents with designed DNA-sequence specificities

    NARCIS (Netherlands)

    Uil, T.G.; Haisma, H.J.; Rots, Marianne

    2003-01-01

    Designer molecules that can specifically target pre-determined DNA sequences provide a means to modulate endogenous gene function. Different classes of sequence-specific DNA-binding agents have been developed, including triplex-forming molecules, synthetic polyamides and designer zinc finger protein

  1. Genomic Characterization of High-Grade Serous Ovarian Cancer: Dissecting Its Molecular Heterogeneity as a Road Towards Effective Therapeutic Strategies.

    Science.gov (United States)

    Mittempergher, Lorenza

    2016-07-01

    High-grade serous ovarian carcinoma (HGSOC) accounts for the majority of the ovarian cancer deaths, but over the last years little improvement in overall survival has been achieved. HGSOC is a molecularly and clinically heterogeneous disease. At genomic level, it represents a C-class malignancy having frequent gene losses (NF1, RB1, PTEN) and gains (CCNE1, MYC). HGSOC shows a simple mutational profile with TP53 nearly always mutated and with other genes mutated at low frequency. Importantly, 50 % of all HGSOCs have genetic features indicating a homologous recombination (HR) deficiency. HR deficient tumors are highly sensitive to PARP inhibitor anticancer agents, which exhibit synthetic lethality with a defective HR pathway. Transcriptionally, HGSOCs can be grouped into different molecular subtypes with distinct biology and prognosis. Molecular stratification of HGSOC based on these genomic features may result in improved therapeutic strategies. PMID:27241520

  2. Studies on therapeutic method of liver cancer(hapatocellular carcinome)by Holmium-166 radionuclide

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Jong Tae; Yoo, H. S.; Kim, M. J.; Han, K. H.; Park, C. I. [Yonsei University Medical College, Seoul (Korea, Republic of)

    1997-07-01

    As the study of radioactive nuclide, Holmium-166 in the treatment of liver cancer(hepatocellular carcinoma), this study was performed under the base of animal experimental. Using dog liver, percutaneous injection of Ho-166 MAA or chitosan with premade dose was done under the ultrasound guidance. Continuously the same procedure as previous one was performed in the skin hapatoma, which was developed by the injection of hepatocellular carcinoma cell in the nude mouse, In case of injected normal liver of dog, imaging study including ultrasound, CT and MRI was done in order to evaluate effect of Ho-166 and pathologic reaction. The result showed well defined nectosis of normal liver as well as skin hepatoma. The area of nectosis is dependent on the dose of injected Ho-166. Generally, pathologic reaction is tissue coagulation nectosis, Ho-166 particles, fibrosis and hemorrhage. In the clinical study, 50 patients with hapatoma was selected for this study under the agreement of patient. Under ultrasound guidance percutaneous injection of Ho-166 Maa or chitosan to tumor was performed and follow-up study was extended from 6 to 12 month. The result showed that 64% of patient were completely treated. Overall, the effect of treatment could be obtained in 41 patient (82%) among 50 hepatoma patient. Conclusively Ho-166 is thought to be a compromising agent in the treatment of hepatocellular carcinoma and one of therapeutic modality, if it is established internally and world-wide. In the future, the popular percutaneous ethanol injection method will be replaced to this method. 19 refs., 1 tabs., 14 figs. (author)

  3. Promise and challenges on the horizon of MET-targeted cancer therapeutics

    Institute of Scientific and Technical Information of China (English)

    Yu-Wen; Zhang

    2015-01-01

    MET(MNNG HOS transforming gene) is one of the receptor tyrosine kinases whose activities are frequently altered in human cancers, and it is a promising therapeutic target. MET is normally activated by its lone ligand, hepatocyte growth factor(HGF), eliciting its diverse biological activities that are crucial for development and physiology. Alteration of the HGF-MET axis results in inappropriate activation of a cascade of intracellular signaling pathways that contributes to hallmark cancer events including deregulated cell proliferation and survival, angiogenesis, invasion, andmetastasis. Aberrant MET activation results from autocrine or paracrine mechanisms due to overexpression of HGF and/or MET or from a ligand-independent mechanism caused by activating mutations or amplification of MET. The literature provides compelling evidence for the role of MET signaling in cancer development and progression. The finding that cancer cells often use MET activation to escape therapies targeting other pathways strengthens the argument for MET-targeted therapeutics. Diverse strategies have been explored to deactivate MET signaling, and compounds and biologics targeting the MET pathway are in clinical development. Despite promising results from various clinical trials, we are still waiting for true MET-targeted therapeutics in the clinic. This review will explore recent progress and hurdles in the pursuit of METtargeted cancer drugs and discuss the challenges in such development.

  4. Advances in the proteomic discovery of novel therapeutic targets in cancer

    Directory of Open Access Journals (Sweden)

    Guo S

    2013-10-01

    Full Text Available Shanchun Guo,1 Jin Zou,2 Guangdi Wang3 1Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine, 2Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, GA, USA; 3Research Centers in Minority Institutions Cancer Research Program, Xavier University of Louisiana, New Orleans, LA, USA Abstract: Proteomic approaches are continuing to make headways in cancer research by helping to elucidate complex signaling networks that underlie tumorigenesis and disease progression. This review describes recent advances made in the proteomic discovery of drug targets for therapeutic development. A variety of technical and methodological advances are overviewed with a critical assessment of challenges and potentials. A number of potential drug targets, such as baculoviral inhibitor of apoptosis protein repeat-containing protein 6, macrophage inhibitory cytokine 1, phosphoglycerate mutase 1, prohibitin 1, fascin, and pyruvate kinase isozyme 2 were identified in the proteomic analysis of drug-resistant cancer cells, drug action, and differential disease state tissues. Future directions for proteomics-based target identification and validation to be more translation efficient are also discussed. Keywords: proteomics, cancer, therapeutic target, signaling network, tumorigenesis

  5. Neoadjuvant Therapy in Patients with Pancreatic Cancer: A Disappointing Therapeutic Approach?

    Energy Technology Data Exchange (ETDEWEB)

    Zimmermann, Carolin, E-mail: carolin.zimmermann@uniklinikum-dresden.de [Department for General, Thoracic and Vascular Surgery and University Cancer Center University Hospital “Carl Gustav Carus”, Technical University Dresden (Germany); Folprecht, Gunnar [Medical Department I and University Cancer Center, University Hospital “Carl Gustav Carus”, Technical University Dresden (Germany); Zips, Daniel [Department of Radiation Oncology and University Cancer Center University Hospital “Carl Gustav Carus”, Technical University Dresden (Germany); Pilarsky, Christian; Saeger, Hans Detlev; Grutzmann, Robert [Department for General, Thoracic and Vascular Surgery and University Cancer Center University Hospital “Carl Gustav Carus”, Technical University Dresden (Germany)

    2011-05-09

    Pancreatic cancer is a devastating disease. It is the fourth leading cause of cancer-related death in Germany. The incidence in 2003/2004 was 16 cases per 100.000 inhabitants. Of all carcinomas, pancreatic cancer has the highest mortality rate, with one- and five-year survival rates of 25% and less than 5%, respectively, regardless of the stage at diagnosis. These low survival rates demonstrate the poor prognosis of this carcinoma. Previous therapeutic approaches including surgical resection combined with adjuvant therapy or palliative chemoradiation have not achieved satisfactory results with respect to overall survival. Therefore, it is necessary to evaluate new therapeutic approaches. Neoadjuvant therapy is an interesting therapeutic option for patients with pancreatic cancer. For selected patients with borderline or unresectable disease, neoadjuvant therapy offers the potential for tumor downstaging, increasing the probability of a margin-negative resection and decreasing the occurrence of lymph node metastasis. Currently, there is no universally accepted approach for treating patients with pancreatic cancer in the neoadjuvant setting. In this review, the most common neoadjuvant strategies will be described, compared and discussed.

  6. Neoadjuvant Therapy in Patients with Pancreatic Cancer: A Disappointing Therapeutic Approach?

    International Nuclear Information System (INIS)

    Pancreatic cancer is a devastating disease. It is the fourth leading cause of cancer-related death in Germany. The incidence in 2003/2004 was 16 cases per 100.000 inhabitants. Of all carcinomas, pancreatic cancer has the highest mortality rate, with one- and five-year survival rates of 25% and less than 5%, respectively, regardless of the stage at diagnosis. These low survival rates demonstrate the poor prognosis of this carcinoma. Previous therapeutic approaches including surgical resection combined with adjuvant therapy or palliative chemoradiation have not achieved satisfactory results with respect to overall survival. Therefore, it is necessary to evaluate new therapeutic approaches. Neoadjuvant therapy is an interesting therapeutic option for patients with pancreatic cancer. For selected patients with borderline or unresectable disease, neoadjuvant therapy offers the potential for tumor downstaging, increasing the probability of a margin-negative resection and decreasing the occurrence of lymph node metastasis. Currently, there is no universally accepted approach for treating patients with pancreatic cancer in the neoadjuvant setting. In this review, the most common neoadjuvant strategies will be described, compared and discussed

  7. Diagnostic and Therapeutic Analysis to 5 Cases of Male Breast Cancer

    Institute of Scientific and Technical Information of China (English)

    JIANGLi; XUEXinbo; 等

    2002-01-01

    Objective to retrospectively review the characteristics and the diagnostic and therapeutic procedure of 5 cases of male breast cancer.Methods To select 5 cases of male breast carcinoma of 1057 patients admitted in our hospital between 1992 and 2002 who suffered breast cancer.Results The incidence of breast cancer is low,ages of patients, are old,The major pathological type was infiltrative ductal cancer.Radical mastectomy is the primary treatment,accompanied,accompanied with adjuvant therapy such as chemotherapy,radiotherapy and antiestrogen therapy,Conclusion Male breast cancer has low incidence,low differentiation,and early metastasis,Patients should accept systemic treatment,and the primary treatment is radical mastectomy.

  8. Bladder Cancer Stem-Like Cells: Their Origin and Therapeutic Perspectives

    Directory of Open Access Journals (Sweden)

    Tomokazu Ohishi

    2015-12-01

    Full Text Available Bladder cancer (BC, the most common cancer arising from the human urinary tract, consists of two major clinicopathological phenotypes: muscle-invasive bladder cancer (MIBC and non-muscle-invasive bladder cancer (NMIBC. MIBC frequently metastasizes and is associated with an unfavorable prognosis. A certain proportion of patients with metastatic BC can achieve a remission with systemic chemotherapy; however, the disease relapses in most cases. Evidence suggests that MIBC comprises a small population of cancer stem cells (CSCs, which may be resistant to these treatments and may be able to form new tumors in the bladder or other organs. Therefore, the unambiguous identification of bladder CSCs and the development of targeted therapies are urgently needed. Nevertheless, it remains unclear where bladder CSCs originate and how they are generated. We review recent studies on bladder CSCs, specifically focusing on their proposed origin and the possible therapeutic options based on the CSC theory.

  9. Is pimecrolimus cream (1%) an appropriate therapeutic agent for the treatment of external ear atopic dermatitis?

    OpenAIRE

    Beriat, Güçlü Kaan; Akmansu, Şefik Halit; Doğan, Cem; Taştan, Eren; Topal, Ferda; Sabuncuoğlu, Bizden

    2012-01-01

    Summary Background In recent years, pimecrolimus 1% cream has been demonstrated to reduce symptoms of atopic dermatitis in patients when applied topically. Material/Methods In our study we compared the therapeutic effects of local 1% pimecrolimus to 1% hydrocortisone, and to a control group in a mouse model with atopic dermatitis in the external ear canals. Atopic dermatitis was created by application of Dinitrochlorobenzene in the external ear canals of mice. The development of atopic dermat...

  10. Squalamine as a broad-spectrum systemic antiviral agent with therapeutic potential

    OpenAIRE

    Zasloff, Michael; Adams, A. Paige; Beckerman, Bernard; Campbell, Ann; Han, Ziying; Luijten, Erik; Meza, Isaura; Julander, Justin; Mishra, Abhijit; Qu, Wei; Taylor, John M; Scott C Weaver; Wong, Gerard C. L.

    2011-01-01

    Antiviral compounds that increase the resistance of host tissues represent an attractive class of therapeutic. Here, we show that squalamine, a compound previously isolated from the tissues of the dogfish shark (Squalus acanthias) and the sea lamprey (Petromyzon marinus), exhibits broad-spectrum antiviral activity against human pathogens, which were studied in vitro as well as in vivo. Both RNA- and DNA-enveloped viruses are shown to be susceptible. The proposed mechanism involves the capacit...

  11. Stem Cell-Derived Exosomes: A Potential Alternative Therapeutic Agent in Orthopaedics

    OpenAIRE

    John Burke; Ravindra Kolhe; Monte Hunter; Carlos Isales; Mark Hamrick; Sadanand Fulzele

    2016-01-01

    Within the field of regenerative medicine, many have sought to use stem cells as a promising way to heal human tissue; however, in the past few years, exosomes (packaged vesicles released from cells) have shown more exciting promise. Specifically, stem cell-derived exosomes have demonstrated great ability to provide therapeutical benefits. Exosomal products can include miRNA, other genetic products, proteins, and various factors. They are released from cells in a paracrine fashion in order to...

