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Sample records for anticancer targeted agents

  1. Anticancer Agents Targeted to Sirtuins

    Directory of Open Access Journals (Sweden)

    Tomohiro Kozako

    2014-12-01

    Full Text Available Sirtuins are nicotinamide adenine dinucleotide+-dependent deacetylases of which there are seven isoforms (SIRT1–7. Sirtuin activity is linked to gene expression, lifespan extension, neurodegeneration, and age-related disorders. Numerous studies have suggested that sirtuins could be of great significance with regard to both antiaging and tumorigenesis, depending on its targets in specific signaling pathways or in specific cancers. Recent studies have identified small chemical compounds that modulate sirtuins, and these modulators have enabled a greater understanding of the biological function and molecular mechanisms of sirtuins. This review highlights the possibility of sirtuins, especially SIRT1 and SIRT2, for cancer therapy targets, and focuses on the therapeutic potential of sirtuin modulators both in cancer prevention and treatment.

  2. Anticancer Agents Targeted to Sirtuins

    OpenAIRE

    Tomohiro Kozako; Takayoshi Suzuki; Makoto Yoshimitsu; Naomichi Arima; Shin-ichiro Honda; Shinji Soeda

    2014-01-01

    Sirtuins are nicotinamide adenine dinucleotide+-dependent deacetylases of which there are seven isoforms (SIRT1–7). Sirtuin activity is linked to gene expression, lifespan extension, neurodegeneration, and age-related disorders. Numerous studies have suggested that sirtuins could be of great significance with regard to both antiaging and tumorigenesis, depending on its targets in specific signaling pathways or in specific cancers. Recent studies have identified small chemical compounds that m...

  3. Mitochondrially targeted anti-cancer agents

    Czech Academy of Sciences Publication Activity Database

    Biasutto, L.; Dong, L.A.; Zoratti, M.; Neužil, Jiří

    2010-01-01

    Roč. 10, č. 6 (2010), s. 670-681. ISSN 1567-7249 Institutional research plan: CEZ:AV0Z50520701 Keywords : Mitochondrial target ing * pro-oxidant effect * reactive oxygen species Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.238, year: 2010

  4. Strategies to Optimize Molecularly Targeted Anti-Cancer Agent Combinations

    Directory of Open Access Journals (Sweden)

    Ayse Erdogan

    2015-12-01

    Full Text Available Cytotoxic agents which are used in cancer chemotherapy reduced several times the number of neoplastic cells but not fully. Therefore, usage of and ldquo;targeted therapeutics" which were developed with much more rational approach is increasing markedly in patients with solid cancer. Targeted therapeutics due to selective targets aims cancer cells with specific molecular defect thereby, kils the cancer cells, which makes it possible to continue normal cells in a healthy environment. The rapid emergence of hundreds of new agents that modulates ever-growing list of the cancer-specific molecular targets promise great hope for cancer patients. Evaluation of the target agent individually, in combination with standard therapy and other target agents bring about important development challenges. As possible combinations of drugs number is unlimited, the identification of the most promising combinations and giving priority to assessing their strategies are very important.In this article important elements of the development strategy of the target agent combinations will be considered. Difficulties in this kind of combinations of rational pre-clinical and clinical evaluation and possible approaches to overcome these challenges will be discussed. [Archives Medical Review Journal 2015; 24(4.000: 432-451

  5. Targeted Anticancer Immunotoxins and Cytotoxic Agents with Direct Killing Moieties

    Directory of Open Access Journals (Sweden)

    Koji Kawakami

    2006-01-01

    Full Text Available Despite the progress of the bioinformatics approach to characterize cell-surface antigens and receptors on tumor cells, it remains difficult to generate novel cancer vaccines or neutralizing monoclonal antibody therapeutics. Among targeted cancer therapeutics, biologicals with targetable antibodies or ligands conjugated or fused to toxins or chemicals for direct cell-killing ability have been developed over the last 2 decades. These conjugated or fused chimeric proteins are termed immunotoxins or cytotoxic agents. Two agents, DAB389IL-2 (ONTAKTM targeting the interleukin-2 receptor and CD33-calicheamicin (Mylotarg®, have been approved by the FDA for cutaneous T-cell lymphoma (CTCL and relapsed acute myeloid leukemia (AML, respectively. Such targetable agents, including RFB4(dsFv-PE38 (BL22, IL13-PE38QQR, and Tf-CRM107, are being tested in clinical trials. Several agents using unique technology such as a cleavable adapter or immunoliposomes with antibodies are also in the preclinical stage. This review summarizes the generation, mechanism, and development of these agents. In addition, possible future directions of this therapeutic approach are discussed.

  6. Supramolecular approach for target transport of photodynamic anticancer agents

    Czech Academy of Sciences Publication Activity Database

    Kejík, Z.; Kaplánek, R.; Bříza, T.; Králová, Jarmila; Martásek, P.; Král, V.

    2012-01-01

    Roč. 24, č. 2 (2012), s. 106-116. ISSN 1061-0278 R&D Projects: GA MŠk(CZ) LC06077; GA MŠk(CZ) 1M0520; GA ČR(CZ) GAP303/11/1291; GA ČR GA203/09/1311 Grant ostatní: MŠMT(CZ) MSM0021620806 Institutional research plan: CEZ:AV0Z50520514 Keywords : photodynamic therapy * photosensitisers * targeted transport * combination therapy * cancer Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 1.546, year: 2012

  7. Antitumor efficacy of conventional anticancer drugs is enhanced by the vascular targeting agent ZD6126

    International Nuclear Information System (INIS)

    Purpose: The present report reviews the preclinical data on combined chemotherapy/vascular targeting agent treatments. Basic principles are illustrated in studies evaluating the antitumor efficacy of the vascular targeting agent ZD6126 (N-acetylcochinol-O-phosphate) when combined with the anticancer drug cisplatin in experimental rodent (KHT sarcoma) and human renal (Caki-1) tumor models. Methods and Materials: C3H/HeJ and NCR/nu-nu mice bearing i.m. tumors were injected i.p. with ZD6126 (0-150 mg/kg) or cisplatin (0-20 mg/kg) either alone or in combination. Tumor response to treatment was assessed by clonogenic cell survival. Results: Treatment with ZD6126 was found to damage existing neovasculature, leading to a rapid vascular shutdown. Histologic evaluation showed dose-dependent morphologic damage of tumor cells within a few hours after drug exposure, followed by extensive central tumor necrosis and neoplastic cell death as a result of prolonged ischemia. ZD6126 doses that led to pathophysiologic effects also enhanced the tumor cell killing of cisplatin when administered either 24 h before or 1-24 h after chemotherapy. In both tumor models, the administration of a 150 mg/kg dose of ZD6126 1 h after a range of doses of cisplatin resulted in an increase in tumor cell kill 10-500-fold greater than that seen with chemotherapy alone. In contrast, the inclusion of the antivascular agent did not increase bone marrow stem cell toxicity associated with this anticancer drug. Conclusion: The results obtained in the KHT and Caki-1 tumor models indicate that ZD6126 effectively enhanced the antitumor effects of cisplatin therapy. These findings are representative of the marked enhancements generally observed when vascular targeting agents are combined with chemotherapy in solid tumor therapy

  8. Bridging academic science and clinical research in the search for novel targeted anti-cancer agents

    Institute of Scientific and Technical Information of China (English)

    Alex Matter

    2015-01-01

    This review starts with a brief history of drug discovery&development, and the place of Asia in this worldwide effort discussed. hTe conditions and constraints of a successful translational R&D involving academic basic research and clinical research are discussed and the Singapore model for pursuit of open R&D described. hTe importance of well-characterized, validated drug targets for the search for novel targeted anti-cancer agents is emphasized, as well as a structured, high quality translational R&D. Furthermore, the characteristics of an attractive preclinical development drug candidate are discussed laying the foundation of a successful preclinical development. hTe most frequent sources of failures are described and risk management at every stage is highly recommended. Organizational factors are also considered to play an important role. hTe factors to consider before starting a new drug discovery&development project are described, and an example is given of a successful clinical project that has had its roots in local universities and was carried through preclinical development into phase I clinical trials.

  9. The prince and the pauper. A tale of anticancer targeted agents.

    Science.gov (United States)

    Dueñas-González, Alfonso; García-López, Patricia; Herrera, Luis Alonso; Medina-Franco, Jose Luis; González-Fierro, Aurora; Candelaria, Myrna

    2008-01-01

    Cancer rates are set to increase at an alarming rate, from 10 million new cases globally in 2000 to 15 million in 2020. Regarding the pharmacological treatment of cancer, we currently are in the interphase of two treatment eras. The so-called pregenomic therapy which names the traditional cancer drugs, mainly cytotoxic drug types, and post-genomic era-type drugs referring to rationally-based designed. Although there are successful examples of this newer drug discovery approach, most target-specific agents only provide small gains in symptom control and/or survival, whereas others have consistently failed in the clinical testing. There is however, a characteristic shared by these agents: -their high cost-. This is expected as drug discovery and development is generally carried out within the commercial rather than the academic realm. Given the extraordinarily high therapeutic drug discovery-associated costs and risks, it is highly unlikely that any single public-sector research group will see a novel chemical "probe" become a "drug". An alternative drug development strategy is the exploitation of established drugs that have already been approved for treatment of non-cancerous diseases and whose cancer target has already been discovered. This strategy is also denominated drug repositioning, drug repurposing, or indication switch. Although traditionally development of these drugs was unlikely to be pursued by Big Pharma due to their limited commercial value, biopharmaceutical companies attempting to increase productivity at present are pursuing drug repositioning. More and more companies are scanning the existing pharmacopoeia for repositioning candidates, and the number of repositioning success stories is increasing. Here we provide noteworthy examples of known drugs whose potential anticancer activities have been highlighted, to encourage further research on these known drugs as a means to foster their translation into clinical trials utilizing the more limited

  10. The prince and the pauper. A tale of anticancer targeted agents

    Directory of Open Access Journals (Sweden)

    González-Fierro Aurora

    2008-10-01

    Full Text Available Abstract Cancer rates are set to increase at an alarming rate, from 10 million new cases globally in 2000 to 15 million in 2020. Regarding the pharmacological treatment of cancer, we currently are in the interphase of two treatment eras. The so-called pregenomic therapy which names the traditional cancer drugs, mainly cytotoxic drug types, and post-genomic era-type drugs referring to rationally-based designed. Although there are successful examples of this newer drug discovery approach, most target-specific agents only provide small gains in symptom control and/or survival, whereas others have consistently failed in the clinical testing. There is however, a characteristic shared by these agents: -their high cost-. This is expected as drug discovery and development is generally carried out within the commercial rather than the academic realm. Given the extraordinarily high therapeutic drug discovery-associated costs and risks, it is highly unlikely that any single public-sector research group will see a novel chemical "probe" become a "drug". An alternative drug development strategy is the exploitation of established drugs that have already been approved for treatment of non-cancerous diseases and whose cancer target has already been discovered. This strategy is also denominated drug repositioning, drug repurposing, or indication switch. Although traditionally development of these drugs was unlikely to be pursued by Big Pharma due to their limited commercial value, biopharmaceutical companies attempting to increase productivity at present are pursuing drug repositioning. More and more companies are scanning the existing pharmacopoeia for repositioning candidates, and the number of repositioning success stories is increasing. Here we provide noteworthy examples of known drugs whose potential anticancer activities have been highlighted, to encourage further research on these known drugs as a means to foster their translation into clinical trials

  11. Urokinase-targeted recombinant bacterial protein toxins-a rationally designed and engineered anticancer agent for cancer therapy

    Institute of Scientific and Technical Information of China (English)

    Yizhen LIU; Shi-Yan LI

    2009-01-01

    Urokinase-targeted recombinant bacterial protein toxins are a sort of rationally designed and engineered anticancer recombinant fusion proteins representing a novel class of agents for cancer therapy.Bacterial protein toxins have long been known as the primary virulence factor(s) for a variety of pathogenic bacteria and are the most powerful human poisons.On the other hand,it has been well documented that urokinase-type plasminogen activator (uPA) and urokinase plasminogen activator receptor (uPAR),making up the uPA system,are overexpressed in a variety of human tumors and tumor cell lines.The expression of uPA system is highly correlated with tumor invasion and metastasis.To exploit these characteristics in the design of tumor cell-selective cytotoxins,two prominent bacterial protein toxins,i.e.,the diphtheria toxin and anthrax toxin are deliberately engineered through placing a sequence targeted specifically by the uPA system to form anticancer recombinant fusion proteins.These uPA system-targeted bacterial protein toxins are activated selectively on the surface of uPA systemexpressing tumor cells,thereby killing these cells.This article provides a review on the latest progress in the exploitation of these recombinant fusion proteins as potent tumoricidal agents.It is perceptible that the strategies for cancer therapy are being innovated by this novel therapeutic approach.

  12. RasGRPs are targets of the anti-cancer agent ingenol-3-angelate.

    Directory of Open Access Journals (Sweden)

    Xiaohua Song

    Full Text Available Ingenol-3-angelate (I3A is a non-tumor promoting phorbol ester-like compound identified in the sap of Euphoria peplus. Similar to tumor promoting phorbol esters, I3A is a diacylglycerol (DAG analogue that binds with high affinity to the C1 domains of PKCs, recruits PKCs to cellular membranes and promotes enzyme activation. Numerous anti-cancer activities have been attributed to I3A and ascribed to I3A's effects on PKCs. We show here that I3A also binds to and activates members of the RasGRP family of Ras activators leading to robust elevation of Ras-GTP and engagement of the Raf-Mek-Erk kinase cascade. In response to I3A, recombinant proteins consisting of GFP fused separately to full-length RasGRP1 and RasGRP3 were rapidly recruited to cell membranes, consistent with direct binding of the compound to RasGRP's C1 domain. In the case of RasGRP3, IA3 treatment led to positive regulatory phosphorylation on T133 and activation of the candidate regulatory kinase PKCδ. I3A treatment of select B non-Hodgkin's lymphoma cell lines resulted in quantitative and qualitative changes in Bcl-2 family member proteins and induction of apoptosis, as previously demonstrated with the DAG analogue bryostatin 1 and its synthetic analogue pico. Our results offer further insights into the anticancer properties of I3A, support the idea that RasGRPs represent potential cancer therapeutic targets along with PKC, and expand the known range of ligands for RasGRP regulation.

  13. 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.

  14. Bacteriocins as potential anticancer agents

    OpenAIRE

    Sukhraj eKaur; Sumanpreet eKaur

    2015-01-01

    Cancer remains one of the leading causes of deaths worldwide, despite advances in its treatment and detection. The conventional chemotherapeutic agents used for the treatment of cancer have nonspecific toxicity towards normal body cells that cause various side effects. Secondly, cancer cells are known to develop chemotherapy resistance in due course of treatment. Thus, the demand for novel anti-cancer agents is increasing day by day. Some of the experimental studies have reported the therapeu...

  15. Bacteriocins as Potential Anticancer Agents

    OpenAIRE

    Kaur, Sumanpreet; Kaur, Sukhraj

    2015-01-01

    Cancer remains one of the leading causes of deaths worldwide, despite advances in its treatment and detection. The conventional chemotherapeutic agents used for the treatment of cancer have non-specific toxicity toward normal body cells that cause various side effects. Secondly, cancer cells are known to develop chemotherapy resistance in due course of treatment. Thus, the demand for novel anti-cancer agents is increasing day by day. Some of the experimental studies have reported the therapeu...

  16. Anticancer agents from marine sponges.

    Science.gov (United States)

    Ye, Jianjun; Zhou, Feng; Al-Kareef, Ammar M Q; Wang, Hong

    2015-01-01

    Marine sponges are currently one of the richest sources of anticancer active compounds found in the marine ecosystems. More than 5300 different known metabolites are from sponges and their associated microorganisms. To survive in the complicated marine environment, most of the sponge species have evolved chemical means to defend against predation. Such chemical adaptation produces many biologically active secondary metabolites including anticancer agents. This review highlights novel secondary metabolites in sponges which inhibited diverse cancer species in the recent 5 years. These natural products of marine sponges are categorized based on various chemical characteristics. PMID:25402340

  17. Synthesis and evaluation of single-wall carbon nanotube-paclitaxel-folic acid conjugate as an anti-cancer targeting agent.

    Science.gov (United States)

    Tavakolifard, Sara; Biazar, Esmaeil; Pourshamsian, Khalil; Moslemin, Mohammad H

    2016-08-01

    Single-wall carbon nanotubes (SWCNT) represent a novel nanomaterial applied in various nanotechnology fields because of their surface chemistry properties and high drug cargo capacity. In this study, SWCNT are pre-functionalized covalently with paclitaxel (PTX) - an anticancer drug, and folic acid (FA), as a targeting agent for many tumors. The samples are investigated and evaluated by different analyses such as Fourier transform infrared (FT-IR) spectroscopy, scanning electron microscopy (SEM), thermal gravimetric analysis (TGA), absorption spectroscopic measurements (UV-Visible), elemental analysis, and cell analyses with cancer cell line cultures. The results show good conjugation of the targeting molecule and the anticancer drug on the surface of the carbon nanotubes (CNT). This work demonstrates that the SWCNT-PTX-FA system is a potentially useful system for the targeted delivery of anticancer drugs. PMID:25783856

  18. Mitochondrial complex II, a novel target for anti-cancer agents

    Czech Academy of Sciences Publication Activity Database

    Klučková, Katarína; Bezawork-Geleta, A.; Rohlena, Jakub; Dong, L.; Neužil, Jiří

    2013-01-01

    Roč. 1827, č. 5 (2013), s. 552-564. ISSN 0005-2728 R&D Projects: GA ČR(CZ) GAP301/10/1937; GA ČR GAP301/12/1851 Institutional research plan: CEZ:AV0Z50520701 Keywords : Mitochondrion * Complex II * Anti- cancer agent Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 4.829, year: 2013

  19. Cyclometalated iridium(III) complexes as mitochondria-targeted anticancer agents.

    Science.gov (United States)

    Xiong, Kai; Chen, Yu; Ouyang, Cheng; Guan, Rui-Lin; Ji, Liang-Nian; Chao, Hui

    2016-06-01

    Four cyclometalated iridium(III) complexes [Ir(dfppy)2(L)](+) (dfppy = 2-(2,4-difluorophenyl)pyridine, L = 6-(pyridin-2-yl)-1,3,5-triazine-2,4-diamine, Ir1; 6-(isoquinolin-1-yl)-1,3,5-triazine-2,4-diamine, Ir2; 6-(quinolin-2-yl)-1,3,5-triazine-2,4-diamine, Ir3; 6-(isoquinolin-3-yl)-1,3,5-triazine-2,4-diamine, Ir4) have been synthesized and characterized. Distinct from cisplatin, Ir1-Ir4 could specifically target mitochondria and induced apoptosis against various cancer cell lines, especially for cisplatin resistant cells. ICP-MS results indicated that Ir1-Ir4 were taken up via different mechanism for cancer cells and normal cells, which resulted in their high selectivity. The structure-activity relationship and signaling pathways were also discussed. PMID:27039888

  20. Synthesis of Rapamycin Derivatives Containing the Triazole Moiety Used as Potential mTOR-Targeted Anticancer Agents.

    Science.gov (United States)

    Xie, Lijun; Huang, Jie; Chen, Xiaoming; Yu, Hui; Li, Kualiang; Yang, Dan; Chen, Xiaqin; Ying, Jiayin; Pan, Fusheng; Lv, Youbing; Cheng, Yuanrong

    2016-06-01

    Rapamycin, a potent antifungal antibiotic, was approved as immunosuppressant, and lately its derivatives have been developed into mTOR targeting anticancer drugs. Structure modification was performed at the C-42 position of rapamycin, and a novel series of rapamycin triazole hybrids (4a-d, 5a-e, 8a-e, and 9a-e) was facilely synthesized via Huisgen's reaction. The anticancer activity of these compounds was evaluated against the Caski, H1299, MGC-803, and H460 human cancer cell lines. Some of the derivatives (8a-e, 9a-e) appeared to have stronger activity than that of rapamycin; however, 4a-d and 5a-e failed to show potential anticancer activity. Compound 9e with a (2,4-dichlorophenylamino)methyl moiety on the triazole ring was the most active anticancer compound, which showed IC50 values of 6.05 (Caski), 7.89 (H1299), 25.88 (MGC-803), and 8.60 μM (H460). In addition, research on the mechanism showed that 9e was able to cause cell morphological changes and to induce apoptosis in the Caski cell line. Most importantly, 9e can decrease the phosphorylation of mTOR and of its downstream key proteins, S6 and P70S6K1, indicating that 9e can effectively inhibit the mTOR signaling pathway. Thus, it may have the potential to become a new mTOR inhibitor against various cancers. PMID:27150260

  1. Heterocyclic chalcone analogues as potential anticancer agents.

    Science.gov (United States)

    Sharma, Vikas; Kumar, Vipin; Kumar, Pradeep

    2013-03-01

    Chalcones, aromatic ketones and enones acting as the precursor for flavonoids such as Quercetin, are known for their anticancer effects. Although, parent chalcones consist of two aromatic rings joined by a three-carbon α,β-unsaturated carbonyl system, various synthetic compounds possessing heterocyclic rings like pyrazole, indole etc. are well known and proved to be effective anticancer agents. In addition to their use as anticancer agents in cancer cell lines, heterocyclic analogues are reported to be effective even against resistant cell lines. In this connection, we hereby highlight the potential of various heterocyclic chalcone analogues as anticancer agents with a brief summary about therapeutic potential of chalcones, mechanism of anticancer action of various chalcone analogues, and current and future prospects related to the chalcones-derived anticancer research. Furthermore, some key points regarding chalcone analogues have been reviewed by analyzing their medicinal properties. PMID:22721390

  2. The disulfide compound α-lipoic acid and its derivatives: A novel class of anticancer agents targeting mitochondria.

    Science.gov (United States)

    Dörsam, Bastian; Fahrer, Jörg

    2016-02-01

    The endogenous disulfide α-lipoic acid (LA) is an essential mitochondrial co-factor. In addition, LA and its reduced counterpart dihydro lipoic acid form a potent redox couple with antioxidative functions, for which it is used as dietary supplement and therapeutic. Recently, it has gained attention due to its cytotoxic effects in cancer cells, which is the key aspect of this review. We initially recapitulate the dietary occurrence, gastrointestinal absorption and pharmacokinetics of LA, illustrating its diverse antioxidative mechanisms. We then focus on its mode of action in cancer cells, in which it triggers primarily the mitochondrial pathway of apoptosis, whereas non-transformed primary cells are hardly affected. Furthermore, LA impairs oncogenic signaling and displays anti-metastatic potential. Novel LA derivatives such as CPI-613, which target mitochondrial energy metabolism, are described and recent pre-clinical studies are presented, which demonstrate that LA and its derivatives exert antitumor activity in vivo. Finally, we highlight clinical studies currently performed with the LA analog CPI-613. In summary, LA and its derivatives are promising candidates to complement the arsenal of established anticancer drugs due to their mitochondria-targeted mode of action and non-genotoxic properties. PMID:26604131

  3. Development of a new anti-cancer agent for targeted radionuclide therapy: β- radiolabeled RAFT-RGD

    International Nuclear Information System (INIS)

    β-emitters radiolabeled RAFT-RGD as new agents for internal targeted radiotherapy. The αvβ3 integrin is known to play an important role in tumor-induced angiogenesis, tumor proliferation, survival and metastasis. Because of its overexpression on neo-endothelial cells such as those present in growing tumors, as well as on tumor cells of various origins, αvβ3 integrin is an attractive molecular target for diagnosis and therapy of the rapidly growing and metastatic tumors. A tetrameric RGD-based peptide, regioselectively addressable functionalized template-(cyclo-[RGDfK])4 (RAFT-RGD), specifically targets integrin αvβ3 in vitro and in vivo. RAFT-RGD has been used for tumor imaging and drug targeting. This study is the first to evaluate the therapeutic potential of the β-emitters radiolabeled tetrameric RGD peptide RAFT-RGD in a Nude mouse model of αvβ3 -expressing tumors. An injection of 37 MBq of 90Y-RAFT-RGD or 177Lu-RAFT-RGD in mice with αvβ3 -positive tumors caused a significant growth delay as compared with mice treated with 37 MBq of 90Y-RAFT-RAD or 177Lu-RAFT-RAD or untreated mice. In comparison, an injection of 30 MBq of 90Y-RAFT-RGD had no efficacy for the treatment of αvβ3 -negative tumors. 90Y-RAFT-RGD and 177Lu-RAFT-RGD are potent αvβ3 -expressing tumor targeting agents for internal targeted radiotherapy. (author)

  4. Histone deacetylase inhibitors (HDACIs: multitargeted anticancer agents

    Directory of Open Access Journals (Sweden)

    Ververis K

    2013-02-01

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

  5. Novel anticancer agents from plant sources

    Institute of Scientific and Technical Information of China (English)

    Shah Unnati; Shah Ripal; Acharya Sanjeev; Acharya Niyati

    2013-01-01

    Plants remain an important source of new drugs,new drug leads and new chemical entities.Plant based drug discovery resulted mainly in the development of anticancer and anti-infectious agents,and continues to contribute to the new leads in clinical trials.Natural product drugs play a dominant role in pharmaceutical care.Several plant-derived compounds are currently successfully employed in cancer treatment.There are many classes of plant-derived cytotoxic natural products studied for further improvement and development of drugs.New anticancer drugs derived from research on plant antitumor agents will be continuously discovered.The basic aim of this review is to explore the potential of newly discovered anticancer compounds from medicinal plants,as a lead for anticancer drug development.It will be helpful to explore the medicinal value of plants and for new drug discovery from them for the researchers and scientists around the globe.

  6. Novel Anticancer Agents from Ascidiacea

    OpenAIRE

    Vervoort, Hélène C.

    1999-01-01

    This thesis presents an effort to contribute to the discovery and development of struc­turally and mechanistically novel anticancer drugs. In order to reach this goal it focusses on the biologically active secondary metabolites of marine invertebrates of the class As­cidiacea (phylum Chordata, subphylum Urochordata (Tunicata), class Ascidacea). Three distinct areas of research were combined. The first part concerns the discovery of two novel, naturally occurring didemnin depsipeptide...

  7. Some medicinal plants as natural anticancer agents

    Directory of Open Access Journals (Sweden)

    Govind Pandey

    2009-01-01

    Full Text Available India is the largest producer of medicinal plants and is rightly called the "Botanical garden of the World". The medicinal plants, besides having natural therapeutic values against various diseases, also provide high quality of food and raw materials for livelihood. Considerable works have been done on these plants to treat cancer, and some plant products have been marketed as anticancer drugs, based on the traditional uses and scientific reports. These plants may promote host resistance against infection by re-stabilizing body equilibrium and conditioning the body tissues. Several reports describe that the anticancer activity of medicinal plants is due to the presence of antioxidants in them. In fact, the medicinal plants are easily available, cheaper and possess no toxicity as compared to the modern (allopathic drugs. Hence, this review article contains 66 medicinal plants, which are the natural sources of anticancer agents.

  8. 1-Benzyl-2-methyl-3-indolylmethylene barbituric acid derivatives: Anti-cancer agents that target nucleophosmin 1 (NPM1).

    Science.gov (United States)

    Penthala, Narsimha Reddy; Ketkar, Amit; Sekhar, Konjeti R; Freeman, Michael L; Eoff, Robert L; Balusu, Ramesh; Crooks, Peter A

    2015-11-15

    In the present study, we have designed and synthesized a series of 1-benzyl-2-methyl-3-indolylmethylene barbituric acid analogs (7a-7h) and 1-benzyl-2-methyl-3-indolylmethylene thiobarbituric acid analogs (7 i-7 l) as nucleophosmin 1 (NPM1) inhibitors and have evaluated them for their anti-cancer activity against a panel of 60 different human cancer cell lines. Among these analogs 7 i, 7 j, and 7 k demonstrated potent growth inhibitory effects in various cancer cell types with GI50 values <2 μM. Compound 7 k exhibited growth inhibitory effects on a sub-panel of six leukemia cell lines with GI50 values in the range 0.22-0.35 μM. Analog 7 i also exhibited GI50 values <0.35 μM against three of the leukemia cell lines in the sub-panel. Analogs 7 i, 7 j, 7 k and 7 l were also evaluated against the mutant NPM1 expressing OCI-AML3 cell line and compounds 7 k and 7 l were found to cause dose-dependent apoptosis (AP50 = 1.75 μM and 3.3 μM, respectively). Compound 7k also exhibited potent growth inhibition against a wide variety of solid tumor cell lines: that is, A498 renal cancer (GI50 = 0.19 μM), HOP-92 and NCI-H522 lung cancer (GI50 = 0.25 μM), COLO 205 and HCT-116 colon cancer (GI50 = 0.20 and 0.26 μM, respectively), CNS cancer SF-539 (GI50 = 0.22 μM), melanoma MDA-MB-435 (GI50 = 0.22 μM), and breast cancer HS 578T (GI50 = 0.22 μM) cell lines. Molecular docking studies suggest that compounds 7 k and 7 l exert their anti-leukemic activity by binding to a pocket in the central channel of the NPM1 pentameric structure. These results indicate that the small molecule inhibitors 7 i, 7 j, 7 k, and 7 l could be potentially developed into anti-NPM1 drugs for the treatment of a variety of hematologic malignancies and solid tumors. PMID:26602084

  9. Novel 1,6-naphthyridin-2(1H)-ones as potential anticancer agents targeting Hsp90.

    OpenAIRE

    Montoir, David; Barillé-Nion, Sophie; Tonnerre, Alain; Juin, Philippe; Duflos, Muriel; Bazin, Marc-Antoine

    2016-01-01

    International audience Hsp90 is an ATP-dependent chaperone known to be overexpressed in many cancers. This way, Hsp90 is an important target for drug discovery. Novobiocin, an aminocoumarin antibiotic, was reported to inhibit Hsp90 targeting C-terminal domain, and showed anti-proliferative properties, leading to the development of new and more active compounds. Consequently, a new set of novobiocin analogs derived from 1,6-naphthyridin-2(1H)-one scaffold was designed, synthesized and evalu...

  10. Anticancer agent-based marine natural products and related compounds.

    Science.gov (United States)

    Chen, Jian-Wei; Wu, Qi-Hao; Rowley, David C; Al-Kareef, Ammar M Q; Wang, Hong

    2015-01-01

    Marine natural products constitute a huge reservoir of anticancer agents. Consequently during the past decades, several marine anticancer compounds have been isolated, identified, and approved for anticancer treatment or are under trials. In this article the sources, structure, bioactivities, mode of actions, and analogs of some promising marine and derived anticancer compounds have been discussed. PMID:25559315

  11. Chemical genetics analysis of an aniline mustard anticancer agent reveals complex I of the electron transport chain as a target

    OpenAIRE

    Fedeles, Bogdan I.; Zhu, Angela Y.; Young, Kellie S.; Hillier, Shawn M.; Proffitt, Kyle D.; Essigmann, John M.; Croy, Robert G.

    2011-01-01

    The antitumor agent 11β (CAS 865070-37-7), consisting of a DNA-damaging aniline mustard linked to an androgen receptor (AR) ligand, is known to form covalent DNA adducts and to induce apoptosis potently in AR-positive prostate cancer cells in vitro; it also strongly prevents growth of LNCaP xenografts in mice. The present study describes the unexpectedly strong activity of 11β against the AR-negative HeLa cells, both in cell culture and tumor xenografts, and uncovers a new mechanism of action...

  12. Novel 1,6-naphthyridin-2(1H)-ones as potential anticancer agents targeting Hsp90.

    Science.gov (United States)

    Montoir, David; Barillé-Nion, Sophie; Tonnerre, Alain; Juin, Philippe; Duflos, Muriel; Bazin, Marc-Antoine

    2016-08-25

    Hsp90 is an ATP-dependent chaperone known to be overexpressed in many cancers. This way, Hsp90 is an important target for drug discovery. Novobiocin, an aminocoumarin antibiotic, was reported to inhibit Hsp90 targeting C-terminal domain, and showed anti-proliferative properties, leading to the development of new and more active compounds. Consequently, a new set of novobiocin analogs derived from 1,6-naphthyridin-2(1H)-one scaffold was designed, synthesized and evaluated against two breast cancer cell lines. Subsequently, cell cycle progression and apoptosis were conducted on best candidates, finally Western Blot analysis was performed to measure their ability to induce degradation of Hsp90 client proteins. PMID:27153346

  13. TAT peptide-based micelle system for potential active targeting of anti-cancer agents to acidic solid tumors

    OpenAIRE

    Sethuraman, Vijay A.; Bae, You Han

    2006-01-01

    A novel drug targeting system for acidic solid tumors has been developed based on ultra pH sensitive polymer and cell penetrating TAT. The delivery system consisted of two components: 1) A polymeric micelle that has a hydrophobic core made of Poly(L-lactic acid) (PLLA) and a hydrophilic shell consisting of Polyethylene Glycol (PEG) conjugated to TAT (TATmicelle), 2) An ultra pH sensitive diblock copolymer of poly(methacryloyl sulfadimethoxine) (PSD) and PEG (PSD-b-PEG). The anionic PSD is com...

  14. A REVIEW: HERBS USED AS ANTICANCER AGENTS

    Directory of Open Access Journals (Sweden)

    Badri Nagarani

    2011-01-01

    Full Text Available Herbs are the plants which will have desirable odour, taste and other medical uses. Anti-cancer agents are effective in cancer treatment. Here an attempt has been made to review some herbs used for the prevention and treatment of cancer. These herbs were found for posses anticancer, cytotoxic or antioxidant activity in various pre-clinical or clinical studies. Cancer is a disease in which body cells become abnormal and divide without control. Cancer cell may invade nearby tissues and they may spread through the blood stream & lymphatic system to other parts of the body. The search for anticancer agents from the plant sources alkaloids in earnest in the 1950s such as Vincristine, Vinblastine and the isolation of cytotoxic Podophyllotoxins will reduce white blood cell count and caused bone marrow depression in rats. Roots, leaves, stem, root, bark and fruity of the plant herbs are used in the treatment of cancer. The dietary antioxidants having anti carcinogenic property are in demand. Identification and characterization of these anti-carcinogens in the diet can be used for reducing the risk of human cancer. Tea (Camellia thea an evergreen plant contains antioxidants which prevent and repair cellular damage caused by reactive free radicals. Supervitamin drinks containing a combination of Hordeum vulgare, Medicago sativa and Spirulina enhances the activity of immune cells against cancer. Mentha species containing antioxidants prevent reocurrence of cancer.

  15. 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

  16. Sphingolipid metabolism enzymes as targets for anticancer therapy

    NARCIS (Netherlands)

    Kok, JW; Sietsma, H

    2004-01-01

    Treatment with anti-cancer agents in most cases ultimately results in apoptotic cell death of the target tumour cells. Unfortunately, tumour cells can develop multidrug resistance, e.g., by a reduced propensity to engage in apoptosis by which they become insensitive to multiple chemotherapeutics. Ce

  17. Exploiting developments in nanotechnology for the preferential delivery of platinum-based anti-cancer agents to tumours: targeting some of the hallmarks of cancer.

    Science.gov (United States)

    Parker, James P; Ude, Ziga; Marmion, Celine J

    2016-01-20

    Platinum drugs as anti-cancer therapeutics are held in extremely high regard. Despite their success, there are drawbacks associated with their use; their dose-limiting toxicity, their limited activity against an array of common cancers and patient resistance to Pt-based therapeutic regimes. Current investigations in medicinal inorganic chemistry strive to offset these shortcomings through selective targeting of Pt drugs and/or the development of Pt drugs with new or multiple modes of action. A comprehensive overview showcasing how liposomes, nanocapsules, polymers, dendrimers, nanoparticles and nanotubes may be employed as vehicles to selectively deliver cytotoxic Pt payloads to tumour cells is provided. PMID:26567482

  18. Polymer anticancer drugs with peptide targeting

    Czech Academy of Sciences Publication Activity Database

    Studenovský, Martin; Pola, Robert; Pechar, Michal; Ulbrich, Karel; Hovorka, Ondřej

    Long Beach : Controlled Release Society, 2007, 771/1-771/2. [Annual Meeting and Exposition of the Controlled Release Society /34./. Long Beach (US), 07.07.2007-11.07.2007] R&D Projects: GA ČR GA204/05/2255 Institutional research plan: CEZ:AV0Z40500505; CEZ:AV0Z50200510 Keywords : angiogenesis * anticancer agents * conjugates * HPMA copolymers Subject RIV: CE - Biochemistry http://www.controlledreleasesociety.org/meeting/program/pdfs/ProgramBook.pdf

  19. Snake venom: a potent anticancer agent.

    Science.gov (United States)

    Jain, Deepika; Kumar, Sudhir

    2012-01-01

    Since cancer is one of the leading causes of death worldwide, and there is an urgent need to find better treatment. In recent years remarkable progress has been made towards the understanding of proposed hallmarks of cancer development and treatment. Treatment modalities comprise radiation therapy, surgery, chemotherapy, immunotherapy and hormonal therapy. Currently, the use of chemotherapeutics remains the predominant option for clinical control. However, one of the major problems with successful cancer therapy using chemotherapeutics is that patients often do not respond or eventually develop resistance after initial treatment. This has led to the increased use of anticancer drugs developed from natural resources. The biodiversity of venoms and toxins makes them a unique source from which novel therapeutics may be developed. In this review, the anticancer potential of snake venom is discussed. Some of the included molecules are under clinical trial and may find application for anticancer drug development in the near future. PMID:23244070

  20. Arene ruthenium complexes as anticancer agents

    OpenAIRE

    Süss-Fink, Georg

    2012-01-01

    Neutral or cationic arene ruthenium complexes providing both hydrophilic as well as hydrophobic properties due to the robustness of the ruthenium–arene unit hold a high potential for the development of metal-based anticancer drugs. Mononuclear arene ruthenium complexes containing P- or N-donor ligands or N,N-, N,O- or O,O-chelating ligands, dinuclear arene ruthenium systems with adjustable organic linkers, trinuclear arene ruthenium clusters containing an oxo cap, tetranuclear arene ruthenium...

  1. Some medicinal plants as natural anticancer agents

    OpenAIRE

    Govind Pandey; S Madhuri

    2009-01-01

    India is the largest producer of medicinal plants and is rightly called the "Botanical garden of the World". The medicinal plants, besides having natural therapeutic values against various diseases, also provide high quality of food and raw materials for livelihood. Considerable works have been done on these plants to treat cancer, and some plant products have been marketed as anticancer drugs, based on the traditional uses and scientific reports. These plants may promote host resistance agai...

  2. Targeting aerobic glycolysis: 3-bromopyruvate as a promising anticancer drug.

    Science.gov (United States)

    Cardaci, Simone; Desideri, Enrico; Ciriolo, Maria Rosa

    2012-02-01

    The Warburg effect refers to the phenomenon whereby cancer cells avidly take up glucose and produce lactic acid under aerobic conditions. Although the molecular mechanisms underlying tumor reliance on glycolysis remains not completely clear, its inhibition opens feasible therapeutic windows for cancer treatment. Indeed, several small molecules have emerged by combinatorial studies exhibiting promising anticancer activity both in vitro and in vivo, as a single agent or in combination with other therapeutic modalities. Therefore, besides reviewing the alterations of glycolysis that occur with malignant transformation, this manuscript aims at recapitulating the most effective pharmacological therapeutics of its targeting. In particular, we describe the principal mechanisms of action and the main targets of 3-bromopyruvate, an alkylating agent with impressive antitumor effects in several models of animal tumors. Moreover, we discuss the chemo-potentiating strategies that would make unparalleled the putative therapeutic efficacy of its use in clinical settings. PMID:22328057

  3. Metformin may function as anti-cancer agent via targeting cancer stem cells: the potential biological significance of tumor-associated miRNAs in breast and pancreatic cancers.

    Science.gov (United States)

    Bao, Bin; Azmi, Asfar S; Ali, Shadan; Zaiem, Feras; Sarkar, Fazlul H

    2014-06-01

    Metformin is one of the most used diabetic drugs for the management of type II diabetes mellitus (DM) in the world. Increased numbers of epidemiological and clinical studies have provided convincing evidence supporting the role of metformin in the development and progression of a variety of human tumors including breast and pancreatic cancer. Substantial pre-clinical evidence from in vitro and in vivo experimental studies strongly suggests that metformin has an anti-cancer activity mediated through the regulation of several cell signaling pathways including activation of AMP kinase (AMPK), and other direct and indirect mechanisms; however, the detailed mechanism(s) has not yet been fully understood. The concept of cancer stem cells (CSCs) has gained significant attention in recent years due its identification and defining its clinical implications in many different tumors including breast cancer and pancreatic cancer. In this review, we will discuss the protective role of metformin in the development of breast and pancreatic cancers. We will further discuss the role of metformin as an anti-cancer agent, which is in part mediated through targeting CSCs. Finally, we will discuss the potential role of metformin in the modulation of tumor-associated or CSC-associated microRNAs (miRNAs) as part of the novel mechanism of action of metformin in the development and progression of breast and pancreatic cancers. PMID:25333034

  4. 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.

  5. Natural compounds as anticancer agents: Experimental evidence

    OpenAIRE

    Wang, Jiao; Jiang, Yang-Fu

    2012-01-01

    Cancer prevention research has drawn much attention worldwide. It is believed that some types of cancer can be prevented by following a healthy life style. Cancer chemoprevention by either natural or synthetic agents is a promising route towards lowering cancer incidence. In recent years, the concept of cancer chemoprevention has evolved greatly. Experimental studies in animal models demonstrate that the reversal or suppression of premalignant lesions by chemopreventive agents is achievable. ...

  6. NSAIDs: Old Drugs Reveal New Anticancer Targets

    Directory of Open Access Journals (Sweden)

    Gary A. Piazza

    2010-05-01

    Full Text Available There is compelling evidence that nonsteroidal anti-inflammatory drugs (NSAIDs and cyclooxygenase-2 selective inhibitors have antineoplastic activity, but toxicity from cyclooxygenase (COX inhibition and the suppression of physiologically important prostaglandins limits their use for cancer chemoprevention. Previous studies as reviewed here suggest that the mechanism for their anticancer properties does not require COX inhibition, but instead involves an off-target effect. In support of this possibility, recent molecular modeling studies have shown that the NSAID sulindac can be chemically modified to selectively design out its COX-1 and COX-2 inhibitory activity. Unexpectedly, certain derivatives that were synthesized based on in silico modeling displayed increased potency to inhibit tumor cell growth. Other experiments have shown that sulindac can inhibit phosphodiesterase to increase intracellular cyclic GMP levels and that this activity is closely associated with its ability to selectively induce apoptosis of tumor cells. Together, these studies suggest that COX-independent mechanisms can be targeted to develop safer and more efficacious drugs for cancer chemoprevention.

  7. Alkaloids Isolated from Natural Herbs as the Anticancer Agents

    Directory of Open Access Journals (Sweden)

    Jin-Jian Lu

    2012-01-01

    Full Text Available Alkaloids are important chemical compounds that serve as a rich reservoir for drug discovery. Several alkaloids isolated from natural herbs exhibit antiproliferation and antimetastasis effects on various types of cancers both in vitro and in vivo. Alkaloids, such as camptothecin and vinblastine, have already been successfully developed into anticancer drugs. This paper focuses on the naturally derived alkaloids with prospective anticancer properties, such as berberine, evodiamine, matrine, piperine, sanguinarine, and tetrandrine, and summarizes the mechanisms of action of these compounds. Based on the information in the literature that is summarized in this paper, the use of alkaloids as anticancer agents is very promising, but more research and clinical trials are necessary before final recommendations on specific alkaloids can be made.

  8. Double layered hydroxides as potential anti-cancer drug delivery agents.

    Science.gov (United States)

    Riaz, Ufana; Ashraf, S M

    2013-04-01

    The emergence of nanotechnology has changed the scenario of the medical world by revolutionizing the diagnosis, monitoring and treatment of cancer. This nanotechnology has been proved miraculous in detecting cancer cells, delivering chemotherapeutic agents and monitoring treatment from non-specific to highly targeted killing of tumor cells. In the past few decades, a number of inorganic materials have been investigated such as calcium phosphate, gold, carbon materials, silicon oxide, iron oxide, and layered double hydroxide (LDH) for examining their efficacy in targeting drug delivery. The reason behind the selection of these inorganic materials was their versatile and unique features efficient in drug delivery, such as wide availability, rich surface functionality, good biocompatibility, potential for target delivery, and controlled release of the drug from these inorganic nanomaterials. Although, the drug-LDH hybrids are found to be quite instrumental because of their application as advanced anti-cancer drug delivery systems, there has not been much research on them. This mini review is set to highlight the advancement made in the use of layered double hydroxides (LDHs) as anti-cancer drug delivery agents. Along with the advantages of LDHs as anti-cancer drug delivery agents, the process of interaction of some of the common anti-cancer drugs with LDH has also been discussed. PMID:23170959

  9. 靶向性抗癌治疗的纳米技术%Nanotechnology for targeted anticancer therapies

    Institute of Scientific and Technical Information of China (English)

    罗育林

    2005-01-01

    Although many anticancer therapies are used in clinic, few are tolerable for their side effects from killing of normal cells. Seeking measures to target anticancer agents to tumors or at least tumor-located organs has been one of the major tasks for researchers. Nanotechnology is greatly helpful for fulfilling this task. There are several ways to direct therapeutic agents carried by nanoparticles to tumor sites. This article focuses on the mechanisms,advantages and disadvantages of different targeting manners, understanding of which may be benefitial to researchers to develop specific targeted anticancer therapy.

  10. Adding pharmacogenomics to the development of new marine-derived anticancer agents

    Directory of Open Access Journals (Sweden)

    Aracil Miguel

    2006-01-01

    Full Text Available Abstract Nature has always been a highly productive tool in the development of anticancer therapies. Renewed interest in the potential of this tool has recently been sparked by the realization that the marine ecosystem can be used for the discovery and development of new compounds with clinical potential in advanced resistant tumors. These compounds can be incorporated into combination approaches in a chronic therapy scenario. Our marine anticancer program is using the sea to develop new agents with activity in resistant solid tumors and to identify new cellular targets for therapeutic intervention. This review describes the integration of different pharmacogenomic tools in the development of Yondelis™, Aplidin® and Kahalalide F, three marine-derived compounds currently in Phase II or III development. Our results are reinforcing the targeted selectivity of these agents and opening the gates for customized therapies in cancer patients in the near future.

  11. Monitoring of occupational exposure to cytostatic anticancer agents.

    Science.gov (United States)

    Sorsa, M; Anderson, D

    1996-08-17

    Many anticancer agents have been shown to be carcinogenic, mutagenic and teratogenic in experimental animals and in in vitro test systems. Epidemiological data on the association of second neoplasms with a specific chemotherapy treatment is available on some 30 agents, and in the case of 10 compounds the overall evidence on human carcinogenicity has been evaluated to be conclusive (Group 1: IARC, 1987 and 1990). The primary source of human exposure to anticancer drugs is from their use in therapy of cancer. However, persons employed in the manufacture, preparation and administration of the drugs to patients and in nursing patients may also be exposed. Safe handling of anticancer drugs, since the introduction of various general handling guidelines, is now good practice in hospitals, pharmacies and drug manufacturing companies of most developed countries. Careless handling of cancer chemotherapeutic agents may lead to exposure of the personnel in amounts detectable with chemical or biological methods in the body fluids or cell samples of the subjects. The exposure is typically to mixed compounds over long-term and to low exposure levels with accidental peaks. Therefore, the use of biological exposure markers is appropriate for the monitoring of such exposure patterns. The biological markers/methods for exposure assessment are either non-specific (e.g., cytogenetic damage, point mutations or 32P-post-labelling adducts in peripheral blood lymphocytes, urinary mutagenicity) or specific for a given compound (immunological methods for DNA adducts, specific analytical methods). Studies have revealed minor amounts of cyclophosphamide in the urine of pharmacy technicians and nurses handling the drug even when taking special safety precautions (Sessink et al. (1994a) J. Occup. Med., 36, 79; Sessink et al. (1994b) Arch. Env. Health, 49, 165). Another study showed surface wipe samples with measurable cyclophosphamide even away from the handling site (McDevitt et al. (1993) J

  12. Selective anti-cancer agents as anti-aging drugs

    OpenAIRE

    Blagosklonny, Mikhail V.

    2013-01-01

    Recent groundbreaking discoveries have revealed that IGF-1, Ras, MEK, AMPK, TSC1/2, FOXO, PI3K, mTOR, S6K, and NFκB are involved in the aging process. This is remarkable because the same signaling molecules, oncoproteins and tumor suppressors, are well-known targets for cancer therapy. Furthermore, anti-cancer drugs aimed at some of these targets have been already developed. This arsenal could be potentially employed for anti-aging interventions (given that similar signaling molecules are inv...

  13. Discovery and development of natural product oridonin-inspired anticancer agents.

    Science.gov (United States)

    Ding, Ye; Ding, Chunyong; Ye, Na; Liu, Zhiqing; Wold, Eric A; Chen, Haiying; Wild, Christopher; Shen, Qiang; Zhou, Jia

    2016-10-21

    Natural products have historically been, and continue to be, an invaluable source for the discovery of various therapeutic agents. Oridonin, a natural diterpenoid widely applied in traditional Chinese medicines, exhibits a broad range of biological effects including anticancer and anti-inflammatory activities. To further improve its potency, aqueous solubility and bioavailability, the oridonin template serves as an exciting platform for drug discovery to yield better candidates with unique targets and enhanced drug properties. A number of oridonin derivatives (e.g. HAO472) have been designed and synthesized, and have contributed to substantial progress in the identification of new agents and relevant molecular mechanistic studies toward the treatment of human cancers and other diseases. This review summarizes the recent advances in medicinal chemistry on the explorations of novel oridonin analogues as potential anticancer therapeutics, and provides a detailed discussion of future directions for the development and progression of this class of molecules into the clinic. PMID:27344488

  14. Synthesis and characterization of Cu(II)-based anticancer chemotherapeutic agent targeting topoisomerase Iα: in vitro DNA binding, pBR322 cleavage, molecular docking studies and cytotoxicity against human cancer cell lines.

    Science.gov (United States)

    Tabassum, Sartaj; Zaki, Mehvash; Afzal, Mohd; Arjmand, Farukh

    2014-03-01

    New metal-based anticancer chemotherapeutic drug candidates [Cu(phen)L](NO₃)₂ (1) and [Zn(phen)L](NO₃)₂ (2) were synthesized from ligand L (derived from pharmacophore scaffold barbituric acid and pyrazole). In vitro DNA binding studies of the L, 1 and 2 were carried out by various biophysical techniques revealing electrostatic mode. Complex 1 cleaves pBR322 DNA via oxidative pathway and recognizes major groove of DNA double helix. The molecular docking study was carried out to ascertain the mode of action towards the molecular target DNA and enzymes. The complex 1 exhibited remarkably good anticancer activity on a panel of human cancer cell lines (GI₅₀ values < 10 μg/ml), and to elucidate the mechanism of cancer inhibition, Topo-I enzymatic activity was carried out. PMID:24508781

  15. Design and synthesis of harzialactone analogues: promising anticancer agents.

    Science.gov (United States)

    Pawar, Vishwas U; Ghosh, Sougata; Chopade, Balu A; Shinde, Vaishali S

    2010-12-15

    New homologues of harzialactone were synthesized using D-glucose as chiral template. Wittig reaction to introduce aromatic moiety in 10 and chemoselective anomeric oxidation of 13 were used as key reactions in our synthesis. Anticancer activity of these target molecules was assessed against five cancer cell lines, P388D1, HL60, COLO-205, Zr-75-1 and HeLa. Both compound 5 and 6, showed significant activity against colon cancer (COLO-205) and cervical cancer (HeLa) and moderate with others. To the best of our knowledge, this is the first report of harzialactone analogues as potent inhibitors of human colon and cervical cancer. PMID:21074431

  16. Polylactide-co-glycolide nanoparticles for controlled delivery of anticancer agents

    Directory of Open Access Journals (Sweden)

    Rouhani H

    2011-04-01

    Full Text Available R Dinarvand1,2, N Sepehri1, S Manoochehri1, H Rouhani1, F Atyabi1,21Department of Pharmaceutics, Faculty of Pharmacy, 2Nanotechnology Research Centre, Tehran University of Medical Sciences, Tehran, IranAbstract: The effectiveness of anticancer agents may be hindered by low solubility in water, poor permeability, and high efflux from cells. Nanomaterials have been used to enable drug delivery with lower toxicity to healthy cells and enhanced drug delivery to tumor cells. Different nanoparticles have been developed using different polymers with or without surface modification to target tumor cells both passively and/or actively. Polylactide-co-glycolide (PLGA, a biodegradable polyester approved for human use, has been used extensively. Here we report on recent developments concerning PLGA nanoparticles prepared for cancer treatment. We review the methods used for the preparation and characterization of PLGA nanoparticles and their applications in the delivery of a number of active agents. Increasing experience in the field of preparation, characterization, and in vivo application of PLGA nanoparticles has provided the necessary momentum for promising future use of these agents in cancer treatment, with higher efficacy and fewer side effects.Keywords: nanotechnology, polymeric nanocarriers, targeting, anticancer agents, surface modification

  17. Phytochemicals and Biogenic Metallic Nanoparticles as Anticancer Agents.

    Science.gov (United States)

    Rao, Pasupuleti Visweswara; Nallappan, Devi; Madhavi, Kondeti; Rahman, Shafiqur; Jun Wei, Lim; Gan, Siew Hua

    2016-01-01

    Cancer is a leading cause of death worldwide. Several classes of drugs are available to treat different types of cancer. Currently, researchers are paying significant attention to the development of drugs at the nanoscale level to increase their target specificity and to reduce their concentrations. Nanotechnology is a promising and growing field with multiple subdisciplines, such as nanostructures, nanomaterials, and nanoparticles. These materials have gained prominence in science due to their size, shape, and potential efficacy. Nanomedicine is an important field involving the use of various types of nanoparticles to treat cancer and cancerous cells. Synthesis of nanoparticles targeting biological pathways has become tremendously prominent due to the higher efficacy and fewer side effects of nanodrugs compared to other commercial cancer drugs. In this review, different medicinal plants and their active compounds, as well as green-synthesized metallic nanoparticles from medicinal plants, are discussed in relation to their anticancer activities. PMID:27057273

  18. Phytochemicals and Biogenic Metallic Nanoparticles as Anticancer Agents

    Directory of Open Access Journals (Sweden)

    Pasupuleti Visweswara Rao

    2016-01-01

    Full Text Available Cancer is a leading cause of death worldwide. Several classes of drugs are available to treat different types of cancer. Currently, researchers are paying significant attention to the development of drugs at the nanoscale level to increase their target specificity and to reduce their concentrations. Nanotechnology is a promising and growing field with multiple subdisciplines, such as nanostructures, nanomaterials, and nanoparticles. These materials have gained prominence in science due to their size, shape, and potential efficacy. Nanomedicine is an important field involving the use of various types of nanoparticles to treat cancer and cancerous cells. Synthesis of nanoparticles targeting biological pathways has become tremendously prominent due to the higher efficacy and fewer side effects of nanodrugs compared to other commercial cancer drugs. In this review, different medicinal plants and their active compounds, as well as green-synthesized metallic nanoparticles from medicinal plants, are discussed in relation to their anticancer activities.

  19. Discovery of a novel anti-cancer agent targeting both topoisomerase I and II in hepatocellular carcinoma Hep 3B cells in vitro and in vivo: Cinnamomum verum component 2-methoxycinnamaldehyde.

    Science.gov (United States)

    Perng, Daw-Shyong; Tsai, Yu-Hsin; Cherng, Jonathan; Kuo, Chih-Wei; Shiao, Chih-Chung; Cherng, Jaw-Ming

    2016-08-01

    Cinnamomum verum has been used as a traditional Chinese herbal medicine. We evaluated the anticancer effect of 2-methoxycinnamaldehyde (2-MCA), a constituent of the bark of the plant, in hepatocellular carcinoma Hep 3B cells. The results show that 2-MCA suppressed proliferation and induced apoptosis as indicated by an up-regulation of pro-apoptotic bax and bak genes and down-regulation of anti-apoptotic bcl-2 and bcl-XL genes, mitochondrial membrane potential loss, cytochrome c release, activation of caspase 3 and 9, increase in the DNA content in sub G1, and morphological characteristics of apoptosis. 2-MCA also induced lysosomal vacuolation with increased volume of acidic compartments (VAC), suppressions of nuclear transcription factors NF-κB, cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), and both topoisomerase I and II activities in a dose-dependent manner. Further study reveals the growth-inhibitory effect of 2-MCA was also evident in a nude mice model. Taken together, the data suggest that the growth-inhibitory effect of 2-MCA against Hep 3B cells is accompanied by downregulations of NF-κB binding activity, inflammatory responses involving COX-2 and PGE2, and proliferative control involving apoptosis, both topoisomerase I and II activities, together with an upregulation of lysosomal vacuolation and VAC. Our data suggest that 2-MCA could be a potential agent for anticancer therapy. PMID:26707867

  20. Targeting tumor glycolysis by a mitotropic agent.

    Science.gov (United States)

    Ganapathy-Kanniappan, Shanmugasundaram

    2016-01-01

    Metabolic reprogramming is one of the hallmarks of cancer. Altered metabolism in cancer cells is exemplified by enhanced glucose utilization, a biochemical signature that is clinically exploited for cancer diagnosis using positron-emission tomography and computed tomography imaging. Accordingly, disrupting the glucose metabolism of cancer cells has been contemplated as a potential therapeutic strategy against cancer. Experimental evidences indicate that targeting glucose metabolism by inhibition of glycolysis or oxidative phosphorylation promotes anticancer effects. Yet, successful clinical translation of antimetabolites or energy blockers to treat cancer remains a challenge, primarily due to lack of efficacy and/or systemic toxicity. Recently, using nanotechnology, Marrache and Dhar have documented the feasibility of delivering a glycolytic inhibitor through triphenylphosphonium (TPP), a mitotropic agent that selectively targets mitochondria based on membrane potential. Furthermore, by utilizing gold nanoparticles the investigators also demonstrated the potential for simultaneous induction of photothermal therapy, thus facilitating an additional line of attack on cancer cells. The report establishes that specific inhibition of tumor glycolysis is achievable through TPP-dependent selective targeting of cancer cells. This nanotechnological approach involving TPP-guided selective delivery of an antiglycolytic agent complemented with photothermal therapy provides a new window of opportunity for effective and specific targeting of tumor glycolysis. PMID:26420565

  1. Current development of the second generation of mTOR inhibitors as anticancer agents

    Institute of Scientific and Technical Information of China (English)

    Hong-Yu Zhou; Shi-Le Huang

    2012-01-01

    The mammalian target of rapamycin (mTOR),a serine/threonine protein kinase,acts as a “master switch” for cellular anabolic and catabolic processes,regulating the rate of cell growth and proliferation.Dysregulation of the mTOR signaling pathway occurs frequently in a variety of human tumors,and thus,mTOR has emerged as an important target for the design of anticancer agents.mTOR is found in two distinct multiprotein complexes within cells,mTORC1 and mTORC2.These two complexes consist of unique mTOR-interacting proteins and are regulated by different mechanisms.Enormous advances have been made in the development of drugs known as mTOR inhibitors.Rapamycin,the first defined inhibitor of mTOR,showed effectiveness as an anticancer agent in various preclinical models.Rapamycin analogues (rapalogs) with better pharmacologic properties have been developed.However,the clinical success of rapalogs has been limited to a few types of cancer.The discovery that mTORC2 directly phosphorylates Akt,an important survival kinase,adds new insight into the role of mTORC2 in cancer.This novel finding prompted efforts to develop the second generation of mTOR inhibitors that are able to target both mTORC1 and mTORC2.Here,we review the recent advances in the mTOR field and focus specifically on the current development of the second generation of mTOR inhibitors as anticancer agents.

  2. Designing piperlongumine-directed anticancer agents by an electrophilicity-based prooxidant strategy: A mechanistic investigation.

    Science.gov (United States)

    Yan, Wen-Jing; Wang, Qi; Yuan, Cui-Hong; Wang, Fu; Ji, Yuan; Dai, Fang; Jin, Xiao-Ling; Zhou, Bo

    2016-08-01

    Piperlongumine (PL), a natural electrophilic alkaloid bearing two α, β-unsaturated imides, is a promising anticancer molecule by targeting the stress response to reactive oxygen species (ROS). Considering that ROS generation depends on electrophilicity of PL, PL-CL was designed as its analog by introducing the α-substituent chlorine on the lactam ring to increase moderately its electrophilicity. In comparison with the parent molecule, this molecule was identified as a stronger ROS (O2(∙-) and H2O2) inducer and cytotoxic agent, and manifested more than 15-fold selectivity toward A549 cells over normal WI-38 cells. Mechanistic study uncovers for the first time that the selenoprotein thioredoxin reductase (TrxR) is one of the targets by which PL-CL promotes the ROS generation. Stronger intracellular TrxR inhibition and higher accumulation of ROS (O2(∙-) and H2O2) are responsible for more effective S-phase arrest and mitochondria-mediated apoptotic induction of A549 cells by PL-CL than PLvia p53-p21-cyclinA/CDK2 and ASK1-JNK/p38 signaling cascade pathways, respectively. This work provides an example of successfully designing PL-directed anticancer agent by an electrophilicity-based prooxidant (ROS-generating agent) strategy and gives added confidence for extending this strategy to other natural products. PMID:27233942

  3. Anticancer activity of streptochlorin, a novel antineoplastic agent, in cholangiocarcinoma

    Directory of Open Access Journals (Sweden)

    Kwak TW

    2015-04-01

    Full Text Available Tae Won Kwak,1,* Hee Jae Shin,2,* Young-Il Jeong,1 Myoung-Eun Han,3 Sae-Ock Oh,3 Hyun-Jung Kim,4 Do Hyung Kim,5 Dae Hwan Kang1 1Biomedical Research Institute, Pusan National University Hospital, Busan, 2Marine Natural Products Chemistry Laboratory, Korea Institute of Ocean Science and Technology, Ansan, 3Department of Anatomy, School of Medicine, Pusan National University, Gyeongnam, 4Genewel Co Ltd. Gyeonggi-do, 5School of Medicine, Pusan National University, Yangsan, Gyeongnam, Republic of Korea *These authors contributed equally to this work Background: The aim of this study is to investigate the anticancer activity of streptochlorin, a novel antineoplastic agent, in cholangiocarcinoma. Methods: The anticancer activity of streptochlorin was evaluated in vitro in various cholangiocarcinoma cell lines for apoptosis, proliferation, invasiveness, and expression of various protein levels. A liver metastasis model was prepared by splenic injection of HuCC-T1 cholangiocarcinoma cells using a BALB/c nude mouse model to study the systemic antimetastatic efficacy of streptochlorin 5 mg/kg at 8 weeks. The antitumor efficacy of subcutaneously injected streptochlorin was also assessed using a solid tumor xenograft model of SNU478 cells for 22 days in the BALB/c nude mouse. Results: Streptochlorin inhibited growth and secretion of vascular endothelial growth factor by cholangiocarcinoma cells in a dose-dependent manner and induced apoptosis in vitro. In addition, streptochlorin effectively inhibited invasion and migration of cholangiocarcinoma cells. Secretion of vascular endothelial growth factor and activity of matrix metalloproteinase-9 in cholangiocarcinoma cells were also suppressed by treatment with streptochlorin. Streptochlorin effectively regulated metastasis of HuCC-T1 cells in a mouse model of liver metastasis. In a tumor xenograft study using SNU478 cells, streptochlorin significantly inhibited tumor growth without changes in body weight

  4. HER2-mediated anticancer drug delivery: strategies to prepare targeting ligands highly specific for the receptor.

    Science.gov (United States)

    Calce, Enrica; Monfregola, Luca; Saviano, Michele; De Luca, Stefania

    2015-01-01

    HER2 receptor, for its involvement in tumorigenesis, has been largely studied as topic in cancer research. In particular, the employment of trastuzumab (Herceptin), a humanized anti-HER2 antibody, showed several clinical benefits in the therapy against the breast cancer. Moreover, for its accessible extracellular domain, this receptor is considered an ideal target to deliver anticancer drugs for the receptormediated anticancer therapy. By now, monoclonal antibody and its fragments, affibody, and some peptides have been employed as targeting agents in order to deliver various drugs to HER2 positive tumor cells. In particular, the ability to perform a fast and reliable screening of a large number of peptide molecules would make possible the selection of highly specific compounds to the receptor target. In this regard, the availability of preparing a simplified synthetic model which is a good mimetic of the receptor target and can be used in a reliable screening method of ligands would be of a strategic importance for the development of selective HER2-targeting peptide molecules. Herein, we illustrate the importance of HER2-targeted anticancer therapies. We also report on a synthetic and effective mimetic of the receptor, which revealed to be a useful tool for the selection of specific HER2 ligands. PMID:25994863

  5. Current developments of coumarin-based anti-cancer agents in medicinal chemistry.

    Science.gov (United States)

    Emami, Saeed; Dadashpour, Sakineh

    2015-09-18

    Cancer is one of the leading health hazards and the prominent cause of death in the world. A number of anticancer agents are currently in clinical practice and used for treatment of various kinds of cancers. There is no doubt that the existing arsenal of anticancer agents is insufficient due to the high incidence of side effects and multidrug resistance. In the efforts to develop suitable anticancer drugs, medicinal chemists have focused on coumarin derivatives. Coumarin is a naturally occurring compound and a versatile synthetic scaffold possessing wide spectrum of biological effects including potential anticancer activity. This review article covers the current developments of coumarin-based anticancer agents and also discusses the structure-activity relationship of the most potent compounds. PMID:26318068

  6. Pharmacophore modeling and in silico toxicity assessment of potential anticancer agents from African medicinal plants

    Directory of Open Access Journals (Sweden)

    Ntie-Kang F

    2016-07-01

    Full Text Available Fidele Ntie-Kang,1,2,* Conrad Veranso Simoben,1,2,* Berin Karaman,1 Valery Fuh Ngwa,3 Philip Neville Judson,4 Wolfgang Sippl,1 Luc Meva’a Mbaze5 1Department of Pharmaceutical Chemistry, Martin-Luther University of Halle-Wittenberg, Halle (Saale, Germany; 2Department of Chemistry, University of Buea, Buea, Cameroon; 3Interuniversity Institute For Biostatistics and Statistical Bioinformatics (I-BioStat, University of Hasselt, Hasselt, Belgium; 4Chemical Bioactivity Information Centre, Harrogate, UK; 5Department of Chemistry, Faculty of Science, University of Douala, Douala, Cameroon *These authors contributed equally to this work Abstract: Molecular modeling has been employed in the search for lead compounds of chemotherapy to fight cancer. In this study, pharmacophore models have been generated and validated for use in virtual screening protocols for eight known anticancer drug targets, including tyrosine kinase, protein kinase B β, cyclin-dependent kinase, protein farnesyltransferase, human protein kinase, glycogen synthase kinase, and indoleamine 2,3-dioxygenase 1. Pharmacophore models were validated through receiver operating characteristic and Güner–Henry scoring methods, indicating that several of the models generated could be useful for the identification of potential anticancer agents from natural product databases. The validated pharmacophore models were used as three-dimensional search queries for virtual screening of the newly developed AfroCancer database (~400 compounds from African medicinal plants, along with the Naturally Occurring Plant-based Anticancer Compound-Activity-Target dataset (comprising ~1,500 published naturally occurring plant-based compounds from around the world. Additionally, an in silico assessment of toxicity of the two datasets was carried out by the use of 88 toxicity end points predicted by the Lhasa’s expert knowledge-based system (Derek, showing that only an insignificant proportion of the promising

  7. 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

  8. PEPTIDE TARGETING OF PLATINUM ANTI-CANCER DRUGS

    OpenAIRE

    Ndinguri, Margaret W.; Solipuram, Rajasree; Gambrell, Robert P.; Aggarwal, Sita; Hansel, William; Hammer, Robert P.

    2009-01-01

    Besides various side effects caused by platinum anticancer drugs, they are not efficiently absorbed by the tumor cells. Two Pt-peptide conjugates; cyclic mPeg-CNGRC-Pt (7) and cyclic mPeg-CNGRC-Pten (8) bearing the Asn-Gly-Arg (NGR) targeting sequence, a malonoyl linker and low molecular weight miniPEG groups have been synthesized. The platinum ligand was attached to the peptide via the carboxylic end of the malonate group at the end of the peptide. The pegylated peptide is non toxic and high...

  9. Lymphatic Targeting of Nanosystems for Anticancer Drug Therapy.

    Science.gov (United States)

    Abellan-Pose, Raquel; Csaba, Noemi; Alonso, Maria Jose

    2016-01-01

    The lymphatic system represents a major route of dissemination in metastatic cancer. Given the lack of selectivity of conventional chemotherapy to prevent lymphatic metastasis, in the last years there has been a growing interest in the development of nanocarriers showing lymphotropic characteristics. The goal of this lymphotargeting strategy is to facilitate the delivery of anticancer drugs to the lymph node-resident cancer cells, thereby enhancing the effectiveness of the anti-cancer therapies. This article focuses on the nanosystems described so far for the active or passive targeting of oncological drugs to the lymphatic circulation. To understand the design and performance of these nanosystems, we will discuss first the physiology of the lymphatic system and how physiopathological changes associated to tumor growth influence the biodistribution of nanocarriers. Second, we provide evidence on how the tailoring of the physicochemical characteristics of nanosystems, i.e. particle size, surface charge and hydrophilicity, allows the modulation of their access to the lymphatic circulation. Finally, we provide an overview of the relationship between the biodistribution and antimetastatic activity of the nanocarriers loaded with oncological drugs, and illustrate the most promising active targeting approaches investigated so far. PMID:26675222

  10. Triterpenoids of Marine Origin as Anti-Cancer Agents

    Directory of Open Access Journals (Sweden)

    Yong-Xin Li

    2013-07-01

    Full Text Available Triterpenoids are the most abundant secondary metabolites present in marine organisms, such as marine sponges, sea cucumbers, marine algae and marine-derived fungi. A large number of triterpenoids are known to exhibit cytotoxicity against a variety of tumor cells, as well as anticancer efficacy in preclinical animal models. In this review efforts have been taken to review the structural features and the potential use of triterpenoids of marine origin to be used in the pharmaceutical industry as potential anti-cancer drug leads.

  11. Synthesis and evaluation of flavanones as anticancer agents

    Directory of Open Access Journals (Sweden)

    Y Murti

    2014-01-01

    Full Text Available A few flavanones were synthesised by cyclisation of corresponding 3-(heteroaryl-1(2-hydroxyphenyl prop-2-en-1-one with sodium acetate in alcohol-water and evaluated for activity. Synthesised compounds were assayed for their in vitro anticancer activity against three human cancer cell lines, mammary adenocarcinoma (MCF7, human colon adenocarcinoma (HT29 and human kidney adenocarcinoma (A498 using sulforhodamine B dye. Results indicated that most of the compounds exhibited significant in vitro anticancer potential. Among them, compound having furan ring showed most potent activity against all the tested cell lines.

  12. Quinones derived from plant secondary metabolites as anti-cancer agents.

    Science.gov (United States)

    Lu, Jin-Jian; Bao, Jiao-Lin; Wu, Guo-Sheng; Xu, Wen-Shan; Huang, Ming-Qing; Chen, Xiu-Ping; Wang, Yi-Tao

    2013-03-01

    Quinones are plant-derived secondary metabolites that present some anti-proliferation and anti-metastasis effects in various cancer types both in vitro and in vivo. This review focuses on the anti-cancer prospects of plant-derived quinones, namely, aloe-emodin, juglone, β-lapachol, plumbagin, shikonin, and thymoquinone. We intend to summarize their anti-cancer effects and investigate the mechanism of actions to promote the research and development of anti-cancer agents from quinones. PMID:22931417

  13. Design and development of polynuclear ruthenium and platinum polypyridyl complexes in search of new anticancer agents

    OpenAIRE

    Schilden, Karlijn van der

    2006-01-01

    The research described in this Ph.D. Thesis has been devoted to the design and development of polynuclear polypyridyl ruthenium and ruthenium-platinum complexes in search of new anticancer agents. A variety of polynuclear ruthenium and ruthenium-platinum complexes has been synthesized with a long and flexible linker. The complexes are characterized and have been studied for anticancer activity. The ruthenium unit of the dinuclear complexes varies in molecular structure, which may result in di...

  14. Potential role of garcinol as an anticancer agent.

    Science.gov (United States)

    Saadat, Nadia; Gupta, Smiti V

    2012-01-01

    Garcinol, a polyisoprenylated benzophenone, is extracted from the rind of the fruit of Garcinia indica, a plant found extensively in tropical regions. Although the fruit has been consumed traditionally over centuries, its biological activities, specifically its anticancer potential is a result of recent scientific investigations. The anticarcinogenic properties of garcinol appear to be moderated via its antioxidative, anti-inflammatory, antiangiogenic, and proapoptotic activities. In addition, garcinol displays effective epigenetic influence by inhibiting histone acetyltransferases (HAT 300) and by possible posttranscriptional modulation by mi RNA profiles involved in carcinogenesis. In vitro as well as some in vivo studies have shown the potential of this compound against several cancers types including breast, colon, pancreatic, and leukemia. Although this is a promising molecule in terms of its anticancer properties, investigations in relevant animal models, and subsequent human trials are warranted in order to fully appreciate and confirm its chemopreventative and/or therapeutic potential. PMID:22745638

  15. Discovery of Natural Product Anticancer Agents from Biodiverse Organisms

    OpenAIRE

    Kinghorn, A. Douglas; Chin, Young-Won; Swanson, Steven M.

    2009-01-01

    For over 40 years, small organic molecules derived naturally from microbes and plants have provided a number of useful cancer chemotherapeutic drugs. The search for naturally occurring lead compounds of this type has continued in recent years, with the constituents of marine fauna and flora as well as those of terrestrial microorganisms and plants being investigated for their anti-cancer activities. In the present short review, selected new compounds or their derivatives are described that ha...

  16. Triterpenoids of Marine Origin as Anti-Cancer Agents

    OpenAIRE

    Yong-Xin Li; Himaya, S.W.A.; Se-Kwon Kim

    2013-01-01

    Triterpenoids are the most abundant secondary metabolites present in marine organisms, such as marine sponges, sea cucumbers, marine algae and marine-derived fungi. A large number of triterpenoids are known to exhibit cytotoxicity against a variety of tumor cells, as well as anticancer efficacy in preclinical animal models. In this review efforts have been taken to review the structural features and the potential use of triterpenoids of marine origin to be used in the pharmaceutical industry ...

  17. Potential Role of Garcinol as an Anticancer Agent

    OpenAIRE

    Gupta, Smiti V.; Nadia Saadat

    2012-01-01

    Garcinol, a polyisoprenylated benzophenone, is extracted from the rind of the fruit of Garcinia indica, a plant found extensively in tropical regions. Although the fruit has been consumed traditionally over centuries, its biological activities, specifically its anticancer potential is a result of recent scientific investigations. The anticarcinogenic properties of garcinol appear to be moderated via its antioxidative, anti-inflammatory, antiangiogenic, and proapoptotic activities. In addition...

  18. Anticancer efficacy of the metabolic blocker 3-bromopyruvate: specific molecular targeting.

    Science.gov (United States)

    Ganapathy-Kanniappan, Shanmugasundaram; Kunjithapatham, Rani; Geschwind, Jean-Francois

    2013-01-01

    The anticancer efficacy of the pyruvate analog 3-bromopyruvate has been demonstrated in multiple tumor models. The chief principle underlying the antitumor effects of 3-bromopyruvate is its ability to effectively target the energy metabolism of cancer cells. Biochemically, the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has been identified as the primary target of 3-bromopyruvate. Its inhibition results in the depletion of intracellular ATP, causing cell death. Several reports have also demonstrated that in addition to GAPDH inhibition, the induction of cellular stress also contributes to 3-bromopyruvate treatment-dependent apoptosis. Furthermore, recent evidence shows that 3-bromopyruvate is taken up selectively by tumor cells via the monocarboxylate transporters (MCTs) that are frequently overexpressed in cancer cells (for the export of lactate produced during aerobic glycolysis). The preferential uptake of 3-bromopyruvate via MCTs facilitates selective targeting of tumor cells while leaving healthy and non-malignant tissue untouched. Taken together, the specificity of molecular (GAPDH) targeting and selective uptake by tumor cells, underscore the potential of 3-bromopyruvate as a potent and promising anticancer agent. In this review, we highlight the mechanistic characteristics of 3-bromopyruvate and discuss its potential for translation into the clinic. PMID:23267123

  19. Second annual progress report on introduction and use of investigational anticancer agents in Australia, 1984-1985. Anticancer Subcommittee of the Australian Drug Evaluation Committee.

    Science.gov (United States)

    1986-03-31

    Since the publication of its first report, the Anticancer Subcommittee of the Australian Drug Evaluation Committee (ADEC) has provided advice to ADEC and to the Commonwealth Department of Health on investigational anticancer agents in all stages of development. This second report outlines the progress in 1984-1985. PMID:3515139

  20. Heat-Shock Protein 90-Targeted Nano Anticancer Therapy.

    Science.gov (United States)

    Rochani, Ankit K; Ravindran Girija, Aswathy; Borah, Ankita; Maekawa, Toru; Sakthi Kumar, D

    2016-04-01

    Suboptimal chemotherapy of anticancer drugs may be attributed to a variety of cellular mechanisms, which synergize to dodge the drug responses. Nearly 2 decades of heat-shock protein 90 (Hsp90)-targeted drug discovery has shown that the mono-therapy with Hsp90 inhibitors seems to be relatively ineffective compared with combination treatment due to several cellular dodging mechanisms. In this article, we have tried to analyze and review the Hsp90 and mammalian target of rapamycin (m-TOR)-mediated drug resistance mechanisms. By using this information we have discussed about the rationale behind use of drug combinations that includes both or any one of these inhibitors for cancer therapy. Currently, biodegradable nano vector (NV)-loaded novel drug delivery systems have shown to resolve the problems of poor bioavailability. NVs of drugs such as paclitaxel, doxorubicin, daunorubicin, and others have been successfully introduced for medicinal use. Hence, looking at the success of NVs, in this article we have also discussed the progress made in the delivery of biodegradable NV-loaded Hsp90 and m-TOR-targeted inhibitors in multiple drug combinations. We have also discussed the possible ways by which the market success of biodegradable NVs can positively impact the clinical trials of anti-Hsp90 and m-TOR combination strategy. PMID:26886301

  1. New water soluble pyrroloquinoline derivatives as new potential anticancer agents.

    Science.gov (United States)

    Ferlin, Maria Grazia; Marzano, Christine; Dalla Via, Lisa; Chilin, Adriana; Zagotto, Giuseppe; Guiotto, Adriano; Moro, Stefano

    2005-08-01

    A new class of water soluble 3H-pyrrolo[3,2-f]quinoline derivatives has been synthesized and investigated as potential anticancer drugs. Water solubility profiles have been used to select the most promising derivatives. The novel compound 10, having two (2-diethylamino-ethyl) side chains linked through positions 3N and 9O, presents a suitable water solubility profile, and it was shown to exhibit cell growth inhibitory properties when tested against the in-house panel of cell lines, in particular those obtained from melanoma. PMID:15936202

  2. (-)-Arctigenin as a lead compound for anticancer agent.

    Science.gov (United States)

    Chen, Gui-Rong; Li, Hong-Fu; Dou, De-Qiang; Xu, Yu-Bin; Jiang, Hong-Shuai; Li, Fu-Rui; Kang, Ting-Guo

    2013-01-01

    (-)-Arctigenin, an important active constituent of the traditional Chinese herb Fructus Arctii, was found to exhibit various bioactivities, so it can be used as a good lead compound for further structure modification in order to find a safer and more potent medicine. (-)-Arctigenin derivatives 1-5 of (-)-arctingen were obtained by modifying with ammonolysis at the lactone ring and sulphonylation at C (6') and C (6″) and O-demethylation at CH3O-C (3'), CH3O-C (3″) and CH3O-C (4″), and their anticancer bioactivities were examined. PMID:23962054

  3. Proof of concept for inhibiting metastasis: circulating tumor cell-triggered localized release of anticancer agent via a structure-switching aptamer.

    Science.gov (United States)

    Chen, Nandi; Yang, Xiaohai; Wang, Qing; Jian, Lixin; Shi, Hui; Qin, Shiya; Wang, Kemin; Huang, Jin; Liu, Wenjing

    2016-05-21

    Existing drug delivery systems were not suitable for killing cells in the circulatory system specifically. Herein, we developed a novel localized drug delivery strategy, in which the release of anticancer agents was specifically triggered by circulating tumor cells. Meanwhile, damage to non-target cells was avoided. PMID:27121864

  4. Novel Microtubule-Targeting 7-Deazahypoxanthines Derived from Marine Alkaloid Rigidins with Potent in Vitro and in Vivo Anticancer Activities.

    Science.gov (United States)

    Medellin, Derek C; Zhou, Qiong; Scott, Robert; Hill, R Matthew; Frail, Sarah K; Dasari, Ramesh; Ontiveros, Steven J; Pelly, Stephen C; van Otterlo, Willem A L; Betancourt, Tania; Shuster, Charles B; Hamel, Ernest; Bai, Ruoli; LaBarbera, Daniel V; Rogelj, Snezna; Frolova, Liliya V; Kornienko, Alexander

    2016-01-14

    Docking studies of tubulin-targeting C2-substituted 7-deazahypoxanthine analogues of marine alkaloid rigidins led to the design and synthesis of compounds containing linear C2-substituents. The C2-alkynyl analogue was found to have double- to single-digit nanomolar antiproliferative IC50 values and showed statistically significant tumor size reduction in a colon cancer mouse model at nontoxic concentrations. These results provide impetus and further guidance for the development of these rigidin analogues as anticancer agents. PMID:26641132

  5. Chrysin-piperazine conjugates as antioxidant and anticancer agents.

    Science.gov (United States)

    Patel, Rahul V; Mistry, Bhupendra; Syed, Riyaz; Rathi, Anuj K; Lee, Yoo-Jung; Sung, Jung-Suk; Shinf, Han-Seung; Keum, Young-Soo

    2016-06-10

    Synthesis of 7-(4-bromobutoxy)-5-hydroxy-2-phenyl-4H-chromen-4-one intermediate treating chrysin with 1,4-dibromobutane facilitated combination of chrysin with a wide range of piperazine moieties which were equipped via reacting the corresponding amines with bis(2-chloroethyl)amine hydrochloride in diethylene glycol monomethyl ether solvent. Free radical scavenging potential of prepared products was analyzed in vitro adopting DPPH and ABTS bioassay in addition to the evaluation of in vitro anticancer efficacies against cervical cancer cell lines (HeLa and CaSki) and an ovarian cancer cell line SK-OV-3 using SRB assay. Bearable toxicity of 7a-w was examined employing Madin-Darby canine kidney (MDCK) cell line. In addition, cytotoxic nature of the presented compounds was inspected utilizing Human bone marrow derived mesenchymal stem cells (hBM-MSCs). Overall, 7a-w indicated remarkable antioxidant power in scavenging DPPH(·) and ABTS(·+), particularly analogs 7f, 7j, 7k, 7l, 7n, 7q, 7v, 7w have shown promising free radical scavenging activity. Analogs 7j and 7o are identified to be highly active candidates against HeLa and CaSki cell lines, whereas 7h and 7l along with 7j proved to be very sensitive towards ovarian cancer cell line SKOV-3. None of the newly prepared scaffolds showed cytotoxic nature toward hBM-MSCs cells. From the structure-activity point of view, nature and position of the electron withdrawing and electron donating functional groups on the piperazine core may contribute to the anticipated antioxidant and anticancer action. Different spectroscopic techniques (FT-IR, (1)H NMR, (13)C NMR, Mass) and elemental analysis (CHN) were utilized to confirm the desired structure of final compounds. PMID:26924226

  6. Polymeric micelles in anticancer therapy : targeting, imaging and triggered release

    NARCIS (Netherlands)

    Oerlemans, Chris; Bult, Wouter; Bos, Mariska; Storm, Gert; Nijsen, J Frank W; Hennink, Wim E

    2010-01-01

    Micelles are colloidal particles with a size around 5-100 nm which are currently under investigation as carriers for hydrophobic drugs in anticancer therapy. Currently, five micellar formulations for anticancer therapy are under clinical evaluation, of which Genexol-PM has been FDA approved for use

  7. Design and development of polynuclear ruthenium and platinum polypyridyl complexes in search of new anticancer agents

    NARCIS (Netherlands)

    Schilden, Karlijn van der

    2006-01-01

    The research described in this Ph.D. Thesis has been devoted to the design and development of polynuclear polypyridyl ruthenium and ruthenium-platinum complexes in search of new anticancer agents. A variety of polynuclear ruthenium and ruthenium-platinum complexes has been synthesized with a long an

  8. Pharmaceutical development of the novel metal-based anticancer agents NAMI-A and AP 5280

    NARCIS (Netherlands)

    Bouma, M. (Marjan)

    2003-01-01

    The pharmaceutical development of the two novel metal-based anticancer agents NAMI-A and AP 5280 is described in this thesis, starting with the development of analytical methods for the quality control of drug substance and final product, via the formulation process leading to a stable, intravenous

  9. Clinical guidance on the perioperative use of targeted agents in solid tumor oncology.

    Science.gov (United States)

    Mellor, James D; Cassumbhoy, Michelle; Jefford, Michael

    2011-06-01

    The use of targeted anti-cancer agents is increasing. It is common to utilize a multi-modal treatment approach towards solid tumors, often including surgical resection, and it has become apparent that some targeted agents can impair wound healing or cause an increased risk of perioperative complications. This article reviews targeted agents used in solid tumor oncology with an emphasis on clinically relevant details. Overall, the evidence of targeted agents causing surgical complications is limited. The greatest amount of evidence exists for bevacizumab causing perioperative complications, possibly due to its extended half-life. There are limited data for cetuximab, sorafenib and sunitinib and very little for other solid tumor targeted agents. Our findings suggest that there should be heightened pharmacovigilence around targeted agents with respect to perioperative complications and increased post-surgical support for patients to aid early detection of postoperative complications until definitive data become available. PMID:21585689

  10. Prolonging the exposure to anti-cancer agents

    NARCIS (Netherlands)

    O. Soepenberg (Otto)

    2004-01-01

    textabstractThis thesis includes phase I clinical and pharmacological studies on second and third generation topoisomerase I inhibitors, either administered orally, or intravenously as a macromolecular drug-delivery system, and on the antimicrotubulin agent, paclitaxel encapsulated in liposomes, to

  11. A translational study "case report" on the small molecule "energy blocker" 3-bromopyruvate (3BP) as a potent anticancer agent: from bench side to bedside.

    Science.gov (United States)

    Ko, Y H; Verhoeven, H A; Lee, M J; Corbin, D J; Vogl, T J; Pedersen, P L

    2012-02-01

    The small alkylating molecule, 3-bromopyruvate (3BP), is a potent and specific anticancer agent. 3BP is different in its action from most currently available chemo-drugs. Thus, 3BP targets cancer cells' energy metabolism, both its high glycolysis ("Warburg Effect") and mitochondrial oxidative phosphorylation. This inhibits/ blocks total energy production leading to a depletion of energy reserves. Moreover, 3BP as an "Energy Blocker", is very rapid in killing such cells. This is in sharp contrast to most commonly used anticancer agents that usually take longer to show a noticeable effect. In addition, 3BP at its effective concentrations that kill cancer cells has little or no effect on normal cells. Therefore, 3BP can be considered a member, perhaps one of the first, of a new class of anticancer agents. Following 3BP's discovery as a novel anticancer agent in vitro in the Year 2000 (Published in Ko et al. Can Lett 173:83-91, 2001), and also as a highly effective and rapid anticancer agent in vivo shortly thereafter (Ko et al. Biochem Biophys Res Commun 324:269-275, 2004), its efficacy as a potent anticancer agent in humans was demonstrated. Here, based on translational research, we report results of a case study in a young adult cancer patient with fibrolamellar hepatocellular carcinoma. Thus, a bench side discovery in the Department of Biological Chemistry at Johns Hopkins University, School of Medicine was taken effectively to bedside treatment at Johann Wolfgang Goethe University Frankfurt/Main Hospital, Germany. The results obtained hold promise for 3BP as a future cancer therapeutic without apparent cyto-toxicity when formulated properly. PMID:22328020

  12. Bacterial biosynthesis and maturation of the didemnin anticancer agents

    OpenAIRE

    Xu, Ying; Kersten, Roland D.; Nam, Sang-Jip; Lu, Liang; Al-Suwailem, Abdulaziz M.; Zheng, Huajun; Fenical, William; Dorrestein, Pieter C.; Moore, Bradley S.; Qian, Pei-Yuan

    2012-01-01

    The antineoplastic agent didemnin B from the Caribbean tunicate Trididemnum solidum was the first marine drug to be clinically tested in humans. Because of its limited supply and its complex cyclic depsipeptide structure, considerable challenges were encountered during didemnin B's development that continue to limit aplidine (dehydrodidemnin B), which is currently being evaluated in numerous clinical trials. Herein we show that the didemnins are bacterial products produced by the marine α-pro...

  13. Repurposing the Clinically Efficacious Antifungal Agent Itraconazole as an Anticancer Chemotherapeutic.

    Science.gov (United States)

    Pace, Jennifer R; DeBerardinis, Albert M; Sail, Vibhavari; Tacheva-Grigorova, Silvia K; Chan, Kelly A; Tran, Raymond; Raccuia, Daniel S; Wechsler-Reya, Robert J; Hadden, M Kyle

    2016-04-28

    Itraconazole (ITZ) is an FDA-approved member of the triazole class of antifungal agents. Two recent drug repurposing screens identified ITZ as a promising anticancer chemotherapeutic that inhibits both the angiogenesis and hedgehog (Hh) signaling pathways. We have synthesized and evaluated first- and second-generation ITZ analogues for their anti-Hh and antiangiogenic activities to probe more fully the structural requirements for these anticancer properties. Our overall results suggest that the triazole functionality is required for ITZ-mediated inhibition of angiogenesis but that it is not essential for inhibition of Hh signaling. The synthesis and evaluation of stereochemically defined des-triazole ITZ analogues also provides key information as to the optimal configuration around the dioxolane ring of the ITZ scaffold. Finally, the results from our studies suggest that two distinct cellular mechanisms of action govern the anticancer properties of the ITZ scaffold. PMID:27014922

  14. Recent Development of Copolymeric Delivery System for Anticancer Agents Based on Cyclodextrin Derivatives.

    Science.gov (United States)

    Feng, Runliang; Deng, Peizong; Teng, Fangfang; Song, Zhimei

    2016-01-01

    Core-shell structured aggregates of amphiphilic block copolymer are hopefully drug delivery system because of their ability to encapsulate hydrophobic drugs, and their hydrophilic shell can prolong retention time of drugs in the blood circulation system. Cyclodextrin is a kind of hydrophilic polysaccharide containing multiple hydroxyl groups, providing an inner hole that can load small molecule through host-guest interaction. These hydroxyl groups or their derived functional ones are utilized in conjugation with polymeric chains to form block copolymers. These copolymers can not only encapsulate hydrophobic drugs, but also encapsulate hydrophilic drugs (like DNA, protein, etc) through hydrophobic, host-guest or electrostatic interactions, which strengthen interaction between drugs and materials compared with general copolymers, indicating that formed drug delivery systems are more stable. By introduction of target molecule, they also achieve selective delivery of drugs to specific tissues or organs. So, several researchers are stimulated to carry out many studies for the development of cyclodextrin copolymeric drug delivery systems in recent. In this review, we focus the cyclodextrin copolymers' application in the anticancer agents' delivery. PMID:26349814

  15. Structure-activity relationships of novel substituted naphthalene diimides as anticancer agents.

    Science.gov (United States)

    Milelli, Andrea; Tumiatti, Vincenzo; Micco, Marialuisa; Rosini, Michela; Zuccari, Guendalina; Raffaghello, Lizzia; Bianchi, Giovanna; Pistoia, Vito; Fernando Díaz, J; Pera, Benet; Trigili, Chiara; Barasoain, Isabel; Musetti, Caterina; Toniolo, Marianna; Sissi, Claudia; Alcaro, Stefano; Moraca, Federica; Zini, Maddalena; Stefanelli, Claudio; Minarini, Anna

    2012-11-01

    Novel 1,4,5,8-naphthalenetetracarboxylic diimide (NDI) derivatives were synthesized and evaluated for their antiproliferative activity on a wide number of different tumor cell lines. The prototypes of the present series were derivatives 1 and 2 characterized by interesting biological profiles as anticancer agents. The present investigation expands on the study of structure-activity relationships of prototypes 1 and 2, namely, the influence of the different substituents of the phenyl rings on the biological activity. Derivatives 3-22, characterized by a different substituent on the aromatic rings and/or a different chain length varying from two to three carbon units, were synthesized and evaluated for their cytostatic and cytotoxic activities. The most interesting compound was 20, characterized by a linker of three methylene units and a 2,3,4-trimethoxy substituent on the two aromatic rings. It displayed antiproliferative activity in the submicromolar range, especially against some different cell lines, the ability to inhibit Taq polymerase and telomerase, to trigger caspase activation by a possible oxidative mechanism, to downregulate ERK 2 protein and to inhibit ERKs phosphorylation, without acting directly on microtubules and tubuline. Its theoretical recognition against duplex and quadruplex DNA structures have been compared to experimental thermodynamic measurements and by molecular modeling investigation leading to putative binding modes. Taken together these findings contribute to define this compound as potential Multitarget-Directed Ligands interacting simultaneously with different biological targets. PMID:22819507

  16. 3D QSAR Analysis on Oxadiazole Derivatives as Anticancer Agents

    Directory of Open Access Journals (Sweden)

    Sanmati K. Jain

    2011-07-01

    Full Text Available Three dimensional quantitative structure activity relationship (3D QSAR study by means of partial least square regression (PLSR method was performed on a series of 3-(Aryl-N-(Aryl-1, 2, 4-Oxadiazol-5-amines as antiproliferative agents using molecular design suite (VLifeMDS. This study was performed with 20 compounds (data set using sphere exclusion (SE algorithm and manual selection method used for the division of the data set into training and test set. PLSR methodology with stepwise (SW forward-backward variable selection method was used for building the QSAR models. Five predictive models were generated with sphere exclusion and two with manual data selection methods using PLSR. The most significant model is having correlation coefficient 0.9334 (squared correlation coefficient r2 = 0.8713 indicating noteworthy correlation between biological activity and descriptors. The model has internal predictivity 74.45% (q2 = 0.7445 and highest external predictivity 81.09 % (pred_r2 = 0.8109 and lowest error term for predictive correlation coefficient (pred_r2se = 0.1321. Model showed that steric (S_1278, S_751 and electrostatic (E_307 interactions play important role in determining antiproliferative activity. The molecular field analysis (MFA contour plots provided further understanding of the relationship between structural features of substituted oxadiazole derivatives and their activities which should be applicable to design newer potential antiproliferative agents.

  17. Phytochemicals and Biogenic Metallic Nanoparticles as Anticancer Agents

    OpenAIRE

    Pasupuleti Visweswara Rao; Devi Nallappan; Kondeti Madhavi; Shafiqur Rahman; Lim Jun Wei; Siew Hua Gan

    2016-01-01

    Cancer is a leading cause of death worldwide. Several classes of drugs are available to treat different types of cancer. Currently, researchers are paying significant attention to the development of drugs at the nanoscale level to increase their target specificity and to reduce their concentrations. Nanotechnology is a promising and growing field with multiple subdisciplines, such as nanostructures, nanomaterials, and nanoparticles. These materials have gained prominence in science due to the...

  18. Photophysical characterization of anticancer drug valrubicin in rHDL nanoparticles and its use as an imaging agent.

    Science.gov (United States)

    Shah, Sunil; Chib, Rahul; Raut, Sangram; Bermudez, Jaclyn; Sabnis, Nirupama; Duggal, Divya; Kimball, Joseph D; Lacko, Andras G; Gryczynski, Zygmunt; Gryczynski, Ignacy

    2016-02-01

    Nanoparticles are target-specific drug delivery agents that are increasingly used in cancer therapy to enhance bioavailability and to reduce off target toxicity of anti-cancer agents. Valrubicin is an anti-cancer drug, currently approved only for vesicular bladder cancer treatment because of its poor water solubility. On the other hand, valrubicin carrying reconstituted high density lipoprotein (rHDL) nanoparticles appear ideally suited for extended applications, including systemic cancer chemotherapy. We determined selected fluorescence properties of the free (unencapsulated) drug vs. valrubicin incorporated into rHDL nanoparticles. We have found that upon encapsulation into rHDL nanoparticles the quantum yield of valrubicin fluorescence increased six fold while its fluorescence lifetime increased about 2 fold. Accordingly, these and potassium iodide (KI) quenching data suggest that upon incorporation, valrubicin is localized deep in the interior of the nanoparticle, inside the lipid matrix. Fluorescence anisotropy of the rHDL valrubicin nanoparticles was also found to be high along with extended rotational correlation time. The fluorescence of valrubicin could also be utilized to assess its distribution upon delivery to prostate cancer (PC3) cells. Overall the fluorescence properties of the rHDL: valrubicin complex reveal valuable novel characteristics of this drug delivery vehicle that may be particularly applicable when used in systemic (intravenous) therapy. PMID:26735001

  19. Can Some Marine-Derived Fungal Metabolites Become Actual Anticancer Agents?

    Science.gov (United States)

    Gomes, Nelson G M; Lefranc, Florence; Kijjoa, Anake; Kiss, Robert

    2015-06-01

    Marine fungi are known to produce structurally unique secondary metabolites, and more than 1000 marine fungal-derived metabolites have already been reported. Despite the absence of marine fungal-derived metabolites in the current clinical pipeline, dozens of them have been classified as potential chemotherapy candidates because of their anticancer activity. Over the last decade, several comprehensive reviews have covered the potential anticancer activity of marine fungal-derived metabolites. However, these reviews consider the term "cytotoxicity" to be synonymous with "anticancer agent", which is not actually true. Indeed, a cytotoxic compound is by definition a poisonous compound. To become a potential anticancer agent, a cytotoxic compound must at least display (i) selectivity between normal and cancer cells (ii) activity against multidrug-resistant (MDR) cancer cells; and (iii) a preferentially non-apoptotic cell death mechanism, as it is now well known that a high proportion of cancer cells that resist chemotherapy are in fact apoptosis-resistant cancer cells against which pro-apoptotic drugs have more than limited efficacy. The present review thus focuses on the cytotoxic marine fungal-derived metabolites whose ability to kill cancer cells has been reported in the literature. Particular attention is paid to the compounds that kill cancer cells through non-apoptotic cell death mechanisms. PMID:26090846

  20. Hormetic Effect of Berberine Attenuates the Anticancer Activity of Chemotherapeutic Agents.

    Directory of Open Access Journals (Sweden)

    Jiaolin Bao

    Full Text Available Hormesis is a phenomenon of biphasic dose response characterized by exhibiting stimulatory or beneficial effects at low doses and inhibitory or toxic effects at high doses. Increasing numbers of chemicals of various types have been shown to induce apparent hormetic effect on cancer cells. However, the underlying significance and mechanisms remain to be elucidated. Berberine, one of the major active components of Rhizoma coptidis, has been manifested with notable anticancer activities. This study aims to investigate the hormetic effect of berberine and its influence on the anticancer activities of chemotherapeutic agents. Our results demonstrated that berberine at low dose range (1.25 ~ 5 μM promoted cell proliferation to 112% ~170% of the untreated control in various cancer cells, while berberine at high dose rage (10 ~ 80 μM inhibited cell proliferation. Further, we observed that co-treatment with low dose berberine could significantly attenuate the anticancer activity of chemotherapeutic agents, including fluorouracil (5-FU, camptothecin (CPT, and paclitaxel (TAX. The hormetic effect and thereby the attenuated anticancer activity of chemotherapeutic drugs by berberine may attributable to the activated protective stress response in cancer cells triggered by berberine, as evidenced by up-regulated MAPK/ERK1/2 and PI3K/AKT signaling pathways. These results provided important information to understand the potential side effects of hormesis, and suggested cautious application of natural compounds and relevant herbs in adjuvant treatment of cancer.

  1. Hedgehog Signaling Inhibitors as Anti-Cancer Agents in Osteosarcoma

    Energy Technology Data Exchange (ETDEWEB)

    Ram Kumar, Ram Mohan, E-mail: rkumar@research.balgrist.ch; Fuchs, Bruno [Laboratory for Orthopaedic Research, Balgrist University Hospital, Sarcoma Center-UZH University of Zurich, Zurich 8008 (Switzerland)

    2015-05-13

    Osteosarcoma is a rare type of cancer associated with a poor clinical outcome. Even though the pathologic characteristics of OS are well established, much remains to be understood, particularly at the molecular signaling level. The molecular mechanisms of osteosarcoma progression and metastases have not yet been fully elucidated and several evolutionary signaling pathways have been found to be linked with osteosarcoma pathogenesis, especially the hedgehog signaling (Hh) pathway. The present review will outline the importance and targeting the hedgehog signaling (Hh) pathway in osteosarcoma tumor biology. Available data also suggest that aberrant Hh signaling has pro-migratory effects and leads to the development of osteoblastic osteosarcoma. Activation of Hh signaling has been observed in osteosarcoma cell lines and also in primary human osteosarcoma specimens. Emerging data suggests that interference with Hh signal transduction by inhibitors may reduce osteosarcoma cell proliferation and tumor growth thereby preventing osteosarcomagenesis. From this perspective, we outline the current state of Hh pathway inhibitors in osteosarcoma. In summary, targeting Hh signaling by inhibitors promise to increase the efficacy of osteosarcoma treatment and improve patient outcome.

  2. Evaluation of Degradation Properties of Polyglycolide and Its Potential as Delivery Vehicle for Anticancer Agents

    International Nuclear Information System (INIS)

    Biodegradable polymers offer a unique combination of properties that can be tailored to suit nearly any controlled drug delivery application. The most common biodegradable polymers used for biomedical applications are semicrystalline polyesters and polyethers which possess good mechanical properties and have been used in many controlled release applications. Drug release from these polymers may be controlled by several mechanisms and these include diffusion of drug through a matrix, dissolution of polymer matrix and degradation of the polymer. This study aims to investigate the degradation and drug release properties of polyglycolide (1.03 dL/g), in which, cis platin, an anticancer agent was used as the model drug. The degradation behaviour of the chosen polymer is thought to largely govern the release of the anticancer agent in vitro.

  3. Pharmaceutical development of selected novel anticancer agents : from drugs substance to dosage form

    OpenAIRE

    Brok, M.W.J. (Monique Wilhelmina Johanna) den

    2004-01-01

    Despite the substantial progress made over the last decades in the treatment of cancer, there still is a great need for novel therapies. Especially for patients with advanced disease, chemotherapy is the best option. Nature is the primary source of anticancer drugs with compounds isolated from plants or micro-organisms. Moreover, the marine ecosystem provides for a growing number of promising agents in clinical trials. Besides natural resources, the increasing knowledge of tumour pathology an...

  4. Caffeine-hydrazones as anticancer agents with pronounced selectivity toward T-lymphoblastic leukaemia cells

    Czech Academy of Sciences Publication Activity Database

    Kaplánek, R.; Jakubek, M.; Rak, J.; Kejik, Z.; Havlík, M.; Dolenský, B.; Frydrych, I.; Hajduch, M.; Kolář, M.; Bogdanová, K.; Králová, Jarmila; Dzubak, P.; Král, V.

    2015-01-01

    Roč. 60, Jun (2015), s. 19-29. ISSN 0045-2068 Grant ostatní: GA MŠk(CZ) EE2.3.30.0060; GA MŠk CZ.1.07/2.3.00/30.0041; GA MŠk(CZ) LO1304 Institutional support: RVO:68378050 Keywords : Anticancer agents * Cancer treatment * Caffeine-hydrazones * Leukaemia * Selectivity Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.152, year: 2014

  5. Polylactide-co-glycolide nanoparticles for controlled delivery of anticancer agents

    OpenAIRE

    Dinarvand, Rasoul

    2011-01-01

    R Dinarvand1,2, N Sepehri1, S Manoochehri1, H Rouhani1, F Atyabi1,21Department of Pharmaceutics, Faculty of Pharmacy, 2Nanotechnology Research Centre, Tehran University of Medical Sciences, Tehran, IranAbstract: The effectiveness of anticancer agents may be hindered by low solubility in water, poor permeability, and high efflux from cells. Nanomaterials have been used to enable drug delivery with lower toxicity to healthy cells and enhanced drug delivery to tumor cells. Different nanoparticle...

  6. Novel glyoxalase-I inhibitors possessing a “zinc-binding feature” as potential anticancer agents

    Directory of Open Access Journals (Sweden)

    Al-Balas QA

    2016-08-01

    Full Text Available Qosay A Al-Balas,1 Mohammad A Hassan,1 Nizar A Al-Shar’i,1 Nizar M Mhaidat,2 Ammar M Almaaytah,3 Fatima M Al-Mahasneh,1 Israa H Isawi1 1Department of Medicinal Chemistry and Pharmacognosy, 2Department of Clinical Pharmacy, 3Department of Pharmaceutical Technology, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan Background: The glyoxalase system including two thiol-dependent enzymes, glyoxalase I (Glo-I and glyoxalase II, plays an important role in a ubiquitous metabolic pathway involved in cellular detoxification of cytotoxic 2-oxoaldehydes. Tumor cells have high glycolytic activity, leading to increased cellular levels of these toxic metabolites. The increased activity of the detoxification system in cancerous cells makes this pathway a viable target for developing novel anticancer agents. In this study, we examined the potential utility of non-glutathione-based inhibitors of the Glo-I enzyme as novel anticancer drugs.Methods: Computer-aided drug design techniques, such as customized pharmacophoric features, virtual screening, and flexible docking, were used to achieve the project goals. Retrieved hits were extensively filtered and subsequently docked into the active site of the enzyme. The biological activities of retrieved hits were assessed using an in vitro assay against Glo-I.Results: Since Glo-I is a zinc metalloenzyme, a customized Zn-binding pharmacophoric feature was used to search for selective inhibitors via virtual screening of a small-molecule database. Seven hits were selected, purchased, and biologically evaluated. Three of the seven hits inhibited Glo-I activity, the most effective of which exerted 76.4% inhibition at a concentration of 25 µM.Conclusion: We successfully identified a potential Glo-I inhibitor that can serve as a lead compound for further optimization. Moreover, our in silico and experimental results were highly correlated. Hence, the docking protocol adopted in this study may

  7. Spectral and electrochemical detection of protonated triplex formation by a small-molecule anticancer agent

    Science.gov (United States)

    Feng, Lingyan; Li, Xi; Peng, Yinghua; Geng, Jie; Ren, Jinsong; Qu, Xiaogang

    2009-10-01

    Triplex helical formation has been the focus of considerable interest because of possible applications in developing new molecular biology tools as well as therapeutic agents and the possible relevance of H-DNA structures in biology system. We report here that a small-molecule anticancer agent, coralyne, has binding preference to the less stable protonated triplex d(C +-T) 6:d(A-G) 6·d(C-T) 6 over duplex d(A-G) 6·d(C-T) 6 and shows different spectral and electrochemical characteristics when binding to triplex and duplex DNA, indicating that electrochemical technique can detect the less stable protonated triplex formation.

  8. Medical applications of nanoparticles in biological imaging, cell labeling, antimicrobial agents, and anticancer nanodrugs.

    Science.gov (United States)

    Singh, Ravina; Nalwa, Hari Singh

    2011-08-01

    This article reviews the applications of nanotechnology in the fields of medical and life sciences. Nanoparticles have shown promising applications from diagnosis to treatment of various types of diseases including cancer. In this review, we discuss the applications of nanostructured materials such as nanoparticles, quantum dots, nanorods, nanowires, and carbon nanotubes in diagnostics, biomarkers, cell labeling, contrast agents for biological imaging, antimicrobial agents, drug delivery systems, and anticancer nanodrugs for treatment of cancer and other infectious diseases. The adverse affects of nanoparticles on human skin from daily use in cosmetics and general toxicology of nanoscale materials are also reviewed. PMID:21870454

  9. New 1,4-anthracene-9,10-dione derivatives as potential anticancer agents.

    Science.gov (United States)

    Zagotto, G; Supino, R; Favini, E; Moro, S; Palumbo, M

    2000-01-01

    The amino-substituted anthracene-9,10-dione (9,10-anthraquinone) derivatives represent one of the most important classes of potential anticancer agents. To better understand the basic rules governing DNA sequence specificity, we have recently synthesized a new class of D- and L-aminoacyl-anthraquinone derivatives. We have tested these new compounds as cytotoxic agents, and we have correlated their activity with the configuration of the chiral aminoacyl moiety. Molecular modeling studies have been performed to compare the test drugs in terms of steric overlapping. PMID:10755224

  10. Can Some Marine-Derived Fungal Metabolites Become Actual Anticancer Agents?

    Directory of Open Access Journals (Sweden)

    Nelson G. M. Gomes

    2015-06-01

    Full Text Available Marine fungi are known to produce structurally unique secondary metabolites, and more than 1000 marine fungal-derived metabolites have already been reported. Despite the absence of marine fungal-derived metabolites in the current clinical pipeline, dozens of them have been classified as potential chemotherapy candidates because of their anticancer activity. Over the last decade, several comprehensive reviews have covered the potential anticancer activity of marine fungal-derived metabolites. However, these reviews consider the term “cytotoxicity” to be synonymous with “anticancer agent”, which is not actually true. Indeed, a cytotoxic compound is by definition a poisonous compound. To become a potential anticancer agent, a cytotoxic compound must at least display (i selectivity between normal and cancer cells (ii activity against multidrug-resistant (MDR cancer cells; and (iii a preferentially non-apoptotic cell death mechanism, as it is now well known that a high proportion of cancer cells that resist chemotherapy are in fact apoptosis-resistant cancer cells against which pro-apoptotic drugs have more than limited efficacy. The present review thus focuses on the cytotoxic marine fungal-derived metabolites whose ability to kill cancer cells has been reported in the literature. Particular attention is paid to the compounds that kill cancer cells through non-apoptotic cell death mechanisms.

  11. Prediction of sensitivity to anticancer agents for patients with advanced or recurrent breast cancer by Tc-99m sestamibi

    International Nuclear Information System (INIS)

    Tc-99m Sestamibi (99mTc-MIBI) is known to be a substrate of P-glycoprotein (P-gp) that effluxes the drugs out of cancer cells. The overexpression of P-gp involved in multidrug resistance phenomenon in patients with advanced or recurrent breast cancers was shown in the plasma membrane of breast cancer cells. In this study, we examined the usefulness of 99mTc-MIBI scintigraphy for the prediction of sensitivity to anticancer agents in 8 cases with advanced or recurrent breast cancer. The retrospective analysis showed that the sensitivity to the chemotherapy could be evaluated in 3 cases by 99mTc-MIBI scintigraphy, but in the other 5 cases 99mTc-MIBI scintigraphy was not eligible for the prediction of sensitivity. Two out of 3 cases showed over 50% in reduction rate of target tumors (PR) with higher accumulation of 99mTc-MIBI, while another case with PD showed lower. These results suggest that the accumulation of 99mTc-MIBI could be associated with the sensitivity to P-gp-related anticancer agents, and that the functional analysis of P-gp by 99mTc-MIBI might be useful for the prediction of responsiveness of chemotherapy in patients with breast cancer. (author)

  12. Essential Oils and Their Constituents as Anticancer Agents: A Mechanistic View

    Directory of Open Access Journals (Sweden)

    Nandini Gautam

    2014-01-01

    Full Text Available Exploring natural plant products as an option to find new chemical entities as anticancer agents is one of the fastest growing areas of research. Recently, in the last decade, essential oils (EOs have been under study for their use in cancer therapy and the present review is an attempt to collect and document the available studies indicating EOs and their constituents as anticancer agents. This review enlists nearly 130 studies of EOs from various plant species and their constituents that have been studied so far for their anticancer potential and these studies have been classified as in vitro and in vivo studies for EOs and their constituents. This review also highlights in-depth various mechanisms of action of different EOs and their constituents reported in the treatment strategies for different types of cancer. The current review indicates that EOs and their constituents act by multiple pathways and mechanisms involving apoptosis, cell cycle arrest, antimetastatic and antiangiogenic, increased levels of reactive oxygen and nitrogen species (ROS/RNS, DNA repair modulation, and others to demonstrate their antiproliferative activity in the cancer cell. The effect of EOs and their constituents on tumour suppressor proteins (p53 and Akt, transcription factors (NF-κB and AP-1, MAPK-pathway, and detoxification enzymes like SOD, catalase, glutathione peroxidase, and glutathione reductase has also been discussed.