  12. Engineered magnetic core shell nanoprobes: Synthesis and applications to cancer imaging and therapeutics.

    Science.gov (United States)

    Mandal, Samir; Chaudhuri, Keya

    2016-02-26

    Magnetic core shell nanoparticles are composed of a highly magnetic core material surrounded by a thin shell of desired drug, polymer or metal oxide. These magnetic core shell nanoparticles have a wide range of applications in biomedical research, more specifically in tissue imaging, drug delivery and therapeutics. The present review discusses the up-to-date knowledge on the various procedures for synthesis of magnetic core shell nanoparticles along with their applications in cancer imaging, drug delivery and hyperthermia or cancer therapeutics. Literature in this area shows that magnetic core shell nanoparticle-based imaging, drug targeting and therapy through hyperthermia can potentially be a powerful tool for the advanced diagnosis and treatment of various cancers.

  13. Thioglycosides as inhibitors of hSGLT1 and hSGLT2: Potential therapeutic agents for the control of hyperglycemia in diabetes

    OpenAIRE

    Castaneda, Francisco; Burse, Antje; Boland, Wilhelm; Kinne, Rolf K-H.

    2007-01-01

    The treatment of diabetes has been mainly focused on maintaining normal blood glucose concentrations. Insulin and hypoglycemic agents have been used as standard therapeutic strategies. However, these are characterized by limited efficacy and adverse side effects, making the development of new therapeutic alternatives mandatory. Inhibition of glucose reabsorption in the kidney, mediated by SGLT1 or SGLT2, represents a promising therapeutic approach. Therefore, the aim of the present study was ...

  14. Nanoparticle strategies for cancer therapeutics: Nucleic acids, polyamines, bovine serum amine oxidase and iron oxide nanoparticles (Review).

    Science.gov (United States)

    Agostinelli, Enzo; Vianello, Fabio; Magliulo, Giuseppe; Thomas, Thresia; Thomas, T J

    2015-01-01

    Nanotechnology for cancer gene therapy is an emerging field. Nucleic acids, polyamine analogues and cytotoxic products of polyamine oxidation, generated in situ by an enzyme-catalyzed reaction, can be developed for nanotechnology-based cancer therapeutics with reduced systemic toxicity and improved therapeutic efficacy. Nucleic acid-based gene therapy approaches depend on the compaction of DNA/RNA to nanoparticles and polyamine analogues are excellent agents for the condensation of nucleic acids to nanoparticles. Polyamines and amine oxidases are found in higher levels in tumours compared to that of normal tissues. Therefore, the metabolism of polyamines spermidine and spermine, and their diamine precursor, putrescine, can be targets for antineoplastic therapy since these naturally occurring alkylamines are essential for normal mammalian cell growth. Intracellular polyamine concentrations are maintained at a cell type-specific set point through the coordinated and highly regulated interplay between biosynthesis, transport, and catabolism. In particular, polyamine catabolism involves copper-containing amine oxidases. Several studies showed an important role of these enzymes in developmental and disease-related processes in animals through the control of polyamine homeostasis in response to normal cellular signals, drug treatment, and environmental and/or cellular stress. The production of toxic aldehydes and reactive oxygen species (ROS), H2O2 in particular, by these oxidases suggests a mechanism by which amine oxidases can be exploited as antineoplastic drug targets. The combination of bovine serum amine oxidase (BSAO) and polyamines prevents tumour growth, particularly well if the enzyme has been conjugated with a biocompatible hydrogel polymer. The findings described herein suggest that enzymatically formed cytotoxic agents activate stress signal transduction pathways, leading to apoptotic cell death. Consequently, superparamagnetic nanoparticles or other

  15. Lapatinib: the evidence for its therapeutic value in metastatic breast cancer

    Directory of Open Access Journals (Sweden)

    Andrew Thomson

    2005-06-01

    Full Text Available Andrew ThomsonCore Medical Publishing, Knutsford, UKIntroduction: Breast cancer is the most common cancer affecting women. Many patients ultimately progress to metastatic disease and optimal management of this disease remains a significant therapeutic challenge. Lapatinib, a dual tyrosine kinase inhibitor, is in clinical development for treatment of this disease. Aims: The objective of this article is to review the published evidence for the treatment of metastatic breast cancer with lapatinib, and assess its therapeutic potential.Evidence review: Most evidence has appeared in meeting abstract reports of phase I and II studies in healthy volunteers and cancer patients. Four studies have included patients with exclusively breast cancer. Complete and partial responses and stable disease has been reported in some patients. Emerging evidence indicates that complete and partial responses can be achieved in some patients with metastatic breast cancer. Lapatinib appears to be well tolerated in cancer patients and the maximum tolerated dose is in the region of 1800 mg/day. In addition, it has been used in combination with other cancer treatments. Five ongoing or planned phase II monotherapy and three phase III combination-therapy studies with lapatinib have been identified.Outcomes summary: The phase I and II studies reported to date have provided safety data and preliminary indications regarding efficacy. There is preliminary evidence that lapatinib can achieve objective response rates of 10–38% in patients with metastatic breast cancer. Patients with tumors overexpressing ErbB1 and/or ErbB2 are likely to benefit from lapatinib treatment. Key words: lapatinib, GW572016, metastatic breast cancer, signal transduction, tyrosine kinase inhibition

  16. Hydrogen Sulfide Signaling Axis as a Target for Prostate Cancer Therapeutics

    Directory of Open Access Journals (Sweden)

    Mingzhe Liu

    2016-01-01

    Full Text Available Hydrogen sulfide (H2S was originally considered toxic at elevated levels; however just in the past decade H2S has been proposed to be an important gasotransmitter with various physiological and pathophysiological roles in the body. H2S can be generated endogenously from L-cysteine by multiple enzymes, including cystathionine gamma-lyase, cystathionine beta-synthase, and 3-mercaptopyruvate sulfurtransferase in combination with cysteine aminotransferase. Prostate cancer is a major health concern and no effective treatment for prostate cancers is available. H2S has been shown to inhibit cell survival of androgen-independent, androgen-dependent, and antiandrogen-resistant prostate cancer cells through different mechanisms. Various H2S-releasing compounds, including sulfide salts, diallyl disulfide, diallyl trisulfide, sulforaphane, and other polysulfides, also have been shown to inhibit prostate cancer growth and metastasis. The expression of H2S-producing enzyme was reduced in both human prostate cancer tissues and prostate cancer cells. Androgen receptor (AR signaling is indispensable for the development of castration resistant prostate cancer, and H2S was shown to inhibit AR transactivation and contributes to antiandrogen-resistant status. In this review, we summarized the current knowledge of H2S signaling in prostate cancer and described the molecular alterations, which may bring this gasotransmitter into the clinic in the near future for developing novel pharmacological and therapeutic interventions for prostate cancer.

  17. Hydrogen Sulfide Signaling Axis as a Target for Prostate Cancer Therapeutics

    Science.gov (United States)

    Liu, Mingzhe; Wu, Lingyun; Montaut, Sabine; Yang, Guangdong

    2016-01-01

    Hydrogen sulfide (H2S) was originally considered toxic at elevated levels; however just in the past decade H2S has been proposed to be an important gasotransmitter with various physiological and pathophysiological roles in the body. H2S can be generated endogenously from L-cysteine by multiple enzymes, including cystathionine gamma-lyase, cystathionine beta-synthase, and 3-mercaptopyruvate sulfurtransferase in combination with cysteine aminotransferase. Prostate cancer is a major health concern and no effective treatment for prostate cancers is available. H2S has been shown to inhibit cell survival of androgen-independent, androgen-dependent, and antiandrogen-resistant prostate cancer cells through different mechanisms. Various H2S-releasing compounds, including sulfide salts, diallyl disulfide, diallyl trisulfide, sulforaphane, and other polysulfides, also have been shown to inhibit prostate cancer growth and metastasis. The expression of H2S-producing enzyme was reduced in both human prostate cancer tissues and prostate cancer cells. Androgen receptor (AR) signaling is indispensable for the development of castration resistant prostate cancer, and H2S was shown to inhibit AR transactivation and contributes to antiandrogen-resistant status. In this review, we summarized the current knowledge of H2S signaling in prostate cancer and described the molecular alterations, which may bring this gasotransmitter into the clinic in the near future for developing novel pharmacological and therapeutic interventions for prostate cancer. PMID:27019751

  18. Liposome Formulation of Fullerene-Based Molecular Diagnostic and Therapeutic Agents

    OpenAIRE

    Zhiguo Zhou

    2013-01-01

    Fullerene medicine is a new but rapidly growing research subject. Fullerene has a number of desired structural, physical and chemical properties to be adapted for biological use including antioxidants, anti-aging, anti-inflammation, photodynamic therapy, drug delivery, and magnetic resonance imaging contrast agents. Chemical functionalization of fullerenes has led to several interesting compounds with very promising preclinical efficacy, pharmacokinetic and safety data. However, there is no c...

  19. Nonspecifically enhanced therapeutic effects of vincristine on multidrug-resistant cancers when coencapsulated with quinine in liposomes

    Directory of Open Access Journals (Sweden)

    Xu YZ

    2015-06-01

    Full Text Available Yuzhen Xu,1 Liyan Qiu2 1College of Pharmaceutical Sciences, 2Ministry of Education Key Laboratory of Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, People’s Republic of China Abstract: The use of vincristine (VCR to treat cancer has been limited by its dose-dependent toxicity and development of drug resistance after repeated administrations. In this study, we investigated the mechanism by which quinine hydrochloride (QN acts as a sensitizer for VCR. Our experiments used three kinds of multidrug-resistant cancer cells and demonstrated that QN worked by inducing intracellular depletion of adenosine triphosphate, increasing adenosine triphosphatase activity, and decreasing P-glycoprotein expression. Based on these results, we designed and prepared a VCR and QN codelivery liposome (VQL and investigated the effect of coencapsulated QN on the in vitro cytotoxicity of VCR in cells and three-dimensional multicellular tumor spheroids. The antitumor effects of the formulation were also evaluated in multidrug-resistant tumor-bearing mice. The results of this in vivo study indicated that VQL could reverse VCR resistance. In addition, it reduced tumor volume 5.4-fold when compared with other test groups. The data suggest that VQL could be a promising nanoscaled therapeutic agent to overcome multidrug resistance, and may have important clinical implications for the treatment of cancer. Keywords: vincristine, quinine, combination therapy, liposome, multidrug resistance reversal, P-glycoprotein 

  20. Nonspecifically enhanced therapeutic effects of vincristine on multidrug-resistant cancers when coencapsulated with quinine in liposomes.

    Science.gov (United States)

    Xu, Yuzhen; Qiu, Liyan

    2015-01-01

    The use of vincristine (VCR) to treat cancer has been limited by its dose-dependent toxicity and development of drug resistance after repeated administrations. In this study, we investigated the mechanism by which quinine hydrochloride (QN) acts as a sensitizer for VCR. Our experiments used three kinds of multidrug-resistant cancer cells and demonstrated that QN worked by inducing intracellular depletion of adenosine triphosphate, increasing adenosine triphosphatase activity, and decreasing P-glycoprotein expression. Based on these results, we designed and prepared a VCR and QN codelivery liposome (VQL) and investigated the effect of coencapsulated QN on the in vitro cytotoxicity of VCR in cells and three-dimensional multicellular tumor spheroids. The antitumor effects of the formulation were also evaluated in multidrug-resistant tumor-bearing mice. The results of this in vivo study indicated that VQL could reverse VCR resistance. In addition, it reduced tumor volume 5.4-fold when compared with other test groups. The data suggest that VQL could be a promising nanoscaled therapeutic agent to overcome multidrug resistance, and may have important clinical implications for the treatment of cancer.

  1. Immune checkpoints aberrations and gastric cancer; assessment of prognostic value and evaluation of therapeutic potentials.

    Science.gov (United States)

    Abdel-Rahman, Omar

    2016-01-01

    Till now, the prognosis of advanced gastric cancer looked dreadful; thus the search for newer better approaches for this lethal disease has been a strategic target for cancer researchers. In recent years, important immunobiological aspects of the tumor have been revealed with the subsequent proposal of immune check point inhibitors to target these pathways. Clinically, unselected use of immune checkpoint inhibitors in gastric cancer has been deemed with failure; in contrast to the clear success of more recent studies reporting on the use of pembrolizumab in molecularly selected patients. This may illustrate that any future use of immune checkpoint inhibitors in gastric cancer has to be molecularly supported. This review provides a delicate dissection of the clinical and immunobiological considerations underlying the use of these agents in addition to a thorough review of the published clinical data of immune checkpoint inhibitors in gastric cancer. PMID:26321371

  2. Bioprospecting the Curculigoside-Cinnamic Acid-Rich Fraction from Molineria latifolia Rhizome as a Potential Antioxidant Therapeutic Agent.