  13. Design and synthesis of novel 4'-demethyl-4-deoxypodophyllotoxin derivatives as potential anticancer agents.

    Science.gov (United States)

    Zhu, Xiong; Fu, Junjie; Tang, Yan; Gao, Yuan; Zhang, Shijin; Guo, Qinglong

    2016-02-15

    A group of podophyllotoxin (PPT) derivatives (7a-j) were synthesized by conjugating aryloxyacetanilide moieties to the 4'-hydroxyl of 4'-demethyl-4-deoxypodophyllotoxin (DDPT), and their anticancer activity was evaluated. It was found that the most potent compound 7d inhibited the proliferation of three cancer cell lines with sub to low micromolar IC50 values. Furthermore, it was demonstrated that 7d induced cell cycle arrest in G2/M phase in MGC-803 cells, and regulated the expression of cell cycle check point proteins, such as cyclin A, cyclin B, CDK1, cdc25c, and p21. Finally, 4 mg/kg of 7d reduced the weights and volumes of HepG2 xenografts in mice. Our findings suggest that 7d might be a potential anticancer agent. PMID:26804229

  14. Explanation of the mechanism of carcinogenesis and syntheses of anticancer agents with high selectivity

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    In 1979, the mechanism of chemical carcinogenesis, a challenging and difficult scientific problem pending for a number of years, was explained by Dai Qianhuan. The mechanism named di-region theory predicted that a carcinogen always metabolizes to form a special bi-functional alkylating agent. This agent induces cross-linkages between the complementary base pairs in DNA and switches on initial mutageneses in genomes including point and frameshift mutations. This, in turn, induces further deep mutageneses including the production of various chimeric chromosomes, deletions and other aberrations found in genomes. In the end this initiates carcinogenesis of the whole cell through the reverse transcription mechanism after a lengthy incubation period. Recently, this laboratory has verified that physical carcinogenesis, including the oncogenesis induced by radiation and asbestos as well as the carcinogenesis induced by endogenous factors such as estrogen or diethylstilbestrol switch on carcinogenesis by inducing the formation of cross-linkages between the complementary base pairs in DNA. Di-region theory has now been supported by many experimental observations such as mutational spectra of various carcinogens. The potential for carcinogenesis, teratogenesis, sterility and mutagenesis lumped together as genetic toxicity appears to originate almost uniformly from the cross-linking between complementary bases, i.e. malignant cross-linking, which is in accordance with di-region theory. Other forms of cross-linking between non-complementary bases, benign cross-linkings, show bi-functional alkylation anticancer activity but lack genetic toxicity. The predictable design and synthesis of a high selectivity anticancer agent with high efficacy and low genetic toxicity, a goal long pursued in cancer chemotherapy, have been realized for the first time in this laboratory by inhibiting malignant and heightening benign cross-linking using the principles of di-region theory. A series of

  15. Early clinical studies exploring new targets in anticancer treatment

    NARCIS (Netherlands)

    F.A.L.M. Eskens (Ferry)

    2001-01-01

    textabstractChemotherapy for cancer has always greatly relied upon the use of cytotoxic agents. These agents exert their activity in the process of nuclear DNA and RNA replication, and their activity in sensitive models leads to cell death and subsequent tumor shrinkage. Although a number of human t

  16. Association Between hTERT rs2736100 Polymorphism and Sensitivity to Anti-cancer Agents

    Directory of Open Access Journals (Sweden)

    Julie eKim

    2013-08-01

    Full Text Available Background: The rs2736100 single nucleotide polymorphism (SNP is located in the intron 2 of human telomerase reverse transcriptase (hTERT gene. Recent genome-wide association studies (GWAS have consistently supported the strong association between this SNP and risk for multiple cancers. Given the important role of the hTERT gene and this SNP in cancer biology, we hypothesize that rs2736100 may also confer susceptibility to anti-cancer drug sensitivity. In this study we aim to investigate the correlation between the rs2736100 genotype and the responsiveness to anti-cancer agents in the NCI-60 cancer cell panel. Methods and Materials: The hTERT rs2736100 was genotyped in the NCI-60 cancer cell lines. The relative telomere length of each cell line was quantified using real-time PCR. The genotype was then correlated with publically available drug sensitivity data of two agents with telomerase-inhibition activity: Geldanamycin (HSP90 inhibitor and RHPS4/BRACO19 (G-quadruplex stabilizer as well as additional 110 commonly used agents with established mechanism of action. The association between rs2736100 and mutation status of TP53 gene was also tested.Results: The C allele of the SNP was significantly correlated with increased sensitivity to RHPS4/BRACO19 with an additive effect (r=-0.35, p=0.009 but not with Geldanamycin. The same allele was also significantly associated with sensitivity to antimitotic agents compared to other agents (p=0.003. The highest correlation was observed between the SNP and paclitaxel (r=-0.36, p=0.005. The telomere length was neither associated with rs2736100 nor with sensitivity to anti-cancer agents. The C allele of rs2736100 was significantly associated with increased mutation rate in TP53 gene (p=0.004.Conclusion: Our data suggested that the cancer risk allele of hTERT rs2736100 polymorphism may also affect the cancer cell response to both TERT inhibitor and anti-mitotic agents, which might be attributed to the elevated

  17. The application of click chemistry in the synthesis of agents with anticancer activity

    Directory of Open Access Journals (Sweden)

    Ma N

    2015-03-01

    Full Text Available Nan Ma,1–3 Ying Wang,3 Bing-Xin Zhao,3 Wen-Cai Ye,1,3 Sheng Jiang2 1Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, 2Laboratory of Medicinal Chemistry, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 3Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Guangzhou, People’s Republic of China Abstract: The copper(I-catalyzed 1,3-dipolar cycloaddition between alkynes and azides (click chemistry to form 1,2,3-triazoles is the most popular reaction due to its reliability, specificity, and biocompatibility. This reaction has the potential to shorten procedures, and render more efficient lead identification and optimization procedures in medicinal chemistry, which is a powerful modular synthetic approach toward the assembly of new molecular entities and has been applied in anticancer drugs discovery increasingly. The present review focuses mainly on the applications of this reaction in the field of synthesis of agents with anticancer activity, which are divided into four groups: topoisomerase II inhibitors, histone deacetylase inhibitors, protein tyrosine kinase inhibitors, and antimicrotubule agents. Keywords: topoisomerase II inhibitors, histone deacetylase inhibitors, protein tyrosine kinase inhibitors, antimicrotubule agents

  18. Rosemary (Rosmarinus officinalis L.) Extract as a Potential Complementary Agent in Anticancer Therapy.

    Science.gov (United States)

    González-Vallinas, Margarita; Reglero, Guillermo; Ramírez de Molina, Ana

    2015-01-01

    Cancer remains an important cause of mortality nowadays and, therefore, new therapeutic approaches are still needed. Rosemary (Rosmarinus officinalis L.) has been reported to possess antitumor activities both in vitro and in animal studies. Some of these activities were attributed to its major components, such as carnosic acid, carnosol, ursolic acid, and rosmarinic acid. Initially, the antitumor effects of rosemary were attributed to its antioxidant activity. However, in recent years, a lack of correlation between antioxidant and antitumor effects exerted by rosemary was reported, and different molecular mechanisms were related to its tumor inhibitory properties. Moreover, supported by the U.S. Food and Drug Administration and the European Food and Safety Authority, specific compositions of rosemary extract were demonstrated to be safe for human health and used as antioxidant additive in foods, suggesting the potential easy application of this agent as a complementary approach in cancer therapy. In this review, we aim to summarize the reported anticancer effects of rosemary, the demonstrated molecular mechanisms related to these effects and the interactions between rosemary and currently used anticancer agents. The possibility of using rosemary extract as a complementary agent in cancer therapy in comparison with its isolated components is discussed. PMID:26452641

  19. The in vitro metabolism of phospho-sulindac amide, a novel potential anticancer agent

    OpenAIRE

    Xie, Gang; Cheng, Ka-Wing; Huang, Liqun; Rigas, Basil

    2014-01-01

    Phospho-sulindac amide (PSA) is a novel potential anti-cancer and anti-inflammatory agent. Here we report the metabolism of PSA in vitro. PSA was rapidly hydroxylated at its butane-phosphate moiety to form two di-hydroxyl-PSA and four mono-hydroxyl-PSA metabolites in mouse and human liver microsomes. PSA also can be oxidized or reduced at its sulindac moiety to form PSA sulfone and PSA sulfide, respectively. PSA was mono-hydroxylated and cleared more rapidly in mouse liver microsomes than in ...

  20. Investigation of Degradation Properties of Poly(lactide-co-glycolide) Matrix for Anticancer Agent Delivery

    International Nuclear Information System (INIS)

    Poly(lactide-co-glycolide)(PLA50GA50) is a biodegradable and biocompatible polymer. It offers tremendous potential as a basis for drug delivery, either as drug delivery system alone or in conjugate with a medical device. The PLA50GA50 is the material of choice for relatively shorter-duration applications, while the homopolymer PLA (poly-L-lactide) and PGA (polyglycolide) are preferred for longer term delivery of drugs. This paper discusses the degradation properties of poly(lactide-co-glycolide)(PLA50GA50) at inherent viscosity of 0.89 dL/g as preliminary studies for anticancer agent delivery.

  1. Multi-Agent Cooperative Target Search

    Directory of Open Access Journals (Sweden)

    Jinwen Hu

    2014-05-01

    Full Text Available This paper addresses a vision-based cooperative search for multiple mobile ground targets by a group of unmanned aerial vehicles (UAVs with limited sensing and communication capabilities. The airborne camera on each UAV has a limited field of view and its target discriminability varies as a function of altitude. First, by dividing the whole surveillance region into cells, a probability map can be formed for each UAV indicating the probability of target existence within each cell. Then, we propose a distributed probability map updating model which includes the fusion of measurement information, information sharing among neighboring agents, information decay and transmission due to environmental changes such as the target movement. Furthermore, we formulate the target search problem as a multi-agent cooperative coverage control problem by optimizing the collective coverage area and the detection performance. The proposed map updating model and the cooperative control scheme are distributed, i.e., assuming that each agent only communicates with its neighbors within its communication range. Finally, the effectiveness of the proposed algorithms is illustrated by simulation.

  2. 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

  3. Preclinical Investigations of PM01183 (Lurbinectedin) as a Single Agent or in Combination with Other Anticancer Agents for Clear Cell Carcinoma of the Ovary

    Science.gov (United States)

    Takahashi, Ryoko; Mabuchi, Seiji; Kawano, Mahiru; Sasano, Tomoyuki; Matsumoto, Yuri; Kuroda, Hiromasa; Kozasa, Katsumi; Hashimoto, Kae; Sawada, Kenjiro; Kimura, Tadashi

    2016-01-01

    Objective The objective of this study was to evaluate the antitumor effects of lurbinectedin as a single agent or in combination with existing anticancer agents for clear cell carcinoma (CCC) of the ovary, which is regarded as an aggressive, chemoresistant, histological subtype. Methods Using human ovarian CCC cell lines, the antitumor effects of lurbinectedin, SN-38, doxorubicin, cisplatin, and paclitaxel as single agents were assessed using the MTS assay. Then, the antitumor effects of combination therapies involving lurbinectedin and 1 of the other 4 agents were evaluated using isobologram analysis to examine whether these combinations displayed synergistic effects. The antitumor activity of each treatment was also examined using cisplatin-resistant and paclitaxel-resistant CCC sublines. Finally, we determined the effects of mTORC1 inhibition on the antitumor activity of lurbinectedin-based chemotherapy. Results Lurbinectedin exhibited significant antitumor activity toward chemosensitive and chemoresistant CCC cells in vitro. An examination of mouse CCC cell xenografts revealed that lurbinectedin significantly inhibits tumor growth. Among the tested combinations, lurbinectedin plus SN-38 resulted in a significant synergistic effect. This combination also had strong synergistic effects on both the cisplatin-resistant and paclitaxel-resistant CCC cell lines. Everolimus significantly enhanced the antitumor activity of lurbinectedin-based chemotherapies. Conclusions Lurbinectedin, a new agent that targets active transcription, exhibits antitumor activity in CCC when used as a single agent and has synergistic antitumor effects when combined with irinotecan. Our results indicate that lurbinectedin is a promising agent for treating ovarian CCC, both as a first-line treatment and as a salvage treatment for recurrent lesions that develop after platinum-based or paclitaxel treatment. PMID:26986199

  4. The Comparison of MTT and CVS Assays for the Assessment of Anticancer Agent Interactions.

    Directory of Open Access Journals (Sweden)

    Lidia Śliwka

    Full Text Available Multiple in vitro tests are widely applied to assess the anticancer activity of new compounds, including their combinations and interactions with other drugs. The MTT (3-(4,5-dimethylthiazol-2-yl-2,5-diphenyl tetrazolium bromide assay is one of the most commonly used assays to assess the efficacy and interactions of anticancer agents. However, it can be significantly influenced by compounds that modify cell metabolism and reaction conditions. Therefore, several assays are sometimes used to screen for potential anticancer drugs. However, the majority of drug interactions are evaluated only with this single method. The aim of our studies was to verify whether the choice of an assay has an impact on determining the type of interaction and to identify the source of discrepancies. We compared the accuracy of MTT and CVS (crystal violet staining assays in the interaction of two compounds characterized by similar anticancer activity: isothiocyanates (ITCs and Selol. Confocal microscopy studies were carried out to assess the influence of these compounds on the reactive oxygen species (ROS level, mitochondrial membrane potential, dead-to-live cell ratio and MTT-tetrazolium salt reduction rate. The MTT assay was less reliable than CVS. The MTT test of Selol and 2-oxoheptyl ITC, which affected the ROS level and MTT reduction rate, gave false negative (2-oxoheptyl ITC or false positive (Selol results. As a consequence, the MTT assay identified an antagonistic interaction between Selol and ITC, while the metabolism-independent CVS test identified an additive or synergistic interaction. In this paper, we show for the first time that the test assay may change the interpretation of the compound interaction. Therefore, the test method should be chosen with caution, considering the mechanism of action of the compound.

  5. The Comparison of MTT and CVS Assays for the Assessment of Anticancer Agent Interactions.

    Science.gov (United States)

    Śliwka, Lidia; Wiktorska, Katarzyna; Suchocki, Piotr; Milczarek, Małgorzata; Mielczarek, Szymon; Lubelska, Katarzyna; Cierpiał, Tomasz; Łyżwa, Piotr; Kiełbasiński, Piotr; Jaromin, Anna; Flis, Anna; Chilmonczyk, Zdzisław

    2016-01-01

    Multiple in vitro tests are widely applied to assess the anticancer activity of new compounds, including their combinations and interactions with other drugs. The MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay is one of the most commonly used assays to assess the efficacy and interactions of anticancer agents. However, it can be significantly influenced by compounds that modify cell metabolism and reaction conditions. Therefore, several assays are sometimes used to screen for potential anticancer drugs. However, the majority of drug interactions are evaluated only with this single method. The aim of our studies was to verify whether the choice of an assay has an impact on determining the type of interaction and to identify the source of discrepancies. We compared the accuracy of MTT and CVS (crystal violet staining) assays in the interaction of two compounds characterized by similar anticancer activity: isothiocyanates (ITCs) and Selol. Confocal microscopy studies were carried out to assess the influence of these compounds on the reactive oxygen species (ROS) level, mitochondrial membrane potential, dead-to-live cell ratio and MTT-tetrazolium salt reduction rate. The MTT assay was less reliable than CVS. The MTT test of Selol and 2-oxoheptyl ITC, which affected the ROS level and MTT reduction rate, gave false negative (2-oxoheptyl ITC) or false positive (Selol) results. As a consequence, the MTT assay identified an antagonistic interaction between Selol and ITC, while the metabolism-independent CVS test identified an additive or synergistic interaction. In this paper, we show for the first time that the test assay may change the interpretation of the compound interaction. Therefore, the test method should be chosen with caution, considering the mechanism of action of the compound. PMID:27196402

  6. Amino acid esters substituted phosphorylated emtricitabine and didanosine derivatives as antiviral and anticancer agents.

    Science.gov (United States)

    Sekhar, Kuruva Chandra; Janardhan, Avilala; Kumar, Yellapu Nanda; Narasimha, Golla; Raju, Chamarthi Naga; Ghosh, S K

    2014-07-01

    Owing to the promising antiviral activity of amino acid ester-substituted phosphorylated nucleosides in the present study, a series of phosphorylated derivatives of emtricitabine and didanosine substituted with bioactive amino acid esters at P-atom were synthesized. Initially, molecular docking studies were screened to predict their molecular interactions with hemagglutinin-neuraminidase protein of Newcastle disease virus and E2 protein of human papillomavirus. The title compounds were screened for their antiviral ability against Newcastle disease virus (NDV) by their in ovo study in embryonated chicken eggs. Compounds 5g and 9c exposed well mode of interactions with HN protein and also exhibited potential growth of NDV inhibition. The remaining compounds exhibited better growth of NDV inhibition than their parent molecules, i.e., emtricitabine (FTC) and didanosine (ddI). In addition, the in vitro anticancer activity of all the title compounds were screenedagainst HeLa cell lines at 10 and 100 μg/mL concentrations. The compounds 5g and 9c showed an effective anticancer activity than that of the remaining title compounds with IC50 values of 40 and 60 μg/mL, respectively. The present in silico and in ovo antiviral and in vitro anticancer results of the title compounds are suggesting that the amino acid ester-substituted phosphorylated FTC and ddI derivatives, especially 5g and 9c, can be used as NDV inhibitors and anticancer agents for the control and management of viral diseases with cancerous condition. PMID:24789416

  7. Nature promises new anticancer agents: Interplay with the apoptosis-related BCL2 gene family.

    Science.gov (United States)

    Christodoulou, Maria-Ioanna; Kontos, Christos K; Halabalaki, Maria; Skaltsounis, Alexios-Leandros; Scorilas, Andreas

    2014-03-01

    Natural products display special attributes in the treatment and prevention of a variety of human disorders including cancer. Their therapeutic capacities along with the fact that nature comprises a priceless pool of new compounds have attracted the interest of researchers worldwide. A significant number of organic compounds from terrestrial and marine organisms exhibit anticancer properties as attested by both in vitro and in vivo studies. Emerging evidence supporting the antineoplastic activity of natural compounds has rendered them promising agents in the fight against cancer. As a result, numerous natural compounds or their derivatives have entered clinical practice and are currently in the forefront of chemotherapeutics, showing beneficial effects for cancer patients. Induction of apoptosis seems to be the major mechanism of action induced by these natural agents in the race against cancer. This is mainly achieved through modulations of the expression of B-cell CLL/lymphoma 2 (BCL2) family members. These molecules appear to be the pivotal players determining cellular fate. In the current review, we provide a comprehensive overview of the major alterations in the gene and/or protein levels of BCL2-family members evoked in cancer cells after treatment with a gamut of natural compounds. The data cited suggest the need for exploitation of newly discovered natural products that, along with the improvement of currently employed chemotherapeutics, will significantly enrich the anticancer armamentarium. PMID:23848203

  8. Rational Combinations of Targeted Agents in AML

    Directory of Open Access Journals (Sweden)

    Prithviraj Bose

    2015-04-01

    Full Text Available Despite modest improvements in survival over the last several decades, the treatment of AML continues to present a formidable challenge. Most patients are elderly, and these individuals, as well as those with secondary, therapy-related, or relapsed/refractory AML, are particularly difficult to treat, owing to both aggressive disease biology and the high toxicity of current chemotherapeutic regimens. It has become increasingly apparent in recent years that coordinated interruption of cooperative survival signaling pathways in malignant cells is necessary for optimal therapeutic results. The modest efficacy of monotherapy with both cytotoxic and targeted agents in AML testifies to this. As the complex biology of AML continues to be elucidated, many “synthetic lethal” strategies involving rational combinations of targeted agents have been developed. Unfortunately, relatively few of these have been tested clinically, although there is growing interest in this area. In this article, the preclinical and, where available, clinical data on some of the most promising rational combinations of targeted agents in AML are summarized. While new molecules should continue to be combined with conventional genotoxic drugs of proven efficacy, there is perhaps a need to rethink traditional philosophies of clinical trial development and regulatory approval with a focus on mechanism-based, synergistic strategies.

  9. New testosterone derivatives as semi-synthetic anticancer agents against prostate cancer: synthesis and preliminary biological evaluation.

    Science.gov (United States)

    Morin, Nathalie; Bruneau, Julie; Fortin, Sebastien; Brasseur, Kevin; Leblanc, Valerie; Asselin, Eric; Berube, Gervais

    2015-01-01

    Prostate cancer (PC) is a major health issue in the world. Treatments of localized PC are quite efficient and usually involve surgery, radiotherapy and/or hormonal therapy. Metastatic PC is however rarely curable to this day. Treatments of metastatic PC involve radiotherapy, chemotherapy and hormonal treatment such as orchiectomy, antiandrogens and luteinizing hormone-releasing hormone agonists. The suppression of tumor growth by hormonal treatment is efficient but overtime resistance still occurs and the disease progresses. Thus, more urgently than ever there is a need for discovery of new treatment options for castration-resistant PC (CRPC). Hence, we designed and tested a series of amide derivatives located at position 7α of testosterone as prospective "natural" or "semisynthetic" anticancer agents against CRPC with the goal of discovering therapeutic alternatives for the disease. This manuscript describes an efficient path towards the target molecules that are made in only 6 or 7 chemical steps from testosterone in good overall yields. This strategy can be used to make several compounds of interest that present higher biological activity than the classic antiandrogen; cyproterone acetate (3). The best testosterone-7α-amide was the N-2-pyridylethylamide (25) which was as active as the antiandrogen cyproterone acetate (3) on androgen-dependent LNCaP cells and 2.7 times more active on androgen-independent PC3 prostate cancer cells. The results obtained show the synthetic feasibility and the potential for future development of this unique class of semi-synthetic anticancer agents that offer the premise of new treatment modalities for patients afflicted with CRPC. PMID:25675439

  10. Isatin Derived Spirocyclic Analogues with α-Methylene-γ-butyrolactone as Anticancer Agents: A Structure-Activity Relationship Study.

    Science.gov (United States)

    Rana, Sandeep; Blowers, Elizabeth C; Tebbe, Calvin; Contreras, Jacob I; Radhakrishnan, Prakash; Kizhake, Smitha; Zhou, Tian; Rajule, Rajkumar N; Arnst, Jamie L; Munkarah, Adnan R; Rattan, Ramandeep; Natarajan, Amarnath

    2016-05-26

    Design, synthesis, and evaluation of α-methylene-γ-butyrolactone analogues and their evaluation as anticancer agents is described. SAR identified a spirocyclic analogue 19 that inhibited TNFα-induced NF-κB activity, cancer cell growth and tumor growth in an ovarian cancer model. A second iteration of synthesis and screening identified 29 which inhibited cancer cell growth with low-μM potency. Our data suggest that an isatin-derived spirocyclic α-methylene-γ-butyrolactone is a suitable core for optimization to identify novel anticancer agents. PMID:27077228

  11. 2-Hydroxypropyl-β-Cyclodextrin Acts as a Novel Anticancer Agent.

    Directory of Open Access Journals (Sweden)

    Masako Yokoo

    Full Text Available 2-Hydroxypropyl-β-cyclodextrin (HP-β-CyD is a cyclic oligosaccharide that is widely used as an enabling excipient in pharmaceutical formulations, but also as a cholesterol modifier. HP-β-CyD has recently been approved for the treatment of Niemann-Pick Type C disease, a lysosomal lipid storage disorder, and is used in clinical practice. Since cholesterol accumulation and/or dysregulated cholesterol metabolism has been described in various malignancies, including leukemia, we hypothesized that HP-β-CyD itself might have anticancer effects. This study provides evidence that HP-β-CyD inhibits leukemic cell proliferation at physiologically available doses. First, we identified the potency of HP-β-CyD in vitro against various leukemic cell lines derived from acute myeloid leukemia (AML, acute lymphoblastic leukemia and chronic myeloid leukemia (CML. HP-β-CyD treatment reduced intracellular cholesterol resulting in significant leukemic cell growth inhibition through G2/M cell-cycle arrest and apoptosis. Intraperitoneal injection of HP-β-CyD significantly improved survival in leukemia mouse models. Importantly, HP-β-CyD also showed anticancer effects against CML cells expressing a T315I BCR-ABL mutation (that confers resistance to most ABL tyrosine kinase inhibitors, and hypoxia-adapted CML cells that have characteristics of leukemic stem cells. In addition, colony forming ability of human primary AML and CML cells was inhibited by HP-β-CyD. Systemic administration of HP-β-CyD to mice had no significant adverse effects. These data suggest that HP-β-CyD is a promising anticancer agent regardless of disease or cellular characteristics.

  12. Biological agents targeting beyond TNF-alpha

    Directory of Open Access Journals (Sweden)

    Sharma Rashmi

    2008-01-01

    Full Text Available Biological agents represent an important addition to the therapies for immuno-inflammatory conditions and have a great impact on the disease course and quality of life of these patients. However, recent reports of serious infections like tuberculosis, demyelinating and neurodegenerative diseases, pancytopenia, cardiovascular diseases, etc. after anti-TNF therapy raised questions on their safety. Hence, focus is shifted towards drugs targeting cytokine checkpoints in the inflammatory cascades beyond TNF-a. Existing therapeutic targets include the biological agents acting as antagonists of various inflammatory cytokines (Anakinra, Tocilizumab, Atlizumab and modulators of CD80 or CD86-CD28 co-stimulatory signal (Abatacept, CD2 receptors on T-cells (Alefacept, CD11a, subunit of leukocyte function-associated antigen 1 (Efalizumab, vitronectin receptor and CD20 antigen on pre-B, immature and mature B cells (Rituximab. With the introduction of these novel molecules the future for immunomodulatory intervention in rheumatology, asthma, crohn′s disease, septic shock etc. looks very promising. These novel therapeutic agents could truly give a new hope to the clinician to modify the disease and achieve tangible improvements in the lives of the patients.

  13. Histone lysine demethylases as targets for anticancer therapy

    DEFF Research Database (Denmark)

    Højfeldt, Jonas W; Agger, Karl; Helin, Kristian

    2013-01-01

    interesting drug targets. The successful introduction of DNA methylation and histone deacetylase (HDAC) inhibitors for the treatment of specific subtypes of cancer has paved the way for the use of epigenetic therapy. Here, we highlight key biological findings demonstrating the roles of members of the histone...

  14. A translational study “case report” on the small molecule “energy blocker” 3-bromopyruvate (3BP) as a potent anticancer agent: from bench side to bedside

    NARCIS (Netherlands)

    Ko, Y.H.; Verhoeven, H.A.; Lee, M.J.; Corbin, D.J.; Vogl, T.J.; Pedersen, P.L.

    2012-01-01

    The small alkylating molecule, 3-bromopyruvate (3BP), is a potent and specific anticancer agent. 3BP is different in its action from most currently available chemo-drugs. Thus, 3BP targets cancer cells’ energy metabolism, both its high glycolysis (“Warburg Effect”) and mitochondrial oxidative phosph

  15. 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. ...

  16. 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...

  17. Cell Targeting in Anti-Cancer Gene Therapy

    OpenAIRE

    Lila, Mohd Azmi Mohd; Siew, John Shia Kwong; Zakaria, Hayati; Saad, Suria Mohd; Ni, Lim Shen; Abdullah, Jafri Malin

    2004-01-01

    Gene therapy is a promising approach towards cancer treatment. The main aim of the therapy is to destroy cancer cells, usually by apoptotic mechanisms, and preserving others. However, its application has been hindered by many factors including poor cellular uptake, non-specific cell targeting and undesirable interferences with other genes or gene products. A variety of strategies exist to improve cellular uptake efficiency of gene-based therapies. This paper highlights advancements in gene th...

  18. Targeted alpha anticancer therapies: update and future prospects

    Directory of Open Access Journals (Sweden)

    Allen BJ

    2014-11-01

    Full Text Available Barry J Allen,1,2 Chen-Yu Huang,3 Raymond A Clarke2 1Faculty of Physics, University of Sydney, Sydney, NSW, Australia; 2Faculty of Medicine, Ingham Institute, University of Western Sydney, Liverpool, NSW, Australia; 3Central Clinical School, University of Sydney, Sydney, NSW, AustraliaAbstract: Targeted alpha therapy (TAT is an emerging option for local and systemic cancer treatment. Preclinical research and clinical trials show that alpha-emitting radionuclides can kill targeted cancer cells while sparing normal cells, thus reducing toxicity. 223RaCl2 (Xofigo® is the first alpha emitting radioisotope to gain registration in the US for palliative therapy of prostate cancer bone metastases by indirect physiological targeting. The alpha emitting radioisotopes 211At, 213Bi, 225Ac and 227Th are being used to label targeting vectors such as monoclonal antibodies for specific cancer therapy indications. In this review, safety and tolerance aspects are considered with respect to microdosimetry, specific energy, Monte Carlo model calculations, biodosimetry, equivalent dose and mutagenesis. The clinical efficacy of TAT for solid tumors may also be enhanced by its capacity for tumor anti-vascular (TAVAT effects. This review emphasizes key aspects of TAT research with respect to the PAI2-uPAR complex and the monoclonal antibodies bevacizumab, C595 and J591. Clinical trial outcomes are reviewed for neuroendocrine tumors, leukemia, glioma, melanoma, non-Hodgkins lymphoma, and prostate bone metastases. Recommendations and future directions are proposed.Keywords: biodosimetry, microdosimetry, mutagenesis, PAI2, bevacizumab, C595, J591, tumors, cancer, metastases

  19. Targeting protein-protein interactions as an anticancer strategy

    OpenAIRE

    Ivanov, Andrei A.; Khuri, Fadlo R.; Fu, Haian

    2013-01-01

    The emergence and convergence of cancer genomics, targeted therapies, and network oncology have significantly expanded the landscape of protein-protein interaction (PPI) networks in cancer for therapeutic discovery. Extensive biological and clinical investigations have led to the identification of protein interaction hubs and nodes that are critical for the acquisition and maintaining characteristics of cancer essential for cell transformation. Such cancer enabling PPIs have become promising ...

  20. Honey as a Potential Natural Anticancer Agent: A Review of Its Mechanisms

    Directory of Open Access Journals (Sweden)

    Sarfraz Ahmed

    2013-01-01

    Full Text Available The main treatment for cancer is by using chemotherapy and radiotherapy which themselves are toxic to other viable cells of the body. Recently, there are many studies focusing on the use of natural products for cancer prevention and treatment. Of these natural products, honey has been extensively researched. The mechanism of the anti-cancer activity of honey as chemopreventive and therapeutic agent has not been completely understood. The possible mechanisms are due to its apoptotic, antiproliferative, antitumor necrosis factor (anti-TNF, antioxidant, anti-inflammatory, estrogenic and immunomodulatory activities. We collate the findings of several studies published in the literature in order to understand the mechanism of its action.

  1. A Possible Anticancer Agent, Type III Interferon, Activates Cell Death Pathways and Produces Antitumor Effects

    Directory of Open Access Journals (Sweden)

    Masatoshi Tagawa

    2011-01-01

    Full Text Available Recently identified interleukin-28 and -29 belong to a novel type III interferon (IFN family, which could have distinct biological properties from type I and II IFNs. Type I IFNs, IFN-α/β, have been clinically applied for treating a certain kind of malignancies for over 30 years, but a wide range of the adverse effects hampered the further clinical applications. Type III IFNs, IFN-λs, have similar signaling pathways as IFN-α/β and inhibits proliferation of tumor cells through cell cycle arrest or apoptosis. Restricted patterns of type III IFN receptor expression in contrast to ubiquitously expressed IFN-α/β receptors suggest that type III IFNs have limited cytotoxicity to normal cells and can be a possible anticancer agent. In this paper, we summarize the current knowledge on the IFN-λs-mediated tumor cell death and discuss the functional difference between type I and III IFNs.

  2. Lesson Learned from Nature for the Development of Novel Anti-Cancer Agents: Implication of Isoflavone, Curcumin, and their Synthetic Analogs

    OpenAIRE

    Sarkar, Fazlul H; Li, Yiwei; Wang, Zhiwei; Padhye, Subhash

    2010-01-01

    In recent years, naturally occurring dietary compounds have received greater attention in the field of cancer prevention and treatment research. Among them, isoflavone genistein and curcumin are very promising anti-cancer agents because of their non-toxic and potent anti-cancer properties. However, it is important to note that the low water solubility, poor in vivo bioavailability and unacceptable pharmacokinetic profile of these natural compounds limit their efficacy as anti-cancer agents fo...

  3. Synthesis and in vitro evaluation of novel triazine analogues as anticancer agents and their interaction studies with bovine serum albumin.

    Science.gov (United States)

    Singla, Prinka; Luxami, Vijay; Paul, Kamaldeep

    2016-07-19

    A novel series of triazine-benzimidazole analogs has been designed and synthesized for their in vitro anticancer activities. Four compounds (6, 16, 17 and 20) were identified as highly potent anticancer agents against 60 human cancer cell lines with GI50 in the nanomolar range. To improve the drug applications toward cancer cells, there is a need to couple these compounds to some carrier macromolecules. Following this approach, the interaction between triazine-benzimidazole analogues and bovine serum albumin (BSA) has been investigated with UV-Visible and fluorescence spectroscopic methods under physiological conditions. The observed fluorescence quenching indicates that these compounds could efficiently bind with BSA and be transported to the target site. PMID:27089212

  4. ADAM10 as a target for anti-cancer therapy.

    Science.gov (United States)

    Moss, Marcia L; Stoeck, Alexander; Yan, Wenbo; Dempsey, Peter J

    2008-02-01

    There is a great unmet medical need in the area of cancer treatment. A potential therapeutic target for intervention in cancer is ADAM10. ADAM10 is a disintegrin-metalloproteinase that processes membrane bound proteins from the cell surface to yield soluble forms. Pharmaceutical companies are actively seeking out inhibitors of ADAM10 for treatments in cancer as the enzyme is known to release the ErbB receptor, HER2/ErbB2 from the cell membrane, an event that is necessary for HER2 positive tumor cells to proliferate. ADAM10 is also capable of processing betacellulin indicating that an inhibitor could be used against EGFR/ErbB1 and/or HER4/ErbB4 receptor positive tumor cells that are betacellulin-dependent. ADAM10 is the principle sheddase for several other molecules associated with cancer proliferation, differentiation, adhesion and migration such as Notch, E-cadherin, CD44 and L1 adhesion molecule indicating that targeting ADAM10 with specific inhibitors could be beneficial. PMID:18289051

  5. Application of CellDesigner to the Selection of Anticancer Drug Targets: Test Case using P53

    OpenAIRE

    Isea, Raul; Hoebeke, Johan; Mayo, Rafael; Alvarez, Fernando; Holmes, David S.

    2013-01-01

    Cancer is a disease involving many genes, consequently it has been difficult to design anticancer drugs that are efficacious over a broad range of cancers. The robustness of cellular responses to gene knockout and the need to reduce undesirable side effects also contribute to the problem of effective anti-cancer drug design. To promote the successful selection of drug targets, each potential target should be subjected to a systems biology scrutiny to locate effective and specific targets whil...

  6. Novel microtubule-targeting agents – the epothilones

    Directory of Open Access Journals (Sweden)

    Daniel R Budman

    2008-10-01

    Full Text Available Kit L Cheng, Thomas Bradley, Daniel R Budman1Monter Cancer Center, North Shore – LIJ Health Systems, Lake Success, New York, USAAbstract: Epothilones are a new class of antimicrotubule agents currently in clinical trials. Their chemical structures are distinct from taxanes and are more amenable to synthetic modification. Six epothilones have been studied in preclinical and clinical trials: patupilone (epothilone B, ixabepilone (BMS247550, BMS 310705, sagopilone (ZK-EPO, KOS-862 (epothilone D, and KOS-1584. In vitro data have shown increased potency in taxane-sensitive and taxane-resistant cancer cell lines. This enhanced cytotoxic effect has been attributed to epothilone being a poor substrate for p-glycoprotein drug resistance protein and having high affinity to the various β tubulin isoforms. Phase I clinical data have shown different dose-limiting toxicities for each of the epothilones. These effects are drug specific, dose specific, and schedule of administration specific. While diarrhea and myelosuppression are the dose-limiting toxicities for patupilone and BMS 310705, respectively, neurologic toxicity, as seen with taxanes, is the dose-limiting toxicity of ixabepilone, sagopilone, and KOS-862. In an effort to decrease neurologic toxicity, investigators have modified dosing schedules with limited success. Ixabepilone has the most mature clinical results with published phase II and III data, and regulatory approval for clinical use in the treatment of breast cancer. Ixabepilone has also been combined with other anticancer agents and has regulatory approval in combination with capecitabine for heavily treated breast cancer.Keywords: microtubule-targeting agents, epothilones, taxanes, ixabepilone

  7. Targeting targeted agents: open issues for clinical trial design

    Directory of Open Access Journals (Sweden)

    Giannarelli Diana

    2009-05-01

    Full Text Available Abstract Molecularly targeted agents for the treatment of solid tumors had entered the market in the last 5 years, with a great impact upon both the scientific community and the society. Many randomized phase III trials conducted in recent years with new targeted agents, despite previous data coming from preclinical research and from phase II trials were often promising, have produced disappointingly negative results. Some other trials have actually met their primary endpoint, demonstrating a statistically significant result favouring the experimental treatment. Unfortunately, with a few relevant exceptions, this advantage is often small, if not negligible, in absolute terms. The difference between statistical significance and clinical relevance should always be considered when translating clinical trials' results in the practice. The reason why this 'revolution' did not significantly impact on cancer treatment to displace chemotherapy from the patient' bedside is in part due to complicated, and in many cases, unknown, mechanisms of action of such drugs; indeed, the traditional way the clinical investigators were used to test the efficacy of 'older' chemotherapeutics, has become 'out of date' from the methodological perspective. As these drugs should be theoretically tailored upon featured bio-markers expressed by the patients, the clinical trial design should follow new rules based upon stronger hypotheses than those developed so far. Indeed, the early phases of basic and clinical drug development are crucial in the correct process which is able to correctly identify the target (when present. Targeted trial designs can result in easier studies, with less, better selected, and supported by stronger proofs of response evidences, patients, in order to not waste time and resources.

  8. Design of targeted B cell killing agents.

    Directory of Open Access Journals (Sweden)

    Alexey V Stepanov

    Full Text Available B cells play an important role in the pathogenesis of both systemic and organ-specific autoimmune diseases. Autoreactive B cells not only produce autoantibodies, but also are capable to efficiently present specific autoantigens to T cells. Furthermore, B cells can secrete proinflammatory cytokines and amplify the vicious process of self-destruction. B cell-directed therapy is a potentially important approach for treatment of various autoimmune diseases. The depletion of B cells by anti-CD20/19 monoclonal antibody Retuximab® used in autoimmune diseases therapy leads to systemic side effects and should be significantly improved. In this study we designed a repertoire of genetically engineered B cell killers that specifically affected one kind of cells carrying a respective B cell receptor. We constructed immunotoxins (ITs, fused with c-myc epitope as a model targeting sequence, based on barnase, Pseudomonas toxin, Shiga-like toxin E.coli and Fc domain of human antibody IgGγ1. C-MYC hybridoma cell line producing anti-c-myc IgG was chosen as a model for targeted cell depletion. C-myc sequence fused with toxins provided addressed delivery of the toxic agent to the target cells. We demonstrated functional activity of designed ITs in vitro and showed recognition of the fusion molecules by antibodies produced by targeted hybridoma. To study specificity of the proposed B cells killing molecules, we tested a set of created ITs ex vivo, using C-MYC and irrelevant hybridoma cell lines. Pseudomonas-containing IT showed one of the highest cytotoxic effects on the model cells, however, possessed promiscuous specificity. Shiga-like toxin construct demonstrated mild both cytotoxicity and specificity. Barnase and Fc-containing ITs revealed excellent balance between their legibility and toxic properties. Moreover, barnase and Fc molecules fused with c-myc epitope were able to selectively deplete c-myc-specific B cells and decrease production of anti

  9. Design, Synthesis, and Biological Evaluation of Novel Selenium (Se-NSAID) Molecules as Anticancer Agents.

    Science.gov (United States)

    Plano, Daniel; Karelia, Deepkamal N; Pandey, Manoj K; Spallholz, Julian E; Amin, Shantu; Sharma, Arun K

    2016-03-10

    The synthesis and anticancer evaluation of novel selenium-nonsteroidal anti-inflammatory drug (Se-NSAID) hybrid molecules are reported. The Se-aspirin analogue 8 was identified as the most effective agent in reducing the viability of different cancer cell lines, particularly colorectal cancer (CRC) cells, was more selective toward cancer cells than normal cells, and was >10 times more potent than 5-FU, the current therapy for CRC. Compound 8 inhibits CRC growth via the inhibition of the cell cycle in G1 and G2/M phases and reduces the cell cycle markers like cyclin E1 and B1 in a dose dependent manner; the inhibition of the cell cycle may be dependent on the ability of 8 to induce p21 expression. Furthermore, 8 induces apoptosis by activating caspase 3/7 and PARP cleavage, and its longer exposure causes increase in intracellular ROS levels in CRC cells. Taken together, 8 has the potential to be developed further as a chemotherapeutic agent for CRC. PMID:26750401

  10. Landscape of Targeted Anti-Cancer Drug Synergies in Melanoma Identifies a Novel BRAF-VEGFR/PDGFR Combination Treatment.

    Directory of Open Access Journals (Sweden)

    Adam A Friedman

    Full Text Available A newer generation of anti-cancer drugs targeting underlying somatic genetic driver events have resulted in high single-agent or single-pathway response rates in selected patients, but few patients achieve complete responses and a sizeable fraction of patients relapse within a year. Thus, there is a pressing need for identification of combinations of targeted agents which induce more complete responses and prevent disease progression. We describe the results of a combination screen of an unprecedented scale in mammalian cells performed using a collection of targeted, clinically tractable agents across a large panel of melanoma cell lines. We find that even the most synergistic drug pairs are effective only in a discrete number of cell lines, underlying a strong context dependency for synergy, with strong, widespread synergies often corresponding to non-specific or off-target drug effects such as multidrug resistance protein 1 (MDR1 transporter inhibition. We identified drugs sensitizing cell lines that are BRAFV600E mutant but intrinsically resistant to BRAF inhibitor PLX4720, including the vascular endothelial growth factor receptor/kinase insert domain receptor (VEGFR/KDR and platelet derived growth factor receptor (PDGFR family inhibitor cediranib. The combination of cediranib and PLX4720 induced apoptosis in vitro and tumor regression in animal models. This synergistic interaction is likely due to engagement of multiple receptor tyrosine kinases (RTKs, demonstrating the potential of drug- rather than gene-specific combination discovery approaches. Patients with elevated biopsy KDR expression showed decreased progression free survival in trials of mitogen-activated protein kinase (MAPK kinase pathway inhibitors. Thus, high-throughput unbiased screening of targeted drug combinations, with appropriate library selection and mechanistic follow-up, can yield clinically-actionable drug combinations.

  11. Cultivation and utility of Piptoporus betulinus fruiting bodies as a source of anticancer agents.

    Science.gov (United States)

    Pleszczyńska, Małgorzata; Wiater, Adrian; Siwulski, Marek; Lemieszek, Marta K; Kunaszewska, Justyna; Kaczor, Józef; Rzeski, Wojciech; Janusz, Grzegorz; Szczodrak, Janusz

    2016-09-01

    Piptoporus betulinus is a wood-rotting basidiomycete used in medicine and biotechnology. However, to date, no indoor method for cultivation of this mushroom fruiting bodies has been developed. Here we present the first report of successful production of P. betulinus mature fruiting bodies in artificial conditions. Four P. betulinus strains were isolated from natural habitats and their mycelia were inoculated into birch sawdust substrate supplemented with organic additives. All the strains effectively colonized the medium but only one of them produced fruiting bodies. Moisture and organic supplementation of the substrate significantly determined the fruiting process. The biological efficiency of the P. betulinus PB01 strain cultivated on optimal substrate (moisture and organic substance content of 55 and 65 and 25 or 35 %, respectively) ranged from 12 to 16 %. The mature fruiting bodies reached weight in the range from 50 to 120 g. Anticancer properties of water and ethanol extracts isolated from both cultured and nature-derived fruiting bodies of P. betulinus were examined in human colon adenocarcinoma, human lung carcinoma and human breast cancer cell lines. The studies revealed antiproliferative and antimigrative properties of all the investigated extracts. Nevertheless the most pronounced effects demonstrated the ethanol extracts, obtained from fruiting bodies of cultured P. betulinus. Summarizing, our studies proved that P. betulinus can be induced to fruit in indoor artificial culture and the cultured fruiting bodies can be used as a source of potential anticancer agents. In this respect, they are at least as valuable as those sourced from nature. PMID:27465851

  12. Hematotoxicity response in rats by the novel copper-based anticancer agent: casiopeina II

    International Nuclear Information System (INIS)

    The in vivo toxicity of the novel copper-based anticancer agent, casiopeina II (Cu(4,7-dimethyl-1,10-phenanthroline)(glycine)NO3) (CII), was investigated. Casiopeinas are a family of copper-coordinated complexes that have shown promising anticancer activity. The major toxic effect attributed to a single i.v. administration of CII (5 mg/kg dose) in the rat was an hemolytic anemia (reduced hemoglobin concentration (HB), red blood cell (RBC) count and packed cell volume (PCV) accompanied by a marked neutrophilic leukocytosis) 12 h and 5 days after administration, attributed to a direct erythrocyte damage. Increased reticulocyte levels and presence of normoblasts in peripheral blood 5 days post-administration indicated an effective erythropoietic response with recovery at 15 days. Increase in spleen weight and the morphological evidence of congestion of the red pulp (RP) with erythrocytes (E) resulting in a higher ratio of red to white pulp (WP) was consistent with increased uptake of damaged erythrocytes by the reticuloendothelial system observed by histopathology and electron microscopy. Extramedullary hemopoiesis was markedly increased at 5 days giving further evidence of a regenerative erythropoietic response that had an effective recovery by 15 days. Morphological changes in spleen cellularity were consistent with hematotoxicity, mainly a reduction of the red pulp/white pulp ratio, increase in erythrocyte content at 12 h, and an infiltration of nucleated cells in the red pulp at 5 days, with a tendency towards recovery 15 days after administration. The erythrocyte damage is attributed to generation of free radicals and oxidative damage on the membrane and within cells resulting from the reduction of Cu(II) and the probable dissociation of the CII complex

  13. Recent advances in targeting the telomeric G-quadruplex DNA sequence with small molecules as a strategy for anticancer therapies.

    Science.gov (United States)

    Islam, Mohammad K; Jackson, Paul Jm; Rahman, Khondaker M; Thurston, David E

    2016-07-01

    Human telomeric DNA (hTelo), present at the ends of chromosomes to protect their integrity during cell division, comprises tandem repeats of the sequence d(TTAGGG) which is known to form a G-quadruplex secondary structure. This unique structural formation of DNA is distinct from the well-known helical structure that most genomic DNA is thought to adopt, and has recently gained prominence as a molecular target for new types of anticancer agents. In particular, compounds that can stabilize the intramolecular G-quadruplex formed within the human telomeric DNA sequence can inhibit the activity of the enzyme telomerase which is known to be upregulated in tumor cells and is a major contributor to their immortality. This provides the basis for the discovery and development of small molecules with the potential for selective toxicity toward tumor cells. This review summarizes the various families of small molecules reported in the literature that have telomeric quadruplex stabilizing properties, and assesses the potential for compounds of this type to be developed as novel anticancer therapies. A future perspective is also presented, emphasizing the need for researchers to adopt approaches that will allow the discovery of molecules with more drug-like properties in order to improve the chances of lead molecules reaching the clinic in the next decade. PMID:27442231

  14. Repurposing Drugs in Oncology (ReDO)—diclofenac as an anti-cancer agent

    Science.gov (United States)

    Pantziarka, Pan; Sukhatme, Vidula; Bouche, Gauthier; Meheus, Lydie; Sukhatme, Vikas P

    2016-01-01

    Diclofenac (DCF) is a well-known and widely used non-steroidal anti-inflammatory drug (NSAID), with a range of actions which are of interest in an oncological context. While there has long been an interest in the use of NSAIDs in chemoprevention, there is now emerging evidence that such drugs may have activity in a treatment setting. DCF, which is a potent inhibitor of COX-2 and prostaglandin E2 synthesis, displays a range of effects on the immune system, the angiogenic cascade, chemo- and radio-sensitivity and tumour metabolism. Both pre-clinical and clinical evidence of these effects, in multiple cancer types, is assessed and summarised and relevant mechanisms of action outlined. Based on this evidence the case is made for further clinical investigation of the anticancer effects of DCF, particularly in combination with other agents - with a range of possible multi-drug and multi-modality combinations outlined in the supplementary materials accompanying the main paper. PMID:26823679

  15. Repurposing Drugs in Oncology (ReDO)-diclofenac as an anti-cancer agent.

    Science.gov (United States)

    Pantziarka, Pan; Sukhatme, Vidula; Bouche, Gauthier; Meheus, Lydie; Sukhatme, Vikas P

    2016-01-01

    Diclofenac (DCF) is a well-known and widely used non-steroidal anti-inflammatory drug (NSAID), with a range of actions which are of interest in an oncological context. While there has long been an interest in the use of NSAIDs in chemoprevention, there is now emerging evidence that such drugs may have activity in a treatment setting. DCF, which is a potent inhibitor of COX-2 and prostaglandin E2 synthesis, displays a range of effects on the immune system, the angiogenic cascade, chemo- and radio-sensitivity and tumour metabolism. Both pre-clinical and clinical evidence of these effects, in multiple cancer types, is assessed and summarised and relevant mechanisms of action outlined. Based on this evidence the case is made for further clinical investigation of the anticancer effects of DCF, particularly in combination with other agents - with a range of possible multi-drug and multi-modality combinations outlined in the supplementary materials accompanying the main paper. PMID:26823679

  16. Microencapsulation of lectin anti-cancer agent and controlled release by alginate beads, biosafety approach.

    Science.gov (United States)

    El-Aassar, M R; Hafez, Elsayed E; El-Deeb, Nehal M; Fouda, Moustafa M G

    2014-08-01

    Hepatocellular carcinoma (HCC) is considered as one of the most aggressive cancer worldwide. In Egypt, the prevalence of HCC is increasing during last years. Recently, drug-loaded microparticles were used to improve the efficiency of various medical treatments. This study is designed to evaluate the anticancer potentialities of lectins against HCC while hinting to its safety usage. The aim is also extended to encapsulate lectins in alginate microbeads for oral drug delivery purposes. The extracted lectins showed anti-proliferative effect against HCC with a percentage of 60.76% by using its nontoxic dose with an up-regulation of P53 gene expression. Concerning the handling of lectin alginate microbeads for oral drug delivery, the prepared lectin alginate beads were ∼100μm in diameter. The efficiency of the microcapsules was checked by scanning electron microscopy, the SEM showed the change on the alginate beads surface revealing the successful lectin encapsulation. The release of lectins from the microbeads depended on a variety of factors as the microbeads forming carriers and the amount-encapsulated lectins. The Pisum sativum extracted lectins may be considered as a promising agent in controlling HCC and this solid dosage form could be suitable for oral administration complemented with/or without the standard HCC drugs. PMID:24857870

  17. Synthesis and biological evaluation of new naphthalene substituted thiosemicarbazone derivatives as potent antifungal and anticancer agents.

    Science.gov (United States)

    Altıntop, Mehlika Dilek; Atlı, Özlem; Ilgın, Sinem; Demirel, Rasime; Özdemir, Ahmet; Kaplancıklı, Zafer Asım

    2016-01-27

    New thiosemicarbazone derivatives (1-10) were obtained via the reaction of 4-(naphthalen-1-yl)thiosemicarbazide with fluoro-substituted aromatic aldehydes. The synthesized compounds were evaluated for their in vitro antifungal effects against pathogenic yeasts and molds using broth microdilution assay. Ames and umuC assays were carried out to determine the genotoxicity of the most effective antifungal derivatives. Furthermore, all compounds were evaluated for their cytotoxic effects on A549 human lung adenocarcinoma and NIH/3T3 mouse embryonic fibroblast cell lines using XTT test. Among these derivatives, 4-(naphthalen-1-yl)-1-(2,3-difluorobenzylidene)thiosemicarbazide (1) and 4-(naphthalen-1-yl)-1-(2,5-difluorobenzylidene)thiosemicarbazide (3) can be identified as the most promising antifungal derivatives due to their notable inhibitory effects on Candida species and no cytotoxicity against NIH/3T3 mouse embryonic fibroblast cell line. According to Ames and umuC assays, compounds 1 and 3 were classified as non-mutagenic compounds. On the other hand, 4-(naphthalen-1-yl)-1-(2,4-difluorobenzylidene)thiosemicarbazide (2) can be considered as the most promising anticancer agent against A549 cell line owing to its notable inhibitory effect on A549 cells with an IC50 value of 31.25 μg/mL when compared with cisplatin (IC50 = 16.28 μg/mL) and no cytotoxicity against NIH/3T3 cells. PMID:26706351

  18. Recent developments in l-asparaginase discovery and its potential as anticancer agent.

    Science.gov (United States)

    Shrivastava, Abhinav; Khan, Abdul Arif; Khurshid, Mohsin; Kalam, Mohd Abul; Jain, Sudhir K; Singhal, Pradeep K

    2016-04-01

    l-Asparaginase (EC3.5.1.1) is an enzyme, which is used for treatment of acute lymphoblastic leukaemia (ALL) and other related blood cancers from a long time. This enzyme selectively hydrolyzes the extracellular amino acid l-asparagine into l-aspartate and ammonia, leading to nutritional deficiencies, protein synthesis inhibition, and ultimately death of lymphoblastic cells by apoptosis. Currently, bacterial asparaginases are used for treatment purpose but offers scepticism due to a number of toxicities, including thrombosis, pancreatitis, hyperglycemia, and hepatotoxicity. Resistance towards bacterial asparaginase is another major disadvantage during cancer management. This situation attracted attention of researchers towards alternative sources of l-asparaginase, including plants and fungi. Present article discusses about potential of l-asparaginase as an anticancer agent, its mechanism of action, and adverse effects related to current asparaginase formulations. This article also provides an outlook for recent developments in l-asparaginase discovery from alternative sources and their potential as a less toxic alternative to current formulations. PMID:25630663

  19. Synthesis and screening of ursolic acid-benzylidine derivatives as potential anti-cancer agents.

    Science.gov (United States)

    Dar, Bilal Ahmad; Lone, Ali Mohd; Shah, Wajaht Amin; Qurishi, Mushtaq Ahmad

    2016-03-23

    Ursolic acid present abundantly in plant kingdom is a well-known compound with various promising biological activities including, anti-cancer, anti-inflammatory, hepatoprotective, antiallergic and anti-HIV properties. Herein, a library of ursolic acid-benzylidine derivatives have been designed and synthesized using Claisen Schmidt condensation of ursolic acid with various aromatic aldehydes in an attempt to develop potent antitumor agents. The compounds were evaluated against a panel of four human carcinoma cell lines including, A-549 (lung), MCF-7 (breast), HCT-116 (colon), THP-1 (leukemia) and a normal human epithelial cell line (FR-2). The results from MTT assay revealed that all the compounds displayed high level of antitumor activities compared with the triazole analogs (previously reported) and the parent ursolic acid. However, compound 3b, the most active derivative was subjected to mechanistic studies to understand the underlying mechanism. The results revealed that compound 3b induced apoptosis in HCT-116 cell lines, arrest cell cycle in the G1 phase, caused accumulation of cytochrome c in the cytosol and increased the expression levels of caspase-9 and caspase-3 proteins. Therefore, compound 3b induces apoptosis in HCT-116 cells through mitochondrial pathway. PMID:26854375

  20. Green design "bioinspired disassembly-reassembly strategy" applied for improved tumor-targeted anticancer drug delivery.

    Science.gov (United States)

    Wang, Ruoning; Gu, Xiaochen; Zhou, Jianping; Shen, Lingjia; Yin, Lifang; Hua, Peiying; Ding, Yang

    2016-08-10

    In this study, a simple and green approach 'bioinspired disassembly-reassembly strategy' was employed to reconstitute lipoprotein nanoparticles (RLNs) using whole-components of endogenous ones (contained dehydrated human lipids and native apolipoproteins). These RLNs were engineered to mimic the configuration and properties of natural lipoproteins for efficient drug delivery. In testing therapeutic targeting to microtubules, paclitaxel (PTX) was reassembled into RLNs to achieve improved targeted anti-carcinoma treatment and minimize adverse effects, demonstrating ultimately more applicable than HDL-like particles which are based on exogenous lipid sources. We have characterized that apolipoprotein-decoration of PTX-loaded RLNs (RLNs-PTX) led to favoring uniformly dispersed distribution, increasing PTX-encapsulation with a sustained-release pattern, while enhancing biostability during blood circulation. The innate biological RLNs induced efficient intracellular trafficking of cargos in situ via multi-targeting mechanisms, including scavenger receptor class B type I (SR-BI)-mediated direct transmembrane delivery, as well as other lipoprotein-receptors associated endocytic pathways. The resulting anticancer treatment from RLNs-PTX was demonstrated a half-maximal inhibitory concentration of 0.20μg/mL, cell apoptosis of 18.04% 24h post-incubation mainly arresting G2/M cell cycle in vitro, and tumor weight inhibition of 70.51% in vivo. Collectively, green-step assembly-based RLNs provided an efficient strategy for mediating tumor-targeted accumulation of PTX and enhanced anticancer efficacy. PMID:27238442

  1. Enhanced targeted anticancer effects and inhibition of tumor metastasis by the TMTP1 compound peptide TMTP1-TAT-NBD.

    Science.gov (United States)

    Liu, Ronghua; Xi, Ling; Luo, Danfeng; Ma, Xiangyi; Yang, Wanhua; Xi, Yandong; Wang, Hongyan; Qian, Ming; Fan, Liangsheng; Xia, Xi; Li, Kezheng; Wang, Daowen; Zhou, Jianfeng; Meng, Li; Wang, Shixuan; Ma, Ding

    2012-08-10

    Micromolecular agents that block tumor development and metastasis hold great promise as cancer-targeted therapies. Tumor molecular targeted peptide 1 (TMTP1) was previously shown to target primary tumors and metastatic foci specifically. In this study, a group of composite peptides were incorporated to TMPT1. The NF-κB essential modulator-binding domain (NBD), and the trans-activator of transcription (TAT) peptide, were synthesized to enhance the targeted anti-tumor effects of TMTP1. TMTP1-NBD did not exhibit strong affinity to tumor cells as we had expected. Conjugating TAT with TMTP1-NBD ameliorated the poor hydrophilicity and negative charge of TMTP1-NBD. Therefore TMTP1-TAT-NBD displayed strong affinity and anti-tumor effects as we expected in vivo and in vitro. Interestingly cytoplasmic glycogen accumulation as well as apoptosis was observed in TMTP1-TAT-NBD treated PC-3M-1E8 cells. The downstream signaling pathways including AKT, GSK-3β, IκBα and NF-κB activity were verified to decrease by TMTP1-TAT-NBD. The pharmacokinetics and distribution of TMTP1-TAT-NBD in MDA-MB-231 tumor-bearing mice model provided some evidence for safety of the composite peptide, which showed the fluorescence of the peptide peaked in the tumor 6h after injection, with little fluorescence detected in normal organs except for very weak fluorescence in kidney. In conclusion, TMTP1-TAT-NBD may be a promising targeted anti-tumor agent for primary tumor and metastatic foci, which enhances the anticancer effects through inhibiting the AKT/GSK-3β/NF-κB pathway comparing with TMTP1. PMID:22580115

  2. Human synthetic lethal inference as potential anti-cancer target gene detection

    Directory of Open Access Journals (Sweden)

    Solé Ricard V

    2009-12-01

    Full Text Available Abstract Background Two genes are called synthetic lethal (SL if mutation of either alone is not lethal, but mutation of both leads to death or a significant decrease in organism's fitness. The detection of SL gene pairs constitutes a promising alternative for anti-cancer therapy. As cancer cells exhibit a large number of mutations, the identification of these mutated genes' SL partners may provide specific anti-cancer drug candidates, with minor perturbations to the healthy cells. Since existent SL data is mainly restricted to yeast screenings, the road towards human SL candidates is limited to inference methods. Results In the present work, we use phylogenetic analysis and database manipulation (BioGRID for interactions, Ensembl and NCBI for homology, Gene Ontology for GO attributes in order to reconstruct the phylogenetically-inferred SL gene network for human. In addition, available data on cancer mutated genes (COSMIC and Cancer Gene Census databases as well as on existent approved drugs (DrugBank database supports our selection of cancer-therapy candidates. Conclusions Our work provides a complementary alternative to the current methods for drug discovering and gene target identification in anti-cancer research. Novel SL screening analysis and the use of highly curated databases would contribute to improve the results of this methodology.