    Science.gov (United States)

    Ooi, Der Jiun; Chan, Kim Wei; Sarega, Nadarajan; Alitheen, Noorjahan Banu; Ithnin, Hairuszah; Ismail, Maznah

    2016-01-01

    Increasing evidence from both experimental and clinical studies depicts the involvement of oxidative stress in the pathogenesis of various diseases. Specifically, disruption of homeostatic redox balance in accumulated body fat mass leads to obesity-associated metabolic syndrome. Strategies for the restoration of redox balance, potentially by exploring potent plant bioactives, have thus become the focus of therapeutic intervention. The present study aimed to bioprospect the potential use of the curculigoside-cinnamic acid-rich fraction from Molineria latifolia rhizome as an antioxidant therapeutic agent. The ethyl acetate fraction (EAF) isolated from M. latifolia rhizome methanolic extract (RME) contained the highest amount of phenolic compounds, particularly curculigoside and cinnamic acid. EAF demonstrated glycation inhibitory activities in both glucose- and fructose-mediated glycation models. In addition, in vitro chemical-based and cellular-based antioxidant assays showed that EAF exhibited high antioxidant activities and a protective effect against oxidative damage in 3T3-L1 preadipocytes. Although the efficacies of individual phenolics differed depending on the structure and concentration, a correlational study revealed strong correlations between total phenolic contents and antioxidant capacities. The results concluded that enriched phenolic contents in EAF (curculigoside-cinnamic acid-rich fraction) contributed to the overall better reactivity. Our data suggest that this bioactive-rich fraction warrants therapeutic potential against oxidative stress-related disorders. PMID:27322226

  3. Bioprospecting the Curculigoside-Cinnamic Acid-Rich Fraction from Molineria latifolia Rhizome as a Potential Antioxidant Therapeutic Agent

    Directory of Open Access Journals (Sweden)

    Der Jiun Ooi

    2016-06-01

    Full Text Available Increasing evidence from both experimental and clinical studies depicts the involvement of oxidative stress in the pathogenesis of various diseases. Specifically, disruption of homeostatic redox balance in accumulated body fat mass leads to obesity-associated metabolic syndrome. Strategies for the restoration of redox balance, potentially by exploring potent plant bioactives, have thus become the focus of therapeutic intervention. The present study aimed to bioprospect the potential use of the curculigoside-cinnamic acid-rich fraction from Molineria latifolia rhizome as an antioxidant therapeutic agent. The ethyl acetate fraction (EAF isolated from M. latifolia rhizome methanolic extract (RME contained the highest amount of phenolic compounds, particularly curculigoside and cinnamic acid. EAF demonstrated glycation inhibitory activities in both glucose- and fructose-mediated glycation models. In addition, in vitro chemical-based and cellular-based antioxidant assays showed that EAF exhibited high antioxidant activities and a protective effect against oxidative damage in 3T3-L1 preadipocytes. Although the efficacies of individual phenolics differed depending on the structure and concentration, a correlational study revealed strong correlations between total phenolic contents and antioxidant capacities. The results concluded that enriched phenolic contents in EAF (curculigoside-cinnamic acid-rich fraction contributed to the overall better reactivity. Our data suggest that this bioactive-rich fraction warrants therapeutic potential against oxidative stress-related disorders.

  4. Bioprospecting the Curculigoside-Cinnamic Acid-Rich Fraction from Molineria latifolia Rhizome as a Potential Antioxidant Therapeutic Agent.

    Science.gov (United States)

    Ooi, Der Jiun; Chan, Kim Wei; Sarega, Nadarajan; Alitheen, Noorjahan Banu; Ithnin, Hairuszah; Ismail, Maznah

    2016-01-01

    Increasing evidence from both experimental and clinical studies depicts the involvement of oxidative stress in the pathogenesis of various diseases. Specifically, disruption of homeostatic redox balance in accumulated body fat mass leads to obesity-associated metabolic syndrome. Strategies for the restoration of redox balance, potentially by exploring potent plant bioactives, have thus become the focus of therapeutic intervention. The present study aimed to bioprospect the potential use of the curculigoside-cinnamic acid-rich fraction from Molineria latifolia rhizome as an antioxidant therapeutic agent. The ethyl acetate fraction (EAF) isolated from M. latifolia rhizome methanolic extract (RME) contained the highest amount of phenolic compounds, particularly curculigoside and cinnamic acid. EAF demonstrated glycation inhibitory activities in both glucose- and fructose-mediated glycation models. In addition, in vitro chemical-based and cellular-based antioxidant assays showed that EAF exhibited high antioxidant activities and a protective effect against oxidative damage in 3T3-L1 preadipocytes. Although the efficacies of individual phenolics differed depending on the structure and concentration, a correlational study revealed strong correlations between total phenolic contents and antioxidant capacities. The results concluded that enriched phenolic contents in EAF (curculigoside-cinnamic acid-rich fraction) contributed to the overall better reactivity. Our data suggest that this bioactive-rich fraction warrants therapeutic potential against oxidative stress-related disorders.

  5. Anti-cancer agents based on 6-trifluoromethoxybenzimidazole derivatives and method of making

    Science.gov (United States)

    Gakh, Andrei A; Vovk, Mykhaylo V; Mel& #x27; nychenko, Nina V; Sukach, Volodymyr A

    2012-10-23

    The present disclosure relates to novel compounds having the structural Formulas (1a,1b), stereoisomers, tautomers, racemics, prodrugs, metabolites thereof, or pharmaceutically acceptable salt and/or solvate thereof as chemotherapy agents for treating of cancer, particularly androgen-independent prostate cancer. The disclosure also relates to methods for preparing said compounds, and to pharmaceutical compositions comprising said compounds.

  6. Nucleic Acid Aptamers as Potential Therapeutic and Diagnostic Agents for Lymphoma

    OpenAIRE

    Shum, Ka-To; Zhou, Jiehua; John J. Rossi

    2013-01-01

    Lymphomas are cancers that arise from white blood cells and usually present as solid tumors. Treatment of lymphoma often involves chemotherapy, and can also include radiotherapy and/or bone marrow transplantation. There is an un-questioned need for more effective therapies and diagnostic tool for lymphoma. Aptamers are single stranded DNA or RNA oligonucleotides whose three-dimensional structures are dictated by their sequences. The immense diversity in function and structure of nucleic acids...

  7. ATP synthase ecto-α-subunit: a novel therapeutic target for breast cancer

    Directory of Open Access Journals (Sweden)

    Pan Jian

    2011-12-01

    Full Text Available Abstract Background Treatment failure for breast cancer is frequently due to lymph node metastasis and invasion to neighboring organs. The aim of the present study was to investigate invasion- and metastasis-related genes in breast cancer cells in vitro and in vivo. Identification of new targets will facilitate the developmental pace of new techniques in screening and early diagnosis. Improved abilities to predict progression and metastasis, therapeutic response and toxicity will help to increase survival of breast cancer patients. Methods Differential protein expression in two breast cancer cell lines, one with high and the other with low metastatic potential, was analyzed using two-dimensional liquid phase chromatographic fractionation (Proteome Lab PF 2D system followed by matrix-assisted laser desorption/time-of-flight mass spectrometry (MALDI-TOF/MS. Results Up regulation of α-subunit of ATP synthase was identified in high metastatic cells compared with low metastatic cells. Immunohistochemical analysis of 168 human breast cancer specimens on tissue microarrays revealed a high frequency of ATP synthase α-subunit expression in breast cancer (94.6% compared to normal (21.2% and atypical hyperplasia (23% breast tissues. Levels of ATP synthase expression levels strongly correlated with large tumor size, poor tumor differentiation and advanced tumor stages (P Conclusions Over-expression of ATP synthase α-subunit may be involved in the progression and metastasis of breast cancer, perhaps representing a potential biomarker for diagnosis, prognosis and a therapeutic target for breast cancer. This finding of this study will help us to better understand the molecular mechanism of tumor metastasis and to improve the screening, diagnosis, as well as prognosis and/or prediction of responses to therapy for breast cancer.

  8. Botanical Agents for the Treatment of Nonmelanoma Skin Cancer

    OpenAIRE

    Millsop, Jillian W.; Sivamani, Raja K; Nasim Fazel

    2013-01-01

    Nonmelanoma skin cancers, including basal cell carcinoma and squamous cell carcinoma, are common neoplasms worldwide and are the most common cancers in the United States. Standard therapy for cutaneous neoplasms typically involves surgical removal. However, there is increasing interest in the use of topical alternatives for the prevention and treatment of nonmelanoma skin cancer, particularly superficial variants. Botanicals are compounds derived from herbs, spices, stems, roots, and other su...

  9. Novel compounds for the treatment of Duchenne muscular dystrophy: emerging therapeutic agents

    Directory of Open Access Journals (Sweden)

    Steve D Wilton

    2011-03-01

    Full Text Available Steve D Wilton, Sue FletcherCentre for Neuromuscular and Neurological Disorders, University of Western Australia, Crawley, Perth, WA, AustraliaAbstract: The identification of dystrophin and the causative role of mutations in this gene in Duchenne and Becker muscular dystrophies (D/BMD was expected to lead to timely development of effective therapies. Despite over 20 years of research, corticosteroids remain the only available pharmacological treatment for DMD, although significant benefits and extended life have resulted from advances in the clinical care and management of DMD individuals. Effective treatment of DMD will require dystrophin restitution in skeletal, cardiac, and smooth muscles and nonmuscle tissues; however, modulation of muscle loss and regeneration has the potential to play an important role in altering the natural history of DMD, particularly in combination with other treatments. Emerging biological, molecular, and small molecule therapeutics are showing promise in ameliorating this devastating disease, and it is anticipated that regulatory environments will need to display some flexibility in order to accommodate the new treatment paradigms.Keywords: Duchenne muscular dystrophy, molecular therapeutics, small molecules

  10. Novel therapeutic agents for HbF induction: a new era for treatment of β thalassemia?

    Directory of Open Access Journals (Sweden)

    S.P. Perrine

    2011-12-01

    Full Text Available Fetal globin is endogenous, normally integrated in hematopoietic stem cells in all humans, and available for reactivation. Inducing expression of fetal globin (g-globin gene expression to 60-70% of a globin synthesis produces β-thalassemia trait globin synthetic ratios, and has been shown to reduce anemia to mild levels which do not require regular blood transfusion. Several classes of therapeutics have induced g-globin expression in β thalassemia patients, raised total hemoglobin levels, and even eliminated transfusion requirements in formerly transfusion-dependent patients, demonstrating proof-of-concept of the approach. However, prior generations of therapeutics were not readily feasible for widespread use. Currently, several recently discovered oral therapeutic candidates are more potent and/ or patientfriendly, requiring low oral doses, have distinct molecular mechanisms of action, and can be used in combination regimens. Tailoring therapeutic regimens to patient subsets stratified for solely β+ or a β0 globin mutation, and for quantitative trait loci (QTL which modulate HbF and clinical severity, can guide more effective and informative clinical trials. These advancements provide methods for a rational approach to applying fetal globin gene induction in therapeutic regimens suitable for use in diverse thalassemia patient populations world-wide. 胎儿珠蛋白是内生的,通常结合在所有人类的造血干细胞中,并可进行再激活。 包括胎儿珠蛋白的表达(g-珠蛋白),60%-70% 珠蛋白合成基因表达产生 β地中海贫血特征珠蛋白合成比率,并且已经显示将贫血降低至轻度水平,这不需要常规输血 几类疗法诱导β地中海贫血患者中的g-珠蛋白的表达,升高了血红蛋白的总体水平,甚至让以前依靠输血的患者不再需要输血,这演示了此方法的概念验证。 不过,先前几代疗法未能进行广泛使用。 目前,最近发

  11. Biological implications and therapeutic significance of DNA methylation regulated genes in cervical cancer.

    Science.gov (United States)

    Bhat, Samatha; Kabekkodu, Shama Prasada; Noronha, Ashish; Satyamoorthy, Kapaettu

    2016-02-01

    Cervical cancer is the second most common cancer among women worldwide. About 528,000 women are diagnosed with cervical cancer contributing to around 266,000 deaths, across the globe every year. Out of these, the burden of 226,000 (85%) deaths occurs in the developing countries, who are less resource intensive to manage the disease. This is despite the fact that cervical cancer is amenable for early detection due to its long and relatively well-known natural history prior to its culmination as invasive disease. Infection with high risk human papillomavirus (hrHPVs) is essential but not sufficient to cause cervical cancer. Although it was thought that genetic mutations alone was sufficient to cause cervical cancer, the current epidemiological and molecular studies have shown that HPV infection along with genetic and epigenetic changes are frequently associated and essential for initiation, development and progression of the disease. Moreover, aberrant DNA methylation in host and HPV genome can be utilized not only as biomarkers for early detection, disease progression, diagnosis and prognosis of cervical cancer but also to design effective therapeutic strategies. In this review, we focus on recent studies on DNA methylation changes in cervical cancer and their potential role as biomarkers for early diagnosis, prognosis and targeted therapy. PMID:26743075

  12. Glycogen Synthase Kinase 3β Inhibition as a Therapeutic Approach in the Treatment of Endometrial Cancer

    Directory of Open Access Journals (Sweden)

    Liang Ma

    2013-08-01

    Full Text Available Alternative strategies beyond current chemotherapy and radiation therapy regimens are needed in the treatment of advanced stage and recurrent endometrial cancers. There is considerable promise for biologic agents targeting the extracellular signal-regulated kinase (ERK pathway for treatment of these cancers. Many downstream substrates of the ERK signaling pathway, such as glycogen synthase kinase 3β (GSK3β, and their roles in endometrial carcinogenesis have not yet been investigated. In this study, we tested the importance of GSK3β inhibition in endometrial cancer cell lines and in vivo models. Inhibition of GSK3β by either lithium chloride (LiCl or specific GSK3β inhibitor VIII showed cytostatic and cytotoxic effects on multiple endometrial cancer cell lines, with little effect on the immortalized normal endometrial cell line. Flow cytometry and immunofluorescence revealed a G2/M cell cycle arrest in both type I (AN3CA, KLE, and RL952 and type II (ARK1 endometrial cancer cell lines. In addition, LiCl pre-treatment sensitized AN3CA cells to the chemotherapy agent paclitaxel. Administration of LiCl to AN3CA tumor-bearing mice resulted in partial or complete regression of some tumors. Thus, GSK3β activity is associated with endometrial cancer tumorigenesis and its pharmacologic inhibition reduces cell proliferation and tumor growth.