  3. Synthesis and evaluation of naphthalene-based thiosemicarbazone derivatives as new anticancer agents against LNCaP prostate cancer cells.

    Science.gov (United States)

    Altintop, Mehlika Dilek; Sever, Belgin; Özdemir, Ahmet; Kuş, Gökhan; Oztopcu-Vatan, Pinar; Kabadere, Selda; Kaplancikli, Zafer Asim

    2016-06-01

    Fourteen new naphthalene-based thiosemicarbazone derivatives were designed as anticancer agents against LNCaP human prostate cancer cells and synthesized. MTT assay indicated that compounds 6, 8 and 11 exhibited inhibitory effect on LNCaP cells. Among these compounds, 4-(naphthalen-1-yl)-1-[1-(4-hydroxyphenyl)ethylidene)thiosemicarbazide (6), which caused more than 50% death on LNCaP cells, was chosen for flow cytometric analysis of apoptosis. Flow cytometric analysis pointed out that compound 6 also showed apoptotic effect on LNCaP cells. Compound 6 can be considered as a promising anticancer agent against LNCaP cells owing to its potent cytotoxic activity and apoptotic effect. PMID:25826149

  4. Immune mechanisms regulating pharmacokinetics and pharmacodynamics of PEGylated liposomal anticancer agents

    Science.gov (United States)

    Song, Gina

    integrated approaches, we were able to identify the immunological mechanisms at the molecular, tissue, and clinical levels that may contribute to inter-individual variability in PK and PD of PLD. This dissertation research has a potential to make an impact on development of future NP-based anticancer therapeutics as well as on clinical use of PLD (DoxilRTM) and other PEGylated liposomal anticancer agents.

  5. Assessment of Performance of Manufacturing Procedures in a Unit for Production of Investigational Anticancer Agents, Using a Mixed Effects Analysis

    OpenAIRE

    van der Schoot, S. C.; Nuijen, B; Huitema, A D R; Beijnen, J.H.

    2007-01-01

    Purpose To identify the magnitude and sources of variability of a generic, aseptic manufacturing process for experimental anticancer agents employed at our facility, and to estimate the effects on product quality. Materials and Methods In-process and quality control data of all products manufactured according to this generic process (composed of weighing, dissolution, filtration, filling, semi-stoppering and lyophilization) over a 3-year period were retrospectively analyzed using mixed-effect...

  6. Telomere and telomerase as targets for anti-cancer and regeneration therapies

    Institute of Scientific and Technical Information of China (English)

    Yi-hsin HSU; Jing-jer LIN

    2005-01-01

    Telomerase is a ribonucleoprotein that directs the synthesis of telomeric sequence.It is detected in majority of malignant tumors, but not in most normal somatic cells.Because telomerase plays a critical role in cell immortality and tumor formation, it has been one of the targets for anti-cancer and regeneration drug development. In this review, we will discuss therapeutic approaches based mainly on small molecules that have been developed to inhibit telomerase activity, modulate telomerase expression, and telomerase directed gene therapy.

  7. Design, synthesis and biological evaluation of novel pyridine derivatives as anticancer agents and phosphodiesterase 3 inhibitors

    Science.gov (United States)

    Abadi, Ashraf H.; Ibrahim, Tamer M.; Abouzid, Khaled M.; Lehmann, Jochen; Tinsley, Heather N.; Gary, Bernard D.; Piazza, Gary A.

    2016-01-01

    Two series of 4,6-diaryl-2-imino-1,2-dihydropyridine-3-carbonitriles and their isosteric 4,6-diaryl-2- oxo-1,2-dihydropyridine-3-carbonitriles were synthesized through a combinatorial approach. The prepared analogues were evaluated for their in vitro capacity to inhibit PDE3A and the growth of the human HT-29 colon adenocarcinoma tumor cell line. Compound 6-(4-bromophenyl)-4-(2-ethoxyphenyl)-2- imino-1,2-dihydropyridine-3-carbonitrile (Id) exhibited the strongest PDE3 inhibition when cGMP but not cAMP is the substrate with a IC50of 27 μM, which indicates a highly selective mechanism of enzyme inhibition. On the other hand, compound 6-(1,3-benzodioxol-5-yl)-4-(2-ethoxyphenyl)-2-imino-1,2- dihydropyridine-3-carbonitrile (Ii) was the most active in inhibiting colon tumor cell growth with a IC50 of 3 μM. The electronic effects, steric effects and conformational aspects of Id seem to be the most crucial for the PDE3 inhibition. Meanwhile, steric factors and the H-bonding capability seem to be the most important factors for tumor cell growth inhibitory activity. Conversely, there is no direct correlation between PDE3 inhibition and anticancer activity for the prepared compounds. An in silico docking experiment indicates the potential involvement of other potential molecular targets such as PIM-1 kinase to explain its tumor cell growth inhibitory activity. PMID:19628397

  8. Novel quinolines carrying pyridine, thienopyridine, isoquinoline, thiazolidine, thiazole and thiophene moieties as potential anticancer agents.

    Science.gov (United States)

    Ghorab, Mostafa M; Alsaid, Mansour S; Al-Dosari, Mohammed S; Ragab, Fatma A; Al-Mishari, Abdullah A; Almoqbil, Abdulaziz N

    2016-06-01

    As a part of ongoing studies in developing new anticancer agents, novel 1,2-dihydropyridine 4, thienopyridine 5, isoquinolines 6-20, acrylamide 21, thiazolidine 22, thiazoles 23-29 and thiophenes 33-35 bearing a biologically active quinoline nucleus were synthesized. The structure of newly synthesized compounds was confirmed on the basis of elemental analyses and spectral data. All the newly synthesized compounds were evaluated for their cytotoxic activity against the breast cancer cell line MCF7. 2,3-Dihydrothiazole-5-carboxamides 27, 25, 4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (34), 1,2-dihydroisoquinoline-7-carbonitrile (7), 5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxamide (35), 1,2-dihydroisoquinoline-7-carbonitrile (6), 2-cyano-3-(dimethylamino)-N-(quinolin-3-yl)acrylamide (21), 1,2-dihydroisoquinoline-7-carbonitriles (11) and (8) exhibited higher activity (IC50 values of 27-45 μmol L-1) compared to doxorubicin (IC50 47.9 μmol L-1). LQ quinolin-3-yl)-1,2-dihydroisoquinoline-7-carbonitrile (12), 2-thioxo-2,3-dihydrothiazole-5-carboxamide (28) and quinolin-3-yl)-1,2-dihydroisoquinoline-7-carbonitrile (15) show activity comparable to doxorubicin, while (quinolin-3-yl)-1,2-dihydroisoquinoline-7-carbonitrile (9), 2,3-dihydrothiazole-5-carboxamide (24), thieno [3,4-c] pyridine-4(5H)-one (5), cyclopenta[b]thiophene-3-carboxamide (33) and (quinolin-3-yl)-6-stryl-1,2-dihydroisoquinoline-7-carbonitrile (10) exhibited moderate activity, lower than doxorubicin. PMID:27279061

  9. Novel quinolines carrying pyridine, thienopyridine, isoquinoline, thiazolidine, thiazole and thiophene moieties as potential anticancer agents

    Directory of Open Access Journals (Sweden)

    Ghorab Mostafa M.

    2016-06-01

    Full Text Available As a part of ongoing studies in developing new anticancer agents, novel 1,2-dihydropyridine 4, thienopyridine 5, isoquinolines 6–20, acrylamide 21, thiazolidine 22, thiazoles 23–29 and thiophenes 33–35 bearing a biologically active quinoline nucleus were synthesized. The structure of newly synthesized compounds was confirmed on the basis of elemental analyses and spectral data. All the newly synthesized compounds were evaluated for their cytotoxic activity against the breast cancer cell line MCF7. 2,3-Dihydrothiazole-5-carboxamides 27, 25, 4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (34, 1,2-dihydroisoquinoline-7-carbonitrile (7, 5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxamide (35, 1,2-dihydroisoquinoline-7-carbonitrile (6, 2-cyano-3-(dimethylamino-N-(quinolin-3-ylacrylamide (21, 1,2-dihydroisoquinoline-7-carbonitriles (11 and (8 exhibited higher activity (IC50 values of 27–45 μmol L–1 compared to doxorubicin (IC50 47.9 μmol L–1. LQ quinolin-3-yl-1,2-dihydroisoquinoline-7-carbonitrile (12, 2-thioxo-2,3-dihydrothiazole-5-carboxamide (28 and quinolin-3-yl-1,2-dihydroisoquinoline-7-carbonitrile (15 show activity comparable to doxorubicin, while (quinolin-3-yl-1,2-dihydroisoquinoline-7-carbonitrile (9, 2,3-dihydrothiazole-5-carboxamide (24, thieno [3,4-c] pyridine-4(5H-one (5, cyclopenta[b]thiophene-3-carboxamide (33 and (quinolin-3-yl-6-stryl-1,2-dihydroisoquinoline-7-carbonitrile (10 exhibited moderate activity, lower than doxorubicin.

  10. Clastogenicity Potential Screening of Pleurotus pulmonarius and Pleurotus ostreatus Metabolites as Potential Anticancer and Antileukaemic Agents Using Micronucleus Assay

    Directory of Open Access Journals (Sweden)

    E.O. Akanni

    2010-11-01

    Full Text Available Development of anticancer agents that will selectively destroy cancer cells without injury to normal cells has led to the discovery of novel immunotherapeutic agents such as Pleurotus pulmonarius and Pleurotus ostreatus metabolites. This study is to screen the agents of dreadful side effects of causing mutation after a prolonged use. Clastogenicity potential of the novel anti-cancer and antileukaemic agents Pleurotus pulmonarius and Pleurotus ostreatus metabolites was evaluated in this study. Wister rats were grouped into four with the test groups inoculated intraperitoneally at doses 64 and 16 mg/kg as 12.8 and 3.2% of the LD50 into the high and low dose rat groups respectively with each metabolite in a separate experiment. The treated rats were sacrificed after 24, 48 and 72 h post treatment. Cyclophosphamide (clastogen was inoculated into the positive control group at doses 112 and 28 mg/kg w hile saline was used for the negative control group. In all the treatment groups, only the rats in the positive control group formed micronuclei in their bone marrow cells. There was only an increase in the formation of normochromatic and polychromatic erythrocytes in rat groups inoculated with Pleurotus ostreatus metabolites. There is no statistically significant difference (p>0.05 between the 3 post treatment sacrificing periods. Similar result was also obtained for Pleurotus pulmonarius group. The chromosomal damaging potential screening reveals that the Pleurotus ostreatus and Pleurotus pulmonarius metabolites are not clastogenic (genotoxic that is, unlikely to cause cancer producing mutations, but rather enhanced erythropoiesis. They could therefore be useful anticancer agents when the potential is fully explored.

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

    Directory of Open Access Journals (Sweden)

    Cui J

    2014-02-01

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

  12. Design and Synthesis of 3-Substituedmethylenethiochroman-4-ones as Anticancer Agents

    Institute of Scientific and Technical Information of China (English)

    MA Zheng-yue; ZHANG Xing-hua; LI Chun-na; ZHENG Ya-jun; YANG Geng-liang; WANG Shi-kui; HE Yang

    2011-01-01

    A series of 3-substituedmethylenethiochroman-4-ones was designed and synthesized,and their structures were confirmed by 1H NMR,13C NMR,MS,IR,UV and elemental analysis.The results of their anticancer activity studies show that almost all 3-chloromethylenethiochroman-4-ones exhibit high anticancer activities and their activities are all better than reference cisplatin.Their IC50 against cancer cells is in a range of 0.80-9.17 μg/mL.Thus they could be promising candidates for anticancer drugs.However,compound 5 has no activity against cancer cells,thus chloromethylene at the 3 position of thiochroman-4-ones seems to play an important role in observed anticancer activities.

  13. Target Tracking and Obstacle Avoidance for Multi-agent Systems

    Institute of Scientific and Technical Information of China (English)

    Jing Yan; Xin-Ping Guan; Fu-Xiao Tan

    2010-01-01

    This paper considers the problems of target tracking and obstacle avoidance for multi-agent systems.To solve the problem that multiple agents cannot effectively track the target while avoiding obstacle in dynamic environment,a novel control algorithm based on potential function and behavior rules is proposed.Meanwhile,the interactions among agents are also considered.According to the state whether an agent is within the area of its neighbors' influence,two kinds of potential functions are presented.Meanwhile,the distributed control input of each agent is determined by relative velocities as well as relative positions among agents,target and obstacle.The maximum linear speed of the agents is also discussed.Finally,simulation studies are given to demonstrate the performance of the proposed algorithm.

  14. Can Some Marine-Derived Fungal Metabolites Become Actual Anticancer Agents?

    OpenAIRE

    Gomes, Nelson G. M.; Florence Lefranc; Anake Kijjoa; Robert Kiss

    2015-01-01

    Marine fungi are known to produce structurally unique secondary metabolites, and more than 1000 marine fungal-derived metabolites have already been reported. Despite the absence of marine fungal-derived metabolites in the current clinical pipeline, dozens of them have been classified as potential chemotherapy candidates because of their anticancer activity. Over the last decade, several comprehensive reviews have covered the potential anticancer activity of marine fungal-derived metabolites. ...

  15. Adding pharmacogenomics to the development of new marine-derived anticancer agents

    OpenAIRE

    Aracil Miguel; Jimeno José; Tercero Juan

    2006-01-01

    Abstract Nature has always been a highly productive tool in the development of anticancer therapies. Renewed interest in the potential of this tool has recently been sparked by the realization that the marine ecosystem can be used for the discovery and development of new compounds with clinical potential in advanced resistant tumors. These compounds can be incorporated into combination approaches in a chronic therapy scenario. Our marine anticancer program is using the sea to develop new agen...

  16. Immune cell-based screening assay for response to anticancer agents: applications in pharmacogenomics

    Directory of Open Access Journals (Sweden)

    Frick A

    2015-02-01

    Full Text Available Amber Frick,1 Yuri Fedoriw,2 Kristy Richards,3,4 Blossom Damania,3,5 Bethany Parks,6 Oscar Suzuki,1 Cristina S Benton,1 Emmanuel Chan,1 Russell S Thomas,7 Tim Wiltshire1,3 1Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, 2Department of Pathology and Laboratory Medicine, School of Medicine, 3Lineberger Comprehensive Cancer Center, School of Medicine, 4Department of Genetics, School of Medicine, 5Department of Microbiology and Immunology, School of Medicine, University of North Carolina, Chapel Hill, NC, USA; 6The Hamner Institutes for Health Sciences, 7Environmental Protection Agency, Research Triangle Park, NC, USA Background: Interpatient variability in immune and chemotherapeutic cytotoxic responses is likely due to complex genetic differences and is difficult to ascertain in humans. Through the use of a panel of genetically diverse mouse inbred strains, we developed a drug screening platform aimed at examining interstrain differences in viability on normal, noncancerous immune cells following chemotherapeutic cytotoxic insult. Drug effects were investigated by comparing selective chemotherapeutic agents, such as BEZ-235 and selumetinib, against conventional cytotoxic agents targeting multiple pathways, including doxorubicin and idarubicin. Methods: Splenocytes were isolated from 36 isogenic strains of mice using standard procedures. Of note, the splenocytes were not stimulated to avoid attributing responses to pathways involved with cellular stimulation rather than toxicity. Cells were incubated with compounds on a nine-point logarithmic dosing scale ranging from 15 nM to 100 µM (37°C, 5% CO2. At 4 hours posttreatment, cells were labeled with antibodies and physiological indicator dyes and fixed with 4% paraformaldehyde. Cellular phenotypes (eg, viability were collected and analyzed using flow cytometry. Dose-response curves with response normalized to the zero dose as a function of log concentration

  17. 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

  18. Preclinical Predictors of Anticancer Drug Efficacy: Critical Assessment with Emphasis on Whether Nanomolar Potency Should Be Required of Candidate Agents

    OpenAIRE

    Wong, C. C.; Cheng, Ka-Wing; Rigas, Basil

    2012-01-01

    In the current paradigm of anticancer drug development, candidate compounds are evaluated by testing their in vitro potency against molecular targets relevant to carcinogenesis, their effect on cultured cancer cells, and their ability to inhibit cancer growth in animal models. We discuss the key assumptions inherent in these approaches. In recent years, great emphasis has been placed on selecting for development compounds with nanomolar in vitro potency, expecting that they will be efficaciou...

  19. Interaction of Radiation Therapy With Molecular Targeted Agents

    OpenAIRE

    Morris, Zachary S.; Harari, Paul M.

    2014-01-01

    The development of molecular targeted therapeutics in oncology builds on many years of scientific investigation into the cellular mechanics of malignant transformation and progression. The past two decades have brought an accelerating pace to the clinical investigation of new molecular targeted agents, particularly in the setting of metastatic disease. The integration of molecular targeted agents into phase III clinical trial design has lagged in the curative treatment setting, particularly i...

  20. Individualization of anticancer therapy; molecular targets of novel drugs in oncology

    Directory of Open Access Journals (Sweden)

    Katarzyna Regulska

    2012-11-01

    Full Text Available Deregulation of cellular signal transduction, caused by gene mutations, has been recognized as a basic factor of cancer initiation, promotion and progression. Thus, the ability to control the activity of overstimulated signal molecules by the use of appropriate inhibitors became the idea of targeted cancer therapy, which has provided an effective tool to normalize the molecular disorders in malignant cells and to treat certain types of cancer. The molecularly targeted drugs are divided into two major pharmaceutical classes: monoclonal antibodies and small-molecule kinase inhibitors. This review presents a summary of their characteristics, analyzing their chemical structures, specified molecular targets, mechanisms of action and indications for use. Also the molecules subjected to preclinical trials or phase I, II and III clinical trials evaluating their efficiency and safety are presented. Moreover, the article discusses further perspectives for development of targeted therapies focusing on three major directions: systematic searching and discovery of new targets that are oncogenic drivers, improving the pharmacological properties of currently known drugs, and developing strategies to overcome drug resistance. Finally, the role of proper pharmacodiagnostics as a key to rational anticancer therapy has been emphasized since the verification of reliable predictive biomarkers is a basis of individualized medicine in oncology. 

  1. Cyclodextrin conjugated magnetic colloidal nanoparticles as a nanocarrier for targeted anticancer drug delivery

    Energy Technology Data Exchange (ETDEWEB)

    Banerjee, Shashwat S; Chen, D.-H. [Department of Chemical Engineering, National Cheng Kung University, Tainan 701, Taiwan (China)], E-mail: chendh@mail.ncku.edu.tw

    2008-07-02

    A novel magnetic nanocarrier (CD-GAMNPs) was fabricated for targeted anticancer drug delivery by grafting cyclodextrin (CD) onto gum arabic modified magnetic nanoparticles (GAMNPs) using hexamethylene diisocyanate (HMDI) as a linker. Analyses by transmission electron microscopy (TEM) and dynamic light scattering (DLS) revealed that the product had a mean diameter of 17.1 nm and a mean hydrodynamic diameter of 44.1 nm. The CD grafting was confirmed by Fourier transform infrared (FTIR) spectroscopy, and thermogravimetric analysis (TGA) indicated that the amount of CD grafted on the GAMNPs was 16.8 mg g{sup -1}. The study on the loading of anticancer drug all-trans-retinoic acid (retinoic acid) revealed that the newly fabricated magnetic nanocarrier possessed a considerably higher adsorption capability as compared to GAMNPs due to the special hydrophobic cavity structure of CD, which could act as a host-guest complex with retinoic acid. Furthermore, it was found that the complexation of CD-GAMNPs with retinoic acid was exothermic and the presence of a surfactant (sodium dodecyl sulfate) led to the decrease in the inclusion of retinoic acid because the linear structure of sodium dodecyl sulfate made it easier to enter the cavity of CD as compared to less linear retinoic acid. In addition, the in vitro release profile of retinoic acid from CD-GAMNPs was characterized by an initial fast release followed by a delayed release phase.

  2. Curcumin-albumin conjugates as an effective anti-cancer agent with immunomodulatory properties.

    Science.gov (United States)

    Aravind, S R; Krishnan, Lissy K

    2016-05-01

    the drug form has the potential to be used as an anticancer agent in affected human subjects. PMID:26927614

  3. The combination of novel targeted molecular agents and radiation in the treatment of pediatric gliomas

    Directory of Open Access Journals (Sweden)

    Tina eDasgupta

    2013-05-01

    Full Text Available Brain tumors are the most common solid pediatric malignancy. For high-grade, recurrent or refractory pediatric brain tumors, radiation therapy (XRT is an integral treatment modality. In the era of personalized cancer therapy, molecularly targeted agents have been designed to inhibit pathways critical to tumorigenesis. Our evolving knowledge of genetic aberrations in low-grade gliomas is being exploited with targeted inhibitors. These agents are also being combined with XRT to increase their efficacy. In this review, we discuss novel agents targeting three different pathways in low-grade gliomas, and their potential combination with XRT. B-Raf is a kinase in the Ras/Raf/MAPK kinase pathway, which is integral to cellular division, survival and metabolism. In low-grade pediatric gliomas, point mutations in BRAF (BRAF V600E or a BRAF fusion mutation (KIAA1549:BRAF causes overactivation of the MEK/MAPK pathway. Pre-clinical data shows cooperation between XRT and tagrgeted inhibitors of BRAF V600E, and MEK and mTOR inhibitors in the gliomas with the BRAF fusion. A second important signaling cascade in pediatric glioma pathogenesis is the PI3 kinase (PI3K/mTOR pathway. Dual PI3K/mTOR inhibitors are poised to enter studies of pediatric tumors. Finally, many brain tumors express potent stimulators of angiogenesis. Several inhibitors of immunomodulators are currently being evaluated in in clinical trials for the treatment of recurrent or refractory pediatric central nervous system (CNS tumors. In summary, combinations of these targeted inhibitors with radiation are currently under investigation in both translational bench research and early clinical trials. We summarize the molecular rationale for, and the pre-clinical data supporting the combinations of these targeted agents with other anti-cancer agents and XRT in pediatric gliomas. Parallels are drawn to adult gliomas, and the molecular mechanisms underlying the efficacy of these agents is discussed

  4. Design, synthesis, and anticancer activity of novel berberine derivatives prepared via CuAAC “click” chemistry as potential anticancer agents

    Directory of Open Access Journals (Sweden)

    Jin X

    2014-08-01

    Full Text Available Xin Jin1,2,* Tian-Hua Yan,3,* Lan Yan,1 Qian Li,4 Rui-Lian Wang,1 Zhen-Lin Hu,1 Yuan-Ying Jiang,1 Qing-Yan Sun,1 Yong-Bing Cao1 1School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China; 2School of Pharmacy, FuJian University of Traditional Chinese Medicine, Fuzhou, People's Republic of China; 3Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing, People's Republic of China; 4Diakite Biological Technology Co., Ltd, Shanghai, People's Republic of China *These authors contributed equally to this work Abstract: A series of novel derivatives of phenyl-substituted berberine triazolyls has been designed and synthesized via copper-catalyzed azide-alkyne cycloaddition click chemistry in an attempt to develop antitumor agents. All of the compounds were evaluated for anticancer activity against a panel of three human cancer cell lines, including MCF-7 (breast, SW-1990 (pancreatic, and SMMC-7721 (liver and the noncancerous human umbilical vein endothelial cell (HUVEC cell lines. The results indicated that most of the compounds displayed notable anticancer activities against the MCF-7 cells compared with berberine. Among these derivatives, compound 16 showed the most potent inhibitory activity against the SW-1990 and SMMC-7721 cell lines, with half-maximal inhibitory concentration (IC50 values of 8.54±1.97 µM and 11.87±1.83 µM, respectively. Compound 36 exhibited the most potent inhibitory activity against the MCF-7 cell line, with an IC50 value of 12.57±1.96 µM. Compound 16 and compound 36 exhibited low cytotoxicity in the HUVEC cell line, with IC50 values of 25.49±3.24 µM and 30.47±3.47 µM. Furthermore, compounds 14, 15, 16, 17, 18, 32, and 36 exhibited much better selectivity than berberine toward the normal cell line HUVEC. Keywords: berberine, anticancer, click chemistry, structure–activity relationship

  5. Cooperative target convergence using multiple agents

    International Nuclear Information System (INIS)

    This work considers the problem of causing multiple (100''s) autonomous mobile robots to converge to a target and provides a follow-the-leader approach to the problem. Each robot has only a limited-range sensor for sending the target and also larger but also limited-range robot-to-robot communication capability. Because of the small amount of information available to the robots, a practical approach to improve convergence to the target is to have a robot follow the robot with the best quality of information. Specifically, each robot emits a signal that informs in-range robots what its status is. A robot has a status value of 0 if it is itself in range of the target. A robot has a status of 1 if it is not in range of the target but is in communication range of a robot that is in range of the target. A robot has a status of 2 if it is not in range of the target but is within range of another robot that has status 1, and so on. Of all the mobile robots that any given robot is in range of, it follows the one with the best status. The emergent behavior is the ant-like trails of robots following each other toward the target. If the robot is not in range of another robot that is either in range of the target or following another robot, the robot will assign-1 to its quality-of-information, and will execute an exhaustive search. The exhaustive search will continue until it encounters either the target or another robot with a nonnegative quality-of-information. The quality of information approach was extended to the case where each robot only has two-bit signals informing it of distance to in-range robots

  6. Design, synthesis and biological activity of piperlongumine derivatives as selective anticancer agents.

    Science.gov (United States)

    Wu, Yuelin; Min, Xiao; Zhuang, Chunlin; Li, Jin; Yu, Zhiliang; Dong, Guoqiang; Yao, Jiangzhong; Wang, Shengzheng; Liu, Yang; Wu, Shanchao; Zhu, Shiping; Sheng, Chunquan; Wei, Yunyang; Zhang, Huojun; Zhang, Wannian; Miao, Zhenyuan

    2014-07-23

    In an effort to expand the structure-activity relationship of the natural anticancer compound piperlongumine, we have prepared sixteen novel piperlongumine derivatives with halogen or morpholine substituents at C2 and alkyl substituents at C7. Most of 2-halogenated piperlongumines showed potent in vitro activity against four cancer cells and modest selectivity for lung normal cells. The highly active anticancer compound 11h exhibited obvious ROS elevation and excellent in vivo antitumor potency with suppressed tumor growth by 48.58% at the dose of 2 mg/kg. The results indicated that halogen substituents as electrophilic group at C2 played an important role in increasing cytotoxicity. PMID:24937186

  7. Design, Synthesis and Biological Evaluation of Novel 5H-Chromenopyridines as Potential Anti-Cancer Agents

    Directory of Open Access Journals (Sweden)

    Souvik Banerjee

    2015-09-01

    Full Text Available A novel series of 5H-chromenopyridines was identified as anticancer agents in our continuing effort to discover and develop new small molecule anti-proliferative agents. Based on our initial lead SP-6-27 compound, we designed and synthesized novel tricyclic 5H-thiochromenopyridine and 5H-chromenopyridine analogs to evaluate the impact of an additional ring, as well as conformational flexibility on cytotoxic activity against human melanoma and glioma cell lines. All of the 5H-thiochromenopyridines have been achieved in good yields (89%–93% using a single-step, three-component cyclization without the need for purification. The 5H-chromenopyridine analog of the potent 5H-thiochromenopyride was obtained in a good yield upon purification. All newly-prepared 5H-thiochromenopyridines showed good to moderate cytotoxicity against three melanoma and two glioma cell lines (3–15 μM. However, the 5H-chromenopyridine analogue that we prepared in our laboratory lost cytotoxic activity. The moderate cytotoxic activity of 5H-thiochromenopyridines shows the promise of developing chromenopyridines as potential anticancer agents.

  8. RAS GTPase AS THE DRUG TARGET FOR ANTI-CANCER DESIGNING OF DRUG FROM TEMPLATE

    Directory of Open Access Journals (Sweden)

    A.S. Krishnapriya and P.K. Krishnan Namboori*

    2013-11-01

    Full Text Available Ras proteins in association with GTP and GDP act as a bio-molecular switch for signaling cell growth, cell survival and signal transduction. The presence of mutated Ras proteins is found to vary in different cancer types and the highest occurrence of about 90% is observed in pancreatic cancer. The Ras GTPase binding site is mainly involved in signal cell proliferation. Hence, this binding site has been considered as a major target. At the same time, targeting a specific protein and designing the drug molecule with respect to that is practically of no use as the target proteins are fast mutating. In this scenario, designing the template from the hot spot of proteins and fitting the template for all the target protein molecules seem to be a promising technique. The templates are initially screened on the basis of pharmacokinetic and pharmacodynamic requirements. Six templates are found to be satisfying conditions like IC50, lipophilic efficiency, ligand efficiency etc. and their efficiencies are compared with standard reference molecules. The computed enrichment factors support these templates to be leads for effective anti-cancer drugs subject to further in vitro and in vivo evaluation.

  9. Quadruplex-targeting anticancer drug BRACO-19 voltammetric and AFM characterization

    International Nuclear Information System (INIS)

    The quadruplex-targeting anticancer drug BRACO-19 adsorption and redox behaviour were investigated by atomic force microscopy (AFM) on a highly oriented pyrolytic graphite surface and by cyclic, differential pulse and square-wave voltammetry at a glassy carbon electrode. The AFM and voltammetric results demonstrated that the BRACO-19 orientation and strong adsorption, with the acridine aromatic core parallel or perpendicular to the carbon electrode surface depending on solution pH, directly influences the peak potentials and redox behaviour. BRACO-19 oxidation was a complex, pH-dependent, four-step electrode process. The first oxidation step was reversible, the second, third and fourth oxidation steps irreversible, and an electroactive irreversibly oxidized BRACO-19 oxidation product was formed. BRACO-19 reduction occurred in two irreversible, pH-independent steps. The proposed redox mechanisms are related to the pyrrolidine and acridine moieties

  10. From METS to malaria: RRx-001, a multi-faceted anticancer agent with activity in cerebral malaria

    OpenAIRE

    Yalçın, Özlem; Oronsky, Bryan; Carvalho, Leonardo J. M.; Kuypers, Frans A.; Scicinski, Jan; Cabrales, Pedro

    2015-01-01

    RESEARCH Open Access From METS to malaria: RRx-001, a multi-faceted anticancer agent with activity in cerebral malaria Ozlem Yalcin1,2, Bryan Oronsky3, Leonardo J. M. Carvalho4,5, Frans A. Kuypers6, Jan Scicinski3 and Pedro Cabrales1* Abstract Background: The survival of malaria parasites, under substantial haem-induced oxidative stress in the red blood cells (RBCs) is dependent on the pentose phosphate pathway (PPP). The PPP is the only source of NADPH in the RBC, ess...

  11. Evaluation of bishexadecyltrimethyl ammonium palladium tetrachloride based dual functional colloidal carrier as an antimicrobial and anticancer agent.

    Science.gov (United States)

    Kaur, Gurpreet; Kumar, Sandeep; Dilbaghi, Neeraj; Kaur, Baljinder; Kant, Ravi; Guru, Santosh Kumar; Bhushan, Shashi; Jaglan, Sundeep

    2016-04-12

    We have developed a dual function carrier using bishexadecyltrimethyl ammonium palladium tetrachloride, which has anticancer as well as antibacterial activity, using a ligand insertion method with a simple and easy work procedure. The complex is prepared by a simple and cost effective method using hexadecyltrimethyl ammonium chloride and palladium chloride under controlled stoichiometry. Herein, we report the aggregation (self assembly) of the metallosurfactant having palladium as a counter ion, in aqueous medium along with its binding affinity with bovine serum albumin. The palladium surfactant has exhibited excellent antimicrobial efficacy against fungus and bacteria (both Gram-positive and Gram-negative bacteria). Cytotoxicity of palladium surfactant against cancerous (Human leukemia HL-60, pancreatic MIA-Pa-Ca-2 and prostate cancer PC-3) and healthy cells (fR2 human breast epithelial cells) was also evaluated using MTT assay. The present dual functional moiety shows a low IC50 value and has potential to be used as an anticancer agent. Our dual function carrier which itself possesses antimicrobial and anticancer activity represents a simple and effective system and can also be utilized as a drug carrier in the future. PMID:26961498

  12. Synthesis, biological evaluation and molecular docking studies of some novel cyclopropane carbohydrazide derivatives as potential anticancer agents

    Indian Academy of Sciences (India)

    PONNAPALLI VEERABHADRA SWAMY; PULLAIAH CHINA KAMBHAMPATI; KOTHAPALLI BONNOTH CHANDRASEKHAR; GUGULOTHU THIRUPATHI; POMBALA SUJITHA; CHITYAL GANESH KUMAR; VEERAMACHANENI GANESH KUMAR

    2016-06-01

    The synthesis of novel series of cyclopropane carbohydrazides is described via Knoevenagel condensationof 2-furfuraldehyde with malonic acid in five steps. Condensation of the key intermediate 2-(furan-2-yl)cyclopropanecarbohydrazide (4) with heteroaryl/aryl aldehydes (a-t) in presence of ZnO NP in ethanolresulted in substituted N- hetero/arylidene-2-(furan-2-yl) cyclopropane carbohydrazides (5a-t). These compoundswere screened for their anticancer activity against a panel of four cancer cell lines and four compoundsshowed promising activity at micromolar concentration against all the tested cell lines with IC50 values rangingbetween 1.9-8.45μM. These compounds were further validated with in silico methods at the anticancer target,colchicine binding site.

  13. 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

  14. Identification of anticancer agents based on the thieno[2,3-b]pyridine and 1H-pyrazole molecular scaffolds.

    Science.gov (United States)

    Eurtivong, Chatchakorn; Reynisdóttir, Inga; Kuczma, Stephanie; Furkert, Daniel P; Brimble, Margaret A; Reynisson, Jóhannes

    2016-08-15

    Structural similarity search of commercially available analogues of thieno[2,3-b]pyridine and 1H-pyrazole derivatives, known anticancer agents, resulted in 717 hits. These were docked into the phosphoinositide specific-phospholipase C (PLC) binding pocket, the putative target of the compounds, to further focus the selection. Thirteen derivatives of the thieno[2,3-b]pyridines were identified and tested against the NCI60 panel of human tumour cell lines. The most active derivative 1 was most potent against the MDA-MB-435 melanoma cell line with GI50 at 30nM. Also, it was found that a piperidine moiety is tolerated on the thieno[2,3-b]pyridine scaffold with GI50=296nM (MDA-MB-435) for derivative 10 considerably expanding the structure activity relationship for the series. For the 1H-pyrazoles four derivatives were identified using the in silico approach and additionally ten were synthesised with various substituents on the phenyl moiety to extend the structural activity relationship but only modest anticancer activity was found. PMID:27288184

  15. Biochemical characterization and molecular dynamic simulation of β-sitosterol as a tubulin-binding anticancer agent.

    Science.gov (United States)

    Mahaddalkar, Tejashree; Suri, Charu; Naik, Pradeep Kumar; Lopus, Manu

    2015-08-01

    Βeta-sitosterol (β-SITO), a phytosterol present in pomegranate, peanut, corn oil, almond, and avocado, has been recognized to offer health benefits and potential clinical uses. β-SITO is orally bioavailable and, as a constituent of edible natural products, is considered to have no undesired side effects. It has also been considered as a potent anticancer agent. However, the molecular mechanism of action of β-SITO as a tubulin-binding anticancer agent and its binding site on tubulin are poorly understood. Using a combination of biochemical analyses and molecular dynamic simulation, we investigated the molecular details of the binding interactions of β-SITO with tubulin. A polymer mass assay comparing the effects of β-SITO and of taxol and vinblastine on tubulin assembly showed that this phytosterol stabilized microtubule assembly in a manner similar to taxol. An 8-anilino-1-naphthalenesulfonic acid assay confirmed the direct interaction of β-SITO with tubulin. Although β-SITO did not show direct binding to the colchicine site on tubulin, it stabilized the colchicine binding. Interestingly, no sulfhydryl groups of tubulin were involved in the binding interaction of β-SITO with tubulin. Based on the results from the biochemical assays, we computationally modeled the binding of β-SITO with tubulin. Using molecular docking followed by molecular dynamic simulations, we found that β-SITO binds tubulin at a novel site (which we call the 'SITO site') adjacent to the colchicine and noscapine sites. Our data suggest that β-SITO is a potent anticancer compound that interferes with microtubule assembly dynamics by binding to a novel site on tubulin. PMID:25912799

  16. Optimization of anti-cancer drugs and a targeting molecule on multifunctional gold nanoparticles

    Science.gov (United States)

    Rizk, Nahla; Christoforou, Nicolas; Lee, Sungmun

    2016-05-01

    Breast cancer is the most common and deadly cancer among women worldwide. Currently, nanotechnology-based drug delivery systems are useful for cancer treatment; however, strategic planning is critical in order to enhance the anti-cancer properties and reduce the side effects of cancer therapy. Here, we designed multifunctional gold nanoparticles (AuNPs) conjugated with two anti-cancer drugs, TGF-β1 antibody and methotrexate, and a cancer-targeting molecule, folic acid. First, optimum size and shape of AuNPs was selected by the highest uptake of AuNPs by MDA-MB-231, a metastatic human breast cancer cell line. It was 100 nm spherical AuNPs (S-AuNPs) that were used for further studies. A fixed amount (900 μl) of S-AuNP (3.8 × 108 particles/ml) was conjugated with folic acid-BSA or methotrexate-BSA. Methotrexate on S-AuNP induced cellular toxicity and the optimum amount of methotrexate-BSA (2.83 mM) was 500 μl. Uptake of S-AuNPs was enhanced by folate conjugation that binds to folate receptors overexpressed by MDA-MB-231 and the optimum uptake was at 500 μl of folic acid-BSA (2.83 mM). TGF-β1 antibody on S-AuNP reduced extracellular TGF-β1 of cancer cells by 30%. Due to their efficacy and tunable properties, we anticipate numerous clinical applications of multifunctional gold nanospheres in treating breast cancer.

  17. Discovery of novel heteroarylmethylcarbamodithioates as potent anticancer agents: Synthesis, structure-activity relationship analysis and biological evaluation.

    Science.gov (United States)

    Li, Ying-Bo; Yan, Xu; Li, Ri-Dong; Liu, Peng; Sun, Shao-Qian; Wang, Xin; Cui, Jing-Rong; Zhou, De-Min; Ge, Ze-Mei; Li, Run-Tao

    2016-04-13

    A series of new analogs based on the structure of lead compound 10 were designed, synthesized and evaluated for their in vitro anti-cancer activities against four selected human cancer cell lines (HL-60, Bel-7402, SK-BR-3 and MDA-MB-468). Several synthesized compounds exhibited improved anti-cancer activities comparing with lead compound 10. Among them, 1,3,4-oxadiazole analogs 17o showed highest bioactivity with IC50 values of 1.23, 0.58 and 4.29 μM against Bel-7402, SK-BR-3 and MDA-MB-468 cells, respectively. It is noteworthy that 17o has potent anti-proliferation activity toward a panel of cancer cells with relatively less cytotoxicity to nonmalignant cells. The further mechanistic study showed that it induced apoptosis and cell cycle arrest through disrupting spindle assembly in mitotic progression, indicating these synthesized dithiocarbamates represented a novel series of anti-cancer compounds targeting mitosis. PMID:26900655

  18. Rational design, synthesis, and biological evaluation of third generation α-noscapine analogues as potent tubulin binding anti-cancer agents.

    Directory of Open Access Journals (Sweden)

    Naresh Kumar Manchukonda

    Full Text Available Systematic screening based on structural similarity of drugs such as colchicine and podophyllotoxin led to identification of noscapine, a microtubule-targeted agent that attenuates the dynamic instability of microtubules without affecting the total polymer mass of microtubules. We report a new generation of noscapine derivatives as potential tubulin binding anti-cancer agents. Molecular modeling experiments of these derivatives 5a, 6a-j yielded better docking score (-7.252 to -5.402 kCal/mol than the parent compound, noscapine (-5.505 kCal/mol and its existing derivatives (-5.563 to -6.412 kCal/mol. Free energy (ΔG bind calculations based on the linear interaction energy (LIE empirical equation utilizing Surface Generalized Born (SGB continuum solvent model predicted the tubulin-binding affinities for the derivatives 5a, 6a-j (ranging from -4.923 to -6.189 kCal/mol. Compound 6f showed highest binding affinity to tubulin (-6.189 kCal/mol. The experimental evaluation of these compounds corroborated with theoretical studies. N-(3-brormobenzyl noscapine (6f binds tubulin with highest binding affinity (KD, 38 ± 4.0 µM, which is ~ 4.0 times higher than that of the parent compound, noscapine (KD, 144 ± 1.0 µM and is also more potent than that of the first generation clinical candidate EM011, 9-bromonoscapine (KD, 54 ± 9.1 µM. All these compounds exhibited substantial cytotoxicity toward cancer cells, with IC50 values ranging from 6.7 µM to 72.9 µM; compound 6f showed prominent anti-cancer efficacy with IC50 values ranging from 6.7 µM to 26.9 µM in cancer cells of different tissues of origin. These compounds perturbed DNA synthesis, delayed the cell cycle progression at G2/M phase, and induced apoptotic cell death in cancer cells. Collectively, the study reported here identified potent, third generation noscapinoids as new anti-cancer agents.

  19. The intracellular controlled release from bioresponsive mesoporous silica with folate as both targeting and capping agent

    Science.gov (United States)

    Guo, Rui; Li, Le-Le; Zhao, Wen-Hua; Chen, Yu-Xi; Wang, Xiao-Zhu; Fang, Chen-Jie; Feng, Wei; Zhang, Tian-Lan; Ma, Xiang; Lu, Meng; Peng, Shi-Qi; Yan, Chun-Hua

    2012-05-01

    A smart mesoporous silica nanocarrier with intracellular controlled release is fabricated, with folic acid as dual-functional targeting and capping agent. The folate not only improves the efficiency of the nanocarrier internalized by the cancer cells, but also blocks the pores of the mesoporous silica to eliminate premature leakage of the drug. With disulfide bonds as linkers to attach the dual-functional folate within the surface of mesoporous silica, the controlled release can be triggered in the presence of reductant dithiothreitol (DTT) or glutathione (GSH). The cellular internalization via folate-receptor-mediated endocytosis and the intracellular controlled release of highly toxic anticancer drug DOX were demonstrated with an in vitro HeLa cell culture, indicating an efficient cancer-targeted drug delivery.A smart mesoporous silica nanocarrier with intracellular controlled release is fabricated, with folic acid as dual-functional targeting and capping agent. The folate not only improves the efficiency of the nanocarrier internalized by the cancer cells, but also blocks the pores of the mesoporous silica to eliminate premature leakage of the drug. With disulfide bonds as linkers to attach the dual-functional folate within the surface of mesoporous silica, the controlled release can be triggered in the presence of reductant dithiothreitol (DTT) or glutathione (GSH). The cellular internalization via folate-receptor-mediated endocytosis and the intracellular controlled release of highly toxic anticancer drug DOX were demonstrated with an in vitro HeLa cell culture, indicating an efficient cancer-targeted drug delivery. Electronic supplementary information (ESI) available: the details of XRD patterns and HRTEM images of the materials, release profile of F⊂M-F in an acidic solution, intracellular uptake measurement with flow cytometry, intracellular release measurement with confocal fluorescence microscopy, selected distance of folate derivatives. See DOI: 10

  20. Hormetic Effect of Berberine Attenuates the Anticancer Activity of Chemotherapeutic Agents

    OpenAIRE

    Jiaolin Bao; Borong Huang; Lidi Zou; Shenghui Chen; Chao Zhang; Yulin Zhang; Meiwan Chen; Jian-Bo Wan; Huanxing Su; Yitao Wang; Chengwei He

    2015-01-01

    Hormesis is a phenomenon of biphasic dose response characterized by exhibiting stimulatory or beneficial effects at low doses and inhibitory or toxic effects at high doses. Increasing numbers of chemicals of various types have been shown to induce apparent hormetic effect on cancer cells. However, the underlying significance and mechanisms remain to be elucidated. Berberine, one of the major active components of Rhizoma coptidis, has been manifested with notable anticancer activities. This st...

  1. ISOLATION AND CHARACTERIZATION OF BIOACTIVE PROTEIN FROM GREEN ALGAE Halimeda macrobola AS ANTIOXIDANT AND ANTICANCER AGENT

    OpenAIRE

    Ahmad, Ahyar

    2014-01-01

    A protein fraction isolated from green algae Halimeda macrobola taken from the sea of Selayar and Kapoposang Island inSouth Sulawesi was tested forantioxidant and anticancer properties.The protein was isolated using buffer Tris (hydroxymethyl) amino methane. Initial purification of protein uses conducted by using the fractionation method with ammonium sulphate, followed by a dialysis process. The protein concentration was determined by Lowry method. The antioxidant assay was done by using DP...

  2. New derivatives of vitamin E as nanovectors for poorly soluble drugs and anticancer agents

    OpenAIRE

    Duhem, Nicolas

    2013-01-01

    The aim of this work was to develop novel vitamin E conjugates for the vectorization of active pharmaceutical ingredients through nanotechnologies. The physico-chemical and biological properties of vitamin E derivatives offer multiple advantages in drug delivery like biocompatibility, improvement of drug solubility and anticancer activity. Nanomedicines have shown high potential in drug delivery since (i) they are appropriate to all route of administration, (ii) they may offer better drug bio...

  3. Enhancement of Selectivity of an Organometallic Anticancer Agent by Redox Modulation.

    Science.gov (United States)

    Romero-Canelón, Isolda; Mos, Magdalena; Sadler, Peter J

    2015-10-01

    Combination with redox modulators can potentiate the anticancer activity and maximize the selectivity of organometallic complexes with redox-based mechanisms of action. We show that nontoxic doses of l-buthionine sulfoximine increase the selectivity of organo-Os complex FY26 for human ovarian cancer cells versus normal lung fibroblasts to 63-fold. This increase is not due to changes in the mechanism of action of FY26 but to the decreased response of cancer cells to oxidative stress. PMID:26397305

  4. [Quod medicina aliis, aliis est acre venenum**--venoms as a source of anticancer agents].

    Science.gov (United States)

    Kucińska, Małgorzata; Ruciński, Piotr; Murias, Marek

    2013-01-01

    Natural product derived from plants and animals were used in folk medicine for centuries. The venoms produced by animals for hunting of self-defence are rich in bioactive compounds with broad spectrum of biological activity. The papers presents the most promising compounds isolated from venoms of snakes, scorpions and toads. For these compounds both: mechanism of anticancer activity as well as possibilities of clinical use are presented. PMID:24466712

  5. Structure-activity relationship for Fe(III)-salen-like complexes as potent anticancer agents.

    Science.gov (United States)

    Ghanbari, Zahra; Housaindokht, Mohammad R; Izadyar, Mohammad; Bozorgmehr, Mohammad R; Eshtiagh-Hosseini, Hossein; Bahrami, Ahmad R; Matin, Maryam M; Khoshkholgh, Maliheh Javan

    2014-01-01

    Quantitative structure activity relationship (QSAR) for the anticancer activity of Fe(III)-salen and salen-like complexes was studied. The methods of density function theory (B3LYP/LANL2DZ) were used to optimize the structures. A pool of descriptors was calculated: 1497 theoretical descriptors and quantum-chemical parameters, shielding NMR, and electronic descriptors. The study of structure and activity relationship was performed with multiple linear regression (MLR) and artificial neural network (ANN). In nonlinear method, the adaptive neuro-fuzzy inference system (ANFIS) was applied in order to choose the most effective descriptors. The ANN-ANFIS model with high statistical significance (R (2) train = 0.99, RMSE = 0.138, and Q (2) LOO = 0.82) has better capability to predict the anticancer activity of the new compounds series of this family. Based on this study, anticancer activity of this compound is mainly dependent on the geometrical parameters, position, and the nature of the substituent of salen ligand. PMID:24955417

  6. Ferns and lycopods--a potential treasury of anticancer agents but also a carcinogenic hazard.

    Science.gov (United States)

    Tomšík, Pavel

    2014-06-01

    Many species of seedless vascular plants-ferns and lycopods-have been used as food and folk medicine since ancient times. Some of them have become the focus of intensive research concerning their anticancer properties. Studies on the anticancer effect of crude extracts are being increasingly replaced by bioactivity-guided fractionation, as well as detailed assessment of the mechanism of action. Numerous compounds-especially flavonoids such as amentoflavone and protoapigenone, and also simpler phenolic compounds, steroids, alkaloids and terpenoids-were isolated and found to be cytotoxic, particularly pro-apoptotic, or to induce cell cycle arrest in cancer cell lines in vitro. In in vivo experiments, some fern-derived compounds inhibited tumour growth with little toxicity. On the other hand, many ferns-not only the well-known Bracken (Pteridium)-may pose a significant hazard to human health due to the fact that they contain carcinogenic sesquiterpenoids and their analogues. The objective of this review is to summarise the recent state of research on the anticancer properties of ferns and lycopods, with a focus on their characteristic bioactive constituents. The carcinogenic hazard posed by ferns is also mentioned. PMID:24123573

  7. Pharmacokinetics and pharmacodynamics of phase II drug metabolizing/antioxidant enzymes gene response by anticancer agent sulforaphane in rat lymphocytes.

    Science.gov (United States)

    Wang, Hu; Khor, Tin Oo; Yang, Qian; Huang, Ying; Wu, Tien-Yuan; Saw, Constance Lay-Lay; Lin, Wen; Androulakis, Ioannis P; Kong, Ah-Ng Tony

    2012-10-01

    This study assesses the pharmacokinetics (PK) and pharmacodynamics (PD) of Nrf2-mediated increased expression of phase II drug metabolizing enzymes (DME) and antioxidant enzymes which represents an important component of cancer chemoprevention in rat lymphocytes following intravenous (iv) administration of an anticancer phytochemical sulforaphane (SFN). SFN was administered intravenously to four groups of male Sprague-Dawley JVC rats each group comprising four animals. Blood samples were drawn at selected time points. Plasma were obtained from half of each of the blood samples and analyzed using a validated LC-MS/MS method. Lymphocytes were collected from the remaining blood samples using Ficoll-Paque Plus centrifuge medium. Lymphocyte RNAs were extracted and converted to cDNA, quantitative real-time PCR analyses were performed, and fold changes were calculated against those at time zero for the relative expression of Nrf2-target genes of phase II DME/antioxidant enzymes. PK-PD modeling was conducted based on Jusko's indirect response model (IDR) using GastroPlus and bootstrap method. SFN plasma concentration declined biexponentially and the pharmacokinetic parameters were generated. Rat lymphocyte mRNA expression levels showed no change for GSTM1, SOD, NF-κB, UGT1A1, or UGT1A6. Moderate increases (2-5-fold) over the time zero were seen for HO-1, Nrf2, and NQO1, and significant increases (>5-fold) for GSTT1, GPx1, and Maf. PK-PD analyses using GastroPlus and the bootstrap method provided reasonable fitting for the PK and PD profiles and parameter estimates. Our present study shows that SFN could induce Nrf2-mediated phase II DME/antioxidant mRNA expression for NQO1, GSTT1, Nrf2, GPx, Maf, and HO-1 in rat lymphocytes after iv administration, suggesting that Nrf2-mediated mRNA expression in lymphocytes may serve as surrogate biomarkers. The PK-PD IDR model simultaneously linking the plasma concentrations of SFN and the PD response of lymphocyte mRNA expression is

  8. Lactobionic acid and carboxymethyl chitosan functionalized graphene oxide nanocomposites as targeted anticancer drug delivery systems.

    Science.gov (United States)

    Pan, Qixia; Lv, Yao; Williams, Gareth R; Tao, Lei; Yang, Huihui; Li, Heyu; Zhu, Limin

    2016-10-20

    In this work, we report a targeted drug delivery system built by functionalizing graphene oxide (GO) with carboxymethyl chitosan (CMC), fluorescein isothiocyanate and lactobionic acid (LA). Analogous systems without LA were prepared as controls. Doxorubicin (DOX) was loaded onto the composites through adsorption. The release behavior from both the LA-functionalized and the LA-free material is markedly pH sensitive. The modified GOs have high biocompatibility with the liver cancer cell line SMMC-7721, but can induce cell death after 24h incubation if loaded with DOX. Tests with shorter (2h) incubation times were undertaken to investigate the selectivity of the GO composites: under these conditions, neither DOX-loaded system was found to be toxic to the non-cancerous L929 cell line, but the LA-containing composite showed the ability to selectively induce cell death in cancerous (SMMC-7721) cells while the LA-free analogue was inactive here also. These findings show that the modified GO materials are strong potential candidates for targeted anticancer drug delivery systems. PMID:27474628

  9. Caleosin-based nanoscale oil bodies for targeted delivery of hydrophobic anticancer drugs

    International Nuclear Information System (INIS)

    Nanoscale artificial oil bodies (NOBs) could be assembled from plant oil, phospholipids (PLs), and oleosin (Ole) as previously reported. NOBs have a lipid-based structure that contains a central oil space enclosed by a monolayer of Ole-bound PLs. As an oil structural protein, Ole functions to maintain the integrity of NOBs. Like Ole, caleosin (Cal) is a plant oil-associated protein. In this study, we investigated the feasibility of NOBs assembled by Cal for targeted delivery of drugs. Cal was first fused with anti-HER2/neu affibody (ZH2), and the resulting fusion gene (Cal–ZH2) was then expressed in Escherichia coli. Consequently, NOBs assembled with the fusion protein were selectively internalized by HER2/neu-positive tumor cells. The internalization efficiency could reach as high as 90%. Furthermore, a hydrophobic anticancer drug, Camptothecin (CPT), was encapsulated into Cal-based NOBs. These CPT-loaded NOBs had a size around 200 nm and were resistant to hemolysis. Release of CPT from NOBs at the non-permissive condition followed a sustained and prolonged profile. After administration of the CPT formulation, Cal–ZH2-displayed NOBs exhibited a strong antitumor activity toward HER2/neu-positive cells both in vitro and in vivo. The result indicates the potential of Cal-based NOBs for targeted delivery of hydrophobic drugs.

  10. Synthesis, biological evaluation, drug-likeness, and in silico screening of novel benzylidene-hydrazone analogues as small molecule anticancer agents.

    Science.gov (United States)

    Alam, Mohammad Sayed; Lee, Dong-Ung

    2016-02-01

    A series of fifteen benzylidene-hydrazone analogues (3a-o), including eight new compounds, were synthesized and evaluated for their cytotoxic activities in four human cancer cell lines and for their antioxidant activities using DPPH. Of the tested compounds 3e, which possesses two methoxy substituents in its benzylidene phenyl ring, was found to be potently cytotoxic to all cancer cell lines tested with IC50 values of 0.12 (lung), 0.024 (ovarian), 0.097 (melanoma), and 0.05 μM (colon), and these IC50 values were comparable to those of the doxorubicin standard (IC50 = 0.021, 0.074, 0.001, and 0.872 μM, respectively). DPPH assay showed compounds 3f, 3i, and 3g had IC50 values of 0.60, 0.99, and 1.30 μM, respectively, which were comparable to that of ascorbic acid (IC50 = 0.87 μM). Computational parameters such as, drug-likeness, ADME properties, toxicity effects, and drug scores were evaluated, and none of the fifteen compounds violated Lipinski's rule of five or Veber's rule, and thus they demonstrated good drug-likeness properties. In addition, all fifteen compounds had a higher drug score than the doxorubicin and BIBR1532. In silico screening was also conducted by docking of the active compounds on the active site of telomerase reverse transcriptase catalytic subunit, an important therapeutic target of anticancer agents, to determine the probable binding properties. The total binding energies of docked compounds are correlated well with cytotoxic potencies (pIC50) against lung, ovarian, melanoma, and colon cancer cell lines indicating that the benzylidene-hydrazones could use for the development of new anticancer agents as a telomerase inhibitor. PMID:26694484

  11. Dual-targeting organometallic ruthenium(II) anticancer complexes bearing EGFR-inhibiting 4-anilinoquinazoline ligands.

    Science.gov (United States)

    Zhang, Yang; Zheng, Wei; Luo, Qun; Zhao, Yao; Zhang, Erlong; Liu, Suyan; Wang, Fuyi

    2015-08-01

    We have recently demonstrated that complexation with (η(6)-arene)Ru(II) fragments confers 4-anilinoquinazoline pharmacophores a higher potential for inducing cellular apoptosis while preserving the highly inhibitory activity of 4-anilinoquinazolines against EGFR and the reactivity of the ruthenium centre to 9-ethylguanine (Chem. Commun., 2013, 49, 10224-10226). Reported herein are the synthesis, characterisation and evaluation of the biological activity of a new series of ruthenium(ii) complexes of the type [(η(6)-arene)Ru(N,N-L)Cl]PF6 (arene = p-cymene, benzene, 2-phenylethanol or indane, L = 4-anilinoquinazolines). These organometallic ruthenium complexes undergo fast hydrolysis in aqueous solution. Intriguingly, the ligation of (arene)Ru(II) fragments with 4-anilinoquinazolines not only makes the target complexes excellent EGFR inhibitors, but also confers the complexes high affinity to bind to DNA minor grooves while maintaining their reactivity towards DNA bases, characterising them with dual-targeting properties. Molecular modelling studies reveal that the hydrolysis of these complexes is a favourable process which increases the affinity of the target complexes to bind to EGFR and DNA. In vitro biological activity assays show that most of this group of ruthenium complexes are selectively active inhibiting the EGF-stimulated growth of the HeLa cervical cancer cell line, and the most active complex [(η(6)-arene)Ru(N,N-L13)Cl]PF6 (, IC50 = 1.36 μM, = 4-(3'-chloro-4'-fluoroanilino)-6-(2-(2-aminoethyl)aminoethoxy)-7-methoxyquinazoline) is 29-fold more active than its analogue, [(η(6)-arene)Ru(N,N-ethylenediamine)Cl]PF6, and 21-fold more active than gefitinib, a well-known EGFR inhibitor in use clinically. These results highlight the strong promise to develop highly active ruthenium anticancer complexes by ligation of cytotoxic ruthenium pharmacophores with bioactive organic molecules. PMID:26106875

  12. Anthracenedione Derivatives as Anticancer Agents Isolated from Secondary Metabolites of the Mangrove Endophytic Fungi

    Directory of Open Access Journals (Sweden)

    Jian-ye Zhang

    2010-04-01

    Full Text Available In this article, we report anticancer activity of 14 anthracenedione derivatives separated from the secondary metabolites of the mangrove endophytic fungi Halorosellinia sp. (No. 1403 and Guignardia sp. (No. 4382. Some of them inhibited potently the growth of KB and KBv200 cells, among which compound 6 displayed strong cytotoxicity with IC50 values of 3.17 and 3.21 μM to KB and KBv200 cells, respectively. Furthermore, we demonstrate that the mechanism involved in the apoptosis induced by compound 6 is probably related to mitochondrial dysfunction. Additionally, the structure-activity relationships of these compounds are discussed.

  13. Design, synthesis, and mechanistic studies of Sansalvamide A derivatives as anti-cancer agents

    OpenAIRE

    Alexander, Leslie Diane

    2012-01-01

    Sansalvamide A (SanA) is a cyclic depsipeptide that was isolated from a marine fungus and demonstrates mid- micromolar anti-cancer activity in the NCI 60-cell line panel. Our laboratory has synthesized over 100 peptide derivatives of this molecule, 5 of which were contributed by the author of this dissertation. The design and solution-phase synthesis of these derivatives is described in Chapter 2. The author was also responsible for attaching PEG-biotin and fluorescein tags to lead SanA deriv...

  14. A network biology approach evaluating the anticancer effects of bortezomib identifies SPARC as a therapeutic target in adult T-cell leukemia cells

    Directory of Open Access Journals (Sweden)

    Yu Zhang

    2008-10-01

    Full Text Available Junko H Ohyashiki1, Ryoko Hamamura2, Chiaki Kobayashi2, Yu Zhang2, Kazuma Ohyashiki21Intractable Immune System Disease Research Center, Tokyo Medical University, Tokyo, Japan; 2First Department of Internal Medicine, Tokyo Medical University, Tokyo, JapanAbstract: There is a need to identify the regulatory gene interaction of anticancer drugs on target cancer cells. Whole genome expression profiling offers promise in this regard, but can be complicated by the challenge of identifying the genes affected by hundreds to thousands of genes that induce changes in expression. A proteasome inhibitor, bortezomib, could be a potential therapeutic agent in treating adult T-cell leukemia (ATL patients, however, the underlying mechanism by which bortezomib induces cell death in ATL cells via gene regulatory network has not been fully elucidated. Here we show that a Bayesian statistical framework by VoyaGene® identified a secreted protein acidic and rich in cysteine (SPARC gene, a tumor-invasiveness related gene, as a possible modulator of bortezomib-induced cell death in ATL cells. Functional analysis using RNAi experiments revealed that inhibition of the expression SPARC by siRNA enhanced the apoptotic effect of bortezomib on ATL cells in accordance with an increase of cleaved caspase 3. Targeting SPARC may help to treat ATL patients in combination with bortezomib. This work shows that a network biology approach can be used advantageously to identify the genetic interaction related to anticancer effects.Keywords: network biology, adult T cell leukemia, bortezomib, SPARC

  15. THE ROLE OF RED PIGMENT PRODIGIOSIN FROM BACTERIA OF EARTHWORM GUT AS AN ANTICANCER AGENT

    Directory of Open Access Journals (Sweden)

    Sruthy P.B.

    2014-12-01

    Full Text Available Earthworms are the most ancient invertebrate animals on earth which can be used as a good source of pharmaceutical compounds. A study was carried out to find out the distribution of microorganisms in the gut of earthworm, Eudrilus eugeniae. Significant number of microbial populations in the gut of earthworm was observed and it was gradually increased from the initial day to final day of composting. Pigmented colonies of bacteria from earthworm gut were selectively isolated, the pigment was extracted from the culture broth and a presumptive test was carried out for the confirmation of prodigiosin. The pigment component was separated using thin layer chromatography and the structural elucidation of the compound was performed using U.V. spectroscopy. The inhibitory effect of prodigiosin on bacterial pathogens was studied and the results confirmed the antibacterial activity against gram positive bacteria. The anticancer activity of the prodigiosin pigment was evaluated under in vitro conditions against the breast cancer cell lines and it was observed that prodigiosin induced the apoptosis in MCF-7 cell lines in a dose dependent manner. Then the potential isolate was subjected to morphological and biochemical analysis and it was confirmed that the colonies were of Serratia marcescens. The results obtained from the present study indicated that earthworm gut is promising and could be a vital source of habitat possessing antimicrobial and anticancer activity.

  16. Synthesis and evaluation of L-glutamic acid analogs as potential anticancer agents

    Directory of Open Access Journals (Sweden)

    Viswanathan C

    2008-01-01

    Full Text Available Four N-(benzenesulfonyl-L-glutamic acid bis(p-substituted phenylhydrazides were synthesized and evaluated for anticancer activity in vitro in DU-145 and PC-3 prostate cancer and in COLO-205 colon cancer cell lines by MTT assay. The analog with the nitro group substitution exhibited potent activity (% Inhibition 84.7 and 72.0 in DU-145 and PC-3 respectively at 80 mg/ml concentration. Another series of substituted 1-(benzenesulfonyl-5-oxopyrrolidine 2-carboxamides (11a-f were synthesized and evaluated for anticancer activity in vitro in colon (COLO-205, breast (Zr-75-1 and prostate (PC-3 cancer cell lines by MTT assay using adriamycin as standard. Test compounds 11a-c showed potent activity (% Inhibition 61.2 to 79.2 at 20 mg/ml and 67.2 to 87.2 at 40 mg/ml in PC-3 cell line which is superior to the activity of Adriamycin. In comparison compounds 11d-f were less potent. In Zr-75-1 cell line 11a-e showed % inhibition ranging from 32.4 to 54.9 at 10 mg/ml concentration while in COLO-205 cell line 11a-f showed poor activity.

  17. Synthesis and Characterization of Celecoxib Derivatives as Possible Anti-Inflammatory, Analgesic, Antioxidant, Anticancer and Anti-HCV Agents

    Directory of Open Access Journals (Sweden)

    Amartya Basu

    2013-03-01

    Full Text Available A series of novel N-(3-substituted aryl/alkyl-4-oxo-1,3-thiazolidin-2-ylidene-4-[5-(4-methylphenyl-3-(trifluoromethyl-1H-pyrazol-1-yl]benzenesulfonamides 2a–e were synthesized by the addition of ethyl a-bromoacetate and anhydrous sodium acetate in dry ethanol to N-(substituted aryl/alkylcarbamothioyl-4-[5-(4-methylphenyl-3-(trifluoro-methyl-1H-pyrazol-1-yl]benzene sulfonamides 1a–e, which were synthesized by the reaction of alkyl/aryl isothiocyanates with celecoxib. The structures of the isolated products were determined by spectral methods and their anti-inflammatory, analgesic, antioxidant, anticancer and anti-HCV NS5B RNA-dependent RNA polymerase (RdRp activities evaluated. The compounds were also tested for gastric toxicity and selected compound 1a was screened for its anticancer activity against 60 human tumor cell lines. These investigations revealed that compound 1a exhibited anti-inflammatory and analgesic activities and further did not cause tissue damage in liver, kidney, colon and brain compared to untreated controls or celecoxib. Compounds 1c and 1d displayed modest inhibition of HCV NS5B RdRp activity. In conclusion, N-(ethylcarbamothioyl-4-[5-(4-methylphenyl-3-(trifluoromethyl-1H-pyrazol-1-yl]benzenesulfonamide (1a may have the potential to be developed into a therapeutic agent.

  18. Curcumin-I Knoevenagel's condensates and their Schiff's bases as anticancer agents: synthesis, pharmacological and simulation studies.

    Science.gov (United States)

    Ali, Imran; Haque, Ashanul; Saleem, Kishwar; Hsieh, Ming Fa

    2013-07-01

    Pyrazolealdehydes (4a-d), Knoevenagel's condensates (5a-d) and Schiff's bases (6a-d) of curcumin-I were synthesized, purified and characterized. Hemolysis assays, cell line activities, DNA bindings and docking studies were carried out. These compounds were lesser hemolytic than standard drug doxorubicin. Minimum cell viability (MCF-7; wild) observed was 59% (1.0 μg/mL) whereas the DNA binding constants ranged from 1.4×10(3) to 8.1×10(5) M(-1). The docking energies varied from -7.30 to -13.4 kcal/mol. It has been observed that DNA-compound adducts were stabilized by three governing forces (Van der Wall's, H-bonding and electrostatic attractions). It has also been observed that compounds 4a-d preferred to enter minor groove while 5a-d and 6a-d interacted with major grooves of DNA. The anticancer activities of the reported compounds might be due to their interactions with DNA. These results indicated the bright future of the reported compounds as anticancer agents. PMID:23643901

  19. 3-PHENYLQUINOLINYLCHALCONE DERIVATIVES: PHARMACOPHORE MODELLING, 3D-QSAR ANALYSIS AND DOCKING STUDIES AS ANTI-CANCER AGENTS

    Directory of Open Access Journals (Sweden)

    Manoj Kumar Mahto

    2014-02-01

    Full Text Available Certain 3-Phenylquinolinylchalcone derivatives were evaluated for their anti-proliferative activities and found to exhibit anti-cancer and anti-inflammatory activities. 3D-QSAR and molecular docking approaches were performed on 3-Phenylquinolinylchalcone derivatives to understand their structural requisites and binding mode of the best fitted ligand for cancer inhibitory activity. Among them, (E-3-(3-(4-methoxyphenylquinolin-2-yl-1-phenylprop-2-en-1-one (6a was the most active compound against the growth of  H460, MCF-7, MDA-MB-231 and SKBR-3 cancer cell line respectively. Four featured hypothesis  AHRR.521 of  H460 was considered to be the best hypothesis which yielded a statistically significant 3D-QSAR model built with PLS values 3, Regression coefficient (R2 = 0.8986, Cross validation coefficient (Q2 = 0.9542, Root Mean Square Deviation (RMSD = 0.0067, Pearson-R = 1. Interestingly, the result of docking was found to correlate with the pharmacophore study where this compound was active against all six oncoproteins p53, Raf Kinase, Aurora-A-Kinase, CDK-2, Resveratrol and HSP90. The results provide detailed insights of 6a compound which can afford guidance for rational drug design of novel potent anti-cancer agents

  20. Current approaches to improve the anticancer chemotherapy with alkylating agents: state of the problem in world and Ukraine.

    Directory of Open Access Journals (Sweden)

    Iatsyshyna A. P.

    2012-01-01

    Full Text Available Alkylating agents are frequently used in many established anticancer chemotherapies. They alkylate the genomic DNA at various sites. Alkylation of the guanine at the O6-position is cytotoxic, it has the strongest mutagenic potential, as well as can cause the tumor development. Alkyl groups at the O6-position of guanine are removed by the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT. The effectiveness of alkylating chemotherapy is limited by MGMT in cancer cells and adverse toxic side effects in normal cells. Different approaches consisting in the modulation of the MGMT expression and activity are under development now to improve the cancer chemotherapy. They include two main directions, in particular, the increase in chemosensitivity of cancer cells to alkylating drugs and the protection of normal cells from the toxic side effects of chemotherapy. This review is focused on current attempts to improve the alkylating chemotherapy of malignant tumours worldwide and state of the issue in Ukraine

  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. Hypersensitivity reactions to anticancer agents: Data mining of the public version of the FDA adverse event reporting system, AERS

    Directory of Open Access Journals (Sweden)

    Sakaeda Toshiyuki

    2011-10-01

    Full Text Available Abstract Background Previously, adverse event reports (AERs submitted to the US Food and Drug Administration (FDA database were reviewed to confirm platinum agent-associated hypersensitivity reactions. The present study was performed to confirm whether the database could suggest the hypersensitivity reactions caused by anticancer agents, paclitaxel, docetaxel, procarbazine, asparaginase, teniposide, and etoposide. Methods After a revision of arbitrary drug names and the deletion of duplicated submissions, AERs involving candidate agents were analyzed. The National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 was applied to evaluate the susceptibility to hypersensitivity reactions, and standardized official pharmacovigilance tools were used for quantitative detection of signals, i.e., drug-associated adverse events, including the proportional reporting ratio, the reporting odds ratio, the information component given by a Bayesian confidence propagation neural network, and the empirical Bayes geometric mean. Results Based on 1,644,220 AERs from 2004 to 2009, the signals were detected for paclitaxel-associated mild, severe, and lethal hypersensitivity reactions, and docetaxel-associated lethal reactions. However, the total number of adverse events occurring with procarbazine, asparaginase, teniposide, or etoposide was not large enough to detect signals. Conclusions The FDA's adverse event reporting system, AERS, and the data mining methods used herein are useful for confirming drug-associated adverse events, but the number of co-occurrences is an important factor in signal detection.

  3. Design and synthesis of diamide-coupled benzophenones as potential anticancer agents.

    Science.gov (United States)

    Zabiulla; Shamanth Neralagundi, H G; Bushra Begum, A; Prabhakar, B T; Khanum, Shaukath Ara

    2016-06-10

    A series of diamide-coupled benzophenone, 2-(4-benzoyl-phenoxy)-N-{2-[2-(4-benzoyl-phenoxy)-acetylamino]-phenyl}-acetamide analogues (9a-l) were synthesized by multistep reactions and all compounds were well characterized. Among the series (9a-l), compound 9k with three methyl groups at ortho position in rings A, B, and D and bromo group at the para position in ring E was selected as a lead compound by screening through multiple cancer cell types by in-vitro cytotoxic and antiproliferative assay systems. Also, the cytotoxic nature of the compound 9k resulted the regression of the tumor growth in-vivo, which could be due to decreased vascularisation in the peritoneum lining of the mice which regress the tumor growth. The results were reconfirmed in-vivo chorioallantoic membrane model which indicates a scope of developing 9k into potent anticancer drug in near future. PMID:27027818

  4. Lappaol F, a novel anticancer agent isolated from plant arctium Lappa L.

    Science.gov (United States)

    Sun, Qing; Liu, Kanglun; Shen, Xiaoling; Jin, Weixin; Jiang, Lingyan; Sheikh, M Saeed; Hu, Yingjie; Huang, Ying

    2014-01-01

    In an effort to search for new cancer-fighting therapeutics, we identified a novel anticancer constituent, Lappaol F, from plant Arctium Lappa L. Lappaol F suppressed cancer cell growth in a time- and dose-dependent manner in human cancer cell lines of various tissue types. We found that Lappaol F induced G(1) and G(2) cell-cycle arrest, which was associated with strong induction of p21 and p27 and reduction of cyclin B1 and cyclin-dependent kinase 1 (CDK1). Depletion of p21 via genetic knockout or short hairpin RNA (shRNA) approaches significantly abrogated Lappaol F-mediated G(2) arrest and CDK1 and cyclin B1 suppression. These results suggest that p21 seems to play a crucial role in Lappaol F-mediated regulation of CDK1 and cyclin B1 and G(2) arrest. Lappaol F-mediated p21 induction was found to occur at the mRNA level and involved p21 promoter activation. Lappaol F was also found to induce cell death in several cancer cell lines and to activate caspases. In contrast with its strong growth inhibitory effects on tumor cells, Lappaol F had minimal cytotoxic effects on nontumorigenic epithelial cells tested. Importantly, our data also demonstrate that Lappaol F exhibited strong growth inhibition of xenograft tumors in nude mice. Lappaol F was well tolerated in treated animals without significant toxicity. Taken together, our results, for the first time, demonstrate that Lappaol F exhibits antitumor activity in vitro and in vivo and has strong potential to be developed as an anticancer therapeutic. PMID:24222662

  5. Electrochemical and calorimetric investigation of interaction of novel biscationic anticancer agents with DNA; Investigacao eletroquimica e calorimetrica da interacao de novos agentes antitumorais biscationicos com DNA

    Energy Technology Data Exchange (ETDEWEB)

    Silva, Lauris Lucia da; Donnici, Claudio Luis; Lopes, Julio Cesar Dias, E-mail: cdonnici@terra.com.br [Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil). Inst. de Ciencias Exatas. Dept. de Quimica; Goulart, Marilia Oliveira Fonseca; Abreu, Fabiane Caxico de; Paula, Francine Santos de [Universidade Federal de Alagoas (UFAL), Maceio, AL (Brazil). Campus A.C. Simoes. Inst. de Quimica e Biotecnologia; Bravo, Carlos E. Salas; Santoro, Marcelo Matos [Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil). Dept. de Bioquimica e Imunologia; Denadai, Angelo Marcio Leite [Centro Federal de Educacao Tecnologica, Timoteo, MG (Brazil). Campus VII; Santos, Alexandre Martins Costa [Universidade Federal do Espirito Santo, Vitoria, ES (Brazil). Dept. de Ciencias Fisiologicas; Montanari, Carlos Alberto [Universidade de Sao Paulo, Sao Carlos, SP (Brazil). Inst. de Quimica

    2012-07-01

    Biscationic amidines bind in the DNA minor groove and present biological activity against a range of infectious diseases. Two new biscationic compounds (bis-{alpha}-{omega}-S-thioureido, amino and sulfide analogues) were synthesized in good yields and fully characterized, and their interaction with DNA was also investigated. Isothermal titration calorimetry (ITC) was used to measure the thermodynamic properties of binding interactions between DNA and these ligands. A double stranded calf thymus DNA immobilized on an electrode surface was used to study the possible DNA-interacting abilities of these compounds towards dsDNA in situ. A remarkable interaction of these compounds with DNA was demonstrated and their potential application as anticancer agents was furthered. (author)

  6. Self-Targeted, Shape-Assisted, and Controlled-Release Self-Delivery Nanodrug for Synergistic Targeting/Anticancer Effect of Cytoplasm and Nucleus of Cancer Cells.

    Science.gov (United States)

    Li, Yang; Lin, Jinyan; Huang, Yu; Li, Yanxiu; Yang, Xiangrui; Wu, Hongjie; Wu, Shichao; Xie, Liya; Dai, Lizong; Hou, Zhenqing

    2015-11-25

    We constructed 10-hydroxycamptothecin (CPT) "nanodrugs" with functionalization of lipid-PEG-methotrexate (MTX) to prepare high-drug-loaded, and sustained/controlled-release MTX-PEG-CPT nanorods (NRs), in which MTX drug itself can serve as a specific "targeting ligand". The self-targeted nanodrug can codeliver both CPT and MTX drugs with distinct anticancer mechanisms. Furthermore, MTX-PEG-CPT NRs significantly reduced burst release, improved blood circulation and tumor accumulation, enhanced cellular uptake, and synergistically increased anticancer effect against tumor cells compared with MTX-PEG-CPT nanospheres (NSs) and either both free drugs or individual free drug. Therefore, the synergistic targeting/therapeuticy nano-multi-drug codelivery assisted by shape design may advantageously offer a promising new strategy for nanomedicine. PMID:26529185

  7. Human synthetic lethal inference as potential anti-cancer target gene detection

    OpenAIRE

    Solé Ricard V; Munteanu Andreea; Conde-Pueyo Nuria; Rodríguez-Caso Carlos

    2009-01-01

    Abstract Background Two genes are called synthetic lethal (SL) if mutation of either alone is not lethal, but mutation of both leads to death or a significant decrease in organism's fitness. The detection of SL gene pairs constitutes a promising alternative for anti-cancer therapy. As cancer cells exhibit a large number of mutations, the identification of these mutated genes' SL partners may provide specific anti-cancer drug candidates, with minor perturbations to the healthy cells. Since exi...

  8. Zampanolide and Dactylolide: Cytotoxic Tubulin-Assembly Agents and Promising Anticancer Leads

    OpenAIRE

    Chen, Qiao-Hong; Kingston, David G. I.

    2014-01-01

    Zampanolide is a marine natural macrolide and a recent addition to the family of microtubule-stabilizing cytotoxic agents. Zampanolide exhibits unique effects on tubulin assembly and is more potent than paclitaxel against several multi-drug resistant cancer cell lines. A high-resolution crystal structure of xB-tubulin in complex with zampanolide explains how taxane-site microtubule-stabilizing agents promote microtubule assemble and stability. This review provides an overview of current devel...

  9. Zampanolide and dactylolide: cytotoxic tubulin-assembly agents and promising anticancer leads

    OpenAIRE

    Chen, Qiao-Hong; Kingston, David G. I.

    2014-01-01

    Covering: through January 2014 Zampanolide is a marine natural macrolide and a recent addition to the family of microtubule-stabilizing cytotoxic agents. Zampanolide exhibits unique effects on tubulin assembly and is more potent than paclitaxel against several multi-drug resistant cancer cell lines. A high-resolution crystal structure of αβ-tubulin in complex with zampanolide explains how taxane-site microtubule-stabilizing agents promote microtubule assemble and stability. This review provid...

  10. Mode of action and resistance studies unveil new roles for tropodithietic acid as an anticancer agent and the γ-glutamyl cycle as a proton sink.

    Science.gov (United States)

    Wilson, Maxwell Z; Wang, Rurun; Gitai, Zemer; Seyedsayamdost, Mohammad R

    2016-02-01

    While we have come to appreciate the architectural complexity of microbially synthesized secondary metabolites, far less attention has been paid to linking their structural features with possible modes of action. This is certainly the case with tropodithietic acid (TDA), a broad-spectrum antibiotic generated by marine bacteria that engage in dynamic symbioses with microscopic algae. TDA promotes algal health by killing unwanted marine pathogens; however, its mode of action (MoA) and significance for the survival of an algal-bacterial miniecosystem remains unknown. Using cytological profiling, we herein determine the MoA of TDA and surprisingly find that it acts by a mechanism similar to polyether antibiotics, which are structurally highly divergent. We show that like polyether drugs, TDA collapses the proton motive force by a proton antiport mechanism, in which extracellular protons are exchanged for cytoplasmic cations. The α-carboxy-tropone substructure is ideal for this purpose as the proton can be carried on the carboxyl group, whereas the basicity of the tropylium ion facilitates cation export. Based on similarities to polyether anticancer agents we have further examined TDA's cytotoxicity and find it to exhibit potent, broad-spectrum anticancer activities. These results highlight the power of MoA-profiling technologies in repurposing old drugs for new targets. In addition, we identify an operon that confers TDA resistance to the producing marine bacteria. Bioinformatic and biochemical analyses of these genes lead to a previously unknown metabolic link between TDA/acid resistance and the γ-glutamyl cycle. The implications of this resistance mechanism in the context of the algal-bacterial symbiosis are discussed. PMID:26802120

  11. SynLethDB: synthetic lethality database toward discovery of selective and sensitive anticancer drug targets.

    Science.gov (United States)

    Guo, Jing; Liu, Hui; Zheng, Jie

    2016-01-01

    Synthetic lethality (SL) is a type of genetic interaction between two genes such that simultaneous perturbations of the two genes result in cell death or a dramatic decrease of cell viability, while a perturbation of either gene alone is not lethal. SL reflects the biologically endogenous difference between cancer cells and normal cells, and thus the inhibition of SL partners of genes with cancer-specific mutations could selectively kill cancer cells but spare normal cells. Therefore, SL is emerging as a promising anticancer strategy that could potentially overcome the drawbacks of traditional chemotherapies by reducing severe side effects. Researchers have developed experimental technologies and computational prediction methods to identify SL gene pairs on human and a few model species. However, there has not been a comprehensive database dedicated to collecting SL pairs and related knowledge. In this paper, we propose a comprehensive database, SynLethDB (http://histone.sce.ntu.edu.sg/SynLethDB/), which contains SL pairs collected from biochemical assays, other related databases, computational predictions and text mining results on human and four model species, i.e. mouse, fruit fly, worm and yeast. For each SL pair, a confidence score was calculated by integrating individual scores derived from different evidence sources. We also developed a statistical analysis module to estimate the druggability and sensitivity of cancer cells upon drug treatments targeting human SL partners, based on large-scale genomic data, gene expression profiles and drug sensitivity profiles on more than 1000 cancer cell lines. To help users access and mine the wealth of the data, we developed other practical functionalities, such as search and filtering, orthology search, gene set enrichment analysis. Furthermore, a user-friendly web interface has been implemented to facilitate data analysis and interpretation. With the integrated data sets and analytics functionalities, SynLethDB would

  12. IGF-1R as an anti-cancer target-trials and tribulations

    Institute of Scientific and Technical Information of China (English)

    Helen X.Chen; Elad Sharon

    2013-01-01

    Type Ⅰ insulin-like growth factor receptor (IGF-1R) has long been recognized for its role in tumorigenesis and growth,but only recently have the tools for targeting the IGF pathway become available.More than 10 IGF/IGF-1R inhibitors have entered clinical trials,and these belong to three main classes:(1)monoclonal antibodies against IGF-1R,(2) monoclonal antibodies against IGF-1R ligands (IGF-1 and IGF-2),and (3) IGF-1R tyrosine kinase inhibitors.These IGF-1R-targeting agents share common effects on IGF-1R signaling but differ in mechanisms of action,spectrum of target inhibition,and pharmacological features.Clinical activity of IGF-1R inhibitors has been demonstrated with sustained responses in a small number of patients with select tumor types,such as Ewing sarcoma and thymoma.However,many large clinical trials involving patients with adult tumors,including non-small cell lung cancer,breast cancer,and pancreatic cancer,failed to show clinical benefit in the overall patient population.Possible reasons for failure include the complexity of the IGF-1R/insulin receptor system and parallel growth and survival pathways,as well as a lack of patient selection markers.While IGF-1R remains a valid target for selected tumor types,identification of predictive markers and rational combinations will be critical to success in future development.

  13. Progress Toward the Development of Noscapine and Derivatives as Anticancer Agents.

    Science.gov (United States)

    DeBono, Aaron; Capuano, Ben; Scammells, Peter J

    2015-08-13

    Many nitrogen-moiety containing alkaloids derived from plant origins are bioactive and play a significant role in human health and emerging medicine. Noscapine, a phthalideisoquinoline alkaloid derived from Papaver somniferum, has been used as a cough suppressant since the mid 1950s, illustrating a good safety profile. Noscapine has since been discovered to arrest cells at mitosis, albeit with moderately weak activity. Immunofluorescence staining of microtubules after 24 h of noscapine exposure at 20 μM elucidated chromosomal abnormalities and the inability of chromosomes to complete congression to the equatorial plane for proper mitotic separation ( Proc. Natl. Acad. Sci. U. S. A. 1998 , 95 , 1601 - 1606 ). A number of noscapine analogues possessing various modifications have been described within the literature and have shown significantly improved antiprolific profiles for a large variety of cancer cell lines. Several semisynthetic antimitotic alkaloids are emerging as possible candidates as novel anticancer therapies. This perspective discusses the advancing understanding of noscapine and related analogues in the fight against malignant disease. PMID:25811651

  14. The Use of 1α,25-Dihydroxyvitamin D3 as an Anticancer Agent

    Directory of Open Access Journals (Sweden)

    Ewa Marcinkowska

    2016-05-01

    Full Text Available The notion that vitamin D can influence the incidence of cancer arose from epidemiological studies. The major source of vitamin D in the organism is skin production upon exposure to ultra violet-B. The very first observation of an inverse correlation between exposure of individuals to the sun and the likelihood of cancer was reported as early as 1941. In 1980, Garland and Garland hypothesised, from findings from epidemiological studies of patients in the US with colon cancer, that vitamin D produced in response to sun exposure is protective against cancer as opposed to sunlight per se. Later studies revealed inverse correlations between sun exposure and the occurrence of prostate and breast cancers. These observations prompted laboratory investigation of whether or not vitamin D had an effect on cancer cells. Vitamin D is not active against cancer cells, but the most active metabolite 1α,25-dihydroxyvitamin D3 (1,25D has profound biological effects. Here, we review the anticancer action of 1,25D, clinical trials of 1,25D to date and the prospects of the future therapeutic use of new and low calcaemic analogues.

  15. Synthesis and evaluation of polymeric gold glyco-conjugates as anti-cancer agents.

    Science.gov (United States)

    Ahmed, Marya; Mamba, Saul; Yang, Xiao-Hong; Darkwa, James; Kumar, Piyush; Narain, Ravin

    2013-06-19

    The antitumor activity of organo-gold compounds is a focus of research from the past two decades. A variety of gold stabilizing ligands such as vitamins and xanthanes have been prepared and explored for their 'chelating effect' as well as for their antitumor activity. Dithiocarbamates (DTC) compounds and their metallic conjugates have been well explored for their antiproliferative activities. In this study, glycopolymer based DTC-conjugates are prepared by reversible addition-fragmentation chain transfer polymerization (RAFT) and subsequently modified with gold(I) phosphine. These polymer-DTC derivatives and their gold compounds are tested for their in vitro toxicity in both normal and cancer cell lines. The Au(I) phosphine conjugated cationic glycopolymers of 10 kDa and 30 kDa are evaluated for their cytotoxicity profiles using MTT assay. Au(I) compounds are well-known for their mitochondrial toxicity, hence hypoxic cell lines bearing unusually enlarged mitochondria are subjected to these anticancer compounds. It is concluded that these polymeric DTC derivatives and their gold conjugates indeed show higher accumulation as well as cytotoxicity to cancer cells under hypoxic conditions in comparison to the normoxic ones. Hypoxic MCF-7 cells showed significant sensitivity toward the low molecular weight (10 kDa) glycopolymer-Au(I) complexes. PMID:23631753

  16. Discovery and optimization of novel dual dithiocarbamates as potent anticancer agents.

    Science.gov (United States)

    Li, Ri-Dong; Wang, Hui-Ling; Li, Ying-Bo; Wang, Zhong-Qing; Wang, Xin; Wang, Yi-Tao; Ge, Ze-Mei; Li, Run-Tao

    2015-03-26

    A series of dual dithiocarbamates were synthesized and evaluated for their in-vitro anticancer activities on human non-small cell lung cancer cell line H460. Nine compounds exhibited significant antiproliferative activities with IC50 less than 1 μM. Among them, compound 14m showed the highest inhibitory activity against H460 cell and inhibited the growth of nine types of tumor cells with IC50 values less than 1 μM. It also achieved IC50 of 54 nM and 23 nM against HepG2 and MCF-7 cell lines, respectively. Preliminary structure-activity relationship study indicated that: a) when the methyl group (region A) is substituted with benzene rings, ortho substitution on the benzene ring is favored for activity; b) substitution with heterocyclic structures at region A exhibited greater impact on the anti-tumor activity of compounds, in which pyridine ring, thiazole ring, coumarin and benzo[b]thiophene are favored and quinoline ring is the most favored; c) substitution with different amines (region B) also showed marked effect on the activity of compounds and dimethylamine and morpholine are preferred to other tested amines. PMID:25725374

  17. The Use of 1α,25-Dihydroxyvitamin D3 as an Anticancer Agent

    Science.gov (United States)

    Marcinkowska, Ewa; Wallace, Graham R.; Brown, Geoffrey

    2016-01-01

    The notion that vitamin D can influence the incidence of cancer arose from epidemiological studies. The major source of vitamin D in the organism is skin production upon exposure to ultra violet-B. The very first observation of an inverse correlation between exposure of individuals to the sun and the likelihood of cancer was reported as early as 1941. In 1980, Garland and Garland hypothesised, from findings from epidemiological studies of patients in the US with colon cancer, that vitamin D produced in response to sun exposure is protective against cancer as opposed to sunlight per se. Later studies revealed inverse correlations between sun exposure and the occurrence of prostate and breast cancers. These observations prompted laboratory investigation of whether or not vitamin D had an effect on cancer cells. Vitamin D is not active against cancer cells, but the most active metabolite 1α,25-dihydroxyvitamin D3 (1,25D) has profound biological effects. Here, we review the anticancer action of 1,25D, clinical trials of 1,25D to date and the prospects of the future therapeutic use of new and low calcaemic analogues. PMID:27187375

  18. The Use of 1α,25-Dihydroxyvitamin D₃ as an Anticancer Agent.

    Science.gov (United States)

    Marcinkowska, Ewa; Wallace, Graham R; Brown, Geoffrey

    2016-01-01

    The notion that vitamin D can influence the incidence of cancer arose from epidemiological studies. The major source of vitamin D in the organism is skin production upon exposure to ultra violet-B. The very first observation of an inverse correlation between exposure of individuals to the sun and the likelihood of cancer was reported as early as 1941. In 1980, Garland and Garland hypothesised, from findings from epidemiological studies of patients in the US with colon cancer, that vitamin D produced in response to sun exposure is protective against cancer as opposed to sunlight per se. Later studies revealed inverse correlations between sun exposure and the occurrence of prostate and breast cancers. These observations prompted laboratory investigation of whether or not vitamin D had an effect on cancer cells. Vitamin D is not active against cancer cells, but the most active metabolite 1α,25-dihydroxyvitamin D₃ (1,25D) has profound biological effects. Here, we review the anticancer action of 1,25D, clinical trials of 1,25D to date and the prospects of the future therapeutic use of new and low calcaemic analogues. PMID:27187375

  19. Synthesis, cytotoxic activity evaluation and HQSAR study of novel isosteviol derivatives as potential anticancer agents.

    Science.gov (United States)

    Liu, Cong-Jun; Yu, Shu-Ling; Liu, Yan-Ping; Dai, Xing-Jie; Wu, Ya; Li, Rui-Jun; Tao, Jing-Chao

    2016-06-10

    A series of novel isosteviol derivatives bearing amino alcohol and thiourea fragments have been stereo-selectively synthesized and screened for their in vitro cytotoxic activities against three human cancer cell lines (HCT-116, HGC-27 and JEKO-1). The results demonstrated that these compounds exhibited prominent cytotoxicities. Especially, the compound Iw displayed the most potent anticancer activities against HCT-116 cell with IC50 value of 1.450 μM. On the basis of this bioassay results, these derivatives were further investigated by the hologram quantitative structure-activity relationship (HQSAR) technique. The optimal HQSAR model with q(2) = 0.663, r(2) = 0.895, SEE = 0.179 was generated using A/B/H/Ch as fragment distinction parameters and 4-7 as fragment size. This model was employed to predict the cytotoxic activities of test set compounds, and the predicted values were in good agreement with the experimental results. The contribution maps derived from the optimal model explained the individual atomic contribution to the total activity of single molecule. PMID:26994841

  20. Modeling of hyaluronic acid containing anti-cancer drugs-loaded polylactic-co-glycolic acid bioconjugates for targeted delivery to cancer cells

    Science.gov (United States)

    Gul-e-Saba, Adulphakdee, A.; Madthing, A.; Zafar, M. N.; Abdullah, M. A.

    2012-09-01

    Molecular modeling of hyaluronan (HA), polylactic-co-glycolic acid (PLGA), polyethylene glycol-bis-amine (PEG-bis-amine), Curcumin, Cisplatin and the conjugate HA-PEG-PLGA containing Curcumin/Cisplatin were performed using Discovery Studio 2.5 to better understand issues and constraints related to targeted delivery of potent anticancer drugs to cancer cells. HA, a versatile biopolymer is a ligand of cancer cell receptor, CD44 that can be particularly useful in a receptor-mediated cellular uptake of drug-incorporated nanoparticles. Biocompatible and biodegradable polymers, PLGA and PEG, serve as polymeric micelles for controlled-release of drug. Curcumin as a natural anticancer agent has poor solubility that limits its use in drug therapeutics, while platinum-based Cisplatin exhibits systemic cytotoxicity. These can be overcome via drug delivery in polymeric biocompatible vehicles. The PLGA-PEG-HA conjugate shows the total measurement of 105 bond length with average bond length of 1.274163 Å. The conjugation between PEG and HA occurs at C8-O1 atoms and can be manipulated to improve properties.

  1. Suprafenacine, an indazole-hydrazide agent, targets cancer cells through microtubule destabilization.

    Directory of Open Access Journals (Sweden)

    Bo-Hwa Choi

    Full Text Available Microtubules are a highly validated target in cancer therapy. However, the clinical development of tubulin binding agents (TBA has been hampered by toxicity and chemoresistance issues and has necessitated the search for new TBAs. Here, we report the identification of a novel cell permeable, tubulin-destabilizing molecule--4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid [1p-tolyl-meth-(E-ylidene]-hydrazide (termed as Suprafenacine, SRF. SRF, identified by in silico screening of annotated chemical libraries, was shown to bind microtubules at the colchicine-binding site and inhibit polymerization. This led to G2/M cell cycle arrest and cell death via a mitochondria-mediated apoptotic pathway. Cell death was preceded by loss of mitochondrial membrane potential, JNK-mediated phosphorylation of Bcl-2 and Bad, and activation of caspase-3. Intriguingly, SRF was found to selectively inhibit cancer cell proliferation and was effective against drug-resistant cancer cells by virtue of its ability to bypass the multidrug resistance transporter P-glycoprotein. Taken together, our results suggest that SRF has potential as a chemotherapeutic agent for cancer treatment and provides an alternate scaffold for the development of improved anti-cancer agents.

  2. Aptamers as targeting delivery devices or anti-cancer drugs for fighting tumors.

    Science.gov (United States)

    Scaggiante, Bruna; Dapas, Barbara; Farra, Rossella; Grassi, Mario; Pozzato, Gabriele; Giansante, Carlo; Fiotti, Nicola; Tamai, Elisa; Tonon, Federica; Grassi, Gabriele

    2013-06-01

    Aptamer researches applied to the treatment of human cancers have increased since their discovery in 1990. This is due to different factors including: 1) the technical possibility to select, by SELEX-based procedures, specific aptamers targeting virtually any given molecule, 2) the aptamer favorable bio-activity in vivo, 3) the low production costs and 4) the ease synthesis and storage for the marketing. In the field of cancer treatments, aptamers have been studied as tumor-specific agents driving drugs into cancer cells; additionally they have been used as anti-neoplastic agents, able to inhibit tumor cell growth and dissemination when administered alone or in combination with conventional anti-neoplastic drugs. Aptamers are gaining an increased interest for pharmaceutical companies and some of them are under clinical evaluation trials. In this review we update the findings about the use of aptamers as "escort" molecules able to drive drugs into the cells and as antineoplastic drugs. Current anti-neoplastic treatments suffer from the intrinsic toxicity related to the un-specific targeting of both normal and tumorigenic proliferating cells. The aptamers could be useful to improve: 1) the selective targeting of molecules essential for the viability and expansion of tumor cells and/or the selective driving of chemotherapies into tumor cells, thus resulting in higher effectiveness and lower systemic side-effects compared to conventional anti-neoplastic drugs alone and 2) to improve the therapeutic index of currently used chemotherapies. Even if some problems related to the in vivo stability and pharmacokinetic/dynamics of aptamers remain to be improved, their potential use in the treatment of different human cancers is getting closer and closer to a practical therapeutic use. PMID:23687927

  3. Preparation, characterization and in vitro evaluation of sterically stabilized liposome containing a naphthalenediimide derivative as anticancer agent.

    Science.gov (United States)

    Parise, Amelia; Milelli, Andrea; Tumiatti, Vincenzo; Minarini, Anna; Neviani, Paolo; Zuccari, Guendalina

    2015-01-01

    The aim of this study was to incorporate a new naphthalenediimide derivative (AN169) with a promising anticancer activity into pegylated liposomes to an extent that allows its in vitro and in vivo testing without use of toxic solvent. AN169-loaded liposomes were prepared using the thin-film hydration method and characterized for size, polydispersity index, drug content and drug release. We examined their lyophilization ability in the presence of cryoprotectants (trehalose, sucrose and lysine) and the long-term stability of the lyophilized products stored at 4 °C for 3 and 6 months by particle size changes and drug leakage. AN169 was successfully loaded into liposomes with an entrapment efficiency of 87.3 ± 2.5%. The hydrodynamic diameter of these liposomes after sonication was ∼ 145 nm with a high degree of monodispersity. Trehalose was found to be superior to the other lyoprotectants. In particular, trehalose 1:10 lipid:cryoprotectant molar ratio may provide stable lyophilized liposomes with the conservation of physicochemical properties upon freeze-drying and long-term storage conditions. We also assessed their in vitro antitumor activity in human cancer cell lines (HTLA-230 neuroblastoma, Mel 3.0 melanoma, OVCAR-3 ovarian carcinoma and SV620 prostate cancer cells). However, only after 72 h incubation, loaded liposomes showed almost the same IC50 as free AN169. In conclusion, we developed a stable lyophilized liposomal formulation for intravenous administration of AN169 as anticancer drug, with the advantage of avoiding the use of potentially toxic solubilizing agents for future in vivo experiments. PMID:24286206

  4. Towards targeting anticancer drugs: ruthenium(ii)-arene complexes with biologically active naphthoquinone-derived ligand systems.

    Science.gov (United States)

    Kubanik, Mario; Kandioller, Wolfgang; Kim, Kunwoo; Anderson, Robert F; Klapproth, Erik; Jakupec, Michael A; Roller, Alexander; Söhnel, Tilo; Keppler, Bernhard K; Hartinger, Christian G

    2016-08-16

    Anticancer active metal complexes with biologically active ligands have the potential to interact with more than one biological target, which could help to overcome acquired and/or intrinsic resistance of tumors to small molecule drugs. In this paper we present the preparation of 2-hydroxy-[1,4]-naphthoquinone-derived ligands and their coordination to a Ru(II)(η(6)-p-cymene)Cl moiety. The synthesis of oxime derivatives resulted in the surprising formation of nitroso-naphthalene complexes, as confirmed by X-ray diffraction analysis. The compounds were shown to be stable in aqueous solution but reacted with glutathione and ascorbic acid rather than undergoing reduction. One-electron reduction with pulse radiolysis revealed different behavior for the naphthoquinone and nitroso-naphthalene complexes, which was also observed in in vitro anticancer assays. PMID:27214822

  5. Methyl-hydroxylamine as an efficacious antibacterial agent that targets the ribonucleotide reductase enzyme.

    Directory of Open Access Journals (Sweden)

    Esther Julián

    Full Text Available The emergence of multidrug-resistant bacteria has encouraged vigorous efforts to develop antimicrobial agents with new mechanisms of action. Ribonucleotide reductase (RNR is a key enzyme in DNA replication that acts by converting ribonucleotides into the corresponding deoxyribonucleotides, which are the building blocks of DNA replication and repair. RNR has been extensively studied as an ideal target for DNA inhibition, and several drugs that are already available on the market are used for anticancer and antiviral activity. However, the high toxicity of these current drugs to eukaryotic cells does not permit their use as antibacterial agents. Here, we present a radical scavenger compound that inhibited bacterial RNR, and the compound's activity as an antibacterial agent together with its toxicity in eukaryotic cells were evaluated. First, the efficacy of N-methyl-hydroxylamine (M-HA in inhibiting the growth of different Gram-positive and Gram-negative bacteria was demonstrated, and no effect on eukaryotic cells was observed. M-HA showed remarkable efficacy against Mycobacterium bovis BCG and Pseudomonas aeruginosa. Thus, given the M-HA activity against these two bacteria, our results showed that M-HA has intracellular antimycobacterial activity against BCG-infected macrophages, and it is efficacious in partially disassembling and inhibiting the further formation of P. aeruginosa biofilms. Furthermore, M-HA and ciprofloxacin showed a synergistic effect that caused a massive reduction in a P. aeruginosa biofilm. Overall, our results suggest the vast potential of M-HA as an antibacterial agent, which acts by specifically targeting a bacterial RNR enzyme.

  6. In vitro and in vivo evaluation of organometallic gold(I) derivatives as anticancer agents.

    Science.gov (United States)

    García-Moreno, Elena; Tomás, Alejandro; Atrián-Blasco, Elena; Gascón, Sonia; Romanos, Eduardo; Rodriguez-Yoldi, Mary Jesus; Cerrada, Elena; Laguna, Mariano

    2016-02-14

    Alkyne gold(I) derivatives with the water soluble phosphanes PTA (1,3,5-triaza-7-phosphaadamantane) and DAPTA (3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane) were described and their anticancer potential against the colon cancer cell line Caco-2 (PD7 and TC7 clones) was studied. Strong antiproliferative effects are found, for all the new complexes, to be even more pronounced than for the reference drug cisplatin, and similar to auranofin. The interaction of these derivatives with bovine serum albumin (BSA) was studied by fluorescence spectroscopy. The types of quenching and binding constants were determined by a fluorescence quenching method. Moderate values of the binding constants are calculated for the tested derivatives indicating that these complexes can be stored and carried easily by this protein in the body. The study of the thermodynamic parameters in the case of [Au(C[triple bond, length as m-dash]CCH2Spyridine)(PTA)] points out to the presence of van der Waals interactions or hydrogen bonding between the metallic complex and the protein. In addition, the complex [Au(C[triple bond, length as m-dash]CCH2Spyridine)(PTA)] has shown inhibition in colon cancer proliferation of HTC-116-luc2 cell lines via the apoptotic pathway and S-phase arrest of the cell cycle. Intraperitoneal injection of this derivative in athymic nude mice inoculated with HTC-116-luc2 cells prolonged their survival and displayed moderate inhibition of the tumour growth with no subsequent organ (kidney and liver) damage after treatment. PMID:26469679

  7. The Quest for a Simple Bioactive Analog of Paclitaxel as a Potential Anticancer Agent

    OpenAIRE

    Kingston, David G I; Snyder, James P.

    2014-01-01

    Conspectus Paclitaxel (PTX), introduced into the clinic in 1991, has revealed itself as an effective antimicrotubule drug for treatment of a range of otherwise intractable cancers. Along with docetaxel (DTX) and in combination with other agents such as cisplatin, it has proven to be a first-line therapy. Unfortunately, PTX and DTX carry severe liabilities such as debilitating side effects, rapid onset of resistance, and rather complex molecular structures offering substantial challenges to ea...

  8. Synthesis and evaluation of nitrate derivatives of colchicine as anticancer agents

    Institute of Scientific and Technical Information of China (English)

    Li Hong Shen; Ya Li; Da Hai Zhang; Yi Sheng Lai; Li Jie Liu

    2011-01-01

    To search for more potent antitumor agent, a series of novel nitric oxide-donating colchicine (Col) derivatives (6a-f, 8a and b) were synthesized by coupling nitrates with N-methyl colchiceinamide. Their cytotoxicity against four human cancer cell lines in vitro were evaluated by MTT assay. It was found that many of the derivatives displayed significant activity, particularly, compounds 6c, 8a and 8b showed more potent cytotoxic activities than Col.

  9. Study of combination treatment effect of the {sup 166}Ho and anticancer agents in-vitro

    Energy Technology Data Exchange (ETDEWEB)

    Jeon, S. M.; Choi, S. J.; Park, K. B. [KAERI, Taejon (Korea, Republic of)

    2003-10-01

    For the development of new controlled drug delivery systems, the application of combination therapy using radioisotopes and tumor static agents has drawn great attention. This study was designed to estimate the treatment effect of the combination therapy with Holmium ({sup 166}Ho) and tumor static agents. Ho-166 was produced at the KAERI using HANARO reactor. The drugs applied were Sunpla, Methotrexate and Doxorubicin. Human glioblastoma (T98G), adenocarcinoma (MKN45), hepatocellular (Hep3B), lung carcinoma (Calu6), ovary adenocarcinoma (NIH:OVCAR- 3) and rat glioma (C6) were used. The cell cytotoxicity on the tumor cell lines determined by MTT assay. In the case where the chemotherapeutic agent was solely applied to the cell lines, the IC{sub 50} values wer e 2.4x10{sup -5}M of the Sunpla for MKN45 and 4.23x10{sup -6}M of the Doxorubicin for Calu6. The radioactivity of Ho-166 occurring 20% apoptosis was 10{mu}Ci. As for Sunpla and Doxorubicin, the value of IC20 was dependent on the cell lines used. The combination treatment of {sup 166}Ho and drug was to improve therapeutic success rate in T98G, MKN45, Hep3B, and Calu6. From this in vitro study it can be concluded that combining 166Ho radionuclide therapy and chemotherapy could enhance the effect of each in eliminating proliferating tumor cells.

  10. shRNA Depletion of cIAP1 Sensitizes Human Ovarian Cancer Cells to Anticancer Agent-Induced Apoptosis.

    Science.gov (United States)

    Jin, Hong; Dong, You-Yuan; Zhang, Hong; Cui, Ying; Xie, Kai; Lou, Ge

    2014-01-01

    Emerging evidence suggests a potential role of cellular inhibitor of apoptosis protein 1 (cIAP1) in the development of human ovarian cancer. However, its function in the progression of ovarian cancer has not been clearly determined. Our study aimed to investigate the effect of cIAP1 gene depletion on the chemosensitivity of ovarian cancer cells. We developed a novel short hairpin RNA (shRNA) plasmid specifically targeting cIAP1. Cell proliferation, invasion, and apoptosis of the shRNA-transfected cells were evaluated using MTT, Transwell chamber, and flow cytometric assays, respectively. The concentration of MMP-9 in the supernatant was detected by ELISA. Targeted depletion of cIAP1 by shRNA significantly reduced expression levels of cIAP1 mRNA and protein, leading to inhibition of cell proliferation and invasion capability in SKOV3 cells. At the same time, cIAP1 downregulation decreased the secretion of MMP-9. shRNA depletion of cIAP1 enhanced chemosensitivity of ovarian cancer cells to Taxol and carboplatin-induced apoptosis. cIAP1 is associated with tumor progression in human ovarian cancer. Therefore, cIAP1 might be a potential target for therapeutic anticancer drugs. PMID:26168135

  11. The Optimum Irradiation Dose in Preservation of Mahkota Dewa (Phaleria macrocarpa (Scheff) Boerl.) As Anticancer Agent

    International Nuclear Information System (INIS)

    The purpose of this experiment was to obtain the optimum irradiation dose, in order to preserve and protect the damage of anticancer compounds in mahkota dewa bark. The specimens of mahkota dewa bark were irradiated using 60Co at the variation doses of 0; 5; 7,5 ; 10; 15; and 20 kGy, respectively at the dose rate of 10 kGy/h. The irradiated and control samples were macerated in n-hexane and ethyl acetate, respectively, then the ethyl acetate extract was then fractionated using chromatography column to obtain 8 fractions. The examination of irradiated and control samples of mahkota dewa bark against microbe contaminants showed that irradiation at doses ≥5 kGy could inhibit the growth of bacteria, mold and yeast and destroyed them. The cytotoxicity test of irradiated ethyl acetate extract of mahkota dewa bark against leukemia L1210 cell showed that irradiation at the dose up to 20 kGy can decreased cytotoxic activities performance, however these IC50 values lower than 50 μg/ml, which is the cytotoxic activity threshold for extract. The cytotoxic activity test of fraction 6, the most active fraction in mahkota dewa bark, showed that irradiation at the dose up to 20 kGy can also decreased the cytotoxic activities performance, however these IC50 values was lower than 20 μg/ml, which is the cytotoxic activity threshold for fraction. Analysis of 2,4’-dihydroxy-4 methoxy benzophenone-2-O-β-D-glucopyranoside by high performance liquid chromatography (HPLC) in fraction 6 of irradiated samples showed that the concentration of this compound in irradiated samples significantly decreased, compared to the control sample. Decreasing the concentration of 2,4’-dihydroxy-4 methoxy benzophenone-2-O-β-D-glucopyranoside was not comparable to the cytotoxic activity of ethyl acetate extract or fraction 6, therefore this compound can not be used as marker of irradiation effect on decreasing the cytotoxic activity of the mahkota dewa bark. Irradiation at doses of 5 up to 20 kGy is

  12. Evaluation of the Efficacy of Targeted Imaging Agents.

    Science.gov (United States)

    Graham, Michael M; Weber, Wolfgang A

    2016-04-01

    This paper presents our adaptation of Fryback and Thornbury's hierarchical scheme for modeling the efficacy of diagnostic imaging systems. The original scheme was designed to evaluate new medical imaging systems but is less successful when applied to evaluate new radiopharmaceuticals. The proposed adaptation, which is specifically directed toward evaluating targeted imaging agents, has 6 levels: in vitro characterization, in vivo animal studies, initial human studies, impact on clinical care (change in management), impact on patient outcome, and societal efficacy. These levels, particularly the first four, implicitly define the sequence of studies needed to move an agent from the radiochemistry synthesis laboratory to the clinic. Completion of level 4 (impact on clinical care) should be sufficient for initial approval and reimbursement. We hope that the adapted scheme will help streamline the process and assist in bringing new targeted radiopharmaceuticals to approval over the next few years. PMID:26769867

  13. Use of Yeast Chemigenomics and COXEN Informatics in Preclinical Evaluation of Anticancer Agents

    Directory of Open Access Journals (Sweden)

    Steven C. Smith

    2011-01-01

    Full Text Available Bladder cancer metastasis is virtually incurable with current platinum-based chemotherapy. We used the novel COXEN informatic approach for in silico drug discovery and identified NSC-637993 and NSC-645809 (C1311, both imidazoacridinones, as agents with high-predicted activity in human bladder cancer. Because even highly effective monotherapy is unlikely to cure most patients with metastasis and NSC-645809 is undergoing clinical trials in other tumor types, we sought to develop the basis for use of C1311 in rational combination with other agents in bladder cancer. Here, we demonstrate in 40 human bladder cancer cells that the in vitro cytotoxicity profile for C1311 correlates with that of NSC-637993 and compares favorably to that of standard of care chemotherapeutics. Using genomewide patterns of synthetic lethality of C1311 with open reading frame knockouts in budding yeast, we determined that combining C1311 with a taxane could provide mechanistically rational combinations. To determine the preclinical relevance of these yeast findings, we evaluated C1311 singly and in doublet combination with paclitaxel in human bladder cancer in the in vivo hollow fiber assay and observed efficacy. By applying COXEN to gene expression data from 40 bladder cancer cell lines and 30 human tumors with associated clinical response data to platinum-based chemotherapy, we provide evidence that signatures of C1311 sensitivity exist within nonresponders to this regimen. Coupling COXEN and yeast chemigenomics provides rational combinations with C1311 and tumor genomic signatures that can be used to select bladder cancer patients for clinical trials with this agent.

  14. A comparison of patient adherence and preference of packaging method for oral anticancer agents using conventional pill bottles versus daily pill boxes.

    Science.gov (United States)

    Macintosh, P W; Pond, G R; Pond, B J; Leung, V; Siu, L L

    2007-07-01

    Adherence to medications is an important issue in oncology due to the increasing number of anticancer agents, such as targeted therapies, formulated for oral dosing. A prospective, crossover design was utilized in which patients on capecitabine were randomly assigned to one of two packaging methods for one cycle, and then switched over to the alternate packaging method in the subsequent cycle. Twenty-five patients were accrued to this study. Adherence rates were similar when using the daily pill boxes (17/21 = 81%) and when using the conventional pill bottles (18/21 = 86%). However, more patients were satisfied with the daily pill boxes (61% versus 11%, P = 0.027), preferred the daily pill boxes (61% versus 17%, P = 0.061), and thought the daily pill boxes were more helpful in reminding them to take their medications (50% versus 11%, P = 0.070). In conclusion, this small pilot study did not demonstrate that the use of daily pill boxes improved patient adherence with capecitabine, but patient satisfaction and preference for this packaging method were greater than for the conventional pill bottles. Further exploration of this intervention in a larger study is warranted. PMID:17587364

  15. Aptamer-functionalized hydrogel as effective anti-cancer drugs delivery agents.

    Science.gov (United States)

    Wang, Zonghua; Xia, Jianfei; Cai, Feng; Zhang, Feifei; Yang, Min; Bi, Sai; Gui, Rijun; Li, Yanhui; Xia, Yanzhi

    2015-10-01

    An aptamer-functionalized hydrogel has been developed, which can be regulated by the AS1411 aptamer with the sol-gel conversion. Also the hydrogel can be further utilized for the controlled encapsulation and release of the cancer drugs. Specially, the AS1411 initiates the hybridization of acrydite-modified oligonucleotides to form the hydrogels and the presence of the target protein nucleolin leads the gel to dissolve as a result of reducing the cross-linking density by competitive target-aptamer binding. Based on the rheology of hydrogels, it is possible to utilize this material for storing and releasing molecules. In this research, the cancer drug doxorubicin is encapsulated inside the gel during the formation of the hydrogel and then released in the presence of nucleolin. Further experiments are carried out to prove the specific recognition of target matter. In vitro researches confirm that the aptamer-functionalized hydrogels can be used as drug carriers in targeted therapy and other biotechnological applications. PMID:26142627

  16. Dual drug delivery using 'smart' liposomes for triggered release of anticancer agents

    Energy Technology Data Exchange (ETDEWEB)

    Jain, Ankit; Gulbake, Arvind; Jain, Ashish; Shilpi, Satish; Hurkat, Pooja; Jain, Sanjay K., E-mail: drskjainin@yahoo.com [Dr. Hari Singh Gour Vishwavidyalaya, Pharmaceutics Research Projects Laboratory, Department of Pharmaceutical Sciences (India)

    2013-07-15

    Ovarian cancer is one of the most fatal gynecologic cancers. In this debut study, dual approach using synergistically active combination of paclitaxel-topotecan (Pac-Top; 20:1, w/w) is investigated with utilization of characteristic features of tumor micro-environment and additionally overexpressed folate receptors (FR-{alpha}) to achieve targeting to tumor site. Various liposomes namely liposomes, PEGylated liposomes, and FR-targeted PEGylated liposomes with lipid compositions viz. DPPC:DMPG (85.5:9.5), DPPC:DMPG:mPEG{sub 2000}-DSPE (85.5:9.5:5), and DPPC:DMPG:mPEG{sub 2000}-DSPE:DSPE-PEG-folate (85.5:9.5:4.5:0.5), respectively, were developed using thin film casting method. These were nanometric in size around 200 nm. In vitro drug release study showed initial burst release followed by sustained release for more than 72 h at physiological milieu (37 {+-} 0.5 Degree-Sign C, pH 7.4) while burst release (i.e., more than 90 %) within 5 min at simulated tumor milieu (41 {+-} 1 Degree-Sign C, pH 4). SRB cytotoxicity assay in OVCAR-3 cell line revealed Pac-Top free (20:1, w/w) to be more toxic (GI{sub 50} = 6.5 {mu}g/ml) than positive control (Adriamycin, GI{sub 50} = 9.1 {mu}g/ml) and FR-targeted PEGylated liposomes GI{sub 50} (14.7 {mu}g/ml). Moreover, florescence microscopy showed the highest cell uptake of FR-targeted PEGylated liposomes so called 'smart liposomes' which has not only mediated effective targeting to FR-{alpha} but also triggered release of drugs upon hyperthermia.