  13. Lovastatin induces apoptosis of ovarian cancer cells and synergizes with doxorubicin: potential therapeutic relevance

    Directory of Open Access Journals (Sweden)

    Goard Carolyn A

    2010-03-01

    Full Text Available Abstract Background Ovarian carcinoma is a rarely curable disease, for which new treatment options are required. As agents that block HMG-CoA reductase and the mevalonate pathway, the statin family of drugs are used in the treatment of hypercholesterolemia and have been shown to trigger apoptosis in a tumor-specific manner. Recent clinical trials show that the addition of statins to traditional chemotherapeutic strategies can increase efficacy of targeting statin-sensitive tumors. Our goal was to assess statin-induced apoptosis of ovarian cancer cells, either alone or in combination with chemotherapeutics, and then determine these mechanisms of action. Methods The effect of lovastatin on ovarian cancer cell lines was evaluated alone and in combination with cisplatin and doxorubicin using several assays (MTT, TUNEL, fixed PI, PARP cleavage and synergy determined by evaluating the combination index. The mechanisms of action were evaluated using functional, molecular, and pharmacologic approaches. Results We demonstrate that lovastatin induces apoptosis of ovarian cancer cells in a p53-independent manner and synergizes with doxorubicin, a chemotherapeutic agent used to treat recurrent cases of ovarian cancer. Lovastatin drives ovarian tumor cell death by two mechanisms: first, by blocking HMG-CoA reductase activity, and second, by sensitizing multi-drug resistant cells to doxorubicin by a novel mevalonate-independent mechanism. This inhibition of drug transport, likely through inhibition of P-glycoprotein, potentiates both DNA damage and tumor cell apoptosis. Conclusions The results of this research provide pre-clinical data to warrant further evaluation of statins as potential anti-cancer agents to treat ovarian carcinoma. Many statins are inexpensive, off-patent generic drugs that are immediately available for use as anti-cancer agents. We provide evidence that lovastatin triggers apoptosis of ovarian cancer cells as a single agent by a

  14. Lovastatin induces apoptosis of ovarian cancer cells and synergizes with doxorubicin: potential therapeutic relevance

    International Nuclear Information System (INIS)

    Ovarian carcinoma is a rarely curable disease, for which new treatment options are required. As agents that block HMG-CoA reductase and the mevalonate pathway, the statin family of drugs are used in the treatment of hypercholesterolemia and have been shown to trigger apoptosis in a tumor-specific manner. Recent clinical trials show that the addition of statins to traditional chemotherapeutic strategies can increase efficacy of targeting statin-sensitive tumors. Our goal was to assess statin-induced apoptosis of ovarian cancer cells, either alone or in combination with chemotherapeutics, and then determine these mechanisms of action. The effect of lovastatin on ovarian cancer cell lines was evaluated alone and in combination with cisplatin and doxorubicin using several assays (MTT, TUNEL, fixed PI, PARP cleavage) and synergy determined by evaluating the combination index. The mechanisms of action were evaluated using functional, molecular, and pharmacologic approaches. We demonstrate that lovastatin induces apoptosis of ovarian cancer cells in a p53-independent manner and synergizes with doxorubicin, a chemotherapeutic agent used to treat recurrent cases of ovarian cancer. Lovastatin drives ovarian tumor cell death by two mechanisms: first, by blocking HMG-CoA reductase activity, and second, by sensitizing multi-drug resistant cells to doxorubicin by a novel mevalonate-independent mechanism. This inhibition of drug transport, likely through inhibition of P-glycoprotein, potentiates both DNA damage and tumor cell apoptosis. The results of this research provide pre-clinical data to warrant further evaluation of statins as potential anti-cancer agents to treat ovarian carcinoma. Many statins are inexpensive, off-patent generic drugs that are immediately available for use as anti-cancer agents. We provide evidence that lovastatin triggers apoptosis of ovarian cancer cells as a single agent by a mevalonate-dependent mechanism. Moreover, we also show lovastatin synergizes

  15. Loss of CHD1 causes DNA repair defects and enhances prostate cancer therapeutic responsiveness

    DEFF Research Database (Denmark)

    Kari, Vijayalakshmi; Mansour, Wael Yassin; Raul, Sanjay Kumar;

    2016-01-01

    The CHD1 gene, encoding the chromo-domain helicase DNA-binding protein-1, is one of the most frequently deleted genes in prostate cancer. Here, we examined the role of CHD1 in DNA double-strand break (DSB) repair in prostate cancer cells. We show that CHD1 is required for the recruitment of Ct...... serve as a marker for prostate cancer patient stratification and the utilization of targeted therapies such as PARP inhibitors, which specifically target tumors with HR defects.......-homologous end joining. Together, we provide evidence for a previously unknown role of CHD1 in DNA DSB repair via HR and show that CHD1 depletion sensitizes cells to PARP inhibitors, which has potential therapeutic relevance. Our findings suggest that CHD1 deletion, like BRCA1/2 mutation in ovarian cancer, may...

  16. Novel compounds for the treatment of Duchenne muscular dystrophy: emerging therapeutic agents.

    Science.gov (United States)

    Wilton, Steve D; Fletcher, Sue

    2011-01-01

    The identification of dystrophin and the causative role of mutations in this gene in Duchenne and Becker muscular dystrophies (D/BMD) was expected to lead to timely development of effective therapies. Despite over 20 years of research, corticosteroids remain the only available pharmacological treatment for DMD, although significant benefits and extended life have resulted from advances in the clinical care and management of DMD individuals. Effective treatment of DMD will require dystrophin restitution in skeletal, cardiac, and smooth muscles and nonmuscle tissues; however, modulation of muscle loss and regeneration has the potential to play an important role in altering the natural history of DMD, particularly in combination with other treatments. Emerging biological, molecular, and small molecule therapeutics are showing promise in ameliorating this devastating disease, and it is anticipated that regulatory environments will need to display some flexibility in order to accommodate the new treatment paradigms. PMID:23776365

  17. Alpha-1 antitrypsin: a potent anti-inflammatory and potential novel therapeutic agent.

    LENUS (Irish Health Repository)

    Bergin, David A

    2012-04-01

    Alpha-1 antitrypsin (AAT) has long been thought of as an important anti-protease in the lung where it is known to decrease the destructive effects of major proteases such as neutrophil elastase. In recent years, the perception of this protein in this simple one dimensional capacity as an anti-protease has evolved and it is now recognised that AAT has significant anti-inflammatory properties affecting a wide range of inflammatory cells, leading to its potential therapeutic use in a number of important diseases. This present review aims to discuss the described anti-inflammatory actions of AAT in modulating key immune cell functions, delineate known signalling pathways and specifically to identify the models of disease in which AAT has been shown to be effective as a therapy.

  18. Strigolactone analogs act as new anti-cancer agents in inhibition of breast cancer in xenograft model.

    Science.gov (United States)

    Mayzlish-Gati, Einav; Laufer, Dana; Grivas, Christopher F; Shaknof, Julia; Sananes, Amiram; Bier, Ariel; Ben-Harosh, Shani; Belausov, Eduard; Johnson, Michael D; Artuso, Emma; Levi, Oshrat; Genin, Ola; Prandi, Cristina; Khalaila, Isam; Pines, Mark; Yarden, Ronit I; Kapulnik, Yoram; Koltai, Hinanit

    2015-01-01

    Strigolactones (SLs) are a novel class of plant hormones. Previously, we found that analogs of SLs induce growth arrest and apoptosis in breast cancer cell lines. These compounds also inhibited the growth of breast cancer stem cell enriched-mammospheres with increased potency. Furthermore, strigolactone analogs inhibited growth and survival of colon, lung, prostate, melanoma, osteosarcoma and leukemia cancer cell lines. To further examine the anti-cancer activity of SLs in vivo, we have examined their effects on growth and viability of MDA-MB-231 tumor xenografts model either alone or in combination with paclitaxel. We show that strigolactone act as new anti-cancer agents in inhibition of breast cancer in xenograft model. In addition we show that SLs affect the integrity of the microtubule network and therefore may inhibit the migratory phenotype of the highly invasive breast cancer cell lines that were examined. PMID:26192476

  19. [Up-to-date drug treatment of disseminated lung cancer--which other drugs are available in addition to conventional cytotoxic agents?].

    Science.gov (United States)

    Koivunen, Jussi; Knuuttila, Aija; Mali, Pekka

    2016-01-01

    In addition to conventional cytotoxic agents, novel drug treatments have in the last few years been introduced for the treatment of non-small cell lung cancer. Whereas some of the novel treatments have brought significant improvement in treatment outcome, the benefit brought about by the treatment has in some cases been quite small in comparison with the costs and adverse effects. In the present review we explore the goals of drug treatments of disseminated lung cancer, assessment of therapeutic benefits as well as most significant research results of novel drug treatments of the lastfew years In addition, we evaluate the effect of the novel drug treatments on Finnish treatment practices.

  20. Therapeutic potential of N-acetylcysteine as an antiplatelet agent in patients with type-2 diabetes

    Directory of Open Access Journals (Sweden)

    MacRury Sandra M

    2011-05-01

    Full Text Available Abstract Background Platelet hyperaggregability is a pro-thrombotic feature of type-2 diabetes, associated with low levels of the antioxidant glutathione (GSH. Clinical delivery of N-acetylcysteine (NAC, a biosynthetic precursor of GSH, may help redress a GSH shortfall in platelets, thereby reducing thrombotic risk in type-2 diabetes patients. We investigated the effect of NAC in vitro, at concentrations attainable with tolerable oral dosing, on platelet GSH concentrations and aggregation propensity in blood from patients with type-2 diabetes. Methods Blood samples (n = 13 were incubated (2 h, 37°C with NAC (10-100 micromolar in vitro. Platelet aggregation in response to thrombin and ADP (whole blood aggregometry was assessed, together with platelet GSH concentration (reduced and oxidized, antioxidant status, reactive oxygen species (ROS generation, and plasma NOx (a surrogate measure of platelet-derived nitric oxide; NO. Results At therapeutically relevant concentrations (10-100 micromolar, NAC increased intraplatelet GSH levels, enhanced the antioxidant effects of platelets, and reduced ROS generation in blood from type-2 diabetes patients. Critically, NAC inhibited thrombin- and ADP-induced platelet aggregation in vitro. Plasma NOx was enhanced by 30 micromolar NAC. Conclusions Our results suggest that NAC reduces thrombotic propensity in type-2 diabetes patients by increasing platelet antioxidant status as a result of elevated GSH synthesis, thereby lowering platelet-derived ROS. This may increase bioavailability of protective NO in a narrow therapeutic range. Therefore, NAC might represent an alternative or additional therapy to aspirin that could reduce thrombotic risk in type-2 diabetes.

  1. Nanodiscs as a therapeutic delivery agent: inhibition of respiratory syncytial virus infection in the lung

    Directory of Open Access Journals (Sweden)

    Numata M

    2013-04-01

    Full Text Available Mari Numata,1 Yelena V Grinkova,2 James R Mitchell,1 Hong Wei Chu,1 Stephen G Sligar,2 Dennis R Voelker1 1Department of Medicine, Program in Cell Biology, National Jewish Health, Denver, CO, USA; 2Department of Biochemistry, University of Illinois, Urbana, IL, USA Abstract: There is increasing interest in the application of nanotechnology to solve the difficult problem of therapeutic administration of pharmaceuticals. Nanodiscs, composed of a stable discoidal lipid bilayer encircled by an amphipathic membrane scaffold protein that is an engineered variant of the human Apo A-I constituent of high-density lipoproteins, have been a successful platform for providing a controlled lipid composition in particles that are especially useful for investigating membrane protein structure and function. In this communication, we demonstrate that nanodiscs are effective in suppressing respiratory syncytial viral (RSV infection both in vitro and in vivo when self-assembled with the minor pulmonary surfactant phospholipid palmitoyloleoylphosphatidylglycerol (POPG. Preparations of nanodiscs containing POPG (nPOPG antagonized interleukin-8 production from Beas2B epithelial cells challenged by RSV infection, with an IC50 of 19.3 µg/mL. In quantitative in vitro plaque assays, nPOPG reduced RSV infection by 93%. In vivo, nPOPG suppressed inflammatory cell infiltration into the lung, as well as IFN-γ production in response to RSV challenge. nPOPG also completely suppressed the histopathological changes in lung tissue elicited by RSV and reduced the amount of virus recovered from lung tissue by 96%. The turnover rate of nPOPG was estimated to have a half-time of 60–120 minutes (m, based upon quantification of the recovery of the human Apo A-I constituent. From these data, we conclude that nPOPG is a potent antagonist of RSV infection and its inflammatory sequelae both in vitro and in vivo. Keywords: nanodiscs, therapeutic delivery, anti-viral, innate immunity

  2. Combined therapeutic potential of nuclear receptors with receptor tyrosine kinase inhibitors in lung cancer

    Energy Technology Data Exchange (ETDEWEB)

    Wairagu, Peninah M. [Department of Biochemistry, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do 220-701 (Korea, Republic of); Institute of Lifestyle Medicine, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do 220-701 (Korea, Republic of); Nuclear Receptor Research Consortium, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do 220-701 (Korea, Republic of); Park, Kwang Hwa [Department of Pathology, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do 220-701 (Korea, Republic of); Kim, Jihye [Department of Biochemistry, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do 220-701 (Korea, Republic of); Institute of Lifestyle Medicine, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do 220-701 (Korea, Republic of); Nuclear Receptor Research Consortium, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do 220-701 (Korea, Republic of); Choi, Jong-Whan; Kim, Hyun-Won; Yeh, Byung-Il [Department of Biochemistry, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do 220-701 (Korea, Republic of); Jung, Soon-Hee [Department of Pathology, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do 220-701 (Korea, Republic of); Yong, Suk-Joong [Department of Internal Medicine, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do 220-701 (Korea, Republic of); Jeong, Yangsik, E-mail: yjeong@yonsei.ac.kr [Department of Biochemistry, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do 220-701 (Korea, Republic of); Institute of Lifestyle Medicine, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do 220-701 (Korea, Republic of); Nuclear Receptor Research Consortium, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do 220-701 (Korea, Republic of)

    2014-05-09

    Highlights: • The 48 NR genes and 48 biological anti-cancer targets are profiled in paired-cells. • Growth inhibition by NR ligands or TKIs is target receptor level-dependent. • T0901317 with gefitinib/PHA665752 shows additive growth inhibition in lung cells. - Abstract: Cancer heterogeneity is a big hurdle in achieving complete cancer treatment, which has led to the emergence of combinational therapy. In this study, we investigated the potential use of nuclear receptor (NR) ligands for combinational therapy with other anti-cancer drugs. We first profiled all 48 NRs and 48 biological anti-cancer targets in four pairs of lung cell lines, where each pair was obtained from the same patient. Two sets of cell lines were normal and the corresponding tumor cell lines while the other two sets consisted of primary versus metastatic tumor cell lines. Analysis of the expression profile revealed 11 NRs and 15 cancer targets from the two pairs of normal versus tumor cell lines, and 9 NRs and 9 cancer targets from the primary versus metastatic tumor cell lines had distinct expression patterns in each category. Finally, the evaluation of nuclear receptor ligand T0901317 for liver X receptor (LXR) demonstrated its combined therapeutic potential with tyrosine kinase inhibitors. The combined treatment of cMET inhibitor PHA665752 or EGFR inhibitor gefitinib with T0901317 showed additive growth inhibition in both H2073 and H1993 cells. Mechanistically, the combined treatment suppressed cell cycle progression by inhibiting cyclinD1 and cyclinB expression. Taken together, this study provides insight into the potential use of NR ligands in combined therapeutics with other biological anti-cancer drugs.

  3. Combined therapeutic potential of nuclear receptors with receptor tyrosine kinase inhibitors in lung cancer

    International Nuclear Information System (INIS)

    Highlights: • The 48 NR genes and 48 biological anti-cancer targets are profiled in paired-cells. • Growth inhibition by NR ligands or TKIs is target receptor level-dependent. • T0901317 with gefitinib/PHA665752 shows additive growth inhibition in lung cells. - Abstract: Cancer heterogeneity is a big hurdle in achieving complete cancer treatment, which has led to the emergence of combinational therapy. In this study, we investigated the potential use of nuclear receptor (NR) ligands for combinational therapy with other anti-cancer drugs. We first profiled all 48 NRs and 48 biological anti-cancer targets in four pairs of lung cell lines, where each pair was obtained from the same patient. Two sets of cell lines were normal and the corresponding tumor cell lines while the other two sets consisted of primary versus metastatic tumor cell lines. Analysis of the expression profile revealed 11 NRs and 15 cancer targets from the two pairs of normal versus tumor cell lines, and 9 NRs and 9 cancer targets from the primary versus metastatic tumor cell lines had distinct expression patterns in each category. Finally, the evaluation of nuclear receptor ligand T0901317 for liver X receptor (LXR) demonstrated its combined therapeutic potential with tyrosine kinase inhibitors. The combined treatment of cMET inhibitor PHA665752 or EGFR inhibitor gefitinib with T0901317 showed additive growth inhibition in both H2073 and H1993 cells. Mechanistically, the combined treatment suppressed cell cycle progression by inhibiting cyclinD1 and cyclinB expression. Taken together, this study provides insight into the potential use of NR ligands in combined therapeutics with other biological anti-cancer drugs

  4. Fate of water borne therapeutic agents and associated effects on nitrifying biofilters in recirculating aquaculture systems

    DEFF Research Database (Denmark)

    Pedersen, Lars-Flemming

    experience is limited. The two main objectives of this Ph.D. project were to 1) investigate the fate of FA in nitrifying aquaculture biofilters, focusing on factors influencing degradation rates, and 2) investigate the fate of HP and PAA in nitrifying aquaculture biofilters and evaluate the effects...... of these agents on biofilter nitrification performance. All experiments were conducted through addition of chemical additives to closed pilot scale recirculating aquaculture systems (RAS) with fixed media submerged biofilters under controlled operating conditions with rainbow trout (Oncorhynchus mykiss......) in a factorial design with true replicates. Biofilter nitrification performances were evaluated by changes in chemical processes, and nitrifying populations were identified by fluorescence in situ hybridisation (FISH) analysis. FA was degraded at a constant rate immediately after addition, and found...

  5. The application of gold nanoparticles as a promising therapeutic approach in breast and ovarian cancer.

    Science.gov (United States)

    Kafshdooz, Leila; Kafshdooz, Taiebeh; Razban, Zohreh; Akbarzadeh, Abolfazl

    2016-08-01

    The development of specialized nanoparticles (NPs) for use in the detection and treatment of cancer is increasing. In the last few years, gold nanoparticles (AuNPs) have been greatly studied in biological and photothermal therapeutic status. AuNPs can bind to a wide range of organic molecules, and their synthesis is easy. In this review, we summarize the characteristics of AuNPs, their contributions to tumor destruction, their toxicity, and their potential in the treatment of breast and ovarian cancer. PMID:25871281

  6. ER maleate is a novel anticancer agent in oral cancer: implications for cancer therapy

    Science.gov (United States)

    Fu, Guodong; Somasundaram, Raj Thani; Jessa, Fatima; Srivastava, Gunjan; MacMillan, Christina; Witterick, Ian; Walfish, Paul G.; Ralhan, Ranju

    2016-01-01

    ER maleate [10-(3-Aminopropyl)-3, 4-dimethyl-9(10H)-acridinone maleate] identified in a kinome screen was investigated as a novel anticancer agent for oral squamous cell carcinoma (OSCC). Our aim was to demonstrate its anticancer effects, identify putative molecular targets and determine their clinical relevance and investigate its chemosensitization potential for platinum drugs to aid in OSCC management. Biologic effects of ER maleate were determined using oral cancer cell lines in vitro and oral tumor xenografts in vivo. mRNA profiling, real time PCR and western blot revealed ER maleate modulated the expression of polo-like kinase 1 (PLK1) and spleen tyrosine kinase (Syk). Their clinical significance was determined in oral SCC patients by immunohistochemistry and correlated with prognosis by Kaplan-Meier survival and multivariate Cox regression analyses. ER maleate induced cell apoptosis, inhibited proliferation, colony formation, migration and invasion in oral cancer cells. Imagestream analysis revealed cell cycle arrest in G2/M phase and increased polyploidy, unravelling deregulation of cell division and cell death. Mechanistically, ER maleate decreased expression of PLK1 and Syk, induced cleavage of PARP, caspase9 and caspase3, and increased chemosensitivity to carboplatin; significantly suppressed tumor growth and increased antitumor activity of carboplatin in tumor xenografts. ER maleate treated tumor xenografts showed reduced PLK1 and Syk expression. Clinical investigations revealed overexpression of PLK1 and Syk in oral SCC patients that correlated with disease prognosis. Our in vitro and in vivo findings provide a strong rationale for pre-clinical efficacy of ER maleate as a novel anticancer agent and chemosensitizer of platinum drugs for OSCC. PMID:26934445

  7. Screening of Streptomycetes for L-Asparaginase, Therapeutic Agent of Lymphocytic Leukemia from Western Ghats of Karnataka, India

    Directory of Open Access Journals (Sweden)

    Mamatha B Salimath

    2016-03-01

    Full Text Available Actinomycetes are the most economically and biotechnologically valuable prokaryotes and are responsible for the production of about half of the discovered bioactive secondary metabolites, antibiotics, anticancer agents and enzymes. The present study was successful in characterizing 25 Streptomycetes isolates inhabiting Agumbe province, of Western Ghats soil of Karnataka, India, for potential source of L-asparaginase enzyme. L- Asparaginase (L-asparagine amido hydrolase E.C.3.5.1.1 is an extracellular enzyme has anti-carcinogenic potential, received increasing awareness in the current years because of its use as an effective agent against Acute Lymphocytic Leukemia (ALL. L-asparagine is a source of essential amino acid necessary for the growth of leukemic cells in higher amounts. Depletion of L-asparagine from the circulatory blood leads to death of malignant cells. Streptomyces isolates have been collected from soil samples by serial dilution and plating method employing Starch Casein Nitrate agar and ISP media. They were identified based on cultural, morphological and biochemical characteristics. When primarily screened for L-asparaginase production by Rapid plate assay using Modified M9 medium containing L-asparagine and Phenol red as indicator, 23 isolates were found to be positive by showing change in color of medium from yellow to pink. Strain V17 isolate proved to be potent producer of the enzyme with higher amount of enzyme up to 22.45 IU/ml. About 92% of the tested isolates were positive for anti-cancerous potential, indicating the Western Ghats soils as potential sources for anti-cancerous agents. Further studies on purification and characterization of enzyme are under progress.

  8. Childhood cancer: feelings expressed by children in chemotherapy during therapeutic toy sessions

    Directory of Open Access Journals (Sweden)

    Luís Paulo Souza e Souza

    2012-09-01

    Full Text Available This study aimed at understanding the feelings experienced by the child with cancer manifested during Therapeutic Toy sessions. This qualitative research was performed with five children aged between three and twelve years, of both sexes. Data collection was carried out through a participatory and systematic observation, coupled with interviews intermediated by Therapeutic Toy Sessions. The data was worked using discourse analysis. The child with cancer was shown as a being full of feelings. The fear of death, pain, sadness on the limitations imposed by the disease, the withdrawal and rebellion with the procedures, the anguish in the face of uncertainties were negative feelings expressed by the children in the dramatizations. However, the development of treatment, the manifestation of a good prognosis and outcome of cure were emerging feelings of hope and happiness before the treatment, optimism in return to usual activities and overcoming amidst the difficulties experienced.

  9. Possible molecular targets for therapeutic applications of caffeic acid phenethyl ester in inflammation and cancer

    Directory of Open Access Journals (Sweden)

    Ghulam Murtaza

    2015-03-01

    Full Text Available Of the various derivatives of caffeic acid, caffeic acid phenethyl ester (CAPE is a hydrophobic, bioactive polyphenolic ester obtained from propolis extract. The objective in writing this review article was to summarize all published studies on therapeutics of CAPE in inflammation and cancer to extract direction for future research. The possible molecular targets for the action of CAPE, include various transcription factors such as nuclear factor-κB, tissue necrosis factor-α, interleukin-6, cyclooxygenase-2, Nrf2, inducible nitric oxide synthase, nuclear factor of activated T cells, hypoxia-inducible factor-1α, and signal transducers and activators of transcription. Based on the valuable data on its therapeutics in inflammation and cancer, clinical studies of CAPE should also be conducted to explore its toxicities, if any.

  10. Bone-targeted agents: preventing skeletal complications in prostate cancer.

    Science.gov (United States)

    Morgans, Alicia K; Smith, Matthew R

    2012-11-01

    In men, prostate cancer is the most common non-cutaneous malignancy and the second most common cause of cancer death. Skeletal complications occur at various points during the disease course, either due to bone metastases directly, or as an unintended consequence of androgen deprivation therapy (ADT). Bone metastases are associated with pathologic fractures, spinal cord compression, and bone pain and can require narcotics or palliative radiation for pain relief. ADT results in bone loss and fragility fractures. This review describes the biology of bone metastases, skeletal morbidity, and recent advances in bone-targeted therapies to prevent skeletal complications of prostate cancer.