  17. Novel histone deacetylase inhibitors in clinical trials as anti-cancer agents

    Directory of Open Access Journals (Sweden)

    Petrillo Richard L

    2010-02-01

    Full Text Available Abstract Histone deacetylases (HDACs can regulate expression of tumor suppressor genes and activities of transcriptional factors involved in both cancer initiation and progression through alteration of either DNA or the structural components of chromatin. Recently, the role of gene repression through modulation such as acetylation in cancer patients has been clinically validated with several inhibitors of HDACs. One of the HDAC inhibitors, vorinostat, has been approved by FDA for treating cutaneous T-cell lymphoma (CTCL for patients with progressive, persistent, or recurrent disease on or following two systemic therapies. Other inhibitors, for example, FK228, PXD101, PCI-24781, ITF2357, MGCD0103, MS-275, valproic acid and LBH589 have also demonstrated therapeutic potential as monotherapy or combination with other anti-tumor drugs in CTCL and other malignancies. At least 80 clinical trials are underway, testing more than eleven different HDAC inhibitory agents including both hematological and solid malignancies. This review focuses on recent development in clinical trials testing HDAC inhibitors as anti-tumor agents.

  18. Challenges in preclinical to clinical translation for anticancer carrier-mediated agents.

    Science.gov (United States)

    Lucas, Andrew T; Madden, Andrew J; Zamboni, William C

    2016-09-01

    Major advances in carrier-mediated agents (CMAs), which include nanoparticles and conjugates, have revolutionized drug delivery capabilities over the past decade. While providing numerous advantages over their small-molecule counterparts, there is substantial variability in how individual CMA formulations and patient characteristics affect the pharmacology, pharmacokinetics (PK), and pharmacodynamics (PD) (efficacy and toxicity) of these agents. Development or selection of animal models is used to predict the effects within a particular human disease. A breadth of studies have begun to emphasize the importance of preclinical animal models in understanding and evaluating the interaction between CMAs and the immune system and tumor matrix, which ultimately influences CMA PK (clearance and distribution) and PD (efficacy and toxicity). It is fundamental to study representative preclinical tumor models that recapitulate patients with diseases (e.g., cancer) and evaluate the interplay between CMAs and the immune system, including the mononuclear phagocyte system (MPS), chemokines, hormones, and other immune modulators. Furthermore, standard allometric scaling using body weight does not accurately predict drug clearance in humans. Future studies are warranted to better understand the complex pharmacology and interaction of CMA carriers within individual preclinical models and their biological systems, such as the MPS and tumor microenvironment, and their application to allometric scaling across species. WIREs Nanomed Nanobiotechnol 2016, 8:642-653. doi: 10.1002/wnan.1394 For further resources related to this article, please visit the WIREs website. PMID:26846457

  19. Synthesis and Evaluation of Some New Aza-B-homocholestane Derivatives as Anticancer Agents

    Directory of Open Access Journals (Sweden)

    Yanmin Huang

    2014-03-01

    Full Text Available Using analogues of some marine steroidal oximes as precursors, a series of aza-B-homocholestane derivatives possessing different substituted groups at the 3-position of the steroidal nucleus were synthesized. Their biological activity against cancer cell proliferation was determined with multiple cancer cell lines. Aza-B-homocholestane derivatives possessing 3-hydroxyl, 3-hydroximino and 3-thiosemicarbazone groups displayed remarkable cytotoxicity to cancer cells via apoptosis inducing mechanism. Compounds 5, 10, 12, 15 and 18 exhibited better potency to inhibit cancer cell proliferation. In addition, compound 15 was further evaluated with three dimensional (3D multicellular spheroids assay to determine its potency against spheroid growth. The structure-activity relationship (SAR generated in the studies is valuable for the design of novel chemotherapeutic agents.

  20. Synthesis, molecular modeling, and biological evaluation of novel chiral thiosemicarbazone derivatives as potent anticancer agents.

    Science.gov (United States)

    Taşdemir, Demet; Karaküçük-İyidoğan, Ayşegül; Ulaşli, Mustafa; Taşkin-Tok, Tuğba; Oruç-Emre, Emİne Elçİn; Bayram, Hasan

    2015-02-01

    A series of new chiral thiosemicarbazones derived from homochiral amines in both enantiomeric forms were synthesized and evaluated for their in vitro antiproliferative activity against A549 (human alveolar adenocarcinoma), MCF-7 (human breast adenocarcinoma), HeLa (human cervical adenocarcinoma), and HGC-27 (human stomach carcinoma) cell lines. Some of compounds showed inhibitory activities on the growth of cancer cell lines. Especially, compound exhibited the most potent activity (IC50 4.6 μM) against HGC-27 as compared with the reference compound, sindaxel (IC50 10.3 μM), and could be used as a lead compound to search new chiral thiosemicarbazone derivatives as antiproliferative agents. PMID:25399965

  1. Novel hederagenin-triazolyl derivatives as potential anti-cancer agents.

    Science.gov (United States)

    Rodríguez-Hernández, Diego; Demuner, Antonio J; Barbosa, Luiz C A; Heller, Lucie; Csuk, René

    2016-06-10

    A series of novel aryl-1H-1,2,3-triazol-4-yl methylester and amide derivatives of the natural product hederagenin was synthesized aiming to develop new antitumor agents, using Huisgen 1,3-dipolar cycloaddition reactions, with yields between 35% and 95%. The structures of all derivatives (2-31) were confirmed by MS, IR, (1)H NMR and (13)C NMR spectroscopic data. The cytotoxic activities of all compounds were screened against a panel of six human cancer cell lines using SRB assay. It was found that most of the compounds displayed higher levels of antitumor activities as compared to parent hederagenin. Compounds 4, 8 and 15 were the most potent against all human cancer cell lines. Furthermore, compound 11 was the most cytotoxic against cell HT29 showing EC50 = 1.6 μM and a selectivity index of 5.4. PMID:27017553

  2. Radiation Recall Reaction: Two Case Studies Illustrating an Uncommon Phenomenon Secondary to Anti-Cancer Agents

    International Nuclear Information System (INIS)

    Radiation recall phenomenon is a tissue reaction that develops throughout a previously irradiated area, precipitated by the administration of certain drugs. Radiation recall is uncommon and easily neglected by physicians; hence, this phenomenon is underreported in literature. This manuscript reports two cases of radiation recall. First, a 44-year-old man with nasopharyngeal carcinoma was treated with radiotherapy in 2010 and subsequently developed multi-site bone metastases. A few days after the docetaxel-based chemotherapy, erythema and papules manifested dermatitis, as well as swallowing pain due to pharyngeal mucositis, developed on the head and neck that strictly corresponded to the previously irradiated areas. Second, a 19-year-old man with recurrent nasal NK/T cell lymphoma initially underwent radiotherapy followed by chemotherapy after five weeks. Erythema and edema appeared only at the irradiated skin. Both cases were considered chemotherapeutic agents that incurred radiation recall reactions. Clinicians should be knowledgeable of and pay attention to such rare phenomenon

  3. Prevention of ocular toxicity by the intra-carotid perfusion of anticancer agents in the treatment of malignant glioma

    International Nuclear Information System (INIS)

    It is a problem of great concern to prevent ocular toxicity from complicating intra-carotid administration of lipophil anticancer agents. Attempts to prevent such a side effect were made during intra-carotid chemotherapy using remodeled catheter tips for epidural anesthesia. Twenty nine patients with malignant glioma received intra-carotid administration of neocarzinostatin (NCS). Six out of 17 patients (35.3 %) who received intra-carotid perfusion through an original catheter without a remodeled tip, developed ocular toxicity. The catheter tip remained proximal to the ophthalmic artery in all cases. On the other hand, 12 patients with a remodeled catheter tip did not develop ocular toxicity. In the latter group the tip of the catheter was located in the internal carotid artery sufficiently distal to the ophthalmic artery, or beyond the carotid bifurcation in 3 cases. Another advantage of the remodeled catheter was that the intra-carotid perfusion was feasible for a longer period with higher doses of NCS, than treatment with the commercial catheter for superselective embolization, which was found to be easily occluded and often ejected out of the carotid artery. Prior to and during the intra-carotid perfusion selective injection of Angiografin was performed through the catheter and the tumor was enhanced in the area of arterial supply, indicating the extent of chemotherapy and the degree of destruction of the blood-brain barrier. (author)

  4. Poor oral bioavailability of a promising anticancer agent andrographolide is due to extensive metabolism and efflux by P-glycoprotein.

    Science.gov (United States)

    Ye, Ling; Wang, Tao; Tang, Lan; Liu, Wei; Yang, Zhen; Zhou, Juan; Zheng, Zhijie; Cai, Zheng; Hu, Ming; Liu, Zhongqiu

    2011-11-01

    Andrographolide (AP), isolated from Andrographis paniculata (Burm. F.) Nees, is an anticancer agent with significant clinical potential. This study determined its oral bioavailability and how intestinal disposition affects its bioavailability. Pharmacokinetics was evaluated in rats. Intestinal disposition was determined using a single-pass rat intestinal perfusion model and the cultured Caco-2 cells and Madin-Darby canine kidney II cells over expressing human P-gp (MDR1-MDCKII). Absolute bioavailability of AP was 2.67%. In the duodenum and jejunum, AP was rapidly metabolized to a sulfonate, identified as 14-deoxy-12-sulfo- andrographolide. AP was also rapidly metabolized by liver S9 fraction and in blank perfusates collected from duodenum and jejunum. The apparent permeability (P(app) ) of AP from basolateral (B) to apical (A) (4.94 × 10 cm/s) in the Caco-2 model was four times higher than the P(app) from A to B (1.14 × 10(-5) cm/s). Moreover, AP was significantly more permeable in the B to A direction than the opposite direction in MDR1-MDCKII cells. In the perfusion model, the effective permeability (P*(eff) ) for AP was highest in the duodenum, followed by jejunum, and then ileum and colon. In the ileum and colon, the P*(eff) for AP was significantly increased by verapamil, a P-glycoprotein (P-gp) inhibitor. AP has poor oral bioavailability because of its rapid biotransformation and efflux by P-gp. PMID:21721007

  5. Synthesis and biological evaluation of 12-N-p-chlorobenzyl sophoridinol derivatives as a novel family of anticancer agents.

    Science.gov (United States)

    Bi, Chongwen; Ye, Cheng; Li, Yinghong; Zhao, Wuli; Shao, Rongguang; Song, Danqing

    2016-05-01

    Taking 12-N-p-chlorobenzyl sophoridinol 2 as a lead, a series of novel sophoridinic derivatives with various 3'-substituents at the 11-side chain were synthesized and evaluated for their anticancer activity from sophoridine (1), a natural antitumor medicine. Among them, the sophoridinic ketones 5a-b, alkenes 7a-b and sophoridinic amines 14a-b displayed reasonable antiproliferative activity with IC50 values ranging from 3.8 to 5.4 μmol/L. Especially, compounds 5a and 7b exhibited an equipotency in both adriamycin (AMD)-susceptible and resistant MCF-7 breast carcinoma cells, indicating a different mechanism from AMD. The primary mechanism of action of 5a was to arrest the cell cycle at the G0/G1 phase, consistent with that of parent compound 1. Thus, we consider 12-chlorobenzyl sophoridinic derivatives with a tricyclic scaffold to be a new class of promising antitumor agents with an advantage of inhibiting drug-resistant cancer cells. PMID:27175333

  6. LGR5 expressing cells of hair follicle as potential targets for antibody mediated anti-cancer laser therapy

    Science.gov (United States)

    Popov, Boris V.

    2013-02-01

    Near infrared laser immunotherapy becomes now a new promising research field to cure the patients with cancers. One of the critical limitation in medical application of this treatment is availability of the specific markers for delivery of laser-sensitive nanoparticles. When coupled to antibodies to the cancer stem cells markers these nanoparticles may be delivered to the cancer tissue and mediate the laser induced thermolysis of the cancer stem cells that initiate and drive growth of cancer. This paper addresses the Lgr5 cell surface marker mediating the Wnt/β-catenin signal transduction as a potential target for anti-cancer laser immunotherapy of skin cancers.

  7. 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

  8. PEG-PE-based micelles co-loaded with paclitaxel and cyclosporine A or loaded with paclitaxel and targeted by anticancer antibody overcome drug resistance in cancer cells.

    Science.gov (United States)

    Sarisozen, Can; Vural, Imran; Levchenko, Tatyana; Hincal, A Atilla; Torchilin, Vladimir P

    2012-05-01

    The over-expression of the P-glycoprotein (P-gp) in cancer cells is one of the main reasons of the acquired Multidrug Resistance (MDR). Combined treatment of MDR cancer cells with P-gp inhibitors and chemotherapeutic agents could result in reversal of resistance in P-gp-expressing cells. In this study, paclitaxel (PTX) was co-encapsulated in actively targeted (anticancer mAb 2C5-modified) polymeric lipid-core PEG-PE-based micelles with Cyclosporine A (CycA), which is one of the most effective first generation P-gp inhibitors. Cell culture studies performed using MDCKII (parental and MDR1) cell lines to investigate the potential MDR reversal effect of the formulations. The average size of both empty and loaded PEG₂₀₀₀-PE/Vitamin E mixed micelles was found between 10 and 25 nm. Zeta potentials of the formulations were found between -7 and -35 mV. The percentage of PTX in the micelles was found higher than 3% for both formulations and cumulative PTX release of about 70% was demonstrated. P-gp inhibition with CycA caused an increase in the cytotoxicity of PTX. Dual-loaded micelles demonstrated significantly higher cytotoxicity in the resistant MDCKII-MDR1 cells than micelles loaded with PTX alone. Micelle modification with mAb 2C5 results in the highest cytotoxicity against resistant cells, with or without P-gp modulator, probably because of better internalization bypassing the P-gp mechanism. Our results suggest that micelles delivering a combination of P-gp modulator and anticancer drug or micelles loaded with only PTX, but targeted with mAb 2C5 represent a promising approach to overcome drug resistance in cancer cells. PMID:22506922

  9. DNA interaction studies of new nano metal based anticancer agent: validation by spectroscopic methods

    Science.gov (United States)

    Tabassum, Sartaj; Sharma, Girish Chandra; Arjmand, Farukh; Azam, Ameer

    2010-05-01

    A new nano dimensional heterobimetallic Cu-Sn containing complex as a potential drug candidate was designed, synthesized and characterized by analytical and spectral methods. The electronic absorption and electron paramagnetic resonance parameters of the complex revealed that the Cu(II) ion exhibits a square pyramidal geometry with the two pyrazole nitrogen atoms, the amine nitrogen atom and the carboxylate oxygen of the phenyl glycine chloride ligand located at the equatorial sites and the coordinated chloride ion occupying an apical position. 119Sn NMR spectral data showed a hexa-coordinated environment around the Sn(IV) metal ion. TEM, AFM and XRD measurements illustrate that the complex could induce the condensation of CT-DNA to a particulate nanostructure. The interaction of the Cu-Sn complex with CT-DNA was investigated by UV-vis absorption and emission spectroscopy, as well as cyclic voltammetric measurements. The results indicated that the complex interacts with DNA through an electrostatic mode of binding with an intrinsic binding constant Kb = 8.42 × 104 M - 1. The Cu-Sn complex exhibits effective cleavage of pBR322 plasmid DNA by an oxidative cleavage mechanism, monitored at different concentrations both in the absence and in the presence of reducing agents.

  10. DNA interaction studies of new nano metal based anticancer agent: validation by spectroscopic methods

    International Nuclear Information System (INIS)

    A new nano dimensional heterobimetallic Cu-Sn containing complex as a potential drug candidate was designed, synthesized and characterized by analytical and spectral methods. The electronic absorption and electron paramagnetic resonance parameters of the complex revealed that the Cu(II) ion exhibits a square pyramidal geometry with the two pyrazole nitrogen atoms, the amine nitrogen atom and the carboxylate oxygen of the phenyl glycine chloride ligand located at the equatorial sites and the coordinated chloride ion occupying an apical position. 119Sn NMR spectral data showed a hexa-coordinated environment around the Sn(IV) metal ion. TEM, AFM and XRD measurements illustrate that the complex could induce the condensation of CT-DNA to a particulate nanostructure. The interaction of the Cu-Sn complex with CT-DNA was investigated by UV-vis absorption and emission spectroscopy, as well as cyclic voltammetric measurements. The results indicated that the complex interacts with DNA through an electrostatic mode of binding with an intrinsic binding constant Kb = 8.42 x 104 M-1. The Cu-Sn complex exhibits effective cleavage of pBR322 plasmid DNA by an oxidative cleavage mechanism, monitored at different concentrations both in the absence and in the presence of reducing agents.

  11. Psoralea glandulosa as a Potential Source of Anticancer Agents for Melanoma Treatment

    Directory of Open Access Journals (Sweden)

    Alejandro Madrid

    2015-04-01

    Full Text Available With the aim of identifying novel agents with antigrowth and pro-apoptotic activity on melanoma cancer, the present study was undertaken to investigate the biological activity of the resinous exudate of aerial parts from Psoralea glandulosa, and its active components (bakuchiol (1, 3-hydroxy-bakuchiol (2 and 12-hydroxy-iso-bakuchiol (3 against melanoma cells (A2058. In addition, the effect in cancer cells of bakuchiol acetate (4, a semi-synthetic derivative of bakuchiol, was examined. The results obtained show that the resinous exudate inhibited the growth of cancer cells with IC50 value of 10.5 μg/mL after 48 h of treatment, while, for pure compounds, the most active was the semi-synthetic compound 4. Our data also demonstrate that resin is able to induce apoptotic cell death, which could be related to an overall action of the meroterpenes present. In addition, our data seem to indicate that the apoptosis correlated to the tested products appears, at least in part, to be associated with an increase of reactive oxygen species (ROS production. In summary, our study provides the first evidence that P. glandulosa may be considered a source of useful molecules in the development of analogues with more potent efficacy against melanoma cells.

  12. Translational approaches targeting the p53 pathway for anti-cancer therapy

    OpenAIRE

    Essmann, Frank; Schulze-Osthoff, Klaus

    2012-01-01

    The p53 tumour suppressor blocks cancer development by triggering apoptosis or cellular senescence in response to oncogenic stress or DNA damage. Consequently, the p53 signalling pathway is virtually always inactivated in human cancer cells. This unifying feature has commenced tremendous efforts to develop p53-based anti-cancer therapies. Different strategies exist that are adapted to the mechanisms of p53 inactivation. In p53-mutated tumours, delivery of wild-type p53 by adenovirus-based gen...

  13. Bacterial biosynthesis and maturation of the didemnin anti-cancer agents

    KAUST Repository

    Xü, Ying

    2012-05-23

    The anti-neoplastic agent didemnin B from the Caribbean tunicate Trididemnum solidum was the first marine drug to be clinically tested in humans. Because of its limited supply and its complex cyclic depsipeptide structure, considerable challenges were encountered during didemnin B\\'s development that continue to limit aplidine (dehydrodidemnin B), which is currently being evaluated in numerous clinical trials. Herein we show that the didemnins are bacterial products produced by the marine α-proteobacteria Tistrella mobilis and Tistrella bauzanensis via a unique post-assembly line maturation process. Complete genome sequence analysis of the 6,513,401 bp T. mobilis strain KA081020-065 with its five circular replicons revealed the putative didemnin biosynthetic gene cluster (did) on the 1,126,962 bp megaplasmid pTM3. The did locus encodes a 13-module hybrid non-ribosomal peptide synthetase-polyketide synthase enzyme complex organized in a collinear arrangement for the synthesis of the fatty acylglutamine ester derivatives didemnins X and Y rather than didemnin B as first anticipated. Imaging mass spectrometry of T. mobilis bacterial colonies captured the time-dependent extracellular conversion of the didemnin X and Y precursors to didemnin B, in support of an unusual post-synthetase activation mechanism. Significantly, the discovery of the didemnin biosynthetic gene cluster may provide a long-term solution to the supply problem that presently hinders this group of marine natural products and pave the way for the genetic engineering of new didemnin congeners. © 2012 American Chemical Society.

  14. Structure and Potential Cellular Targets of HAMLET-like Anti-Cancer Compounds made from Milk Components.

    Science.gov (United States)

    Rath, Emma M; Duff, Anthony P; Håkansson, Anders P; Vacher, Catherine S; Liu, Guo Jun; Knott, Robert B; Church, William Bret

    2015-01-01

    The HAMLET family of compounds (Human Alpha-lactalbumin Made Lethal to Tumours) was discovered during studies on the properties of human milk, and is a class of protein-lipid complexes having broad spectrum anti-cancer, and some specific anti-bacterial properties. The structure of HAMLET-like compounds consists of an aggregation of partially unfolded protein making up the majority of the compound's mass, with fatty acid molecules bound in the hydrophobic core. This is a novel protein-lipid structure and has only recently been derived by small-angle X-ray scattering analysis. The structure is the basis of a novel cytotoxicity mechanism responsible for anti-cancer activity to all of the around 50 different cancer cell types for which the HAMLET family has been trialled. Multiple cytotoxic mechanisms have been hypothesised for the HAMLET-like compounds, but it is not yet clear which of those are the initiating cytotoxic mechanism(s) and which are subsequent activities triggered by the initiating mechanism(s). In addition to the studies into the structure of these compounds, this review presents the state of knowledge of the anti-cancer aspects of HAMLET-like compounds, the HAMLET-induced cytotoxic activities to cancer and non-cancer cells, and the several prospective cell membrane and intracellular targets of the HAMLET family. The emerging picture is that HAMLET-like compounds initiate their cytotoxic effects on what may be a cancer-specific target in the cell membrane that has yet to be identified. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID:26626257

  15. Pilot Study of a Next-Generation Sequencing-Based Targeted Anticancer Therapy in Refractory Solid Tumors at a Korean Institution

    Science.gov (United States)

    Park, Hyung Soon; Lim, Sun Min; Kim, Sora; Kim, Sangwoo; Kim, Hye Ryun; Kwack, KyuBum; Lee, Min Goo; Kim, Joo-Hang; Moon, Yong Wha

    2016-01-01

    We evaluated the preliminary efficacy and feasibility of a next-generation sequencing (NGS)-based targeted anticancer therapy in refractory solid tumors at a Korean institution. Thirty-six patients with advanced cancer underwent molecular profiling with NGS with the intent of clinical application of available matched targeted agents. Formalin-fixed paraffin-embedded (FFPE) tumors were sequenced using the Comprehensive Cancer Panel (CCP) or FoundationOne in the Clinical Laboratory Improvement Amendments-certified laboratory in the USA. Response evaluations were performed according to RECIST v1.1. Four specimens did not pass the DNA quality test and 32 specimens were successfully sequenced with CCP (n = 31) and FoundationOne (n = 1). Of the 32 sequenced patients, 10 (31.3%) were ≤40 years. Twelve patients (37.5%) had received ≥3 types of prior systemic therapies. Of 24 patients with actionable mutations, five were given genotype-matched drugs corresponding to actionable mutations: everolimus to PIK3CA mutation in parotid carcinosarcoma (partial response) and tracheal squamous cell carcinoma (stable disease; 21% reduction), sorafenib to PDGFRA mutation in auditory canal adenocarcinoma (partial response), sorafenib to BRAF mutation in microcytic adnexal carcinoma (progressive disease), and afatinib to ERBB2 mutation in esophageal adenocarcinoma (progressive disease). Nineteen of 24 patients with actionable mutations could not undergo targeted therapy based on genomic testing because of declining performance status (10/24, 41.7%), stable disease with previous treatment (5/24, 20.8%), and lack of access to targeted medication (4/24, 16.7%). NGS-based targeted therapy may be a good option in selected patients with refractory solid tumors. To pursue this strategy in Korea, lack of access to clinical-grade NGS assays and a limited number of genotype-matched targeted medications needs to be addressed and resolved. PMID:27105424

  16. Betulinyl Sulfamates as Anticancer Agents and Radiosensitizers in Human Breast Cancer Cells

    Directory of Open Access Journals (Sweden)

    Matthias Bache

    2015-11-01

    Full Text Available Betulinic acid (BA, a natural compound of birch bark, is cytotoxic for many tumors. Recently, a betulinyl sulfamate was described that inhibits carbonic anhydrases (CA, such as CAIX, an attractive target for tumor-selective therapy strategies in hypoxic cancer cells. Data on combined CAIX inhibition with radiotherapy are rare. In the human breast cancer cell lines MDA-MB231 and MCF7, the effects of BA and betulinyl sulfamates on cellular and radiobiological behavior under normoxia and hypoxia were evaluated. The two most effective betulinyl sulfamates CAI 1 and CAI 3 demonstrated a 1.8–2.8-fold higher cytotoxicity than BA under normoxia in breast cancer cells, with IC50 values between 11.1 and 18.1 µM. BA exhibits its strongest cytotoxicity with IC50 values of 8.2 and 16.4 µM under hypoxia. All three substances show a dose-dependent increase in apoptosis, inhibition of migration, and inhibition of hypoxia-induced gene expression. In combination with irradiation, betulinyl sulfamates act as radiosensitizers, with DMF10 values of 1.47 (CAI 1 and 1.75 (CAI 3 under hypoxia in MDA-MB231 cells. BA showed additive effects in combination with irradiation. Taken together; our results suggest that BA and betulinyl sulfamates seem to be attractive substances to combine with radiotherapy; particularly for hypoxic breast cancer.

  17. Anti-cancer drug loaded iron-gold core-shell nanoparticles (Fe@Au) for magnetic drug targeting.

    Science.gov (United States)

    Kayal, Sibnath; Ramanujan, Raju Vijayaraghavan

    2010-09-01

    Magnetic drug targeting, using core-shell magnetic carrier particles loaded with anti-cancer drugs, is an emerging and significant method of cancer treatment. Gold shell-iron core nanoparticles (Fe@Au) were synthesized by the reverse micelle method with aqueous reactants, surfactant, co-surfactant and oil phase. XRD, XPS, TEM and magnetic property measurements were utilized to characterize these core-shell nanoparticles. Magnetic measurements showed that the particles were superparamagnetic at room temperature and that the saturation magnetization decreased with increasing gold concentration. The anti-cancer drug doxorubicin (DOX) was loaded onto these Fe@Au nanoparticle carriers and the drug release profiles showed that upto 25% of adsorbed drug was released in 80 h. It was found that the amine (-NH2) group of DOX binds to the gold shell. An in vitro apparatus simulating the human circulatory system was used to determine the retention of these nanoparticle carriers when exposed to an external magnetic field. A high percentage of magnetic carriers could be retained for physiologically relevant flow speeds of fluid. The present findings show that DOX loaded gold coated iron nanoparticles are promising for magnetically targeted drug delivery. PMID:21133071

  18. Telomerase:a novel target of antitumor agents

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Telomerase activity was found to be high in various human cancers, but absent in most normal tissues. Its expression pattern made it a novel target for antitumor agents. Several strategies against telomerase were presented in this review. Targeting the telomerase RNA component by oligonucleotide/ribozyme was considered to be one of the most hopeful approaches. Some progresses were made in this area, such as the use of PANs and 2- 5A antisense compounds. The relationships among telomerase activity and cell differentiation, signal transduction, oncogene, tumor suppressor gene as well as cell cycle modulation also provided a series of valuable ideas in designing anti-telomerase drugs for cancer therapy. In conclusion, although there is still a long way in understanding the mechanism and regulation of telomerase, the advance of studies on telomerase has allowed the development of numerous strategies for the treatment of cancer.

  19. Amino Acid transporters in cancer and their relevance to "glutamine addiction": novel targets for the design of a new class of anticancer drugs.

    Science.gov (United States)

    Bhutia, Yangzom D; Babu, Ellappan; Ramachandran, Sabarish; Ganapathy, Vadivel

    2015-05-01

    Tumor cells have an increased demand for amino acids because of their rapid proliferation rate. In addition to their need in protein synthesis, several amino acids have other roles in supporting cancer growth. There are approximately two-dozen amino acid transporters in humans, and tumor cells must upregulate one or more of these transporters to satisfy their demand for amino acids. If the transporters that specifically serve this purpose in tumor cells are identified, they can be targeted for the development of a brand new class of anticancer drugs; the logical basis of such a strategy would be to starve the tumor cells of an important class of nutrients. To date, four amino acid transporters have been found to be expressed at high levels in cancer: SLC1A5, SLC7A5, SLC7A11, and SLC6A14. Their induction occurs in a cancer type-specific manner with a direct or indirect involvement of the oncogene c-Myc. Further, these transporters are functionally coupled, thus maximizing their ability to promote cancer growth and chemoresistance. Progress has been made in preclinical studies, exploiting these transporters as drug targets in cancer therapy. These transporters also show promise in development of new tumor-imaging probes and in tumor-specific delivery of appropriately designed chemotherapeutic agents. PMID:25855379

  20. Repositioning Clofazimine as a Macrophage-Targeting Photoacoustic Contrast Agent.

    Science.gov (United States)

    Keswani, Rahul K; Tian, Chao; Peryea, Tyler; Girish, Gandikota; Wang, Xueding; Rosania, Gus R

    2016-01-01

    Photoacoustic Tomography (PAT) is a deep-tissue imaging modality, with potential clinical applications in the diagnosis of arthritis, cancer and other disease conditions. Here, we identified Clofazimine (CFZ), a red-pigmented dye and anti-inflammatory FDA-approved drug, as a macrophage-targeting photoacoustic (PA) imaging agent. Spectroscopic experiments revealed that CFZ and its various protonated forms yielded optimal PAT signals at wavelengths -450 to 540 nm. CFZ's macrophage-targeting chemical and structural forms were detected with PA microscopy at a high contrast-to-noise ratio (CNR > 22 dB) as well as with macroscopic imaging using synthetic gelatin phantoms. In vivo, natural and synthetic CFZ formulations also demonstrated significant anti-inflammatory activity. Finally, the injection of CFZ was monitored via a real-time ultrasound-photoacoustic (US-PA) dual imaging system in a live animal and clinically relevant human hand model. These results demonstrate an anti-inflammatory drug repurposing strategy, while identifying a new PA contrast agent with potential applications in the diagnosis and treatment of arthritis. PMID:27000434

  1. Biocompatible Nanocomplexes for Molecular Targeted MRI Contrast Agent

    Science.gov (United States)

    Chen, Zhijin; Yu, Dexin; Wang, Shaojie; Zhang, Na; Ma, Chunhong; Lu, Zaijun

    2009-07-01

    Accurate diagnosis in early stage is vital for the treatment of Hepatocellular carcinoma. The aim of this study was to investigate the potential of poly lactic acid-polyethylene glycol/gadolinium-diethylenetriamine-pentaacetic acid (PLA-PEG/Gd-DTPA) nanocomplexes using as biocompatible molecular magnetic resonance imaging (MRI) contrast agent. The PLA-PEG/Gd-DTPA nanocomplexes were obtained using self-assembly nanotechnology by incubation of PLA-PEG nanoparticles and the commercial contrast agent, Gd-DTPA. The physicochemical properties of nanocomplexes were measured by atomic force microscopy and photon correlation spectroscopy. The T1-weighted MR images of the nanocomplexes were obtained in a 3.0 T clinical MR imager. The stability study was carried out in human plasma and the distribution in vivo was investigated in rats. The mean size of the PLA-PEG/Gd-DTPA nanocomplexes was 187.9 ± 2.30 nm, and the polydispersity index was 0.108, and the zeta potential was -12.36 ± 3.58 mV. The results of MRI test confirmed that the PLA-PEG/Gd-DTPA nanocomplexes possessed the ability of MRI, and the direct correlation between the MRI imaging intensities and the nano-complex concentrations was observed ( r = 0.987). The signal intensity was still stable within 2 h after incubation of the nanocomplexes in human plasma. The nanocomplexes gave much better image contrast effects and longer stagnation time than that of commercial contrast agent in rat liver. A dose of 0.04 mmol of gadolinium per kilogram of body weight was sufficient to increase the MRI imaging intensities in rat livers by five-fold compared with the commercial Gd-DTPA. PLA-PEG/Gd-DTPA nanocomplexes could be prepared easily with small particle sizes. The nanocomplexes had high plasma stability, better image contrast effect, and liver targeting property. These results indicated that the PLA-PEG/Gd-DTPA nanocomplexes might be potential as molecular targeted imaging contrast agent.

  2. Biocompatible Nanocomplexes for Molecular Targeted MRI Contrast Agent

    Directory of Open Access Journals (Sweden)

    Yu Dexin

    2009-01-01

    Full Text Available Abstract Accurate diagnosis in early stage is vital for the treatment of Hepatocellular carcinoma. The aim of this study was to investigate the potential of poly lactic acid–polyethylene glycol/gadolinium–diethylenetriamine-pentaacetic acid (PLA–PEG/Gd–DTPA nanocomplexes using as biocompatible molecular magnetic resonance imaging (MRI contrast agent. The PLA–PEG/Gd–DTPA nanocomplexes were obtained using self-assembly nanotechnology by incubation of PLA–PEG nanoparticles and the commercial contrast agent, Gd–DTPA. The physicochemical properties of nanocomplexes were measured by atomic force microscopy and photon correlation spectroscopy. The T1-weighted MR images of the nanocomplexes were obtained in a 3.0 T clinical MR imager. The stability study was carried out in human plasma and the distribution in vivo was investigated in rats. The mean size of the PLA–PEG/Gd–DTPA nanocomplexes was 187.9 ± 2.30 nm, and the polydispersity index was 0.108, and the zeta potential was −12.36 ± 3.58 mV. The results of MRI test confirmed that the PLA–PEG/Gd–DTPA nanocomplexes possessed the ability of MRI, and the direct correlation between the MRI imaging intensities and the nano-complex concentrations was observed (r = 0.987. The signal intensity was still stable within 2 h after incubation of the nanocomplexes in human plasma. The nanocomplexes gave much better image contrast effects and longer stagnation time than that of commercial contrast agent in rat liver. A dose of 0.04 mmol of gadolinium per kilogram of body weight was sufficient to increase the MRI imaging intensities in rat livers by five-fold compared with the commercial Gd–DTPA. PLA–PEG/Gd–DTPA nanocomplexes could be prepared easily with small particle sizes. The nanocomplexes had high plasma stability, better image contrast effect, and liver targeting property. These results indicated that the PLA–PEG/Gd–DTPA nanocomplexes might be potential as molecular

  3. Molecular and Pharmacologic Properties of the Anticancer Quinolone Derivative Vosaroxin: A New Therapeutic Agent for Acute Myeloid Leukemia.

    Science.gov (United States)

    Jamieson, Gene C; Fox, Judith A; Poi, Ming; Strickland, Stephen A

    2016-09-01

    Vosaroxin is a first-in-class anticancer quinolone derivative that targets topoisomerase II and induces site-selective double-strand breaks in DNA, leading to tumor cell apoptosis. Vosaroxin has chemical and pharmacologic characteristics distinct from other topoisomerase II inhibitors due to its quinolone scaffold. The efficacy and safety of vosaroxin in combination with cytarabine were evaluated in patients with relapsed/refractory acute myeloid leukemia (AML) in a phase III, randomized, multicenter, double-blind, placebo-controlled study (VALOR). In this study, the addition of vosaroxin produced a 1.4-month improvement in median overall survival (OS; 7.5 months with vosaroxin/cytarabine vs. 6.1 months with placebo/cytarabine; hazard ratio [HR] 0.87, 95 % confidence interval [CI] 0.73-1.02; unstratified log-rank p [Formula: see text] 0.061; stratified log-rank p [Formula: see text]0.024), with the greatest OS benefit observed in patients ≥60 years of age (7.1 vs. 5.0 months; HR 0.75, 95 % CI 0.62-0.92; p [Formula: see text]0.003) and patients with early relapse (6.7 vs. 5.2 months; HR 0.77, 95 % CI 0.59-1.00; p [Formula: see text] 0.039), two AML patient groups that typically have poor prognosis. Here we review the chemical and pharmacologic properties of vosaroxin, how these properties are distinct from those of currently available topoisomerase II inhibitors, how they may contribute to the efficacy and safety profile observed in the VALOR trial, and the status of clinical development of vosaroxin for treatment of AML. PMID:27484675

  4. Synthesis of 1-benzyl-3-(5-hydroxymethyl-2-furyl)selenolo[3,2-c]pyrazole derivatives as new anticancer agents.

    Science.gov (United States)

    Chou, Li-Chen; Huang, Li-Jiau; Hsu, Mei-Hua; Fang, Mei-Chi; Yang, Jai-Sing; Zhuang, Shi-Hong; Lin, Hui-Yi; Lee, Fang-Yu; Teng, Che-Ming; Kuo, Sheng-Chu

    2010-04-01

    As part of our continuing search for potential anticancer drug candidates among YC-1 analogs, 1, 3-disubstituted selenolo[3,2-c]pyrazole derivatives were synthesized and evaluated for their cytotoxicity against NCI-H226 non-small cell lung cancer and A-498 renal cancer cell lines. Significant cytotoxicity was observed in 3-(5-hydroxymethyl-2-furyl) derivatives (2, 33, 36 and 37). Among them, compound 2 was found to have the most potent activity. The mode of action of compound 2 seems to differ from those of the 175 anticancer agents listed in NCI's standard database and resembles that of YC-1. Thus, we recommend that compound 2 should be developed further as new drug candidate for treatment of non-small cell lung cancer and renal cancer. PMID:20097456

  5. Targeting Reactive Carbonyl Species with Natural Sequestering Agents

    Directory of Open Access Journals (Sweden)

    Sung Won Hwang

    2016-02-01

    Full Text Available Reactive carbonyl species generated by the oxidation of polyunsaturated fatty acids and sugars are highly reactive due to their electrophilic nature, and are able to easily react with the nucleophilic sites of proteins as well as DNA causing cellular dysfunction. Levels of reactive carbonyl species and their reaction products have been reported to be elevated in various chronic diseases, including metabolic disorders and neurodegenerative diseases. In an effort to identify sequestering agents for reactive carbonyl species, various analytical techniques such as spectrophotometry, high performance liquid chromatography, western blot, and mass spectrometry have been utilized. In particular, recent advances using a novel high resolution mass spectrometry approach allows screening of complex mixtures such as natural products for their sequestering ability of reactive carbonyl species. To overcome the limited bioavailability and bioefficacy of natural products, new techniques using nanoparticles and nanocarriers may offer a new attractive strategy for increased in vivo utilization and targeted delivery of bioactives.

  6. Targeting Reactive Carbonyl Species with Natural Sequestering Agents.

    Science.gov (United States)

    Hwang, Sung Won; Lee, Yoon-Mi; Aldini, Giancarlo; Yeum, Kyung-Jin

    2016-01-01

    Reactive carbonyl species generated by the oxidation of polyunsaturated fatty acids and sugars are highly reactive due to their electrophilic nature, and are able to easily react with the nucleophilic sites of proteins as well as DNA causing cellular dysfunction. Levels of reactive carbonyl species and their reaction products have been reported to be elevated in various chronic diseases, including metabolic disorders and neurodegenerative diseases. In an effort to identify sequestering agents for reactive carbonyl species, various analytical techniques such as spectrophotometry, high performance liquid chromatography, western blot, and mass spectrometry have been utilized. In particular, recent advances using a novel high resolution mass spectrometry approach allows screening of complex mixtures such as natural products for their sequestering ability of reactive carbonyl species. To overcome the limited bioavailability and bioefficacy of natural products, new techniques using nanoparticles and nanocarriers may offer a new attractive strategy for increased in vivo utilization and targeted delivery of bioactives. PMID:26927058

  7. CancerHSP: anticancer herbs database of systems pharmacology

    Science.gov (United States)

    Tao, Weiyang; Li, Bohui; Gao, Shuo; Bai, Yaofei; Shar, Piar Ali; Zhang, Wenjuan; Guo, Zihu; Sun, Ke; Fu, Yingxue; Huang, Chao; Zheng, Chunli; Mu, Jiexin; Pei, Tianli; Wang, Yuan; Li, Yan; Wang, Yonghua

    2015-06-01

    The numerous natural products and their bioactivity potentially afford an extraordinary resource for new drug discovery and have been employed in cancer treatment. However, the underlying pharmacological mechanisms of most natural anticancer compounds remain elusive, which has become one of the major obstacles in developing novel effective anticancer agents. Here, to address these unmet needs, we developed an anticancer herbs database of systems pharmacology (CancerHSP), which records anticancer herbs related information through manual curation. Currently, CancerHSP contains 2439 anticancer herbal medicines with 3575 anticancer ingredients. For each ingredient, the molecular structure and nine key ADME parameters are provided. Moreover, we also provide the anticancer activities of these compounds based on 492 different cancer cell lines. Further, the protein targets of the compounds are predicted by state-of-art methods or collected from literatures. CancerHSP will help reveal the molecular mechanisms of natural anticancer products and accelerate anticancer drug development, especially facilitate future investigations on drug repositioning and drug discovery. CancerHSP is freely available on the web at http://lsp.nwsuaf.edu.cn/CancerHSP.php.

  8. Anticancer chemotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Weller, R.E.

    1988-10-01

    Despite troubled beginnings, anticancer chemotherapy has made significant contribution to the control of cancer in man, particularly within the last two decades. Early conceptual observations awakened the scientific community to the potentials of cancer chemotherapy. There are now more than 50 agents that are active in causing regression of clinical cancer. Chemotherapy's major conceptual contributions are two-fold. First, there is now proof that patients with overt metastatic disease can be cured, and second, to provide a strategy for control of occult metastases. In man, chemotherapy has resulted in normal life expectancy for some patients who have several types of metastatic cancers, including choriocarcinoma, Burkitt's lymphomas, Wilm's tumor, acute lymphocytic leukemia, Hodgkins disease, diffuse histiocytic lymphoma and others. Anticancer chemotherapy in Veterinary medicine has evolved from the use of single agents, which produce only limited remissions, to the concept of combination chemotherapy. Three basic principles underline the design of combination chemotherapy protocols; the fraction of tumor cell killed by one drug is independent of the fraction killed by another drug; drugs with different mechanisms of action should be chosen so that the antitumor effects will be additive; and since different classes of drugs have different toxicities the toxic effects will not be additive.

  9. Anticancer compound plumbagin and its molecular targets: a structural insight into the inhibitory mechanisms using computational approaches.

    Directory of Open Access Journals (Sweden)

    Mohammad S Jamal

    Full Text Available Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone is a naphthoquinone derivative from the roots of plant Plumbago zeylanica and belongs to one of the largest and diverse groups of plant metabolites. The anticancer and antiproliferative activities of plumbagin have been observed in animal models as well as in cell cultures. Plumbagin exerts inhibitory effects on multiple cancer-signaling proteins, however, the binding mode and the molecular interactions have not yet been elucidated for most of these protein targets. The present study is the first attempt to provide structural insights into the binding mode of plumbagin to five cancer signaling proteins viz. PI3Kγ, AKT1/PKBα, Bcl-2, NF-κB, and Stat3 using molecular docking and (unbinding simulation analysis. We validated plumbagin docking to these targets with previously known important residues. The study also identified and characterized various novel interacting residues of these targets which mediate the binding of plumbagin. Moreover, the exact modes of inhibition when multiple mode of inhibition existed was also shown. Results indicated that the engaging of these important interacting residues in plumbagin binding leads to inhibition of these cancer-signaling proteins which are key players in the pathogenesis of cancer and thereby ceases the progression of the disease.

  10. Screening the yeast genome for energetic metabolism pathways involved in a phenotypic response to the anti-cancer agent 3-bromopyruvate

    OpenAIRE

    Lis, Paweł; Jurkiewicz, Paweł; Cal-Bąkowska, Magdalena; Ko, Young H.; Pedersen, Peter L.; Goffeau, Andre; Ułaszewski, Stanisław

    2016-01-01

    In this study the detailed characteristic of the anti-cancer agent 3-bromopyruvate (3-BP) activity in the yeast Saccharomyces cerevisiae model is described, with the emphasis on its influence on energetic metabolism of the cell. It shows that 3-BP toxicity in yeast is strain-dependent and influenced by the glucose-repression system. Its toxic effect is mainly due to the rapid depletion of intracellular ATP. Moreover, lack of the Whi2p phosphatase results in strongly increased sensitivity of y...

  11. Kinetics and thermochemistry of hydrolysis mechanism of a novel anticancer agent trans-[PtCl2(dimethylamine)(isopropylamine)]: A DFT study

    Science.gov (United States)

    Hussain, Iftikar; Gour, N. K.; Deka, Ramesh Ch.

    2016-05-01

    Theoretical investigation has been made on the hydrolysis mechanism of a novel transplatin anticancer agent trans-[PtCl2(dimethylamine)(isopropylamine)] in gas as well as aqueous phases using DFT method. The transition state geometries along with other stationary points on potential energy surface are optimized and characterized. The calculated activation barrier and the predicted relative free energies for the two successive steps are in good agreement with the experimental data reported in the literature. The rate constants are calculated using Eyring equation and results show that the second step is the rate-limiting process having higher activation energy compared to that of the first step.

  12. CYP3A4 overexpression enhances apoptosis induced by anticancer agent imidazoacridinone C-1311, but does not change the metabolism of C-1311 in CHO cells

    OpenAIRE

    Pawłowska, Monika; Augustin, Ewa; Mazerska, Zofia

    2013-01-01

    Aim: To examine whether CYP3A4 overexpression influences the metabolism of anticancer agent imidazoacridinone C-1311 in CHO cells and the responses of the cells to C-1311. Methods: Wild type CHO cells (CHO-WT), CHO cells overexpressing cytochrome P450 reductase (CPR) [CHO-HR] and CHO cells coexpressing CPR and CYP3A4 (CHO-HR-3A4) were used. Metabolic transformation of C-1311 and CYP3A4 activity were measured using RP-HPLC. Flow cytometry analyses were used to examine cell cycle, caspase-3 act...

  13. Efficacy of a non-hypercalcemic vitamin-D2 derived anti-cancer agent (MT19c and inhibition of fatty acid synthesis in an ovarian cancer xenograft model.

    Directory of Open Access Journals (Sweden)

    Richard G Moore

    Full Text Available BACKGROUND: Numerous vitamin-D analogs exhibited poor response rates, high systemic toxicities and hypercalcemia in human trials to treat cancer. We identified the first non-hypercalcemic anti-cancer vitamin D analog MT19c by altering the A-ring of ergocalciferol. This study describes the therapeutic efficacy and mechanism of action of MT19c in both in vitro and in vivo models. METHODOLOGY/PRINCIPAL FINDING: Antitumor efficacy of MT19c was evaluated in ovarian cancer cell (SKOV-3 xenografts in nude mice and a syngenic rat ovarian cancer model. Serum calcium levels of MT19c or calcitriol treated animals were measured. In-silico molecular docking simulation and a cell based VDR reporter assay revealed MT19c-VDR interaction. Genomewide mRNA analysis of MT19c treated tumors identified drug targets which were verified by immunoblotting and microscopy. Quantification of cellular malonyl CoA was carried out by HPLC-MS. A binding study with PPAR-Y receptor was performed. MT19c reduced ovarian cancer growth in xenograft and syngeneic animal models without causing hypercalcemia or acute toxicity. MT19c is a weak vitamin-D receptor (VDR antagonist that disrupted the interaction between VDR and coactivator SRC2-3. Genome-wide mRNA analysis and western blot and microscopy of MT19c treated xenograft tumors showed inhibition of fatty acid synthase (FASN activity. MT19c reduced cellular levels of malonyl CoA in SKOV-3 cells and inhibited EGFR/phosphoinositol-3kinase (PI-3K activity independently of PPAR-gamma protein. SIGNIFICANCE: Antitumor effects of non-hypercalcemic agent MT19c provide a new approach to the design of vitamin-D based anticancer molecules and a rationale for developing MT19c as a therapeutic agent for malignant ovarian tumors by targeting oncogenic de novo lipogenesis.

  14. Synthesis and evaluation of multi-wall carbon nanotube–paclitaxel complex as an anti-cancer agent

    Science.gov (United States)

    Ghasemvand, Fariba; Biazar, Esmaeil; Tavakolifard, Sara; Khaledian, Mohammad; Rahmanzadeh, Saeid; Momenzadeh, Daruosh; Afroosheh, Roshanak; Zarkalami, Faezeh; Shabannezhad, Marjan; Hesami Tackallou, Saeed; Massoudi, Nilofar; Heidari Keshel, Saeed

    2016-01-01

    Aim: The aim of this study was to design multi-walled carbon nanotubes (MWCNTs) loaded with paclitaxel (PTX) anti-cancer drug and investigate its anti-cancerous efficacy of human gastric cancer. Background: Carbon nanotubes (CNTs) represent a novel nano-materials applied in various fields such as drug delivery due to their unique chemical properties and high drug loading. Patients and methods: In this study, multi-walled carbon nanotubes (MWCNTs) pre-functionalized covalently with a paclitaxel (PTX) as an anti-cancer drug and evaluated by different analyses including, scanning electron microscope (SEM), particle size analyzer and cellular analyses. Results: A well conjugated of anti-cancer drug on the carbon nanotube surfaces was shown. This study demonstrates that the MWCN-PTX complex is a potentially useful system for delivery of anti-cancer drugs. The flow cytometry, CFU and MTT assay results have disclosed that MWCNT/PTXs might promote apoptosis in MKN-45 gastric adenocarcinoma cell line. Conclusion: According to results, our simple method can be designed a candidate material for chemotherapy. It has presented a few bio-related applications including, their successful use as a nano-carriers for drug transport. PMID:27458512

  15. N-Phenyl-2-p-tolylthiazole-4-carboxamide derivatives: Syn-thesis and cytotoxicity evaluation as anticancer agents

    Directory of Open Access Journals (Sweden)

    Ahmad Mohammadi-Farani

    2014-07-01

    Conclusion: A new series of phenylthiazole derivatives were synthesized and their anticancer activity was assessed against cancerous cell lines. More structural modifications and derivatization is necessary to achieve to the more potent compounds.       

  16. Vitamin E analogs, a novel group of "mitocans," as anticancer agents: The importance of being redox-silent

    Czech Academy of Sciences Publication Activity Database

    Neužil, Jiří; Tomasetti, M.; Zhao, Y.; Dong, L.F.; Birringer, M.; Wang, X. F.; Low, P.; Wu, K.; Salvatore, B.A.; Ralph, S.J.

    2007-01-01

    Roč. 71, č. 5 (2007), s. 1185-1199. ISSN 0026-895X Institutional research plan: CEZ:AV0Z50520514; CEZ:AV0Z50520701 Keywords : vitamin E analogs * redox-silence * anticancer drugs Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.622, year: 2007

  17. DNA-Destabilizing Agents as an Alternative Approach for Targeting DNA: Mechanisms of Action and Cellular Consequences

    Directory of Open Access Journals (Sweden)

    Gaëlle Lenglet

    2010-01-01

    Full Text Available DNA targeting drugs represent a large proportion of the actual anticancer drug pharmacopeia, both in terms of drug brands and prescription volumes. Small DNA-interacting molecules share the ability of certain proteins to change the DNA helix's overall organization and geometrical orientation via tilt, roll, twist, slip, and flip effects. In this ocean of DNA-interacting compounds, most stabilize both DNA strands and very few display helix-destabilizing properties. These types of DNA-destabilizing effect are observed with certain mono- or bis-intercalators and DNA alkylating agents (some of which have been or are being developed as cancer drugs. The formation of locally destabilized DNA portions could interfere with protein/DNA recognition and potentially affect several crucial cellular processes, such as DNA repair, replication, and transcription. The present paper describes the molecular basis of DNA destabilization, the cellular impact on protein recognition, and DNA repair processes and the latter's relationships with antitumour efficacy.

  18. Anticancer Molecular Mechanisms of Resveratrol

    Science.gov (United States)

    Varoni, Elena M.; Lo Faro, Alfredo Fabrizio; Sharifi-Rad, Javad; Iriti, Marcello

    2016-01-01

    Resveratrol is a pleiotropic phytochemical belonging to the stilbene family. Though it is only significantly present in grape products, a huge amount of preclinical studies investigated its anticancer properties in a plethora of cellular and animal models. Molecular mechanisms of resveratrol involved signaling pathways related to extracellular growth factors and receptor tyrosine kinases; formation of multiprotein complexes and cell metabolism; cell proliferation and genome instability; cytoplasmic tyrosine kinase signaling (cytokine, integrin, and developmental pathways); signal transduction by the transforming growth factor-β super-family; apoptosis and inflammation; and immune surveillance and hormone signaling. Resveratrol also showed a promising role to counteract multidrug resistance: in adjuvant therapy, associated with 5-fluoruracyl and cisplatin, resveratrol had additive and/or synergistic effects increasing the chemosensitization of cancer cells. Resveratrol, by acting on diverse mechanisms simultaneously, has been emphasized as a promising, multi-target, anticancer agent, relevant in both cancer prevention and treatment.

  19. Melanoma cell surface-expressed phosphatidylserine as a therapeutic target for cationic anticancer peptide, temporin-1CEa.

    Science.gov (United States)

    Wang, Che; Chen, Yin-Wang; Zhang, Liang; Gong, Xian-Ge; Zhou, Yang; Shang, De-Jing

    2016-07-01

    We have previously reported that temporin-1CEa, a cationic antimicrobial peptide, exerts preferential cytotoxicity toward cancer cells. However, the exact molecular mechanism for this cancer-selectivity is still largely unknown. Here, we found that the negatively charged phosphatidylserine (PS) expressed on cancer cell surface serves as a target for temporin-1CEa. Our results indicate that human A375 melanoma cells express 50-fold more PS than non-cancerous HaCaT cells. The expression of cell surface PS in various cancer cell lines closely correlated with their ability to be recognized, bound and killed by temporin-1CEa. Additionally, the cytotoxicity of temporin-1CEa against A375 cells can be ameliorated by annexin V, which binds to cell surface PS with high affinity. Moreover, the data of isothermal titration calorimetry assay further confirmed a direct binding of temporin-1CEa to PS, at a ratio of 1:5 (temporin-1CEa:PS). Interestingly, the circular dichroism spectra analysis using artificial biomembrane revealed that PS not only provides electrostatic attractive sites for temporin-1CEa but also confers the membrane-bound temporin-1CEa to form α-helical structure, therefore, enhances the affinity and membrane disrupting ability of temporin-1CEa. In summary, these findings suggested that the melanoma cells expressed PS may serve as a promising target for temporin-1CEa or other cationic anticancer peptides. PMID:26596643

  20. External influences and priority-setting for anti-cancer agents: a case study of media coverage in adjuvant trastuzumab for breast cancer

    Directory of Open Access Journals (Sweden)

    Fralick John

    2007-06-01

    Full Text Available Abstract Background Setting priorities for the funding of new anti-cancer agents is becoming increasingly complex. The funding of adjuvant trastuzumab for breast cancer has brought this dilemma to the fore. In this paper we review external factors that may influence decision-making bodies and present a case study of media response in Ontario, Canada to adjuvant trastuzumab for breast cancer. Methods A comprehensive search of the databases of Canadian national and local newspapers and television was performed. Articles pertaining to trastuzumab in adjuvant breast cancer as well as 17 other anti-cancer drugs and indications were retrieved. The search period was from the date when individual trial results were announced to the date funding was made available in Ontario. Results During the 2.6 months between the release of the trastuzumab results to funding approval in Ontario, we identified 51 episodes of media coverage. For the 17 other drugs/indications (7 breast and 10 non-breast, the median time to funding approval was 31 months (range 14–46. Other recent major advances in oncology such as adjuvant vinorelbine/cisplatin for resected NSCLC and docetaxel for advanced prostate cancer received considerably less media attention (17 media reports for each than trastuzumab. The median number of media reports for breast cancer drugs was 4.5 compared to 2.5 for non-breast cancer drugs (p = 0.56. Conclusion Priority-setting for novel anti-cancer agents is a complex process that tries to ensure fair use of constrained resources to fund therapies with the best evidence of clinical benefit. However, this process is subject to external factors including the influence of media, patient advocates, politicians, and industry. The data in this case study serve to illustrate the significant involvement one (or all of these external factors may play in the debate over priority-setting.

  1. Could the FDA-approved anti-HIV PR inhibitors be promising anticancer agents? An answer from enhanced docking approach and molecular dynamics analyses

    Directory of Open Access Journals (Sweden)

    Arodola OA

    2015-11-01

    Full Text Available Olayide A Arodola, Mahmoud ES SolimanMolecular Modelling and Drug Design Lab, School of Health Sciences, Westville Campus, University of KwaZulu-Natal, Durban, South AfricaAbstract: Based on experimental data, the anticancer activity of nelfinavir (NFV, a US Food and Drug Administration (FDA-approved HIV-1 protease inhibitor (PI, was reported. Nevertheless, the mechanism of action of NFV is yet to be verified. It was hypothesized that the anticancer activity of NFV is due to its inhibitory effect on heat shock protein 90 (Hsp90, a promising target for anticancer therapy. Such findings prompted us to investigate the potential anticancer activity of all other FDA-approved HIV-1 PIs against human Hsp90. To accomplish this, “loop docking” – an enhanced in-house developed molecular docking approach – followed by molecular dynamic simulations and postdynamic analyses were performed to elaborate on the binding mechanism and relative binding affinities of nine FDA-approved HIV-1 PIs against human Hsp90. Due to the lack of the X-ray crystal structure of human Hsp90, homology modeling was performed to create its 3D structure for subsequent simulations. Results showed that NFV has better binding affinity (ΔG =−9.2 kcal/mol when compared with other PIs: this is in a reasonable accordance with the experimental data (IC50 3.1 µM. Indinavir, saquinavir, and ritonavir have close binding affinity to NFV (ΔG =−9.0, −8.6, and −8.5 kcal/mol, respectively. Per-residue interaction energy decomposition analysis showed that hydrophobic interaction (most importantly with Val534 and Met602 played the most predominant role in drug binding. To further validate the docking outcome, 5 ns molecular dynamic simulations were performed in order to assess the stability of the docked complexes. To our knowledge, this is the first account of detailed computational investigations aimed to investigate the potential anticancer activity and the binding

  2. [Response of Pharmaceutical Companies to the Crisis of Post-Marketing Clinical Trials of Anti-Cancer Agents -- Results of Questionnaires to Pharmaceutical Companies].