  11. Therapeutic potential of snake venom in cancer therapy:current perspectives

    Institute of Scientific and Technical Information of China (English)

    Vivek Kumar Vyas; Keyur Brahmbhatt; Hardik Bhatt; Utsav Parmar

    2013-01-01

    Many active secretions produced by animals have been employed in the development of new drugs to treat diseases such as hypertension and cancer. Snake venom toxins contributed significantly to the treatment of many medical conditions. There are many published studies describing and elucidating the anti-cancer potential of snake venom. Cancer therapy is one of the main areas for the use of protein peptides and enzymes originating from animals of different species. Some of these proteins or peptides and enzymes from snake venom when isolated and evaluated may bind specifically to cancer cell membranes, affecting the migration and proliferation of these cells. Some of substances found in the snake venom present a great potential as anti-tumor agent. In this review, we presented the main results of recent years of research involving the active compounds of snake venom that have anticancer activity.

  12. Antiretroviral Drug Interactions: Overview of Interactions Involving New and Investigational Agents and the Role of Therapeutic Drug Monitoring for Management

    Directory of Open Access Journals (Sweden)

    R. Chris Rathbun

    2011-10-01

    Full Text Available Antiretrovirals are prone to drug-drug and drug-food interactions that can result in subtherapeutic or supratherapeutic concentrations. Interactions between antiretrovirals and medications for other diseases are common due to shared metabolism through cytochrome P450 (CYP450 and uridine diphosphate glucuronosyltransferase (UGT enzymes and transport by membrane proteins (e.g., p-glycoprotein, organic anion-transporting polypeptide. The clinical significance of antiretroviral drug interactions is reviewed, with a focus on new and investigational agents. An overview of the mechanistic basis for drug interactions and the effect of individual antiretrovirals on CYP450 and UGT isoforms are provided. Interactions between antiretrovirals and medications for other co-morbidities are summarized. The role of therapeutic drug monitoring in the detection and management of antiretroviral drug interactions is also briefly discussed.

  13. Heat shock proteins 27, 40, and 70 as combinational and dual therapeutic cancer targets

    OpenAIRE

    McConnell, Jeanette R.; McAlpine, Shelli R.

    2013-01-01

    The heat shock proteins are essential players in the development of cancer and they are prime therapeutic targets. Targeting multiple hsps in dual therapies decreases the likelihood of drug resistance compared to utilizing mono-therapies. Further, employing an hsp inhibitor in combination with another therapy has proven clinically successful. Examples of efficacious strategies include the inhibition of hsp27, which prevents protein aggregation, controlling hsp40’s role as an ATPase modulator,...

  14. Cell Survival and Apoptosis Signaling as Therapeutic Target for Cancer: Marine Bioactive Compounds

    OpenAIRE

    Kim Se-Kwon; Senthilkumar Kalimuthu

    2013-01-01

    Inhibition of apoptosis leads to activation of cell survival factors (e.g., AKT) causes continuous cell proliferation in cancer. Apoptosis, the major form of cellular suicide, is central to various physiological processes and the maintenance of homeostasis in multicellular organisms. A number of discoveries have clarified the molecular mechanism of apoptosis, thus clarifying the link between apoptosis and cell survival factors, which has a therapeutic outcome. Induction of apoptosis and inhib...

  15. Chemopreventive and Therapeutic Effects of Edible Berries: A Focus on Colon Cancer Prevention and Treatment.

    Science.gov (United States)

    Afrin, Sadia; Giampieri, Francesca; Gasparrini, Massimiliano; Forbes-Hernandez, Tamara Y; Varela-López, Alfonso; Quiles, José L; Mezzetti, Bruno; Battino, Maurizio

    2016-01-01

    Colon cancer is one of the most prevalent diseases across the world. Numerous epidemiological studies indicate that diets rich in fruit, such as berries, provide significant health benefits against several types of cancer, including colon cancer. The anticancer activities of berries are attributed to their high content of phytochemicals and to their relevant antioxidant properties. In vitro and in vivo studies have demonstrated that berries and their bioactive components exert therapeutic and preventive effects against colon cancer by the suppression of inflammation, oxidative stress, proliferation and angiogenesis, through the modulation of multiple signaling pathways such as NF-κB, Wnt/β-catenin, PI3K/AKT/PKB/mTOR, and ERK/MAPK. Based on the exciting outcomes of preclinical studies, a few berries have advanced to the clinical phase. A limited number of human studies have shown that consumption of berries can prevent colorectal cancer, especially in patients at high risk (familial adenopolyposis or aberrant crypt foci, and inflammatory bowel diseases). In this review, we aim to highlight the findings of berries and their bioactive compounds in colon cancer from in vitro and in vivo studies, both on animals and humans. Thus, this review could be a useful step towards the next phase of berry research in colon cancer.

  16. Therapeutic potential of targeting protein for Xklp2 silencing for pancreatic cancer

    International Nuclear Information System (INIS)

    The targeting protein for Xklp2 (TPX2) is a microtubule- and, cell cycle-associated protein who’s overexpression has been reported in various malignancies. In this study, we verified the overexpression of TPX2 in both surgically resected specimens of pancreatic cancer and multiple pancreatic cancer cell lines. Subsequently, we found that TPX2 siRNA effectively suppressed the proliferation of pancreatic cancer cells in culture, and the direct injection of TPX2 siRNA into subcutaneously implanted pancreatic cancer cells in nude mice revealed antiproliferative effects. These results implied a therapeutic potential of TPX2 siRNA in pancreatic cancer. Among 56 angiogenesis-related factors examined using angiogenesis arrays, the average protein levels of insulin-like growth factor-binding protein-3 (IGFBP-3) were significantly higher in TPX2 siRNA-treated tumors than in the Control siRNA-treated tumors. Moreover, we demonstrated that CD34-positive microvessels were significantly reduced in tumors treated with TPX2 siRNA compared to tumors that treated with Control siRNA. The attenuated expression of CD34 in TPX2 siRNA-treated tumors coincided with the overexpression of IGFBP-3. These results indicated that TPX2 has an impact on tumor angiogenesis in pancreatic cancer. The results also implied that the antiangiogenic effect observed in TPX2 siRNA-treated pancreatic cancer cells may be partly explained by the upregulation of IGFBP-3

  17. Glutathione-Garlic Sulfur Conjugates: Slow Hydrogen Sulfide Releasing Agents for Therapeutic Applications

    Directory of Open Access Journals (Sweden)

    Ashif Iqbal Bhuiyan

    2015-01-01

    Full Text Available Natural organosulfur compounds (OSCs from Allium sativum L. display antioxidant and chemo-sensitization properties, including the in vitro inhibition of tumor cell proliferation through the induction of apoptosis. Garlic water- and oil-soluble allyl sulfur compounds show distinct properties and the capability to inhibit the proliferation of tumor cells. In the present study, we optimized a new protocol for the extraction of water-soluble compounds from garlic at low temperatures and the production of glutathionyl-OSC conjugates during the extraction. Spontaneously, Cys/GSH-mixed-disulfide conjugates are produced by in vivo metabolism of OSCs and represent active molecules able to affect cellular metabolism. Water-soluble extracts, with (GSGaWS or without (GaWS glutathione conjugates, were here produced and tested for their ability to release hydrogen sulfide (H2S, also in the presence of reductants and of thiosulfate:cyanide sulfurtransferase (TST enzyme. Thus, the TST catalysis of the H2S-release from garlic OSCs and their conjugates has been investigated by molecular in vitro experiments. The antiproliferative properties of these extracts on the human T-cell lymphoma cell line, HuT 78, were observed and related to histone hyperacetylation and downregulation of GAPDH expression. Altogether, the results presented here pave the way for the production of a GSGaWS as new, slowly-releasing hydrogen sulfide extract for potential therapeutic applications.

  18. Glutathione-garlic sulfur conjugates: slow hydrogen sulfide releasing agents for therapeutic applications.

    Science.gov (United States)

    Bhuiyan, Ashif Iqbal; Papajani, Vilma Toska; Paci, Maurizio; Melino, Sonia

    2015-01-01

    Natural organosulfur compounds (OSCs) from Allium sativum L. display antioxidant and chemo-sensitization properties, including the in vitro inhibition of tumor cell proliferation through the induction of apoptosis. Garlic water- and oil-soluble allyl sulfur compounds show distinct properties and the capability to inhibit the proliferation of tumor cells. In the present study, we optimized a new protocol for the extraction of water-soluble compounds from garlic at low temperatures and the production of glutathionyl-OSC conjugates during the extraction. Spontaneously, Cys/GSH-mixed-disulfide conjugates are produced by in vivo metabolism of OSCs and represent active molecules able to affect cellular metabolism. Water-soluble extracts, with (GSGaWS) or without (GaWS) glutathione conjugates, were here produced and tested for their ability to release hydrogen sulfide (H2S), also in the presence of reductants and of thiosulfate:cyanide sulfurtransferase (TST) enzyme. Thus, the TST catalysis of the H2S-release from garlic OSCs and their conjugates has been investigated by molecular in vitro experiments. The antiproliferative properties of these extracts on the human T-cell lymphoma cell line, HuT 78, were observed and related to histone hyperacetylation and downregulation of GAPDH expression. Altogether, the results presented here pave the way for the production of a GSGaWS as new, slowly-releasing hydrogen sulfide extract for potential therapeutic applications. PMID:25608858

  19. NADPH oxidase enzymes in skin fibrosis: molecular targets and therapeutic agents.

    Science.gov (United States)

    Babalola, Olubukola; Mamalis, Andrew; Lev-Tov, Hadar; Jagdeo, Jared

    2014-05-01

    Fibrosis is characterized by the excessive deposition of extracellular matrix components eventually resulting in organ dysfunction and failure. In dermatology, fibrosis is the hallmark component of many skin diseases, including systemic sclerosis, graft-versus-host disease, hypertrophic scars, keloids, nephrogenic systemic fibrosis, porphyria cutanea tarda, restrictive dermopathy and other conditions. Fibrotic skin disorders may be debilitating and impair quality of life. There are few FDA-approved anti-fibrotic drugs; thus, research in this area is crucial in addressing this deficiency. Recent investigations elucidating the pathogenesis of skin fibrosis have implicated endogenous reactive oxygen species produced by the multicomponent nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) enzyme complex. In this review, we discuss Nox enzymes and their role in skin fibrosis. An overview of the Nox enzyme family is presented and their role in the pathogenesis of skin fibrosis is discussed. The mechanisms by which Nox enzymes influence specific fibrotic skin disorders are also reviewed. Finally, we describe the therapeutic approaches to ameliorate skin fibrosis by directly targeting Nox enzymes with the use of statins, p47phox subunit modulators, or GKT137831, a competitive inhibitor of Nox enzymes. Nox enzymes can also be targeted indirectly via scavenging ROS with antioxidants. We believe that Nox modulators are worthy of further investigation and have the potential to transform the management of skin fibrosis by dermatologists.

  20. NADPH oxidase enzymes in skin fibrosis: molecular targets and therapeutic agents.

    Science.gov (United States)

    Babalola, Olubukola; Mamalis, Andrew; Lev-Tov, Hadar; Jagdeo, Jared

    2014-05-01

    Fibrosis is characterized by the excessive deposition of extracellular matrix components eventually resulting in organ dysfunction and failure. In dermatology, fibrosis is the hallmark component of many skin diseases, including systemic sclerosis, graft-versus-host disease, hypertrophic scars, keloids, nephrogenic systemic fibrosis, porphyria cutanea tarda, restrictive dermopathy and other conditions. Fibrotic skin disorders may be debilitating and impair quality of life. There are few FDA-approved anti-fibrotic drugs; thus, research in this area is crucial in addressing this deficiency. Recent investigations elucidating the pathogenesis of skin fibrosis have implicated endogenous reactive oxygen species produced by the multicomponent nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) enzyme complex. In this review, we discuss Nox enzymes and their role in skin fibrosis. An overview of the Nox enzyme family is presented and their role in the pathogenesis of skin fibrosis is discussed. The mechanisms by which Nox enzymes influence specific fibrotic skin disorders are also reviewed. Finally, we describe the therapeutic approaches to ameliorate skin fibrosis by directly targeting Nox enzymes with the use of statins, p47phox subunit modulators, or GKT137831, a competitive inhibitor of Nox enzymes. Nox enzymes can also be targeted indirectly via scavenging ROS with antioxidants. We believe that Nox modulators are worthy of further investigation and have the potential to transform the management of skin fibrosis by dermatologists. PMID:24155025

  1. Stem Cell-Derived Exosomes: A Potential Alternative Therapeutic Agent in Orthopaedics

    Directory of Open Access Journals (Sweden)

    John Burke

    2016-01-01

    Full Text Available Within the field of regenerative medicine, many have sought to use stem cells as a promising way to heal human tissue; however, in the past few years, exosomes (packaged vesicles released from cells have shown more exciting promise. Specifically, stem cell-derived exosomes have demonstrated great ability to provide therapeutical benefits. Exosomal products can include miRNA, other genetic products, proteins, and various factors. They are released from cells in a paracrine fashion in order to combat local cellular stress. Because of this, there are vast benefits that medicine can obtain from stem cell-derived exosomes. If exosomes could be extracted from stem cells in an efficient manner and packaged with particular regenerative products, then diseases such as rheumatoid arthritis, osteoarthritis, bone fractures, and other maladies could be treated with cell-free regenerative medicine via exosomes. Many advances must be made to get to this point, and the following review highlights the current advances of stem cell-derived exosomes with particular attention to regenerative medicine in orthopaedics.