    Science.gov (United States)

    Nakajima, Toshifusa

    2016-04-01

    Investigator-oriented post-marketing clinical trials of anti-cancer agents are faced to financial crisis due to drastic decrease in research-funds from pharmaceutical companies caused by a scandal in 2013. In order to assess the balance of research funds between 2012 and 2014, we made queries to 26 companies manufacturing anti-cancer agents, and only 10 of 26 responded to our queries. Decrease in the fund was observed in 5 of 10, no change in 1, increase in 3 and no answer in 1. Companies showed passive attitude to carry out doctor-oriented clinical trials of off-patent drugs or unapproved drugs according to advanced medical care B program, though some companies answered to proceed approved routines of these drugs if clinical trials showed good results. Most companies declined to make comments on the activity of Japan Agency for Medical Research and Development (AMED), but some insisted to produce good corroboration between AMED and pharmaceutical companies in order to improve the quality of trials. Further corroboration must be necessary for this purpose among researchers, governmental administrative organs, pharmaceutical companies, patients' groups, and mass-media. PMID:27220801

  3. Design, Synthesis and Biological Evaluation of Novel Bromophenol Derivatives Incorporating Indolin-2-One Moiety as Potential Anticancer Agents

    Directory of Open Access Journals (Sweden)

    Li-Jun Wang

    2015-02-01

    Full Text Available A series of bromophenol derivatives containing indolin-2-one moiety were designed and evaluated that for their anticancer activities against A549, Bel7402, HepG2, HeLa and HCT116 cancer cell lines using MTT assay in vitro. Among them, seven compounds (4g–4i, 5h, 6d, 7a, 7b showed potent activity against the tested five human cancer cell lines. Wound-healing assay demonstrated that compound 4g can be used as a potent compound for inactivating invasion and metastasis by inhibiting the migration of cancer cells. The structure–activity relationships (SARs of bromophenol derivatives had been discussed, which were useful for exploring and developing bromophenol derivatives as novel anticancer drugs.

  4. Studies of the effect on the cell cycle and of the radiosensitization of a novel anti-cancer agent TZT-1027

    International Nuclear Information System (INIS)

    The anticancer agent TZT-1027, an analog of dolastatin 10 originated from a marine organism, is an anti-microtubule agent and the present studies were performed to elucidate its activities in the title. Cell cycle analysis was done in mouse breast carcinoma tsFT210 cell line by flow-cytometry, which revealed that TZT-1027 specifically acted at G2/M, the stage most sensitive to radiation. Human non-small cell lung cancer H460 cell line was used for clonogenic assay: the dose enhancement factor at survival 0.1, estimated by the survival curve of cells irradiated by 60Co gamma ray at 0-6 Gy with or without TZT-1027, was found to be 1.2, which revealed the enhancement of radiosenstivity. In addition, their radiation-induced apoptosis was found to be also enhanced by the agent. When nude-mice transplanted with H460 cells were treated with TZT-1027 and 60Co gamma ray at 10 Gy, radiosensitization and apoptosis enhancement by the agent were also clear in vivo. Thus, TZT-1027 enhances the anti-tumor effect of radiation and this radiosensitizing mechanism involves the apoptotic process at least partly, both of which are conceivably the basis of future clinical trial of the agent. (T.I.)

  5. Liquid Chromatography - Triple Quadrupole Mass Spectrometry : The gold standard for quantitative bioanalysis of anti-cancer agents

    OpenAIRE

    Vainchtein, L.D.

    2008-01-01

    To understand the pharmacologic mechanisms of action, efficacy and toxicity of any anti-cancer drug it is important to know how the compound is transformed in the body: either into active metabolites or inactive and toxic (degradation) products. This information may lead to the success or failure of a drug in arresting cancer cell growth, and facilitates the design of more effective drugs. To quantify the drug and to follow its absorption, distribution, metabolism, and elimination (ADME) in b...

  6. Isolation and characterization of bioactive protein from green algae Halimeda macrobola acting as antioxidant and anticancer agent

    OpenAIRE

    Ahmad, Ahyar

    2014-01-01

    A protein fraction isolated from green algae Halimeda macrobola taken from the sea of Selayar and Kapoposang Island in South Sulawesi was tested for antioxidant and anticancer properties. The protein was isolated using buffer Tris (hydroxymethyl) amino methane. Initial purification of protein was conducted by using the fractionation method with ammonium sulphate, followed by dialysis process. Protein concentration was determined by Lowry method. Antioxidant assay was done by using DPPH method...

  7. 3-PHENYLQUINOLINYLCHALCONE DERIVATIVES: PHARMACOPHORE MODELLING, 3D-QSAR ANALYSIS AND DOCKING STUDIES AS ANTI-CANCER AGENTS

    OpenAIRE

    2014-01-01

    Certain 3-Phenylquinolinylchalcone derivatives were evaluated for their anti-proliferative activities and found to exhibit anti-cancer and anti-inflammatory activities. 3D-QSAR and molecular docking approaches were performed on 3-Phenylquinolinylchalcone derivatives to understand their structural requisites and binding mode of the best fitted ligand for cancer inhibitory activity. Among them, (E)-3-(3-(4-methoxyphenyl)quinolin-2-yl)-1-phenylprop-2-en-1-one (6a) was the most active compound ag...

  8. Integrin-targeted pH-responsive micelles for enhanced efficiency of anticancer treatment in vitro and in vivo

    Science.gov (United States)

    Liu, Jinjian; Deng, Hongzhang; Liu, Qiang; Chu, Liping; Zhang, Yumin; Yang, Cuihong; Zhao, Xuefei; Huang, Pingsheng; Deng, Liandong; Dong, Anjie; Liu, Jianfeng

    2015-02-01

    The key to developing more nanocarriers for the delivery of drugs in clinical applications is to consider the route of the carrier from the administration site to the target tissue and to look for a simple design to complete this whole journey. We synthesized the amphiphilic copolymer cRGDfK-poly(ethylene glycol)-b-poly(2,4,6-trimethoxybenzylidene-1,1,1-tris(hydroxymethyl) ethane methacrylate) (cRGD-PETM) to construct multifunctional micelles. These micelles combined enhanced drug-loading efficiency with tumor-targeting properties, visual detection and controllable intracellular drug release, resulting in an improved chemotherapeutic effect in vivo. Doxorubicin (DOX) was encapsulated within the cRGD-PETM micelles as a model drug (termed as cRGD-PETM/DOX Ms). The size and morphology of the micelles were characterized systematically. As a result of the hydrophobic interaction and the π-π conjugation between the DOX molecules and the PTTMA copolymers, the cRGD-PETM/DOX Ms showed an excellent drug-loading capacity. The results of in vitro drug-release studies indicated that the cumulative release of DOX from cRGD-PETM/DOX Ms at pH 5.0 was twice that at pH 7.4. The results of fluorescent microscopic analysis showed that the cRGD-PETM/DOX Ms could be internalized by 4T1 and HepG2 cells via receptor-mediated endocytosis with rapid intracellular drug release, which resulted in increased cytotoxicity compared with free DOX. Ex vivo imaging studies showed that the cRGD-PETM/DOX Ms improved the accumulation and retention of the drug in tumor tissues. Studies of the in vivo anticancer effects showed that the cRGD-PETM/DOX Ms had a significantly higher therapeutic efficacy with lower side-effects than free DOX and PETM/DOX Ms. These results show that the multifunctional cRGD-PETM/DOX Ms have great potential as vehicles for the delivery of hydrophobic anticancer drugs.

  9. Design of antibody-functionalized carbon nanotubes filled with radioactivable metals towards a targeted anticancer therapy

    Science.gov (United States)

    Spinato, Cinzia; Perez Ruiz de Garibay, Aritz; Kierkowicz, Magdalena; Pach, Elzbieta; Martincic, Markus; Klippstein, Rebecca; Bourgognon, Maxime; Wang, Julie Tzu-Wen; Ménard-Moyon, Cécilia; Al-Jamal, Khuloud T.; Ballesteros, Belén; Tobias, Gerard; Bianco, Alberto

    2016-06-01

    In the present work we have devised the synthesis of a novel promising carbon nanotube carrier for the targeted delivery of radioactivity, through a combination of endohedral and exohedral functionalization. Steam-purified single-walled carbon nanotubes (SWCNTs) have been initially filled with radioactive analogues (i.e. metal halides) and sealed by high temperature treatment, affording closed-ended CNTs with the filling material confined in the inner cavity. The external functionalization of these filled CNTs was then achieved by nitrene cycloaddition and followed by the derivatization with a monoclonal antibody (Cetuximab) targeting the epidermal growth factor receptor (EGFR), overexpressed by several cancer cells. The targeting efficiency of the so-obtained conjugate was evaluated by immunostaining with a secondary antibody and by incubation of the CNTs with EGFR positive cells (U87-EGFR+), followed by flow cytometry, confocal microscopy or elemental analyses. We demonstrated that our filled and functionalized CNTs can internalize more efficiently in EGFR positive cancer cells.In the present work we have devised the synthesis of a novel promising carbon nanotube carrier for the targeted delivery of radioactivity, through a combination of endohedral and exohedral functionalization. Steam-purified single-walled carbon nanotubes (SWCNTs) have been initially filled with radioactive analogues (i.e. metal halides) and sealed by high temperature treatment, affording closed-ended CNTs with the filling material confined in the inner cavity. The external functionalization of these filled CNTs was then achieved by nitrene cycloaddition and followed by the derivatization with a monoclonal antibody (Cetuximab) targeting the epidermal growth factor receptor (EGFR), overexpressed by several cancer cells. The targeting efficiency of the so-obtained conjugate was evaluated by immunostaining with a secondary antibody and by incubation of the CNTs with EGFR positive cells (U87

  10. DNA G-quadruplex and its potential as anticancer drug target

    Science.gov (United States)

    Buket, ONEL; Clement, LIN; DanZhou, YANG

    2016-01-01

    G-quadruplex secondary structures are four-stranded globular nucleic acid structures form in the specific DNA and RNA G-rich sequences with biological significance such as human telomeres, oncogene-promoter regions, replication initiation sites, and 5′ and 3′-untranslated (UTR) regions. The non-canonical G-quadruplex secondary structures can readily form under physiologically relevant ionic conditions and are considered to be new molecular target for cancer therapeutics. This review discusses the essential progress in our lab related to the structures and functions of biologically relevant DNA G-quadruplexes in human gene promoters and telomeres, and the opportunities presented for the development of G-quadruplex-targeted small- molecule drugs.

  11. Caffeine-based gold(I) N-heterocyclic carbenes as possible anticancer agents: synthesis and biological properties.

    Science.gov (United States)

    Bertrand, Benoît; Stefan, Loic; Pirrotta, Marc; Monchaud, David; Bodio, Ewen; Richard, Philippe; Le Gendre, Pierre; Warmerdam, Elena; de Jager, Marina H; Groothuis, Geny M M; Picquet, Michel; Casini, Angela

    2014-02-17

    A new series of gold(I) N-heterocyclic carbene (NHC) complexes based on xanthine ligands have been synthesized and characterized by mass spectrometry, NMR, and X-ray diffraction. The compounds have been tested for their antiproliferative properties in human cancer cells and nontumorigenic cells in vitro, as well as for their toxicity in healthy tissues ex vivo. The bis-carbene complex [Au(caffein-2-ylidene)2][BF4] (complex 4) appeared to be selective for human ovarian cancer cell lines and poorly toxic in healthy organs. To gain preliminary insights into their actual mechanism of action, two biologically relevant in cellulo targets were studied, namely, DNA (more precisely a higher-order DNA structure termed G-quadruplex DNA that plays key roles in oncogenetic regulation) and a pivotal enzyme of the DNA damage response (DDR) machinery (poly-(adenosine diphosphate (ADP)-ribose) polymerase 1 (PARP-1), strongly involved in the cancer resistance mechanism). Our results indicate that complex 4 acts as an efficient and selective G-quadruplex ligand while being a modest PARP-1 inhibitor (i.e., poor DDR impairing agent) and thus provide preliminary insights into the molecular mechanism that underlies its antiproliferative behavior. PMID:24499428

  12. Crystal structure of human T cell leukemia virus protease, a novel target for anticancer drug design

    OpenAIRE

    Li, Mi; Laco, Gary S.; Jaskolski, Mariusz; Rozycki, Jan; Alexandratos, Jerry; Wlodawer, Alexander; Gustchina, Alla

    2005-01-01

    The successful development of a number of HIV-1 protease (PR) inhibitors for the treatment of AIDS has validated the utilization of retroviral PRs as drug targets and necessitated their detailed structural study. Here we report the structure of a complex of human T cell leukemia virus type 1 (HTLV-1) PR with a substrate-based inhibitor bound in subsites P5 through P5′. Although HTLV-1 PR exhibits an overall fold similar to other retroviral PRs, significant structural differences are present i...

  13. Human sterol 14α-demethylase as a target for anticancer chemotherapy: towards structure-aided drug design.

    Science.gov (United States)

    Hargrove, Tatiana Y; Friggeri, Laura; Wawrzak, Zdzislaw; Sivakumaran, Suneethi; Yazlovitskaya, Eugenia M; Hiebert, Scott W; Guengerich, F Peter; Waterman, Michael R; Lepesheva, Galina I

    2016-08-01

    Rapidly multiplying cancer cells synthesize greater amounts of cholesterol to build their membranes. Cholesterol-lowering drugs (statins) are currently in clinical trials for anticancer chemotherapy. However, given at higher doses, statins cause serious side effects by inhibiting the formation of other biologically important molecules derived from mevalonate. Sterol 14α-demethylase (CYP51), which acts 10 steps downstream, is potentially a more specific drug target because this portion of the pathway is fully committed to cholesterol production. However, screening a variety of commercial and experimental inhibitors of microbial CYP51 orthologs revealed that most of them (including all clinical antifungals) weakly inhibit human CYP51 activity, even if they display high apparent spectral binding affinity. Only one relatively potent compound, (R)-N-(1-(3,4'-difluorobiphenyl-4-yl)-2-(1H-imidazol-1-yl)ethyl)-4-(5-phenyl-1,3,4-oxadiazol-2-yl)benzamide (VFV), was identified. VFV has been further tested in cellular experiments and found to decrease proliferation of different cancer cell types. The crystal structures of human CYP51-VFV complexes (2.0 and 2.5 Å) both display a 2:1 inhibitor/enzyme stoichiometry, provide molecular insights regarding a broader substrate profile, faster catalysis, and weaker susceptibility of human CYP51 to inhibition, and outline directions for the development of more potent inhibitors. PMID:27313059

  14. Could B7-H4 serve as a target to activate anti-cancer immunity?

    Science.gov (United States)

    Wang, Lijuan; Heng, Xueyuan; Lu, Yong; Cai, Zhen; Yi, Qing; Che, Fengyuan

    2016-09-01

    It has been over 13years since the identification of B7-H4, the co-stimulatory molecule of B7 family members. While B7-H4 mRNA is widely distributed protein expression seems to be limited on tissues. Various cytokines and inflammatory mediators induce the expression of B7-H4. However, the specific regulatory mechanisms of B7-H4 remain to be defined. Recently, it has been shown that B7-H4 executes an inhibitory function in the T-cell response via reduced expansion, cell cycle arrest, decreased cytokine secretion and induced apoptosis of activated T-cells. Furthermore, B7-H4 suppresses the function of antigen presenting cells (APCs) and promotes the proliferation and development of regulatory T-cells (Treg). Moreover, a growing body of literature demonstrates that various cancers express B7-H4 and that the expression levels of B7-H4 correlate with cancer size, histological type, pathologic stage, grade, infiltration, lymph node metastasis, cancer progression, recurrence and death. The over-expression of B7-H4 in cancer may be related to an increased resistance to immune responses. The aim of this review is to supply an overview of the advances in the regulation and function of B7-H4. Additionally, many studies have suggested that B7-H4 is a molecular target for therapeutic intervention in cancer and that targeting B7-H4 may have promising potential for improving the efficacy of immunotherapy for cancer patients. PMID:27258187

  15. Benzene-Poly-Carboxylic Acid Complex, a Novel Anti-Cancer Agent Induces Apoptosis in Human Breast Cancer Cells

    OpenAIRE

    Fares, Fuad; Azzam, Naiel; Fares, Basem; Larsen, Stig; Lindkaer-Jensen, Steen

    2014-01-01

    Some cases of breast cancer are composed of clones of hormonal-independent growing cells, which do not respond to therapy. In the present study, the effect of Benzene-Poly-Carboxylic Acid Complex (BP-C1) on growth of human breast-cancer cells was tested. BP-C1 is a novel anti-cancer complex of benzene-poly-carboxylic acids with a very low concentration of cis-diammineplatinum (II) dichloride. Human breast cancer cells, MCF-7 and T47D, were used. Cell viability was detected by XTT assay and ap...

  16. Integrating Activity-Based Costing with Target Costing and Principal-Agent Incentives

    OpenAIRE

    Xiaoyuan Huang; Lijun Li; Liping Yu

    2009-01-01

    The current studies of cost management mainly focus on the cost control of transactions and activities, which is a basic function of cost management. This paper analyzes activity-based costing (ABC) and principal-agent incentives, and target costing (TC) and principal-agent incentives with regard to both functional and institutional aspects of cost management in agent theory framework, and reaches the point that a integration of activity-based costing and target costing based on principal-age...

  17. Clearing the fog of anticancer patents from 1993-2013: through an in-depth technology landscape & target analysis from pioneer research institutes and universities worldwide.

    Directory of Open Access Journals (Sweden)

    Ajay Dara

    Full Text Available BACKGROUND: In a search for an effective anticancer therapy the R&D units from leading universities and institutes reveal numerous technologies in the form of patent documents. The article addressed comparative anticancer patent landscape and technology assessment of Council of Scientific and Industrial Research (CSIR: India's largest R&D organisation with top twenty international public funded universities and institutes from eight different countries. METHODOLOGY/PRINCIPAL FINDINGS: The methodology include quantitative and qualitative assessment based on the bibliometric parameters and manual technology categorisation to understand the changing patent trends and recent novel technologies. The research finding analysed 25,254 patent documents from the year 1993 to 2013 and reported the insights of latest anticancer technologies and targets through categorisation studies at the level of drug discovery, development and treatment & diagnosis. The article has reported the technology correlation matrix of twelve secondary class technologies with 34 tertiary sub-class research area to identify the leading technologies and scope of future research through whitespaces analysis. In addition, the results have also addressed the target analysis, leading inventor, assignee, collaboration network, geographical distribution, patent trend analysis, citation maps and technology assessment with respect to international patent classification systems such as CPC, IPC and CPI codes. CONCLUSIONS/SIGNIFICANCE: The result suggested peptide technology as the dominating research area next to gene therapy, vaccine and medical preparation containing organic compounds. The Indian CSIR has ranked itself at seventh position among the top 20 universities. Globally, the anticancer research was focused in the area of genetics and immunology, whereas Indian CSIR reported more patents related to plant extract and organic preparation. The article provided a glimpse of two decade

  18. From COX-2 inhibitor nimesulide to potent anti-cancer agent: synthesis, in vitro, in vivo and pharmacokinetic evaluation.

    Science.gov (United States)

    Zhong, Bo; Cai, Xiaohan; Chennamaneni, Snigdha; Yi, Xin; Liu, Lili; Pink, John J; Dowlati, Afshin; Xu, Yan; Zhou, Aimin; Su, Bin

    2012-01-01

    Cyclooxygenase-2 (COX-2) inhibitor nimesulide inhibits the proliferation of various types of cancer cells mainly via COX-2 independent mechanisms, which makes it a good lead compound for anti-cancer drug development. In the presented study, a series of new nimesulide analogs were synthesized based on the structure-function analysis generated previously. Some of them displayed very potent anti-cancer activity with IC(50)s around 100 nM-200 nM to inhibit SKBR-3 breast cancer cell growth. CSUOH0901 (NSC751382) from the compound library also inhibits the growth of the 60 cancer cell lines used at National Cancer Institute Developmental therapeutics Program (NCIDTP) with IC(50)s around 100 nM-500 nM. Intraperitoneal injection with a dosage of 5  mg/kg/d of CSUOH0901 to nude mice suppresses HT29 colorectal xenograft growth. Pharmacokinetic studies demonstrate the good bioavailability of the compound. PMID:22119125

  19. Specific Design of Titanium(IV) Phenolato Chelates Yields Stable and Accessible, Effective and Selective Anticancer Agents.

    Science.gov (United States)

    Meker, Sigalit; Braitbard, Ori; Hall, Matthew D; Hochman, Jacob; Tshuva, Edit Y

    2016-07-11

    Octahedral titanium(IV) complexes of phenolato hexadentate ligands were developed and showed very high stability for days in water solutions. In vitro cytotoxicity studies showed that, whereas tetrakis(phenolato) systems are generally of low activity presumably due to inaccessibility, smaller bis(phenolato)bis(alkoxo) complexes feature high anticancer activity and accessibility even without formulations, also toward a cisplatin-resistant cell line. An all-aliphatic control complex was unstable and inactive. A leading phenolato complex also revealed: 1) high durability in fully aqueous solutions; accordingly, negligible loss of activity after preincubation for three days in medium or in serum; 2) maximal cellular accumulation and induction of apoptosis following 24-48 h of administration; 3) reduced impact on noncancerous fibroblast cells; 4) in vivo efficacy toward lymphoma cells in murine model; 5) high activity in NCI-60 panel, with average GI50 of 4.6±2 μm. This newly developed family of Ti(IV) complexes is thus of great potential for anticancer therapy. PMID:27320784

  20. Synthesis and anticancer activity of some novel indolo[3,2-b]andrographolide derivatives as apoptosis-inducing agents.

    Science.gov (United States)

    Song, Yaping; Xin, Zhengyuan; Wan, Yumeng; Li, Jiabin; Ye, Boping; Xue, Xiaowen

    2015-01-27

    A series of novel indolo[3,2-b]andrographolide derivatives were designed, synthesized and screened in vitro against three human cancer cell lines MCF7 (human breast cancer), HCT116 (human colon cancer), and DU145 (human prostate cancer). Fourteen compounds 6b, 6e, 6i, 6j, 6l, 6m, 6n, 12a, 12b, 13a, 13b, 15a, 17a, and 17b exhibited better anti-cancer activities than andrographolide for all three human cancer lines, with compound 6l displaying best activity with IC50 values of 1.85, 1.22 and 1.24 μM against MCF7, HCT116 and DU145 respectively. Preliminary anti-cancer mechanistic investigation was performed in terms of the cell cycle arrest and cell apoptosis assays of compound 6l against HCT116 using flow cytometry, and the results suggested that compound 6l inhibited tumor proliferation through inducing early and late cellular apoptosis in a concentration-dependent manner and causing cell cycle arrest in the S-phase. PMID:25506809

  1. 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

  2. Effects of intra-arterial chemotherapy with a new lipophilic anticancer agent, estradiol-chlorambucil (KM2210), dissolved in lipiodol on experimental liver tumor in rats

    International Nuclear Information System (INIS)

    Anticancer effects and biodistribution of a new lipophilic anticancer agent, estradiol-chlorambucil (KM2210), dissolved in lipiodol (LPD) were investigated as an intra-arterial chemotherapy (IAC) on Walker 256 carcinosarcoma grown in the liver of 136 Wistar rats. All rats treated with KM2210 (10 mg)-LPD survived for 90 days after administration, whereas none of the rats with LPD alone were alive for more than 19 days. Histological examination revealed that there was no viable tumor cell in the encapsulated necrotic tumor at 21 days after administration. There was no significant liver dysfunction or leukopenia due to KM2210. The biodistribution study using [14C, 3H]KM2210-LPD solution showed that KM2210 accumulated selectively in tumor and that the tumor-to-normal-liver and tumor-to-blood ratios were 10 and 1,000, respectively, at 21 days after administration. These results suggest that KM2210 has potential clinical application in the treatment of human liver cancer

  3. Evaluation of a curcumin analog as an anti-cancer agent inducing ER stress-mediated apoptosis in non-small cell lung cancer cells

    International Nuclear Information System (INIS)

    Recent advances have highlighted the importance of the endoplasmic reticulum (ER) in cell death processes. Pharmacological interventions that effectively enhance tumor cell death through activating ER stress have attracted a great deal of attention for anti-cancer therapy. A bio-evaluation on 113 curcumin analogs against four cancer cell lines was performed through MTT assay. Furthermore, real time cell assay and flow cytometer were used to evaluate the apoptotic induction of (1E,4E)-1,5-bis(5-bromo-2-ethoxyphenyl)penta-1,4-dien-3-one (B82). Western blot, RT-qPCR, and siRNA were then utilized to confirm whether B82-induced apoptosis is mediated through activating ER stress pathway. Finally, the in vivo anti-tumor effect of B82 was evaluated. B82 exhibited strong anti-tumor activity in non-small cell lung cancer (NSCLC) H460 cells. Treatment with B82 significantly induced apoptosis in H460 cells in vitro and inhibited H460 tumor growth in vivo. Further studies demonstrated that the B82-induced apoptosis is mediated by activating ER stress both in vitro and in vivo. A new monocarbonyl analog of curcumin, B82, exhibited anti-tumor effects on H460 cells via an ER stress-mediated mechanism. B82 could be further explored as a potential anticancer agent for the treatment of NSCLC

  4. Essential oils from Egyptian aromatic plants as antioxidant and novel anticancer agents in human cancer cell lines

    Directory of Open Access Journals (Sweden)

    Ramadan, M. M.

    2015-06-01

    Full Text Available Inhibitors of tumor growth using extracts from aromatic plants are rapidly emerging as important new drug candidates for cancer therapy. The cytotoxicity and in vitro anticancer evaluation of the essential oils from thyme, juniper and clove has been assessed against five different human cancer cell lines (liver HepG2, breast MCF-7, prostate PC3, colon HCT116 and lung A549. A GC/MS analysis revealed that α-pinene, thymol and eugenol are the major components of Egyptian juniper, thyme and clove oils with concentrations of 31.19%, 79.15% and 82.71%, respectively. Strong antioxidant profiles of all the oils are revealed in vitro by DPPH and β-carotene bleaching assays. The results showed that clove oil was similarly potent to the reference drug, doxorubicin in prostate, colon and lung cell lines. Thyme oil was more effective than the doxorubicin in breast and lung cell lines while juniper oil was more effective than the doxorubicin in all the tested cancer cell lines except prostate cancer. In conclusion, the essential oils from Egyptian aromatic plants can be used as good candidates for novel therapeutic strategies for cancer as they possess significant anticancer activity.Los inhibidores de crecimiento de tumores usando extractos de plantas aromáticas están emergiendo con rapidez como nuevos e importantes medicamentos para el tratamiento del cáncer. La citotoxicidad y la acción anticancerígena in vitro de aceites esenciales de tomillo, enebro y clavo han sido evaluadas en cinco líneas celulares de cáncer humano (hígado HepG2, mama MCF-7, próstata PC3, colon HCT116 y pulmón A549. Los análisis de GC/MS mostraron que α-pineno, timol y eugenol son los principales componentes de los aceites egipcios de enebro, tomillo y clavo, con concentraciones de 31,19%, 79,15% y 82,71%, respectivamente. Se demuestra, mediante ensayos in vitro de blanqueo de DPPH y β-caroteno, el enérgico perfil antioxidante de todos los aceites. Los resultados

  5. The anti-cancer agent guttiferone-A permeabilizes mitochondrial membrane: Ensuing energetic and oxidative stress implications

    International Nuclear Information System (INIS)

    Guttiferone-A (GA) is a natural occurring polyisoprenylated benzophenone with cytotoxic action in vitro and anti-tumor action in rodent models. We addressed a potential involvement of mitochondria in GA toxicity (1-25 μM) toward cancer cells by employing both hepatic carcinoma (HepG2) cells and succinate-energized mitochondria, isolated from rat liver. In HepG2 cells GA decreased viability, dissipated mitochondrial membrane potential, depleted ATP and increased reactive oxygen species (ROS) levels. In isolated rat-liver mitochondria GA promoted membrane fluidity increase, cyclosporine A/EGTA-insensitive membrane permeabilization, uncoupling (membrane potential dissipation/state 4 respiration rate increase), Ca2+ efflux, ATP depletion, NAD(P)H depletion/oxidation and ROS levels increase. All effects in cells, except mitochondrial membrane potential dissipation, as well as NADPH depletion/oxidation and permeabilization in isolated mitochondria, were partly prevented by the a NAD(P)H regenerating substrate isocitrate. The results suggest the following sequence of events: 1) GA interaction with mitochondrial membrane promoting its permeabilization; 2) mitochondrial membrane potential dissipation; 3) NAD(P)H oxidation/depletion due to inability of membrane potential-sensitive NADP+ transhydrogenase of sustaining its reduced state; 4) ROS accumulation inside mitochondria and cells; 5) additional mitochondrial membrane permeabilization due to ROS; and 6) ATP depletion. These GA actions are potentially implicated in the well-documented anti-cancer property of GA/structure related compounds. - Graphical abstract: Guttiferone-A permeabilizes mitochondrial membrane and induces cancer cell death Display Omitted Highlights: → We addressed the involvement of mitochondria in guttiferone (GA) toxicity toward cancer cells. → GA promoted membrane permeabilization, membrane potential dissipation, NAD(P)H depletion, ROS accumulation and ATP depletion. → These actions could be

  6. 'Smartening' anticancer therapeutic nanosystems using biomolecules.

    Science.gov (United States)

    Núñez-Lozano, Rebeca; Cano, Manuel; Pimentel, Belén; de la Cueva-Méndez, Guillermo

    2015-12-01

    To be effective, anticancer agents must induce cell killing in a selective manner, something that is proving difficult to achieve. Drug delivery systems could help to solve problems associated with the lack of selectivity of classical chemotherapeutic agents. However, to realize this, such systems must overcome multiple physiological barriers. For instance, they must evade surveillance by the immune system, attach selectively to target cells, and gain access to their interior. Furthermore, there they must escape endosomal entrapment, and release their cargoes in a controlled manner, without affecting their functionality. Here we review recent efforts aiming at using biomolecules to confer these abilities to bare nanoparticles, to transform them into smart anticancer therapeutic nanosystems. PMID:26277646

  7. 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) ...

  8. Synthesis of some new heterocyclic compounds bearing a sulfonamide moiety and studying their combined anticancer effect with γ-radiation

    International Nuclear Information System (INIS)

    In search for new cytotoxic agents with improved anticancer profile, some new halogen-containing quinoline and pyrimido[4,5-b]quinoline derivatives bearing a free sulfonamide moiety were synthesized. All the newly synthesized target compounds were subjected to in vitro anticancer screening against human breast cancer cell line (MCF7). The most potent compounds, as concluded from the in vitro anticancer screening, were selected to be evaluated again for their in vitro anticancer activity in combination with radiation. Also, the newly synthesized compounds were docked in the active site of the carbonic anhydrase enzyme

  9. Targeting Antibacterial Agents by Using Drug-Carrying Filamentous Bacteriophages

    OpenAIRE

    Yacoby, Iftach; Shamis, Marina; Bar, Hagit; Shabat, Doron; Benhar, Itai

    2006-01-01

    Bacteriophages have been used for more than a century for (unconventional) therapy of bacterial infections, for half a century as tools in genetic research, for 2 decades as tools for discovery of specific target-binding proteins, and for nearly a decade as tools for vaccination or as gene delivery vehicles. Here we present a novel application of filamentous bacteriophages (phages) as targeted drug carriers for the eradication of (pathogenic) bacteria. The phages are genetically modified to d...

  10. Molecular Targets of TRAIL-Sensitizing Agents in Colorectal Cancer

    Directory of Open Access Journals (Sweden)

    Giovanni Monteleone

    2012-06-01

    Full Text Available Tumor necrosis factor (TNF-related apoptosis inducing ligand (TRAIL, a member of the TNF superfamily, interacts with its functional death receptors (DRs and induces apoptosis in a wide range of cancer cell types. Therefore, TRAIL has been considered as an attractive agent for cancer therapy. However, many cancers are resistant to TRAIL-based therapies mainly due to the reduced expression of DRs and/or up-regulation of TRAIL pathway-related anti-apoptotic proteins. Compounds that revert such defects restore the sensitivity of cancer cells to TRAIL, suggesting that combined therapies could help manage neoplastic patients. In this article, we will focus on the TRAIL-sensitizing effects of natural products and synthetic compounds in colorectal cancer (CRC cells and discuss the molecular mechanisms by which such agents enhance the response of CRC cells to TRAIL.

  11. Marine-Sourced Anti-Cancer and Cancer Pain Control Agents in Clinical and Late Preclinical Development

    Directory of Open Access Journals (Sweden)

    David J. Newman

    2014-01-01

    Full Text Available 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 as a warhead, have been approved for use in humans (Adcetris®. In this review, we show the compounds derived from marine sources that are currently in clinical trials against cancer. We have included brief discussions of the approved agents, where they are in trials to extend their initial approved activity (a common practice once an agent is approved, and have also included an extensive discussion of the use of auristatin derivatives as warheads, plus an area that has rarely been covered, the use of marine-derived agents to ameliorate the pain from cancers in humans, and to act as an adjuvant in immunological therapies.

  12. Targeting Reactive Carbonyl Species with Natural Sequestering Agents

    OpenAIRE

    Sung Won Hwang; Yoon-Mi Lee; Giancarlo Aldini; Kyung-Jin Yeum

    2016-01-01

    Reactive carbonyl species generated by the oxidation of polyunsaturated fatty acids and sugars are highly reactive due to their electrophilic nature, and are able to easily react with the nucleophilic sites of proteins as well as DNA causing cellular dysfunction. Levels of reactive carbonyl species and their reaction products have been reported to be elevated in various chronic diseases, including metabolic disorders and neurodegenerative diseases. In an effort to identify sequestering agents...

  13. Targeting advanced glycation with pharmaceutical agents: where are we now?

    Science.gov (United States)

    Borg, Danielle J; Forbes, Josephine M

    2016-08-01

    Advanced glycation end products (AGEs) are the final products of the Maillard reaction, a complex process that has been studied by food chemists for a century. Over the past 30 years, the biological significance of advanced glycation has also been discovered. There is mounting evidence that advanced glycation plays a homeostatic role within the body and that food-related Maillard products, intermediates such as reactive α-dicarbonyl compounds and AGEs, may influence this process. It remains to be understood, at what point AGEs and their intermediates become pathogenic and contribute to the pathogenesis of chronic diseases that inflict current society. Diabetes and its complications have been a major focus of AGE biology due to the abundance of excess sugar and α-dicarbonyls in this family of diseases. While further temporal information is required, a number of pharmacological agents that inhibit components of the advanced glycation pathway have already showed promising results in preclinical models. These therapies appear to have a wide range of mechanistic actions to reduce AGE load. Some of these agents including Alagebrium, have translated successfully to clinical trials, while others such as aminoguanidine, have had undesirable side-effect profiles. This review will discuss different pharmacological agents that have been used to reduce AGE burden in preclinical models of disease with a focus on diabetes and its complications, compare outcomes of those therapies that have reached clinical trials, and provide further rationale for the use of inhibitors of the glycation pathway in chronic diseases. PMID:27392438

  14. Toxicities of anticancer drugs and its management

    Directory of Open Access Journals (Sweden)

    Ambili Remesh

    2012-02-01

    Full Text Available One of the characteristics that distinguish anticancer agents from other drugs is the frequency and severity of side effects at therapeutic doses. Most cytotoxic drugs target rapidly multiplying cells and the putative targets are the nucleic acids and their precursors, which are rapidly synthesised during cell division. Many solid tumours have a lower growth fraction than the normal bone marrow, gastro intestinal lining, reticuloendothelial system and gonads. Drugs affect these tissues in a dose dependant manner and there is individual susceptibility also. So toxicities are more frequently associated with these tissues. The side effects may be acute or chronic, self-limited, permanent, mild or potentially life threatening. Management of these side effects is of utmost importance because they affect the treatment, tolerability and overall quality of life. This paper gives an overview of different toxicities of anticancer drugs and its management. [Int J Basic Clin Pharmacol 2012; 1(1.000: 2-12

  15. Benzene-Poly-Carboxylic Acid Complex, a Novel Anti-Cancer Agent Induces Apoptosis in Human Breast Cancer Cells

    Science.gov (United States)

    Fares, Fuad; Azzam, Naiel; Fares, Basem; Larsen, Stig; Lindkaer-Jensen, Steen

    2014-01-01

    Some cases of breast cancer are composed of clones of hormonal-independent growing cells, which do not respond to therapy. In the present study, the effect of Benzene-Poly-Carboxylic Acid Complex (BP-C1) on growth of human breast-cancer cells was tested. BP-C1 is a novel anti-cancer complex of benzene-poly-carboxylic acids with a very low concentration of cis-diammineplatinum (II) dichloride. Human breast cancer cells, MCF-7 and T47D, were used. Cell viability was detected by XTT assay and apoptosis was detected by Flow Cytometry and by annexin V/FITC/PI assay. Caspases were detected by western blot analysis and gene expression was measured by using the Applied Biosystems® TaqMan® Array Plates. The results showed that exposure of the cells to BP-C1 for 48 h, significantly (P<0.001) reduced cell viability, induced apoptosis and activated caspase 8 and caspace 9. Moreover, gene expression experiments indicated that BP-C1 increased the expression of pro-apoptotic genes (CASP8AP1, TNFRSF21, NFkB2, FADD, BCL10 and CASP8) and lowered the level of mRNA transcripts of inhibitory apoptotic genes (BCL2L11, BCL2L2 and XIAP. These findings may lead to the development of new therapeutic strategies for treatment of human cancer using BP-C1 analog. PMID:24523856

  16. Synthesis and Cytotoxicity Evaluation of 13-n-Alkyl Berberine and Palmatine Analogues as Anticancer Agents

    Directory of Open Access Journals (Sweden)

    Lei Zhang

    2012-09-01

    Full Text Available By introducing long carbon-chain alkyl groups at the C-13 position of berberine and palmatine, 13-n-hexyl/13-n-octyl berberine and palmatine chloride analogues 4ad were synthesized and examined by MTT assays for cytotoxic activity in seven human cancer cell lines (7701QGY, SMMC7721, HepG2, CEM, CEM/VCR, KIII, Lewis, yielding IC50 values of 0.02 ± 0.01–13.58 ± 2.84 μM. 13-n-Octyl palmatine (compound 4d gave the most potent inhibitor activity, with an IC50 of 0.02 ± 0.01 μM for SMMC7721. In all cases, the 13-n-alkyl berberine and palmatine analogues 4ad were more cytotoxic than berberine and palmatine. In addition, compounds 4ad also exhibited more potent cytotoxicity than berberine and palmatine in mice with S180 sarcoma xenografted in vivo. The primary screening results indicated that the 13-n-hexyl/13-n-octyl berberine and palmatine analogues might be valuable source for new potent anticancer drug candidates.

  17. 3-D QSAR CoMFA study of nitrogen mustards possessing new chemical entities as possible anticancer agents

    Directory of Open Access Journals (Sweden)

    Anand R

    2006-01-01

    Full Text Available This present work is an investigation of anticancer activities of the nitrogen mustards possessing quinazolinone, benzimidazole, benzoxazole, and benzothiazole nuclei by the three-dimensional Quantitative Structure Activity paradigm, Comparative Molecular Field Analysis. A total of 39 compounds were modelled in SYBYL 6.7 (Tripos, USA. The molecules were aligned by root-mean-square fit of atoms and field fit of the steric and electrostatic molecular fields and the resulting databases analysed by partial least squares analysis with cross-validation, leave-one-out and no validation to extract the optimum number of components. The analysis was then repeated with bootstrapping to give the final Quantitative Structure Activity Relationship models. Eight compounds, which were kept separately as test set, were used to test the predictive ability of the Comparative Molecular Field Analysis models. Out of the two models generated, one was found to be useful. The predicted activities of the test set were in good agreement with experimentally determined values.

  18. Stimuli-responsive protamine-based biodegradable nanocapsules for enhanced bioavailability and intracellular delivery of anticancer agents

    International Nuclear Information System (INIS)

    Enzyme- and pH-responsive polyelectrolyte nanocapsules having diameters in the range of 200 ± 20 nm were fabricated by means of Layer-by-Layer assembly of biopolymers, protamine, and heparin, and then loaded with anticancer drug doxorubicin. The incorporation of the FDA-approved peptide drug protamine as a wall component rendered the capsules responsive to enzyme stimuli. The stimuli-responsive drug release from these nanocapsules was evaluated, and further modulation of capsule permeability to avoid premature release was demonstrated by crosslinking the wall components. The interaction of the nanocapsules with cancer cells was studied using MCF-7 breast cancer cells. These capsules were readily internalized and disintegrated inside the cells, culminating in the release of the loaded doxorubicin and subsequent cell death as observed by confocal microscopy and MTT Assay. The bioavailability studies performed using BALB/c mice revealed that the encapsulated doxorubicin exhibited enhanced bioavailability compared to free doxorubicin. Our results indicate that this stimuli-responsive system fabricated from clinically used FDA-approved molecules and exhibiting minimal premature release has great potential for drug-delivery applications.

  19. Stimuli-responsive protamine-based biodegradable nanocapsules for enhanced bioavailability and intracellular delivery of anticancer agents

    Energy Technology Data Exchange (ETDEWEB)

    Radhakrishnan, Krishna; Thomas, Midhun B.; Pulakkat, Sreeranjini [Indian Institute of Science, Department of Materials Engineering (India); Gnanadhas, Divya P.; Chakravortty, Dipshikha [Indian Institute of Science, Department of Microbiology and Cell Biology (India); Raichur, Ashok M., E-mail: amr@materials.iisc.ernet.in [Indian Institute of Science, Department of Materials Engineering (India)

    2015-08-15

    Enzyme- and pH-responsive polyelectrolyte nanocapsules having diameters in the range of 200 ± 20 nm were fabricated by means of Layer-by-Layer assembly of biopolymers, protamine, and heparin, and then loaded with anticancer drug doxorubicin. The incorporation of the FDA-approved peptide drug protamine as a wall component rendered the capsules responsive to enzyme stimuli. The stimuli-responsive drug release from these nanocapsules was evaluated, and further modulation of capsule permeability to avoid premature release was demonstrated by crosslinking the wall components. The interaction of the nanocapsules with cancer cells was studied using MCF-7 breast cancer cells. These capsules were readily internalized and disintegrated inside the cells, culminating in the release of the loaded doxorubicin and subsequent cell death as observed by confocal microscopy and MTT Assay. The bioavailability studies performed using BALB/c mice revealed that the encapsulated doxorubicin exhibited enhanced bioavailability compared to free doxorubicin. Our results indicate that this stimuli-responsive system fabricated from clinically used FDA-approved molecules and exhibiting minimal premature release has great potential for drug-delivery applications.

  20. Autonomous Collaborative Agents for Onboard Multi-Sensor Re-Targeting Project

    Data.gov (United States)

    National Aeronautics and Space Administration — In our Phase I effort we developed a prototype software-agent based framework to provide for autonomous re-targeting of sensors hosted on satellites in polar...

  1. Development of an LC-MS/MS method for analysis of interconvertible Z/E isomers of the novel anticancer agent, Bp4eT.

    Science.gov (United States)

    Stariat, Ján; Kovaríková, Petra; Klimes, Jirí; Kalinowski, Danuta S; Richardson, Des R

    2010-05-01

    This study was focused on a liquid chromatography/tandem mass spectrometry (LC/MS/MS) method development for quantification of a novel potential anticancer agent, 2-benzoylpyridine 4-ethyl-3-thiosemicarbazone (Bp4eT), in aqueous media. Solid Bp4eT was found to consist predominantly of the Z isomer, while in aqueous media, both isomers coexist. Sufficient separation of both isomers was achieved on a Synergi 4u Polar RP column with a mobile phase composed of 2 mM ammonium formate, acetonitrile, and methanol (30:63:7; v/v/v). The photo diode array analysis of both isomers demonstrated different absorption spectra which hindered UV-based quantification. However, an equal and reproducible response was found for both isomers using an MS detector, which enables the determination of the total content of Bp4eT (i.e., both E- and Z- isomeric forms) by summation of the peak areas of both isomers. 2-Hydroxy-1-naphthylaldehyde 4-methyl-3-thiosemicarbazone (N4mT) was selected as the internal standard. Quantification was performed in selective reaction monitoring using the main fragments of [M+H](+) (240 m/z for Bp4eT and 229 m/z for N4mT). The method was validated over 20-600 ng/ml. This procedure was applied to a preformulation study to determine the proper vehicle for parenteral administration. It was found that Bp4eT was poorly soluble in aqueous media. However, the solubility can be effectively improved using pharmaceutical cosolvents. In fact, a 1:1 mixture of PEG 300/0.14 M saline markedly increased solubility and may be a useful drug formulation for intravenous administration. This investigation further accelerates development of novel anticancer thiosemicarbazones. The described methods will be useful for analogs currently under development and suffering the same analytical issue. PMID:20127082

  2. Novel microtubule-targeted agent 6-chloro-4-(methoxyphenyl) coumarin induces G2-M arrest andapoptosis in HeLa cells

    Institute of Scientific and Technical Information of China (English)

    Yi-ming MA; Yu-bo ZHOU; Chuan-ming XIE; Dong-mei CHEN; Jia LI

    2012-01-01

    To identify a novel coumarin analogue with the highest anticancer activity and to further investigate its anticancer mechanisms.Methods:The viability of cancer cells was investigated using the MTT assay.The cell cycle progression was evaluated using both flow cytometric and Western blotting analysis.Microtubule depolymerization was observed with immunocytochemistry in vivo and a tubu-lin depolymerization assay in vitro.Apoptosis was demonstrated using Annexin V/Propidium Iodide (PI) double-staining and sub-G1analysis.Results:Among 36 analogues of coumarin,6-chloro-4-(methoxyphenyl) coumarin showed the best anticancer activity (IC50 value about 200 nmol/L) in HCT116 cells.The compound had a broad spectrum of anticancer activity against 9 cancer cell lines derived from colon cancer,breast cancer,liver cancer,cervical cancer,leukemia,epidermoid cancer with IC5o value of 75 nmol/L-1.57 μmol/L but with low cytotocitity against WI-38 human lung fibroblasts (IC50 value of 12.128 μmol/L).The compound (0.04-10 μmol/L) induced G2-M phase arrest in HeLa cells in a dose-dependent manner,which was reversible after the compound was removed.The compound (10-300 μmol/L) induced the depolymerization of purified porcine tubulin in vitro.Finally,the compound (0.04-2.5 μmol/L) induced apoptosis of HeLa cells in dose- and time-dependent manners.Conclusion:6-Chloro-4-(methoxyphenyl) coumarin is a novel microtubule-targeting agent that induces G2-M arrest and apoptosis in HeLa cells.

  3. Tumor lysis syndrome in the era of novel and targeted agents in patients with hematologic malignancies: a systematic review.

    Science.gov (United States)

    Howard, Scott C; Trifilio, Steven; Gregory, Tara K; Baxter, Nadine; McBride, Ali

    2016-03-01

    Effective new treatments are now available for patients with hematologic malignancies. However, their propensity to cause tumor lysis syndrome (TLS) has not been systematically examined. A literature search identified published Phase I-III clinical trials of monoclonal antibodies (otlertuzumab, brentuximab, obinutuzumab, ibritumomab, ofatumumab); tyrosine kinase inhibitors (alvocidib [flavopiridol], dinaciclib, ibrutinib, nilotinib, dasatinib, idelalisib, venetoclax [ABT-199]); proteasome inhibitors (oprozomib, carfilzomib); chimeric antigen receptor (CAR) T cells; and the proapoptotic agent lenalidomide. Abstracts from major congresses were also reviewed. Idelalisib and ofatumumab had no reported TLS. TLS incidence was ≤5 % with brentuximab vedotin (for anaplastic large-cell lymphoma), carfilzomib and lenalidomide (for multiple myeloma), dasatinib (for acute lymphoblastic leukemia), and oprozomib (for various hematologic malignancies). TLS incidences were 8.3 and 8.9 % in two trials of venetoclax (for chronic lymphocytic leukemia [CLL]) and 10 % in trials of CAR T cells (for B-cell malignancies) and obinutuzumab (for non-Hodgkin lymphoma). TLS rates of 15 % with dinaciclib and 42 and 53 % with alvocidib (with sequential cytarabine and mitoxantrone) were seen in trials of acute leukemias. TLS mitigation was employed routinely in clinical trials of alvocidib and lenalidomide. However, TLS mitigation strategies were not mentioned or stated only in general terms for many studies of other agents. The risk of TLS persists in the current era of novel and targeted therapy for hematologic malignancies and was seen to some extent with most agents. Our findings underscore the importance of continued awareness, risk assessment, and prevention to reduce this serious potential complication of effective anticancer therapy. PMID:26758269

  4. Synthesis and serotonin transporter activity of sulphur-substituted alpha-alkyl phenethylamines as a new class of anticancer agents

    DEFF Research Database (Denmark)

    Cloonan, Suzanne M.; Keating, John J.; Butler, Stephen G.;

    2009-01-01

    The discovery that some serotonin reuptake transporter (SERT) ligands have the potential to act as pro-apoptotic agents in the treatment of cancer adds greatly to their diverse pharmacological application. 4-Methylthioamphetamine (MTA) is a selective ligand for SERT over other monoamine transport......The discovery that some serotonin reuptake transporter (SERT) ligands have the potential to act as pro-apoptotic agents in the treatment of cancer adds greatly to their diverse pharmacological application. 4-Methylthioamphetamine (MTA) is a selective ligand for SERT over other monoamine...... transporters. In this study, a novel library of structurally diverse 4-MTA analogues were synthesised with or without N-alkyl and/or C-alpha methyl or ethyl groups so that their potential SERT-dependent antiproliferative activity could be assessed. Many of the compounds displayed SERT-binding activity as well...

  5. Development of PET molecular targeting agents with gallium-68

    International Nuclear Information System (INIS)

    The utilization of positron emission tomography (PET) is increasing due to its superior imaging quality and its ability to be used for in vivo quantification. Radionuclides that decay by positron emission can be attached to the same chelators used for radiotherapy applications in diagnosis and staging. One such isotope is 68Ga (T1/2 = 68 min), which can be obtained from a long-lived generator by decay of the parent 68Ge (T1/2 = 270.8 d). The availability of 68Ga from a generator plus its ability to be stably incorporated with a variety of chelates hold promise for expanding PET utilization to facilities unable to afford their own cyclotron. In collaboration with researchers at the University of Missouri, we have developed and evaluated peptides that target the melanocortin-1 receptor and the gastrin-releasing peptide (GRP) receptor for peptide guided imaging and therapy. The melanocortin-1 receptor is an attractive target for peptide guided melanoma imaging and therapy. The limited number of receptors per cell, approximately 900-5000, requires high specific activity radiolabeled peptide ligands to prevent target saturation and ensure optimal cellular uptake. GRP receptors are over-expressed by a variety of human cancers such as breast, lung, pancreatic and prostate tumors, and due to bombesin's toxicity, it is necessary to label it in high specific activity. Results are presented on NOTA and DOTA bifunctionalized α-MSH and bombesin peptides, highlighting the differences in specific activity, preparation time and in vivo characteristics.

  6. Studies in Multifunctional Drug Development: Preparation and Evaluation of 11beta-Substituted Estradiol-Drug Conjugates, Cell Membrane Targeting Imaging Agents, and Target Multifunctional Nanoparticles

    Science.gov (United States)

    Dao, KinhLuan Lenny D.

    Cancer is the second leading cause of death after cardiovascular disease in the United State. Despite extensive research in development of antitumor drugs, most of these therapeutic entities often possess nonspecific toxicity, thus they can only be used to treat tumors in higher doses or more frequently. Because of the cytotoxicity and severe side effects, the drug therapeutic window normally is limited. Beside the toxicity issue, antitumor drug are also not selectively taken up by tumor cells, thus the necessitating concentrations that would eradicate the tumor can often not be used. In addition, tumor cells tend to develop resistance against the anticancer drugs after prolonged treatment. Therefore, alleviating the systemic cytotoxicity and side effects, improving in tumor selectivity, high potency, and therapeutic efficacy are still major obstacles in the area of anticancer drug development. A more promising approach for developing a selective agent for cancer is to conjugate a potent therapeutic drug, or an imaging agent with a targeting group, such as antibody or a high binding-specificity small molecule, that selectively recognize the overexpressed antigens or proteins on tumor cells. My research combines several approaches to describe this strategy via using different targeting molecules to different diseases, as well as different potent cytotoxic drugs for different therapies. Three studies related to the preparation and biological evaluation of new therapeutic agents, such as estradiol-drug hybrids, cell membrane targeted molecular imaging agents, and multifunctional NPs will be discussed. The preliminary results of these studies indicated that our new reagents achieved their initial objectives and can be further improved for optimized synthesis and in vivo experiments. The first study describes the method in which we employed a modular assembly approach to synthesize a novel 11beta-substituted steroidal anti-estrogen. The key intermediate was synthesized

  7. A novel hybrid drug between two potent anti-tubulin agents as a potential prolonged anticancer approach.

    Science.gov (United States)

    Marchetti, Paolo; Pavan, Barbara; Simoni, Daniele; Baruchello, Riccardo; Rondanin, Riccardo; Mischiati, Carlo; Feriotto, Giordana; Ferraro, Luca; Hsu, Lih-Ching; Lee, Ray M; Dalpiaz, Alessandro

    2016-08-25

    We report the design, synthesis and biological characterisation of a novel hybrid drug by conjugation of two tubulin inhibitors, a hemiasterlin derivative A (H-Mpa-Tle-Aha-OH), obtained by condensation of three non-natural amino acids, and cis-3,4',5-trimethoxy-3'aminostilbene (B). As we have previously demonstrated synergy between A and B, we used a monocarbonyl derivative of triethylene glycol as linker (L) to synthesise compounds A-L and A-L-B; via HPLC we analysed the release of its potential hydrolysis products A, A-L, B and B-L in physiological fluids: the hybrid A-L-B undergo hydrolysis in rat whole blood of the ester bond between A and L (half-life=118.2±9.5min) but not the carbamate bond between B and L; the hydrolysis product B-L was further hydrolyzed, but with a slower rate (half-life=288±12min). The compound A-L was the faster hydrolyzed conjugate (half-life=25.4±1.1min). The inhibitory activity of the compounds against SKOV3 ovarian cancer cell growth was analysed. The IC50 values were 7.48±1.27nM for A, 40.3±6.28nM for B, 738±38.5nM for A-L and 37.9±2.11nM for A-L-B. The anticancer effect of A-L-B was evidenced to be obtained via microtubule dynamics suppression. Finally, we stated the expression of the active efflux transporters P-gp (ABCB1) and MRP1 (ABCC1) in the human normal colon epithelial NCM460 cell line by reverse-transcription PCR. Via permeation studies across NCM460 monolayers we demonstrate the poor aptitude of A to interact with active efflux transporters (AET): indeed, the ratio between its permeability coefficients for the basolateral (B)→apical (A) and B→A transport was 1.5±0.1, near to the ratio of taltobulin (1.12±0.06), an hemiasterlin derivative able to elude AETs, and significantly different form the ratio of celiprolol (3.4±0.2), an AET substrate. PMID:27262542

  8. Development of PET molecular targeting agents with gallium-68

    Energy Technology Data Exchange (ETDEWEB)

    Cutler, C.S.; Cantorias, M. [Univ. of Missouri Research Reactor Center (MURR), Columbia, MO (United States). Radiopharmaceutical Sciences Inst.; Sisay, N. [Univ. of Missouri, Columbia, MO (United States). Dept. of Chemistry; Galazzi, F.; Quinn, T.P. [Univ. of Missouri, Columbia, MO (United States). Dept. of Biochemistry; Smith, C.J. [Univ. of Missouri School of Medicine and Harry S. Truman Memorial Veterans Hospital, Columbia, MO (United States). Dept. of Radiology and Research Reactor Center

    2011-07-01

    The utilization of positron emission tomography (PET) is increasing due to its superior imaging quality and its ability to be used for in vivo quantification. Radionuclides that decay by positron emission can be attached to the same chelators used for radiotherapy applications in diagnosis and staging. One such isotope is {sup 68}Ga (T{sub 1/2} = 68 min), which can be obtained from a long-lived generator by decay of the parent {sup 68}Ge (T{sub 1/2} = 270.8 d). The availability of {sup 68}Ga from a generator plus its ability to be stably incorporated with a variety of chelates hold promise for expanding PET utilization to facilities unable to afford their own cyclotron. In collaboration with researchers at the University of Missouri, we have developed and evaluated peptides that target the melanocortin-1 receptor and the gastrin-releasing peptide (GRP) receptor for peptide guided imaging and therapy. The melanocortin-1 receptor is an attractive target for peptide guided melanoma imaging and therapy. The limited number of receptors per cell, approximately 900-5000, requires high specific activity radiolabeled peptide ligands to prevent target saturation and ensure optimal cellular uptake. GRP receptors are over-expressed by a variety of human cancers such as breast, lung, pancreatic and prostate tumors, and due to bombesin's toxicity, it is necessary to label it in high specific activity. Results are presented on NOTA and DOTA bifunctionalized {alpha}-MSH and bombesin peptides, highlighting the differences in specific activity, preparation time and in vivo characteristics.