  2. Preparation and standardization of a herbal agent for the therapeutic management of asthma.

    Science.gov (United States)

    Emeje, Martins; Izuka, Amaka; Isimi, Christiana; Ofoefule, Sabinus; Kunle, Olobayo

    2011-04-01

    This study aims to develop a suitable single tablet dosage form containing a mixture of hot water stem back extracts of Anogeissus leiocarpus and Prosopis africana (AA1), suitable for use in the therapeutic management of asthma. The compaction characteristics of the oven-dried hot water extract (HWE) were studied using the Heckel equation. The mechanical properties as well as disintegration and dissolution profile of the compacts were also assessed. The results showed that AA1 exhibited high densification due to dye filling while the subsequent rearrangement of the granules did not contribute, significantly, to their densification. The granules had enhanced plasticity as shown by the low yield point, Py. The tablets produced from the extract had good mechanical properties, with hardness increasing with compression pressure while the friability decreased. Of the four disintegrants tested, tablets containing Explotab had the shortest disintegration time of 11 min while tablets containing Prosolv had the longest disintegration time of 40 min. The order of disintegrant property is Explotab > Cellactose > Emcocel > Maize starch > Prosolv. Dissolution results (t(90%)) show that tablets containing Explotab released 100% of the drug in 20 min proving to be the most suitable in acute asthma attack. The order of dissolution is Explotab > Cellactose > Maize starch > Prosolv > Emcocel. It is concluded that incorporation of Explotab (10%w/w) as a disintegrant in AA1 preparation produced tablets of suitable compressional properties and ensured adequate drug release for the management of acute asthma. PMID:20141501

  3. Numerical indices based on circulating tumor DNA for the evaluation of therapeutic response and disease progression in lung cancer patients

    Science.gov (United States)

    Kato, Kikuya; Uchida, Junji; Kukita, Yoji; Kumagai, Toru; Nishino, Kazumi; Inoue, Takako; Kimura, Madoka; Oba, Shigeyuki; Imamura, Fumio

    2016-01-01

    Monitoring of disease/therapeutic conditions is an important application of circulating tumor DNA (ctDNA). We devised numerical indices, based on ctDNA dynamics, for therapeutic response and disease progression. 52 lung cancer patients subjected to the EGFR-TKI treatment were prospectively collected, and ctDNA levels represented by the activating and T790M mutations were measured using deep sequencing. Typically, ctDNA levels decreased sharply upon initiation of EGFR-TKI, however this did not occur in progressive disease (PD) cases. All 3 PD cases at initiation of EGFR-TKI were separated from other 27 cases in a two-dimensional space generated by the ratio of the ctDNA levels before and after therapy initiation (mutation allele ratio in therapy, MART) and the average ctDNA level. For responses to various agents after disease progression, PD/stable disease cases were separated from partial response cases using MART (accuracy, 94.7%; 95% CI, 73.5–100). For disease progression, the initiation of ctDNA elevation (initial positive point) was compared with the onset of objective disease progression. In 11 out of 28 eligible patients, both occurred within ±100 day range, suggesting a detection of the same change in disease condition. Our numerical indices have potential applicability in clinical practice, pending confirmation with designed prospective studies. PMID:27381430

  4. Anticancer Drug-Incorporated Layered Double Hydroxide Nanohybrids and Their Enhanced Anticancer Therapeutic Efficacy in Combination Cancer Treatment

    Directory of Open Access Journals (Sweden)

    Tae-Hyun Kim

    2014-01-01

    Full Text Available Objective. Layered double hydroxide (LDH nanoparticles have been studied as cellular delivery carriers for anionic anticancer agents. As MTX and 5-FU are clinically utilized anticancer drugs in combination therapy, we aimed to enhance the therapeutic performance with the help of LDH nanoparticles. Method. Anticancer drugs, MTX and 5-FU, and their combination, were incorporated into LDH by reconstruction method. Simply, LDHs were thermally pretreated at 400°C, and then reacted with drug solution to simultaneously form drug-incorporated LDH. Thus prepared MTX/LDH (ML, 5-FU/LDH (FL, and (MTX + 5-FU/LDH (MFL nanohybrids were characterized by X-ray diffractometer, scanning electron microscopy, infrared spectroscopy, thermal analysis, zeta potential measurement, dynamic light scattering, and so forth. The nanohybrids were administrated to the human cervical adenocarcinoma, HeLa cells, in concentration-dependent manner, comparing with drug itself to verify the enhanced therapeutic efficacy. Conclusion. All the nanohybrids successfully accommodated intended drug molecules in their house-of-card-like structures during reconstruction reaction. It was found that the anticancer efficacy of MFL nanohybrid was higher than other nanohybrids, free drugs, or their mixtures, which means the multidrug-incorporated LDH nanohybrids could be potential drug delivery carriers for efficient cancer treatment via combination therapy.

  5. Dehydroascorbic acid as an anti-cancer agent.

    Science.gov (United States)

    Toohey, John I

    2008-05-18

    Three discoveries together point the way to a potential treatment for cancer. In 1982, Poydock and colleagues found that dehydroascorbic acid has the remarkable ability to eliminate the aggressive mouse tumours, L1210, P388, Krebs sarcoma, and Ehrlich carcinoma. In 1993, Jakubowski found that cancer cells (but not normal cells) contain measurable quantities of homocysteine thiolactone. Recently, the author found that dehydroascorbic acid reacts with homocysteine thiolactone converting it to the toxic compound, 3-mercaptopropionaldehyde. Taken together, these findings suggest that rapidly-dividing tumour cells make unusually large amounts of homocysteine thiolactone and that administered dehydroascorbic acid enters the cells and converts the thiolactone to mercaptopropionaldehyde which kills the cancer cells. The effectiveness of dehydroascorbic acid might be further increased by combining it with methionine and/or methotrexate to increase the homocysteine concentration in cancer cells.

  6. Metals and Breast Cancer: Risk Factors or Healing Agents?

    Directory of Open Access Journals (Sweden)

    Ana-Maria Florea

    2011-01-01

    Full Text Available Metals and metal compounds are part of our environment. Several metals are essential for physiological functions (e.g., zinc or magnesium; while the beneficial effects of others are uncertain (e.g., manganese, some metals are proven to be toxic (e.g., mercury, lead. Additionally there are organic metal compounds; some of them are extremely toxic (e.g., trimethyltin, methylmercury, but there is very little knowledge available how they are handled by organisms. Scientific evidence indicates that long-term exposure to (some metallic compounds induces different forms of cancer, including breast cancer. On the other side, several metal compounds have clinical use in treating life-threatening diseases such as cancer. In this paper we discuss the recent literature that shows a correlation between metal exposure and breast cancer.

  7. Targeted Agents Active Against Breast Cancer: Q&A

    Science.gov (United States)

    ALTTO was a clinical trial designed to determine whether the combination of the monoclonal antibody trastuzumab (Herceptin) and the drug lapatinib (Tykerb) was more effective in treating HER2/ErbB2-positive breast cancer when combined with chemotherapy.

  8. Cardiotoxicity of cancer therapeutics: current issues in screening, prevention and therapy

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    Richard Joseph Sheppard

    2013-03-01

    Full Text Available In the context of modern cancer chemotherapeutics, cancer survivors are living longer and being exposed to potential comorbidities related to non-cancer side effects of such treatments. With close monitoring of cancer patients receiving potentially cardiotoxic medical therapies, oncologists and cardiologists alike are identifying patients in both clinical and subclinical phases of cardiovascular disease related to such chemotherapies. Specifically, cardiotoxicity at the level of the myocardium and potential for the development of heart failure are becoming a growing concern with increasing survival of cancer patients.Traditional chemotherapeutic agents used commonly in the treatment of breast cancer and hematologic malignancies, such as anthracyclines and HER-2 antagonists, are well known to be associated with cardiovascular sequelae. Patients often present without symptoms and an abnormal cardiac imaging study performed as part of routine evaluation of patients receiving cardiotoxic therapies. Additionally, patients can present with signs and symptoms of cardiovascular disease months to years after receiving the chemotherapies. As the understanding of the physiology underlying the various cancers has grown, therapies have been developed that target specific molecules that represent key aspects of physiologic pathways responsible for cancer growth. Inhibition of these pathways, such as those involving tyrosine kinases, has lead to the potential for cardiotoxicity as well. In view of the potential cardiotoxicity of specific chemotherapies, there is a growing interest in identifying patients who are at risk of cardiotoxicity prior to becoming symptomatic or developing cardiotoxicity that may limit the use of potentially life-saving chemotherapy agents. Serological markers and novel cardiac imaging techniques have become the source of many investigations with the goal of screening patients for pre-clinical cardiotoxicity. Additionally, studies have

  9. BRCA1 and miRNAs: An Emerging Therapeutic Target and Intervention Tool in Breast Cancer

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    Mintu Pal*

    2013-01-01

    Full Text Available Reduced BRCA1 activity, either by germ-line mutations in inherited breast cancer or by epigenetic down-regulation in sporadic cancers,represents a key pathway in tumour development and progression. Although best known for its role in the maintenance of chromosome integrity, BRCA1 has recently been found to play a role in chromatin remodelling and transcriptional regulation, as well as in mammary epithelial stem cell differentiation or mammary stem cell fate decision. While BRCA1 potentially plays a significant role in both mammary tumour development and malignant progression, its function connection to tumor development is poorly understood. Recent studies have uncovered a new role of BRCA1 in the regulation of small (~19-25 nucleotides non-coding microRNA (miRNA expression in breast cancer cells. Several studies have also shown that aggressive breast cancers and breast cancer stem cells exhibit distinctive profiles of miRNA expression, suggesting that BRCA1 associated differential expression of miRNAs can regulate important cellular functions facilitating the maintenance of breast cancer stem cells and/or promoting breast cancer aggression. In this context, we will review recent progress in the understanding of the BRCA1 function, with emphasis on the implication of the development and progression of breast cancer via differential expression of miRNAs and discuss how these studies can improve our understanding of breast cancer pathogenesis. We will also discuss the perspectives of BRCA1 function through miRNAs and the role of miRNAs in regulating BRCA1 in breast cancer, more specifically tumor suppressor, miR-125 and oncogene, mir-155 as diagnostic and prognostic tools in clinical practice, and as new avenues for therapeutic interventions.

  10. Molecular pathways: novel approaches for improved therapeutic targeting of Hedgehog signaling in cancer stem cells.

    Science.gov (United States)

    Justilien, Verline; Fields, Alan P

    2015-02-01

    The Hedgehog (Hh) signaling pathway is critical for embryonic development. In adult tissues, Hh signaling is relatively quiescent with the exception of roles in tissue maintenance and repair. Aberrant activation of Hh signaling is implicated in multiple aspects of transformation, including the maintenance of the cancer stem cell (CSC) phenotype. Preclinical studies indicate that CSCs from many tumor types are sensitive to Hh pathway inhibition and that Hh-targeted therapeutics block many aspects of transformation attributed to CSCs, including drug resistance, relapse, and metastasis. However, to date, Hh inhibitors, specifically those targeting Smoothened [such as vismodegib, BMS-833923, saridegib (IPI-926), sonidegib/erismodegib (LDE225), PF-04449913, LY2940680, LEQ 506, and TAK-441], have demonstrated good efficacy as monotherapy in patients with basal cell carcinoma and medulloblastoma, but have shown limited activity in other tumor types. This lack of success is likely due to many factors, including a lack of patient stratification in early trials, cross-talk between Hh and other oncogenic signaling pathways that can modulate therapeutic response, and a limited knowledge of Hh pathway activation mechanisms in CSCs from most tumor types. Here, we discuss Hh signaling mechanisms in the context of human cancer, particularly in the maintenance of the CSC phenotype, and consider new therapeutic strategies that hold the potential to expand considerably the scope and therapeutic efficacy of Hh-directed anticancer therapy. PMID:25646180

  11. Recombinant IκBα-loaded curcumin nanoparticles for improved cancer therapeutics

    International Nuclear Information System (INIS)

    The field of recombinant protein therapeutics has been evolving rapidly, making significant impact on clinical applications for several diseases, including cancer. However, the functional aspects of proteins rely exclusively on their structural integrity, in which nanoparticle mediated delivery offers unique advantages over free proteins. In the present work, a novel strategy has been developed where the nanoparticles (NPs) used for the delivery of the recombinant protein could contribute to enhancing the therapeutic efficacy of the recombinant protein. The transcription factor, NFκB, involved in cell growth and its inhibitor, IκBα, regulates its proliferation. Another similar naturally available molecule, which inhibits the function of NFκB, is curcumin. Hence, we have developed a ‘green synthesis’ method for preparing water-soluble curcumin nanoparticles to stabilize recombinant IκBα protein. The NPs were characterized by UV–vis and fluorescence spectroscopy, transmission electron microscopy (TEM) and dynamic light scattering before administration into human cervical carcinoma (HeLa) and glioblastoma (U87MG) cells. Experimental results demonstrated that this combined module had enhanced therapeutic efficacy, causing apoptotic cell death, which was confirmed by cytotoxicity assay and flowcytometry analyses. The expression of apoptotic genes studied by semi-quantitative reverse transcription PCR delineated the molecular pathways involved in cell death. Thus, our study revealed that the functional delivery of recombinant IκBα-loaded curcumin NPs has promise as a natural-product-based protein therapeutics against cancer cells. (paper)

  12. Recombinant IκBα-loaded curcumin nanoparticles for improved cancer therapeutics

    Science.gov (United States)

    Banerjee, Subhamoy; Sahoo, Amaresh Kumar; Chattopadhyay, Arun; Sankar Ghosh, Siddhartha

    2014-08-01

    The field of recombinant protein therapeutics has been evolving rapidly, making significant impact on clinical applications for several diseases, including cancer. However, the functional aspects of proteins rely exclusively on their structural integrity, in which nanoparticle mediated delivery offers unique advantages over free proteins. In the present work, a novel strategy has been developed where the nanoparticles (NPs) used for the delivery of the recombinant protein could contribute to enhancing the therapeutic efficacy of the recombinant protein. The transcription factor, NFκB, involved in cell growth and its inhibitor, IκBα, regulates its proliferation. Another similar naturally available molecule, which inhibits the function of NFκB, is curcumin. Hence, we have developed a ‘green synthesis’ method for preparing water-soluble curcumin nanoparticles to stabilize recombinant IκBα protein. The NPs were characterized by UV-vis and fluorescence spectroscopy, transmission electron microscopy (TEM) and dynamic light scattering before administration into human cervical carcinoma (HeLa) and glioblastoma (U87MG) cells. Experimental results demonstrated that this combined module had enhanced therapeutic efficacy, causing apoptotic cell death, which was confirmed by cytotoxicity assay and flowcytometry analyses. The expression of apoptotic genes studied by semi-quantitative reverse transcription PCR delineated the molecular pathways involved in cell death. Thus, our study revealed that the functional delivery of recombinant IκBα-loaded curcumin NPs has promise as a natural-product-based protein therapeutics against cancer cells.

  13. Response to microtubule-interacting agents in primary epithelial ovarian cancer cells

    Science.gov (United States)

    2013-01-01

    Background Ovarian cancer constitutes nearly 4% of all cancers among women and is the leading cause of death from gynecologic malignancies in the Western world. Standard first line adjuvant chemotherapy treatments include Paclitaxel (Taxol) and platinum-based agents. Taxol, epothilone B (EpoB) and discodermolide belong to a family of anti-neoplastic agents that specifically interferes with microtubules and arrests cells in the G2/M phase of the cell cycle. Despite initial success with chemotherapy treatment, many patients relapse due to chemotherapy resistance. In vitro establishment of primary ovarian cancer cells provides a powerful tool for better understanding the mechanisms of ovarian cancer resistance. We describe the generation and characterization of primary ovarian cancer cells derived from ascites fluids of patients with epithelial ovarian cancer. Methods Chemosensitivity of these cell lines to Taxol, EpoB and discodermolide was tested, and cell cycle analysis was compared to that of immortalized ovarian cancer cell lines SKOV3 and Hey. The relationship between drug resistance and αβ-tubulin and p53 status was also investigated. Results All newly generated primary cancer cells were highly sensitive to the drugs. αβ-tubulin mutation was not found in any primary cell lines tested. However, one cell line that harbors p53 mutation at residue 72 (Arg to Pro) exhibits altered cell cycle profile in response to all drug treatments. Immortalized ovarian cancer cells respond differently to EpoB treatment when compared to primary ovarian cancer cells, and p53 polymorphism suggests clinical significance in the anti-tumor response in patients. Conclusions The isolation and characterization of primary ovarian cancer cells from ovarian cancer patients’ specimens contribute to further understanding the nature of drug resistance to microtubule interacting agents (MIAs) currently used in clinical settings. PMID:23574945

  14. Androgen deprivation of prostate cancer: Leading to a therapeutic dead end.

    Science.gov (United States)

    Katzenwadel, Arndt; Wolf, Philipp

    2015-10-10

    Androgen deprivation therapy (ADT) is considered as the standard therapy for men with de novo or recurrent metastatic prostate cancer. ADT commonly leads to initial biochemical and clinical responses. However, several months after the beginning of treatment, tumors become castration-resistant and virtually all patients show disease progression. At this stage, tumors are no longer curable and cancer treatment options are only palliative. In this review, we describe molecular alterations in tumor cells during ADT, which lead to deregulation of different signaling pathways and castration-resistance, and how they might interfere with the clinical outcome of different second-line therapeutics. A recent breakthrough finding that early chemotherapy is associated with a significant survival benefit in metastatic hormone-sensitive disease highlights the fact that there is time for a fundamental paradigm shift in the treatment of advanced prostate cancer. Therapeutic intervention seems to be indicated before a castration-resistant stage is reached to improve therapeutic outcome and to reduce undesirable side effects. PMID:26185001

  15. Current and Future Therapeutic Agents in the Management of Heart Failure

    Institute of Scientific and Technical Information of China (English)

    2003-01-01

    Congestive heart failare is a disease in which initially compensutory changes in car-diac, vascular, and renal functions become detrimental over time. The changes are mediated by a largenamber of neurohormones and cytokines. Counter-regalutory hormones also play a role, but ave general-ly insuffwient to offset the adverse effects of the neurohormones or progression of the disease. Symp-toms of heart failure occurs in the presence of systolic dysfunction, usually documented by a decrease inejection fraction, or can present with impaired diastolic function occasionally labeled as heart failureuith preserved systolic function of the left ventricle. Heart failure and its treatment represent a medicalproblem of significant importance because of the high mortality associated with it despite the current ther-apy, which has substantial evidence of reduction in mortality and morbidity. Prevention or slowing of theprogressive deterioration in function of the heart and other organs involved through utilizing new agentsthat affect more or differentneurohormonal pathways may be beneficial and forms the focus of heartfailure research and drug development. However, the multiplicity of hormonal effects mandate the useof complex therapy in the management of congestive heart failure( CHF ). The new agents in addition tothe conventional therapy used in the management of heart failure are; Human B-type natriuretic peptide(in the treatment of decompensated CHF), endothelin receptor antagonists, calcium sensitizers, neutralendopeptidase ( NEP ) and vasopeptidase inhibitors, vasopressin antagonists and cytokine inhibitors.

  16. A role for plasma cell targeting agents in immune tolerance induction in autoimmune disease and antibody responses to therapeutic proteins.

    Science.gov (United States)

    Rosenberg, A S; Pariser, A R; Diamond, B; Yao, L; Turka, L A; Lacana, E; Kishnani, P S

    2016-04-01

    Antibody responses to life saving therapeutic protein products, such as enzyme replacement therapies (ERT) in the setting of lysosomal storage diseases, have nullified product efficacy and caused clinical deterioration and death despite treatment with immune-suppressive therapies. Moreover, in some autoimmune diseases, pathology is mediated by a robust antibody response to endogenous proteins such as is the case in pulmonary alveolar proteinosis, mediated by antibodies to Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF). In this work, we make the case that in such settings, when the antibody response is high titered, sustained, and refractory to immune suppressive treatments, the antibody response is mediated by long-lived plasma cells which are relatively unperturbed by immune suppressants including rituximab. However, long-lived plasma cells can be targeted by proteasome inhibitors such as bortezomib. Recent reports of successful reversal of antibody responses with bortezomib in the settings of ERT and Thrombotic Thrombocytopenic Purpura (TTP) argue that the safety and efficacy of such plasma cell targeting agents should be evaluated in larger scale clinical trials to delineate the risks and benefits of such therapies in the settings of antibody-mediated adverse effects to therapeutic proteins and autoantibody mediated pathology. PMID:26928739

  17. Engineering Multi-Walled Carbon Nanotube Therapeutic Bionanofluids to Selectively Target Papillary Thyroid Cancer Cells.

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    Idit Dotan

    Full Text Available The incidence of papillary thyroid carcinoma (PTC has risen steadily over the past few decades as well as the recurrence rates. It has been proposed that targeted ablative physical therapy could be a therapeutic modality in thyroid cancer. Targeted bio-affinity functionalized multi-walled carbon nanotubes (BioNanofluid act locally, to efficiently convert external light energy to heat thereby specifically killing cancer cells. This may represent a promising new cancer therapeutic modality, advancing beyond conventional laser ablation and other nanoparticle approaches.Thyroid Stimulating Hormone Receptor (TSHR was selected as a target for PTC cells, due to its wide expression. Either TSHR antibodies or Thyrogen or purified TSH (Thyrotropin were chemically conjugated to our functionalized Bionanofluid. A diode laser system (532 nm was used to illuminate a PTC cell line for set exposure times. Cell death was assessed using Trypan Blue staining.TSHR-targeted BioNanofluids were capable of selectively ablating BCPAP, a TSHR-positive PTC cell line, while not TSHR-null NSC-34 cells. We determined that a 2:1 BCPAP cell:α-TSHR-BioNanofluid conjugate ratio and a 30 second laser exposure killed approximately 60% of the BCPAP cells, while 65% and >70% of cells were ablated using Thyrotropin- and Thyrogen-BioNanofluid conjugates, respectively. Furthermore, minimal non-targeted killing was observed using selective controls.A BioNanofluid platform offering a potential therapeutic path for papillary thyroid cancer has been investigated, with our in vitro results suggesting the development of a potent and rapid method of selective cancer cell killing. Therefore, BioNanofluid treatment emphasizes the need for new technology to treat patients with local recurrence and metastatic disease who are currently undergoing either re-operative neck explorations, repeated administration of radioactive iodine and as a last resort external beam radiation or chemotherapy, with

  18. Engineering Multi-Walled Carbon Nanotube Therapeutic Bionanofluids to Selectively Target Papillary Thyroid Cancer Cells

    Science.gov (United States)

    Paliouras, Miltiadis; Mitmaker, Elliot J.; Trifiro, Mark A.

    2016-01-01

    Background The incidence of papillary thyroid carcinoma (PTC) has risen steadily over the past few decades as well as the recurrence rates. It has been proposed that targeted ablative physical therapy could be a therapeutic modality in thyroid cancer. Targeted bio-affinity functionalized multi-walled carbon nanotubes (BioNanofluid) act locally, to efficiently convert external light energy to heat thereby specifically killing cancer cells. This may represent a promising new cancer therapeutic modality, advancing beyond conventional laser ablation and other nanoparticle approaches. Methods Thyroid Stimulating Hormone Receptor (TSHR) was selected as a target for PTC cells, due to its wide expression. Either TSHR antibodies or Thyrogen or purified TSH (Thyrotropin) were chemically conjugated to our functionalized Bionanofluid. A diode laser system (532 nm) was used to illuminate a PTC cell line for set exposure times. Cell death was assessed using Trypan Blue staining. Results TSHR-targeted BioNanofluids were capable of selectively ablating BCPAP, a TSHR-positive PTC cell line, while not TSHR-null NSC-34 cells. We determined that a 2:1 BCPAP cell:α-TSHR-BioNanofluid conjugate ratio and a 30 second laser exposure killed approximately 60% of the BCPAP cells, while 65% and >70% of cells were ablated using Thyrotropin- and Thyrogen-BioNanofluid conjugates, respectively. Furthermore, minimal non-targeted killing was observed using selective controls. Conclusion A BioNanofluid platform offering a potential therapeutic path for papillary thyroid cancer has been investigated, with our in vitro results suggesting the development of a potent and rapid method of selective cancer cell killing. Therefore, BioNanofluid treatment emphasizes the need for new technology to treat patients with local recurrence and metastatic disease who are currently undergoing either re-operative neck explorations, repeated administration of radioactive iodine and as a last resort external beam

  19. Marine-Sourced Anti-Cancer and Cancer Pain Control Agents in Clinical and Late Preclinical Development †

    OpenAIRE

    Newman, David J; Cragg, Gordon M.

    2014-01-01

    The marine habitat has produced a significant number of very potent marine-derived agents that have the potential to inhibit the growth of human tumor cells in vitro and, in a number of cases, in both in vivo murine models and in humans. Although many agents have entered clinical trials in cancer, to date, only Cytarabine, Yondelis® (ET743), Eribulin (a synthetic derivative based on the structure of halichondrin B), and the dolastatin 10 derivative, monomethylauristatin E (MMAE or vedotin) ...

  20. THERAPEUTIC EFFECT OF SOLASODINE RHAMNOSYL GLYCOSIDES FOR LARGE SKIN CANCERS: TWO CLINICAL CASES

    Directory of Open Access Journals (Sweden)

    Bill E. Cham

    2012-01-01

    Full Text Available Solasodine rhamnosyl glycosides (BEC are a new class of antineoplastics, the efficiency of which administered via intravenous, intraperitoneal, and intratumoral routes is higher than that of many other antitumor agents. Early investigations have established the efficiency of topical BEC applications as a treatment option for non-melanoma skin cancers. There have recently been two clinical cases that count in favor of the fact that the cream formulation Curaderm containing BEC has a very high efficacy in the treatment of large non-melanoma skin cancers that are incurable by other existing methods. Also, Curaderm treatment shows a splendid cosmetic effect.