  9. Newly Synthesized Water Soluble Cholinium-Purpurin Photosensitizers and Their Stabilized Gold Nanoparticles as Promising Anticancer Agents

    Directory of Open Access Journals (Sweden)

    Young Key Shim

    2008-05-01

    Full Text Available For possible future use in Photodynamic Therapy (PDT and/or Photothermal Therapy (PTT of cancer and screening of cancer cells a new type of ionic liquid photosensitizer –Cholinium-Purpurin-18 (Chol-Pu-18 – was synthesized and small gold (Au nanoparticles, stabilized by this photosensitizer were prepared without adding any particular reducing agents and CTAB. UV-Vis spectroscopy and Transmission Electron Microscopy (TEM were used for characterization of the nanoparticles and FAB-MS and NMR of the ionic liquid choline hydroxide, purpurin carboxylate and their ionic liquid type of photosensitizer were obtained.

  10. Synthesis and biological evaluation of non-glucose glycoconjugated N-hydroyxindole class LDH inhibitors as anticancer agents

    OpenAIRE

    Di Bussolo, Valeria; Calvaresi, Emilia C.; Granchi, Carlotta; Del Bino, Linda; Frau, Ileana; Lang, Maria Chiara Dasso; Tuccinardi, Tiziano; Macchia, Marco; Martinelli, Adriano; Hergenrother, Paul J.; Minutolo, Filippo

    2015-01-01

    Inhibitors of human lactate dehydrogenase A (LDH-A) are promising therapeutic agents against cancer. The development of LDH-A inhibitors that possess cellular activities has so far proved to be particularly challenging, since the enzyme’s active site is narrow and highly polar. In the recent past, we were able to develop a glucose-conjugated N-hydroxyindole-based LDH-A inhibitor designed to exploit the sugar avidity expressed by cancer cells (the Warburg effect). Herein we describe a structur...

  11. Synthesis of new secretory phospholipase A2-inhibitory indole containing isoxazole derivatives as anti-inflammatory and anticancer agents.

    Science.gov (United States)

    Pedada, Srinivasa Rao; Yarla, Nagendra Sastry; Tambade, Pawan J; Dhananjaya, Bhadrapura Lakkappa; Bishayee, Anuapam; Arunasree, Kalle M; Philip, Gundala Harold; Dharmapuri, Gangappa; Aliev, Gjumrach; Putta, Swathi; Rangaiah, Gururaja

    2016-04-13

    Secretory phospholipase A2 (sPLA2) is an important enzyme that plays a key role in various inflammatory diseases including cancer and its inhibitors have been developed as preventive or therapeutic agents. In the present study, a series of new indole containing isoxazole derivatives (10a-10o) is synthesized and evaluated for their sPLA2 inhibitory activities. All compounds (10a-10o) showed significant sPLA2 inhibition activities both in vitro and in vivo studies which is substantiated in in silico studies. Among all the tested compounds, 10o showed potent sPLA2 inhibition activity, that is comparable or more to ursolic acid (positive control). Further studies demonstrated that 10o showed in vitro antiproliferative activity when tested against MCF-7 breast and DU145 prostate cancer cells. Furthermore, compounds 10a-10o obeyed lipinsky's rule of 5 and suggesting druggable properties. The in vitro, in vivo and in silico results are encouraging and warrant pre-clinical studies to develop sPLA2-inhibitory compound 10o as novel therapeutic agent for various inflammatory disorders and several malignancies. PMID:26907155

  12. 3-Bromopyruvate (3BP) a fast acting, promising, powerful, specific, and effective "small molecule" anti-cancer agent taken from labside to bedside: introduction to a special issue.

    Science.gov (United States)

    Pedersen, Peter L

    2012-02-01

    Although the "Warburg effect", i.e., elevated glucose metabolism to lactic acid (glycolysis) even in the presence of oxygen, has been recognized as the most common biochemical phenotype of cancer for over 80 years, its biochemical and genetic basis remained unknown for over 50 years. Work focused on elucidating the underlying mechanism(s) of the "Warburg effect" commenced in the author's laboratory in 1969. By 1985 among the novel findings made two related most directly to the basis of the "Warburg effect", the first that the mitochondrial content of tumors exhibiting this phenotype is markedly decreased relative to the tissue of origin, and the second that such mitochondria have markedly elevated amounts of the enzyme hexokinase-2 (HK2) bound to their outer membrane. HK2 is the first of a number of enzymes in cancer cells involved in metabolizing the sugar glucose to lactic acid. At its mitochondrial location HK2 binds at/near the protein VDAC (voltage dependent anion channel), escapes inhibition by its product glucose-6-phosphate, and gains access to mitochondrial produced ATP. As shown by others, it also helps immortalize cancer cells, i.e., prevents cell death. Based on these studies, the author's laboratory commenced experiments to elucidate the gene basis for the overexpression of HK2 in cancer. These studies led to both the discovery of a unique HK2 promoter region markedly activated by both hypoxic conditions and moderately activated by several metabolites (e.g., glucose), Also discovered was the promoter's regulation by epigenetic events (i.e., methylation, demethylation). Finally, the author's laboratory turned to the most important objective. Could they selectively and completely destroy cancerous tumors in animals? This led to the discovery in an experiment conceived, designed, and conducted by Young Ko that the small molecule 3-bromopyruvate (3BP), the subject of this mini-review series, is an incredibly powerful and swift acting anticancer agent

  13. Anticancer Compound Plumbagin and Its Molecular Targets: A Structural Insight into the Inhibitory Mechanisms Using Computational Approaches

    OpenAIRE

    Mohammad S Jamal; Shadma Parveen; Mohd A Beg; Mohd Suhail; Chaudhary, Adeel G. A.; Damanhouri, Ghazi A.; Abuzenadah, Adel M; Mohd Rehan

    2014-01-01

    Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) is a naphthoquinone derivative from the roots of plant Plumbago zeylanica and belongs to one of the largest and diverse groups of plant metabolites. The anticancer and antiproliferative activities of plumbagin have been observed in animal models as well as in cell cultures. Plumbagin exerts inhibitory effects on multiple cancer-signaling proteins, however, the binding mode and the molecular interactions have not yet been elucidated for most of...

  14. Screening the yeast genome for energetic metabolism pathways involved in a phenotypic response to the anti-cancer agent 3-bromopyruvate.

    Science.gov (United States)

    Lis, Paweł; Jurkiewicz, Paweł; Cal-Bąkowska, Magdalena; Ko, Young H; Pedersen, Peter L; Goffeau, Andre; Ułaszewski, Stanisław

    2016-03-01

    In this study the detailed characteristic of the anti-cancer agent 3-bromopyruvate (3-BP) activity in the yeast Saccharomyces cerevisiae model is described, with the emphasis on its influence on energetic metabolism of the cell. It shows that 3-BP toxicity in yeast is strain-dependent and influenced by the glucose-repression system. Its toxic effect is mainly due to the rapid depletion of intracellular ATP. Moreover, lack of the Whi2p phosphatase results in strongly increased sensitivity of yeast cells to 3-BP, possibly due to the non-functional system of mitophagy of damaged mitochondria through the Ras-cAMP-PKA pathway. Single deletions of genes encoding glycolytic enzymes, the TCA cycle enzymes and mitochondrial carriers result in multiple effects after 3-BP treatment. However, it can be concluded that activity of the pentose phosphate pathway is necessary to prevent the toxicity of 3-BP, probably due to the fact that large amounts of NADPH are produced by this pathway, ensuring the reducing force needed for glutathione reduction, crucial to cope with the oxidative stress. Moreover, single deletions of genes encoding the TCA cycle enzymes and mitochondrial carriers generally cause sensitivity to 3-BP, while totally inactive mitochondrial respiration in the rho0 mutant resulted in increased resistance to 3-BP. PMID:26862728

  15. Differential cytotoxic pathways of topoisomerase I and II anticancer agents after overexpression of the E2F-1/DP-1 transcription factor complex

    DEFF Research Database (Denmark)

    Hofland, K; Petersen, B O; Falck, J;

    2000-01-01

    The transcription factor complex E2F-1/DP-1 regulates the G1-to-S-phase transition and has been associated with sensitivity to the S-phase-specific anticancer agents camptothecin and etoposide, which poison DNA topoisomerase I and II, respectively. To investigate the relationship between E2F-1 and...... drug sensitivity in detail, we established human osteosarcoma U-20S-TA cells expressing full-length E2F-1/ DP-1 under the control of a tetracycline-responsive promoter, designated UE1DP-1 cells. Topoisomerase I levels and activity as well as the number of camptothecin-induced DNA single- and double......-strand breaks were unchanged in UEIDP-1/tc- cells with >10-fold E2F-1/DP-1 overexpression. However, UE1DP-1/tc- cells were hypersensitive to camptothecin in both a clonogenic assay and four different apoptotic assays. This indicates that camptothecin-induced toxicity in this model is due to the activation of an...

  16. Systematic Analysis of the Anticancer Agent Taxol-Producing Capacity in Colletotrichum Species and Use of the Species for Taxol Production

    Science.gov (United States)

    Choi, Jinhee; Park, Jae Gyu; Ali, Md. Sarafat

    2016-01-01

    Paclitaxel (taxol) has long been used as a potent anticancer agent for the treatment of many cancers. Ever since the fungal species Taxomyces andreanae was first shown to produce taxol in 1993, many endophytic fungal species have been recognized as taxol accumulators. In this study, we analyzed the taxol-producing capacity of different Colletotrichum spp. to determine the distribution of a taxol biosynthetic gene within this genus. Distribution of the taxadiene synthase (TS) gene, which cyclizes geranylgeranyl diphosphate to produce taxadiene, was analyzed in 12 Colletotrichum spp., of which 8 were found to contain the unique skeletal core structure of paclitaxel. However, distribution of the gene was not limited to closely related species. The production of taxol by Colletotrichum dematium, which causes pepper anthracnose, depended on the method in which the fungus was stored, with the highest production being in samples stored under mineral oil. Based on its distribution among Colletotrichum spp., the TS gene was either integrated into or deleted from the bacterial genome in a species-specific manner. In addition to their taxol-producing capacity, the simple genome structure and easy gene manipulation of these endophytic fungal species make them valuable resources for identifying genes in the taxol biosynthetic pathway. PMID:27433121

  17. 6-125I-iodo-2-methyl-1,4-naphthoquinol bis (diammonium phosphate) as a potential radio-halogenated anti-cancer agent

    International Nuclear Information System (INIS)

    6-125I-iodo-2-methyl-1,4-naphthoquinol bis (diammonium phosphate) (6-125I-iodo-MNDP) has been synthesised and studied as the prototype of a class of potential radio-halogenated anti-cancer agents. The incorporated 125I provides Auger electron radiations which behave like high LET radiations in the treatment of tumours, though the accompanying X- and γ-radiations make an undersirable contribution to the total body dose. The in vitro experiments reported show that 6-125I-iodo-MNDP is selectively concentrated in the cells of some human malignant tumours by factor of about 15 to 20 or more in relation to the cells of normal origin studied. On the basis of dosimetric considerations and comparison with clinical treatment with tritiated methylnaphthoquinol diphosphate, practical dosage of 6-125I-iodo-MNDP is suggested and clinical indications and safety of use are discussed. The types of tumour of particular interest are inoperable cases of carcinoma of the colon, carcinoma of the pancreas, malignant melanoma and osteosarcoma. Further investigations are in progress. (orig.)

  18. A potential anticancer agent: 5-chloro-7-iodo-8-hydroxyquinolinium dichlorido(5-chloro-7-iodoquinolin-8-olato-κ2N,Opalladium(II dihydrate

    Directory of Open Access Journals (Sweden)

    Peter Vranec

    2011-11-01

    Full Text Available The title PdII coordination compound, (C9H6ClINO[PdCl2(C9H4ClINO]·2H2O, was prepared as a potential anticancer agent. Its structure is ionic and consists of a square-planar [PdCl2(CQ]− complex anion (CQ is 5-chloro-7-iodoquinolin-8-olate, with the PdII atom surrounded by two chloride ligands in a cis configuration and one N,O-bidentate CQ molecule, a protonated anion of CQ as counter-cation and two non-coordinated water molecules. The water molecules are involved in O—H...O and N—H...O hydrogen bonds, which interconnect the HCQ+ cations into a chain parallel to [010]. Apart from these interactions, the structure is also stabilized by face-to-face π–π interactions [centroid–centroid = 3.546 (3 Å], which occur between the phenolic parts of the complex anions and cations.

  19. Synergistic effect of pH-responsive folate-functionalized poloxamer 407-TPGS-mixed micelles on targeted delivery of anticancer drugs

    Directory of Open Access Journals (Sweden)

    Butt AM

    2015-02-01

    Full Text Available Adeel Masood Butt, Mohd Cairul Iqbal Mohd Amin, Haliza Katas Centre for Drug Delivery Research, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia Background: Doxorubicin (DOX, an anthracycline anticancer antibiotic, is used for treating various types of cancers. However, its use is associated with toxicity to normal cells and development of resistance due to overexpression of drug efflux pumps. Poloxamer 407 (P407 and vitamin E TPGS (d-α-tocopheryl polyethylene glycol succinate, TPGS are widely used polymers as drug delivery carriers and excipients for enhancing the drug retention times and stability. TPGS reduces multidrug resistance, induces apoptosis, and shows selective anticancer activity against tumor cells. Keeping in view the problems, we designed a mixed micelle system encapsulating DOX comprising TPGS for its selective anticancer activity and P407 conjugated with folic acid (FA for folate-mediated receptor targeting to cancer cells. Methods: FA-functionalized P407 was prepared by carbodiimide crosslinker chemistry. P407-TPGS/FA-P407-TPGS-mixed micelles were prepared by thin-film hydration method. Cytotoxicity of blank micelles, DOX, and DOX-loaded micelles was determined by alamarBlue® assay. Results: The size of micelles was less than 200 nm with encapsulation efficiency of 85% and 73% for P407-TPGS and FA-P407-TPGS micelles, respectively. Intracellular trafficking study using nile red-loaded micelles indicated improved drug uptake and perinuclear drug localization. The micelles show minimal toxicity to normal human cell line WRL-68, enhanced cellular uptake of DOX, reduced drug efflux, increased DOX–DNA binding in SKOV3 and DOX-resistant SKOV3 human ovarian carcinoma cell lines, and enhanced in vitro cytotoxicity as compared to free DOX. Conclusion: FA-P407-TPGS-DOX micelles show potential as a targeted nano-drug delivery system for DOX due to their multiple synergistic factors of selective anticancer

  20. Mechanistic and quantitative insight into cell surface targeted molecular imaging agent design.

    Science.gov (United States)

    Zhang, Liang; Bhatnagar, Sumit; Deschenes, Emily; Thurber, Greg M

    2016-01-01

    Molecular imaging agent design involves simultaneously optimizing multiple probe properties. While several desired characteristics are straightforward, including high affinity and low non-specific background signal, in practice there are quantitative trade-offs between these properties. These include plasma clearance, where fast clearance lowers background signal but can reduce target uptake, and binding, where high affinity compounds sometimes suffer from lower stability or increased non-specific interactions. Further complicating probe development, many of the optimal parameters vary depending on both target tissue and imaging agent properties, making empirical approaches or previous experience difficult to translate. Here, we focus on low molecular weight compounds targeting extracellular receptors, which have some of the highest contrast values for imaging agents. We use a mechanistic approach to provide a quantitative framework for weighing trade-offs between molecules. Our results show that specific target uptake is well-described by quantitative simulations for a variety of targeting agents, whereas non-specific background signal is more difficult to predict. Two in vitro experimental methods for estimating background signal in vivo are compared - non-specific cellular uptake and plasma protein binding. Together, these data provide a quantitative method to guide probe design and focus animal work for more cost-effective and time-efficient development of molecular imaging agents. PMID:27147293

  1. Molecular targeted agents-where we are and where we are going

    Institute of Scientific and Technical Information of China (English)

    Li Yan

    2013-01-01

    A total of 23 new cancer medicines or indication expansions were approved by the U.S.Food and Drug Administration in 2012.Among these,12 are new molecular entities (NMEs)-new chemical or biological drugs approved for the first time for oncologic use-and 10 of these NMEs are molecular targeted agents.Among the 10 targeted agents,4 are anti-angiogenesis agents and 2 are Bcr-Abl pathway inhibitors,targeting well established targets validated by previously approved agents such as bevacizumab (Avastin) or imatinib (Gleevec).Despite this progress,several questions remain:Do these newly approved agents provide sufficient treatment options to manage the broad spectrum of cancers we deal with in the clinic? Where will the next wave of new cancer drugs come from? Where should R&D efforts be invested to continue improve cancer treatment and management,especially for tumor types uniquely prevalent in China?This editorial and the review articles in this special issue of Chinese Journal of Cancer provide an in depth review of the progress and challenges in developing targeted cancer therapies,as well as an outlook of new research areas where near term breakthroughs are expected to overcome some of these challenges.

  2. Molecular targeted agents--where we are and where we are going

    Directory of Open Access Journals (Sweden)

    Li Yan

    2013-05-01

    Full Text Available A total of 23 new cancer medicines or indication expansions were approved by the U. S. Food and Drug Administration in 2012. Among these, 12 are new molecular entities (NMEs--new chemical or biological drugs approved for the first time for oncologic use--and 10 of these NMEs are molecular targeted agents. Among the 10 targeted agents, 4 are anti-angiogenesis agents and 2 are Bcr-Abl pathway inhibitors, targeting well established targets validated by previously approved agents such as bevacizumab (Avastin or imatinib (Gleevec. Despite this progress, several questions remain: Do these newly approved agents provide sufficient treatment options to manage the broad spectrum of cancers we deal with in the clinic? Where will the next wave of new cancer drugs come from? Where should R&D efforts be invested to continue improve cancer treatment and management, especially for tumor types uniquely prevalent in China? This editorial and the review articles in this special issue of Chinese Journal of Cancer provide an in depth review of the progress and challenges in developing targeted cancer therapies, as well as an outlook of new research areas where near term breakthroughs are expected to overcome some of these challenges.

  3. Mechanistic and quantitative insight into cell surface targeted molecular imaging agent design

    Science.gov (United States)

    Zhang, Liang; Bhatnagar, Sumit; Deschenes, Emily; Thurber, Greg M.

    2016-05-01

    Molecular imaging agent design involves simultaneously optimizing multiple probe properties. While several desired characteristics are straightforward, including high affinity and low non-specific background signal, in practice there are quantitative trade-offs between these properties. These include plasma clearance, where fast clearance lowers background signal but can reduce target uptake, and binding, where high affinity compounds sometimes suffer from lower stability or increased non-specific interactions. Further complicating probe development, many of the optimal parameters vary depending on both target tissue and imaging agent properties, making empirical approaches or previous experience difficult to translate. Here, we focus on low molecular weight compounds targeting extracellular receptors, which have some of the highest contrast values for imaging agents. We use a mechanistic approach to provide a quantitative framework for weighing trade-offs between molecules. Our results show that specific target uptake is well-described by quantitative simulations for a variety of targeting agents, whereas non-specific background signal is more difficult to predict. Two in vitro experimental methods for estimating background signal in vivo are compared – non-specific cellular uptake and plasma protein binding. Together, these data provide a quantitative method to guide probe design and focus animal work for more cost-effective and time-efficient development of molecular imaging agents.

  4. New Oxidovanadium Complexes Incorporating Thiosemicarbazones and 1, 10-Phenanthroline Derivatives as DNA Cleavage, Potential Anticancer Agents, and Hydroxyl Radical Scavenger.

    Science.gov (United States)

    Ying, Peng; Zeng, Pengfei; Lu, Jiazheng; Chen, Hongyuan; Liao, Xiangwen; Yang, Ning

    2015-10-01

    Four novel oxidovanadium(IV) complexes, [VO(hntdtsc)(PHIP)] (1) (hntdtsc = 2-hydroxy-1-naphthaldehyde thiosemicarbazone, PHIP= 2-phenyl-imidazo[4,5-f]1,10-phenanthroline), [VO(hntdtsc)(DPPZ)](2)(DPPZ= dipyrido[3,2-a:2',3'-c]phenazine), [VO(satsc)(PHIP)](3) (satsc=salicylaldehyde thiosemicarbazone), and [VO(satsc)(DPPZ)](4), have been prepared and characterized. The chemical nuclease activities and photocleavage reactions of the complexes were tested. All four complexes can efficiently cleave pBR322 DNA, and complex 1 has the best cleaving ability. The antitumor properties of these complexes were examined with three different tumor cell lines using MTT assay. Their antitumor mechanism has been analyzed using cell cycle analysis, fluorescence microscopy of apoptosis, and Annexin V-FITC/PI assay. The results showed that the growth of human neuroblastoma (SH-SY5Y, SK-N-SH) and human breast adenocarcinoma (MCF-7) cells were inhibited significantly with very low IC50 values. Complex 1 was found to be the most potent antitumor agent among the four complexes. It can cause G0/G1 phase arrest of the cell cycle and exhibited significant induced apoptosis in SK-N-SH cells and displayed typical morphological apoptotic characteristics. In addition, they all displayed reasonable abilities to scavenge hydroxyl radical, and complex 1 was the best inhibitor. PMID:25659415

  5. Evaluation of SD-208, a TGF-β-RI Kinase Inhibitor, as an Anticancer Agent in Retinoblastoma.

    Science.gov (United States)

    Fadakar, Puran; Akbari, Abolfazl; Ghassemi, Fariba; Mobini, Gholam Reza; Mohebi, Masoumeh; Bolhassani, Manzar; Abed Khojasteh, Hoda; Heidari, Mansour

    2016-06-01

    Retinoblastoma is the most common intraocular tumor in children resulting from genetic alterations and transformation of mature retinal cells. The objective of this study was to investigate the effects of SD-208, TGF-β-RI kinase inhibitor, on the expression of some miRNAs including a miR-17/92 cluster in retinoblastoma cells. Prior to initiate this work, the cell proliferation was studied by Methyl Thiazolyl Tetrazolium (MTT) and bromo-2'-deoxyuridine (BrdU) assays. Then, the expression patterns of four miRNAs (18a, 20a, 22, and 34a) were investigated in the treated SD-208 (0.0, 1, 2 and 3 µM) and untreated Y-79 cells. A remarkable inhibition of the cell proliferation was found in Y-79 cells treated with SD-208 versus untreated cells. Also, the expression changes were observed in miRNAs 18a, 20a, 22 and 34a in response to SD-208 treatment (Pretinoblastoma cell line. To the best of the researchers' knowledge, this is the first report demonstrating that the SD-208 could alter the expression of tumor suppressive miRNAs as well as oncomiRs in vitro. In conclusion, the present data suggest that SD-208 could be an alternative agent in retinoblastoma treatment. PMID:27306340

  6. Using immunoadjuvant agent glycated chitosan to enhance anti-cancer stem like cell immunity induced by HIFU

    Science.gov (United States)

    Chen, Y.-L.; Chen, W.-R.; Liu, R.-S.; Yang, F.-Y.; Wang, C.-Y.; Lee, Y.-J.

    2013-02-01

    Thermal therapy is based on the observation that tumor cells are sensitive to increased temperature, which is important for tumor control. In this study, the high intensity focused ultrasound (HIFU) system was used to simulate thermal therapy on breast cancer control in the small animal model. Additionally, the immunoadjuvant agent, so called glycated chitosan (GC), was used to enhance the immunological effects on tumor control. The bioluminescent imaging showed that tumor metastasis was apparently suppressed by a combined treatment using HIFU and GC, but not in HIFU or GC alone. Using immunohistochemical (IHC) staining, lung metastasis of 4T1-3R tumor cells further agree the observations obtained from non-invasive in vivo imaging. We also found that plasma collected from mice treated with combined HIFU and GC could significantly suppress the viability of cultured 4T1 cells compared to untreated or single treated group. In summary, these results suggest that the HIFU therapy combined with GC can enhance the tumor immunogenicity and tumor control.

  7. Design, synthesis and structural studies of meta-xylyl linked bis-benzimidazolium salts: potential anticancer agents against ‘human colon cancer’

    Directory of Open Access Journals (Sweden)

    Haque Rosenani A

    2012-07-01

    Full Text Available Abstract Background Benzimidazole derivatives are structurally bioisosteres of naturally occurring nucleotides, which makes them compatible with biopolymers of living systems. This property gives benzimidazole a biological and clinical importance. In the last decade, this class of compounds has been reported to possess anti-allergic, anti-diabatic, anti-HIV, anti-hypertensive, anti-inflammatory, anti-mycobacterial, anti-oxidant, anti-protozoal, and anti-viral properties. The researchers are now interested to explore their potential as anti-cancer agents. In the present study, an effort was made to further explore this area of research. Furthermore, in order to increase the solubility and efficacy of these heterocycles, the interest is now shifted to the salts of these compounds. With this background, we planned to synthesize a series of meta-xylyl linked bis-benzimidazolium salts to assess their anti-proliferation efficacy on human colon cancer cell line (HCT 116. Results A number of N-alkylbenzimidazoles were synthesized by reactions of benzimidazole with alkyl halides (i-PrBr, PrBr, EthBr, Pent-2-ylBr, BuBr, BenzCl, HeptBr. The subsequent treatment of the resulting N-alkylbenzimidazoles with 1,3-(bromomethylenebenzene afforded corresponding bis-benzimidazolium salts. All synthesized compounds were characterized by spectroscopic techniques (Additional file 1: NMR & FT-IR and microanalysis. Molecular structures of selected compounds were established through single crystal x-ray diffraction studies. All the compounds were assessed for their anti-proliferation test on human colorectal cancer cell line (HCT 116. Results showed that the compounds exhibited dose dependent cytotoxicity towards the colon cancer cells with IC50 ranges between 0.1 to 17.6 μM. The anti-proliferation activity of all compounds was more pronounced than that of standard reference drug 5-flourouracil (IC50 =19.2 μM. Conclusions All the synthesized bis-benzimidazolium salts

  8. Mechanistic studies of cancer cell mitochondria- and NQO1-mediated redox activation of beta-lapachone, a potentially novel anticancer agent

    International Nuclear Information System (INIS)

    Beta-lapachone (beta-Lp) derived from the Lapacho tree is a potentially novel anticancer agent currently under clinical trials. Previous studies suggested that redox activation of beta-Lp catalyzed by NAD(P)H:quinone oxidoreductase 1 (NQO1) accounted for its killing of cancer cells. However, the exact mechanisms of this effect remain largely unknown. Using chemiluminescence and electron paramagnetic resonance (EPR) spin-trapping techniques, this study for the first time demonstrated the real-time formation of ROS in the redox activation of beta-lapachone from cancer cells mediated by mitochondria and NQO1 in melanoma B16–F10 and hepatocellular carcinoma HepG2 cancer cells. ES936, a highly selective NQO1 inhibitor, and rotenone, a selective inhibitor of mitochondrial electron transport chain (METC) complex I were found to significantly block beta-Lp meditated redox activation in B16–F10 cells. In HepG2 cells ES936 inhibited beta-Lp-mediated oxygen radical formation by ∼ 80% while rotenone exerted no significant effect. These results revealed the differential contribution of METC and NQO1 to beta-lapachone-induced ROS formation and cancer cell killing. In melanoma B16–F10 cells that do not express high NQO1 activity, both NOQ1 and METC play a critical role in beta-Lp redox activation. In contrast, in hepatocellular carcinoma HepG2 cells expressing extremely high NQO1 activity, redox activation of beta-Lp is primarily mediated by NQO1 (METC plays a minor role). These findings will contribute to our understanding of how cancer cells are selectively killed by beta-lapachone and increase our ability to devise strategies to enhance the anticancer efficacy of this potentially novel drug while minimizing its possible adverse effects on normal cells. - Highlights: • Both isolated mitochondria and purified NQO1 are able to generate ROS by beta-Lp. • The differential roles of mitochondria and NQO1 in mediating redox activation of beta-Lp • In cancer cells with

  9. Mechanistic studies of cancer cell mitochondria- and NQO1-mediated redox activation of beta-lapachone, a potentially novel anticancer agent

    Energy Technology Data Exchange (ETDEWEB)

    Li, Jason Z. [Virginia Tech CRC, Blacksburg, VA (United States); Ke, Yuebin [Shenzhen Center for Disease Control and Prevention, Shenzhen 518055 (China); Misra, Hara P. [Virginia Tech CRC, Blacksburg, VA (United States); Trush, Michael A. [Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD (United States); Li, Y. Robert [Campbell University School of Osteopathic Medicine, Buies Creek, NC (United States); Virginia Tech-Wake Forest University SBES, Blacksburg, VA (United States); Department of Biology, University of North Carolina at Greensboro, NC (United States); Zhu, Hong, E-mail: zhu@campbell.edu [Campbell University School of Osteopathic Medicine, Buies Creek, NC (United States); Jia, Zhenquan, E-mail: z_jia@uncg.edu [Department of Biology, University of North Carolina at Greensboro, NC (United States)

    2014-12-15

    Beta-lapachone (beta-Lp) derived from the Lapacho tree is a potentially novel anticancer agent currently under clinical trials. Previous studies suggested that redox activation of beta-Lp catalyzed by NAD(P)H:quinone oxidoreductase 1 (NQO1) accounted for its killing of cancer cells. However, the exact mechanisms of this effect remain largely unknown. Using chemiluminescence and electron paramagnetic resonance (EPR) spin-trapping techniques, this study for the first time demonstrated the real-time formation of ROS in the redox activation of beta-lapachone from cancer cells mediated by mitochondria and NQO1 in melanoma B16–F10 and hepatocellular carcinoma HepG2 cancer cells. ES936, a highly selective NQO1 inhibitor, and rotenone, a selective inhibitor of mitochondrial electron transport chain (METC) complex I were found to significantly block beta-Lp meditated redox activation in B16–F10 cells. In HepG2 cells ES936 inhibited beta-Lp-mediated oxygen radical formation by ∼ 80% while rotenone exerted no significant effect. These results revealed the differential contribution of METC and NQO1 to beta-lapachone-induced ROS formation and cancer cell killing. In melanoma B16–F10 cells that do not express high NQO1 activity, both NOQ1 and METC play a critical role in beta-Lp redox activation. In contrast, in hepatocellular carcinoma HepG2 cells expressing extremely high NQO1 activity, redox activation of beta-Lp is primarily mediated by NQO1 (METC plays a minor role). These findings will contribute to our understanding of how cancer cells are selectively killed by beta-lapachone and increase our ability to devise strategies to enhance the anticancer efficacy of this potentially novel drug while minimizing its possible adverse effects on normal cells. - Highlights: • Both isolated mitochondria and purified NQO1 are able to generate ROS by beta-Lp. • The differential roles of mitochondria and NQO1 in mediating redox activation of beta-Lp • In cancer cells with

  10. Pyrithione-based ruthenium complexes as inhibitors of aldo-keto reductase 1C enzymes and anticancer agents.

    Science.gov (United States)

    Kljun, Jakob; Anko, Maja; Traven, Katja; Sinreih, Maša; Pavlič, Renata; Peršič, Špela; Ude, Žiga; Codina, Elisa Esteve; Stojan, Jure; Lanišnik Rižner, Tea; Turel, Iztok

    2016-08-01

    Four ruthenium complexes of clinically used zinc ionophore pyrithione and its oxygen analog 2-hydroxypyridine N-oxide were prepared and evaluated as inhibitors of enzymes of the aldo-keto reductase subfamily 1C (AKR1C). A kinetic study assisted with docking simulations showed a mixed type of inhibition consisting of a fast reversible and a slow irreversible step in the case of both organometallic compounds 1A and 1B. Both compounds also showed a remarkable selectivity towards AKR1C1 and AKR1C3 which are targets for breast cancer drug design. The organoruthenium complex of ligand pyrithione as well as pyrithione itself also displayed toxicity on the hormone-dependent MCF-7 breast cancer cell line with EC50 values in the low micromolar range. PMID:27357845

  11. Metabolic network analysis-based identification of antimicrobial drug targets in category A bioterrorism agents.

    Directory of Open Access Journals (Sweden)

    Yong-Yeol Ahn

    Full Text Available The 2001 anthrax mail attacks in the United States demonstrated the potential threat of bioterrorism, hence driving the need to develop sophisticated treatment and diagnostic protocols to counter biological warfare. Here, by performing flux balance analyses on the fully-annotated metabolic networks of multiple, whole genome-sequenced bacterial strains, we have identified a large number of metabolic enzymes as potential drug targets for each of the three Category A-designated bioterrorism agents including Bacillus anthracis, Francisella tularensis and Yersinia pestis. Nine metabolic enzymes- belonging to the coenzyme A, folate, phosphatidyl-ethanolamine and nucleic acid pathways common to all strains across the three distinct genera were identified as targets. Antimicrobial agents against some of these enzymes are available. Thus, a combination of cross species-specific antibiotics and common antimicrobials against shared targets may represent a useful combinatorial therapeutic approach against all Category A bioterrorism agents.

  12. 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

  13. Differential penetration of targeting agents into multicellular spheroids derived from human neuroblastoma

    International Nuclear Information System (INIS)

    The authors have used a multicellular tumour spheroid model for determination of the penetration of various targeting agents of potential use in the treatment of neuroblastoma. Both the radiopharmaceutical meta-iodobenzylguanidine (mIBG) and the β subunit of nerve growth factor (β-NGF) distributed uniformly throughout spheroids, though the latter was poorly concentrated relative to mIBG. In contrast, the anti-neuroectodermal monoclonal antibody. UJ13A bound only to peripheral cell layers with little accumulation in the spheroid interior. Differential penetration of targeting agents may influence the choice of conjugated radionuclide which is likely to achieve maximum therapeutic benefit

  14. Preparation of thermo and pH-responsive polymer@Au/Fe3O4 core/shell nanoparticles as a carrier for delivery of anticancer agent

    International Nuclear Information System (INIS)

    In this work, a thermo and pH-responsive poly-N-isopropylacrylamide-co-itaconic acid containing thiol side groups were successfully synthesized to prepare Doxorubicin-loaded polymer@Au/Fe3O4 core/shell nanoparticles (DOX-NPs). Copolymer and NPs were fully characterized by FT-IR, HNMR, photo-correlation spectroscopy, SEM, X-ray diffraction, vibrating-sample magnetometer, thermal gravimetric analysis, and UV–Vis spectroscopy. The stimuli-responsive characteristics of NPs were evaluated by in vitro release study in simulated cancerous environment. The biocompatibility and cytotoxic properties of NPs and DOX-NPs are explored by MTT method. The prepared NPs with the size of 50 nm showed paramagnetic characteristics with suitable and stable dispersion at physiological medium and high loading capacity (up to 55 %) of DOX. DOX-NPs yielded a pH- and temperature-triggered release of entrapped drugs at tumor tissue environment (59 % of DOX release) compared to physiological condition (20 % of DOX release) during 48 h. In vitro cytotoxicity studies indicated that the NPs showed no cytotoxicity on A549 cells at different amounts after incubation for 72 h confirming its suitability as a drug carrier. DOX-NPs, on the other hand, caused an efficient anticancer performance as verified by MTT assay test. It was concluded that developed NPs by us in this study may open the possibilities for targeted delivery of DOX to the cancerous tissues

  15. The Anticancer Agent Di-2-pyridylketone 4,4-Dimethyl-3-thiosemicarbazone (Dp44mT) Overcomes Prosurvival Autophagy by Two Mechanisms

    Science.gov (United States)

    Gutierrez, Elaine; Richardson, Des R.; Jansson, Patric J.

    2014-01-01

    Autophagy functions as a survival mechanism during cellular stress and contributes to resistance against anticancer agents. The selective antitumor and antimetastatic chelator di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) causes lysosomal membrane permeabilization and cell death. Considering the integral role of lysosomes in autophagy and cell death, it was important to assess the effect of Dp44mT on autophagy to further understand its mechanism of action. Notably, Dp44mT affected autophagy by two mechanisms. First, concurrent with its antiproliferative activity, Dp44mT increased the expression of the classical autophagic marker LC3-II as a result of induced autophagosome synthesis. Second, this effect was supplemented by a reduction in autophagosome degradation as shown by the accumulation of the autophagic substrate and receptor p62. Conversely, the classical iron chelator desferrioxamine induced autophagosome accumulation only by inhibiting autophagosome degradation. The formation of redox-active iron or copper Dp44mT complexes was critical for its dual effect on autophagy. The cytoprotective antioxidant N-acetylcysteine inhibited Dp44mT-induced autophagosome synthesis and p62 accumulation. Importantly, Dp44mT inhibited autophagosome degradation via lysosomal disruption. This effect prevented the fusion of lysosomes with autophagosomes to form autolysosomes, which is crucial for the completion of the autophagic process. The antiproliferative activity of Dp44mT was suppressed by Beclin1 and ATG5 silencing, indicating the role of persistent autophagosome synthesis in Dp44mT-induced cell death. These studies demonstrate that Dp44mT can overcome the prosurvival activity of autophagy in cancer cells by utilizing this process to potentiate cell death. PMID:25301941

  16. Genome-wide functional genetic screen with the anticancer agent AMPI-109 identifies PRL-3 as an oncogenic driver in triple-negative breast cancers.

    Science.gov (United States)

    Gari, Hamid H; Gearheart, Christy M; Fosmire, Susan; DeGala, Gregory D; Fan, Zeying; Torkko, Kathleen C; Edgerton, Susan M; Lucia, M Scott; Ray, Rahul; Thor, Ann D; Porter, Christopher C; Lambert, James R

    2016-03-29

    Triple-negative breast cancers (TNBC) are among the most aggressive and heterogeneous cancers with a high propensity to invade, metastasize and relapse. Here, we demonstrate that the anticancer compound, AMPI-109, is selectively efficacious in inhibiting proliferation and inducing apoptosis of multiple TNBC subtype cell lines as assessed by activation of pro-apoptotic caspases-3 and 7, PARP cleavage and nucleosomal DNA fragmentation. AMPI-109 had little to no effect on growth in the majority of non-TNBC cell lines examined. We therefore utilized AMPI-109 in a genome-wide shRNA screen in the TNBC cell line, BT-20, to investigate the utility of AMPI-109 as a tool in helping to identify molecular alterations unique to TNBC. Our screen identified the oncogenic phosphatase, PRL-3, as a potentially important driver of TNBC growth, migration and invasion. Through stable lentiviral knock downs and transfection with catalytically impaired PRL-3 in TNBC cells, loss of PRL-3 expression, or functionality, led to substantial growth inhibition. Moreover, AMPI-109 treatment, downregulation of PRL-3 expression or impairment of PRL-3 activity reduced TNBC cell migration and invasion. Histological evaluation of human breast cancers revealed PRL-3 was significantly, though not exclusively, associated with the TNBC subtype and correlated positively with regional and distant metastases, as well as 1 and 3 year relapse free survival. Collectively, our study is proof-of-concept that AMPI-109, a selectively active agent against TNBC cell lines, can be used as a molecular tool to uncover unique drivers of disease progression, such as PRL-3, which we show promotes oncogenic phenotypes in TNBC cells. PMID:26909599

  17. Anticancer Properties of Lamellarins

    OpenAIRE

    Christian Bailly

    2015-01-01

    In 1985 the first lamellarins were isolated from a small oceanic sea snail. Today, more than 50 lamellarins have been inventoried and numerous derivatives synthesized and tested as antiviral or anticancer agents. The lead compound in the family is lamellarin D, characterized as a potent inhibitor of both nuclear and mitochondrial topoisomerase I but also capable of directly interfering with mitochondria to trigger cancer cell death. The pharmacology and chemistry of lamellarins are discussed ...

  18. Organometallic Iridium(III) anticancer complexes with new mechanisms of action: NCI-60 screening, mitochondrial targeting, and apoptosis.

    Science.gov (United States)

    Hearn, Jessica M; Romero-Canelón, Isolda; Qamar, Bushra; Liu, Zhe; Hands-Portman, Ian; Sadler, Peter J

    2013-01-01

    Platinum complexes related to cisplatin, cis-[PtCl2(NH3)2], are successful anticancer drugs; however, other transition metal complexes offer potential for combating cisplatin resistance, decreasing side effects, and widening the spectrum of activity. Organometallic half-sandwich iridium (Ir(III)) complexes [Ir(Cp(x))(XY)Cl](+/0) (Cp(x) = biphenyltetramethylcyclopentadienyl and XY = phenanthroline (1), bipyridine (2), or phenylpyridine (3)) all hydrolyze rapidly, forming monofunctional G adducts on DNA with additional intercalation of the phenyl substituents on the Cp(x) ring. In comparison, highly potent complex 4 (Cp(x) = phenyltetramethylcyclopentadienyl and XY = N,N-dimethylphenylazopyridine) does not hydrolyze. All show higher potency toward A2780 human ovarian cancer cells compared to cisplatin, with 1, 3, and 4 also demonstrating higher potency in the National Cancer Institute (NCI) NCI-60 cell-line screen. Use of the NCI COMPARE algorithm (which predicts mechanisms of action (MoAs) for emerging anticancer compounds by correlating NCI-60 patterns of sensitivity) shows that the MoA of these Ir(III) complexes has no correlation to cisplatin (or oxaliplatin), with 3 and 4 emerging as particularly novel compounds. Those findings by COMPARE were experimentally probed by transmission electron microscopy (TEM) of A2780 cells exposed to 1, showing mitochondrial swelling and activation of apoptosis after 24 h. Significant changes in mitochondrial membrane polarization were detected by flow cytometry, and the potency of the complexes was enhanced ca. 5× by co-administration with a low concentration (5 μM) of the γ-glutamyl cysteine synthetase inhibitor L-buthionine sulfoximine (L-BSO). These studies reveal potential polypharmacology of organometallic Ir(III) complexes, with MoA and cell selectivity governed by structural changes in the chelating ligands. PMID:23618382

  19. 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.

  20. Câncer e agentes antineoplásicos ciclo-celular específicos e ciclo-celular não específicos que interagem com o DNA: uma introdução Cancer and cell cicle-specific and cell cicle nonspecific anticancer DNA-interactive agents: an introduction

    Directory of Open Access Journals (Sweden)

    Vera Lúcia de Almeida

    2005-02-01

    Full Text Available The chemotherapy agents against cancer may be classified as "cell cycle-specific" or "cell cycle-nonspecific". Nevertheless, several of them have their biological activity related to any kind of action on DNA such as: antimetabolic agents (DNA synthesis inhibition, inherently reactive agents (DNA alkylating electrophilic traps for macromolecular nucleophiles from DNA through inter-strand cross-linking - ISC - alkylation and intercalating agents (drug-DNA interactions inherent to the binding made due to the agent penetration in to the minor groove of the double helix. The earliest and perhaps most extensively studied and most heavily employed clinical anticancer agents in use today are the DNA inter-strand cross-linking agents.

  1. Natural Products as Promising Antitumoral Agents in Breast Cancer: Mechanisms of Action and Molecular Targets.

    Science.gov (United States)

    Bonofiglio, Daniela; Giordano, Cinzia; De Amicis, Francesca; Lanzino, Marilena; Andò, Sebastiano

    2016-01-01

    Extensive research over the past several decades has identified numerous dietary and phytochemical compounds that have chemopreventive potential and could represent an important source of anti-cancer lead molecules. In this scenario several nutritional factors have attracted considerable attention as modifiable risk factor in the prevention of breast cancer, the most frequently diagnosed cancer and a major cause of death among women worldwide. There is an immediate need for more effective and less toxic therapeutic and preventive strategies for breast cancers able also to counteract the recurrent phenomenon of resistance to hormonal and targeted therapy that represent the first-line treatment in the management of breast cancer patients. The present review focuses on chemopreventive and anti-cancer activities of different bioactive compounds obtained from dietary sources such as Omega-3 fatty acids, naturally present in fish, Resveratrol (3,5,40-trihydroxy-transstilbene), a phytoalexin found in grapes and Epigallocatechin Gallate, a polyphenolic compound found in green tea, or purified from medicinal plant (Oldenlandia Diffusa) and fruits (Ziziphus Jujube) highlighting their potential use in breast cancer treatment. Herein, we discuss the molecular mechanisms by which the bioactive compounds can inhibit carcinogenesis by regulating antioxidant enzyme activities, and inducing antiproliferative and apoptotic effects in different breast cancer cell lines. Understanding the mechanism of action of dietary compounds or traditionally used herbs having potential preventive and therapeutic effects on cancer may provide a rationale for further translational studies. This review emphasizes the importance, in the next future, of a proper scientific validation of these natural bioactive compounds for clinical use in the therapeutic portfolio for breast cancer. PMID:26156544

  2. Aurora kinases as druggable targets in pediatric leukemia: heterogeneity in target modulation activities and cytotoxicity by diverse novel therapeutic agents.

    Directory of Open Access Journals (Sweden)

    Aarthi Jayanthan

    Full Text Available Leukemia is the most common pediatric malignancy, constituting more than 30% of all childhood cancers. Although cure rates have improved greatly, approximately one in five children relapse and poor survival rates post relapse remain a challenge. Given this, more effective and innovative therapeutic strategies are needed in order to improve prognosis. Aurora kinases, a family of serine/threonine kinases essential for the regulation of several mitotic processes, have been identified as potential targets for cancer therapeutics. Elevated expression of Aurora kinases has been demonstrated in several malignancies and is associated with aberrant mitotic activity, aneuploidy and alterations in chromosomal structure and genome instability. Based on this rationale, a number of small molecule inhibitors have been formulated and advanced to human studies in the recent past. A comparative analysis of these agents in cytotoxicity and target modulation analyses against a panel of leukemia cells provides novel insights into the unique mechanisms and codependent activity pathways involved in targeting Aurora kinases, constituting a distinctive preclinical experimental framework to identify appropriate agents and combinations in future clinical studies.

  3. Advance of Molecular Imaging Technology and Targeted Imaging Agent in Imaging and Therapy

    Directory of Open Access Journals (Sweden)

    Zhi-Yi Chen

    2014-01-01

    Full Text Available Molecular imaging is an emerging field that integrates advanced imaging technology with cellular and molecular biology. It can realize noninvasive and real time visualization, measurement of physiological or pathological process in the living organism at the cellular and molecular level, providing an effective method of information acquiring for diagnosis, therapy, and drug development and evaluating treatment of efficacy. Molecular imaging requires high resolution and high sensitive instruments and specific imaging agents that link the imaging signal with molecular event. Recently, the application of new emerging chemical technology and nanotechnology has stimulated the development of imaging agents. Nanoparticles modified with small molecule, peptide, antibody, and aptamer have been extensively applied for preclinical studies. Therapeutic drug or gene is incorporated into nanoparticles to construct multifunctional imaging agents which allow for theranostic applications. In this review, we will discuss the characteristics of molecular imaging, the novel imaging agent including targeted imaging agent and multifunctional imaging agent, as well as cite some examples of their application in molecular imaging and therapy.

  4. Mitocans as anti-cancer agents targeting mitochondria: lessons from studies with vitamin E analogues, inhibitors of complex II

    Czech Academy of Sciences Publication Activity Database

    Neužil, Jiří; Dyason, J.C.; Freeman, R.; Dong, L.F.; Procházka, L.; Wang, X. F.; Scheffler, I.; Ralph, S.J.

    2007-01-01

    Roč. 39, č. 1 (2007), s. 65-72. ISSN 0145-479X Institutional research plan: CEZ:AV0Z50520701; CEZ:AV0Z50520514 Keywords : mitocans * mitochondria * complex II Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.634, year: 2007

  5. Vitamin E analogues as a novel group of mitocans: Anti-cancer agents that act by targeting mitochondria

    Czech Academy of Sciences Publication Activity Database

    Neužil, Jiří; Dong, L.F.; Ramanathapuram, L.; Hahn, T.; Chladová, Miroslava; Wang, X. F.; Zobalová, Renata; Procházka, L.; Gold, M.; Freeman, R.; Turánek, J.; Akporiaye, E.T.; Dyason, J.C.; Ralph, S.J.

    2007-01-01

    Roč. 28, 5-6 (2007), s. 607-645. ISSN 0098-2997 Institutional research plan: CEZ:AV0Z50520701; CEZ:AV0Z50520514 Keywords : tocopherol analogues * apoptosis * reactive oxygen species Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 7.386, year: 2007

  6. Sesterterpenoids with Anticancer Activity.

    Science.gov (United States)

    Evidente, Antonio; Kornienko, Alexander; Lefranc, Florence; Cimmino, Alessio; Dasari, Ramesh; Evidente, Marco; Mathieu, Véronique; Kiss, Robert

    2015-01-01

    Terpenes have received a great deal of attention in the scientific literature due to complex, synthetically challenging structures and diverse biological activities associated with this class of natural products. Based on the number of C5 isoprene units they are generated from, terpenes are classified as hemi- (C5), mono- (C10), sesqui- (C15), di- (C20), sester- (C25), tri (C30), and tetraterpenes (C40). Among these, sesterterpenes and their derivatives known as sesterterpenoids, are ubiquitous secondary metabolites in fungi, marine organisms, and plants. Their structural diversity encompasses carbotricyclic ophiobolanes, polycyclic anthracenones, polycyclic furan-2-ones, polycyclic hydroquinones, among many other carbon skeletons. Furthermore, many of them possess promising biological activities including cytotoxicity and the associated potential as anticancer agents. This review discusses the natural sources that produce sesterterpenoids, provides sesterterpenoid names and their chemical structures, biological properties with the focus on anticancer activities and literature references associated with these metabolites. A critical summary of the potential of various sesterterpenoids as anticancer agents concludes the review. PMID:26295461

  7. Anticancer molecule AS1411 exhibits low nanomolar antiviral activity against HIV-1.

    Science.gov (United States)

    Métifiot, Mathieu; Amrane, Samir; Mergny, Jean-Louis; Andreola, Marie-Line

    2015-11-01

    During clinical trials, a number of fully characterized molecules are dropped along the way because they do not provide enough benefit for the patient. Some of them show limited side effects and might be of great use for other applications. AS1411 is a nucleolin-targeting aptamer that underwent phase II clinical trials as anticancer agent. Here, we show that AS1411 exhibits extremely potent antiviral activity and is therefore an attractive new lead as anti-HIV agent. PMID:26363100

  8. Biocompatibility of ferritin-based nanoparticles as targeted MRI contrast agents.

    Science.gov (United States)

    Charlton, Jennifer R; Pearl, Valeria M; Denotti, Anna R; Lee, Jonathan B; Swaminathan, Sundararaman; Scindia, Yogesh M; Charlton, Nathan P; Baldelomar, Edwin J; Beeman, Scott C; Bennett, Kevin M

    2016-08-01

    Ferritin is a naturally occurring iron storage protein, proposed as a clinically relevant nanoparticle with applications as a diagnostic and therapeutic agent. Cationic ferritin is a targeted, injectable contrast agent to measure kidney microstructure with MRI. Here, the toxicity of horse spleen ferritin is assessed as a step to clinical translation. Adult male mice received cationic, native and high dose cationic ferritin (CF, NF, or HDCF) or saline and were monitored for 3weeks. Transient weight loss occurred in the ferritin groups with no difference in renal function parameters. Ferritin-injected mice demonstrated a lower serum iron 3weeks after administration. In ferritin-injected animals pre-treated with hydrocortisone, there were no structural or weight differences in the kidneys, liver, lung, heart, or spleen. This study demonstrates a lack of significant detrimental effects of horse-derived ferritin-based nanoparticles at MRI-detectable doses, allowing further exploration of these agents in basic research and clinical diagnostics. PMID:27071333

  9. Minimalism in fabrication of self-organized nanogels holding both anti-cancer drug and targeting moiety.

    Science.gov (United States)

    Kim, Sungwon; Park, Kyong Mi; Ko, Jin Young; Kwon, Ick Chan; Cho, Hyeon Geun; Kang, Dongmin; Yu, In Tag; Kim, Kwangmeyung; Na, Kun

    2008-05-01

    Recent researches to develop nano-carrier systems in anti-cancer drug delivery have focused on more complicated design to improve therapeutic efficacy and to reduce side effects. Although such efforts have great impact to biomedical science and engineering, the complexity has been a huddle because of clinical and economic problems. In order to overcome the problems, a simplest strategy to fabricate nano-carriers to deliver doxorubicin (DOX) was proposed in the present study. Two significant subjects (i) formation of nanoparticles loading and releasing DOX and (ii) binding specificity of them to cells, were examined. Folic acid (FA) was directly coupled with pullulan (Pul) backbone by ester linkage (FA/Pul conjugate) and the degree of substitution (DS) was varied, which were confirmed by 1H NMR and UV spectrophotometry. Light scattering results revealed that the nanogels possessed two major size distributions around 70 and 270 nm in an aqueous solution. Their critical aggregation concentrations (CACs) were less than 10 microg/mL, which are lower than general critical micelle concentrations (CMCs) of low-molecular-weight surfactants. Transmission electron microscopy (TEM) images showed well-dispersed nanogel morphology in a dried state. Depending on the DS, the nanogels showed different DOX-loading and releasing profiles. The DOX release rate from FA8/Pul (with the highest DS) for 24h was slower than that from FA4/or FA6/Pul, indicating that the FA worked as a hydrophobic moiety for drug holding. Cellular uptake of the nanogels (KB cells) was also monitored by confocal microscopy. All nanogels were internalized regardless of the DS of FA. Based on the results, the objectives of this study, to suggest a new method overcoming the complications in the drug carrier design, were successfully verified. PMID:18164602

  10. Synthesis of functionalized magnetite nanoparticles to use as liver targeting MRI contrast agent

    Science.gov (United States)

    Yazdani, Farshad; Fattahi, Bahare; Azizi, Najmodin

    2016-05-01

    The aim of this research was the preparation of functionalized magnetite nanoparticles to use as a liver targeting contrast agent in magnetic resonance imaging (MRI). For this purpose, Fe3O4 nanoparticles were synthesized via the co-precipitation method. The synthesized nanoparticles were coated with silica via the Stober method and finally the coated nanoparticles were functionalized with mebrofenin. Formation of crystalline magnetite particles was confirmed by X-ray diffraction (XRD) analysis. The Fourier transform infrared spectroscopy (FTIR) and energy dispersive X-ray analyzer (EDX) of the final product showed that silica had been effectively bonded onto the surface of the magnetite nanoparticles and the coated nanoparticles functionalized with mebrofenin. The magnetic resonance imaging of the functional nanoparticles showed that the Fe3O4-SiO2-mebrofenin composite is an effective MRI contrast agent for liver targeting.

  11. Oral delivery of anticancer drugs

    DEFF Research Database (Denmark)

    Thanki, Kaushik; Gangwal, Rahul P; Sangamwar, Abhay T;

    2013-01-01

    The present report focuses on the various aspects of oral delivery of anticancer drugs. The significance of oral delivery in cancer therapeutics has been highlighted which principally includes improvement in quality of life of patients and reduced health care costs. Subsequently, the challenges...... incurred in the oral delivery of anticancer agents have been especially emphasized. Sincere efforts have been made to compile the various physicochemical properties of anticancer drugs from either literature or predicted in silico via GastroPlus™. The later section of the paper reviews various emerging...... trends to tackle the challenges associated with oral delivery of anticancer drugs. These invariably include efflux transporter based-, functional excipient- and nanocarrier based-approaches. The role of drug nanocrystals and various others such as polymer based- and lipid based-nanocarriers in the...

  12. 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

  13. Methyl-hydroxylamine as an efficacious antibacterial agent that targets the ribonucleotide reductase enzyme

    OpenAIRE

    Julián Gómez, Esther; Baelo, Aida; Gavaldà Santapau, Juan; Torrents Serra, Eduard

    2015-01-01

    The emergence of multidrug-resistant bacteria has encouraged vigorous efforts to develop antimicrobial agents with new mechanisms of action. Ribonucleotide reductase (RNR) is a key enzyme in DNA replication that acts by converting ribonucleotides into the corresponding deoxyribonucleotides, which are the building blocks of DNA replication and repair. RNR has been extensively studied as an ideal target for DNA inhibition, and several drugs that are already available on the market are used for ...

  14. The fatty acid synthase inhibitor triclosan: repurposing an anti-microbial agent for targeting prostate cancer

    OpenAIRE

    Sadowski, Martin C.; Pouwer, Rebecca H.; Jennifer H. Gunter; Lubik, Amy A.; Quinn, Ronald J.; Nelson, Colleen C.

    2014-01-01

    Inhibition of FASN has emerged as a promising therapeutic target in cancer, and numerous inhibitors have been investigated. However, severe pharmacological limitations have challenged their clinical testing. The synthetic FASN inhibitor triclosan, which was initially developed as a topical antibacterial agent, is merely affected by these pharmacological limitations. Yet, little is known about its mechanism in inhibiting the growth of cancer cells. Here we compared the cellular and molecular e...

  15. Anticancer properties of lamellarins.

    Science.gov (United States)

    Bailly, Christian

    2015-03-01

    In 1985 the first lamellarins were isolated from a small oceanic sea snail. Today, more than 50 lamellarins have been inventoried and numerous derivatives synthesized and tested as antiviral or anticancer agents. The lead compound in the family is lamellarin D, characterized as a potent inhibitor of both nuclear and mitochondrial topoisomerase I but also capable of directly interfering with mitochondria to trigger cancer cell death. The pharmacology and chemistry of lamellarins are discussed here and the mechanistic portrait of lamellarin D is detailed. Lamellarins frequently serve as a starting point in the design of anticancer compounds. Extensive efforts have been devoted to create novel structures as well as to improve synthetic methods, leading to lamellarins and related pyrrole-derived marine alkaloids. PMID:25706633

  16. Anticancer Properties of Lamellarins

    Directory of Open Access Journals (Sweden)

    Christian Bailly

    2015-02-01

    Full Text Available In 1985 the first lamellarins were isolated from a small oceanic sea snail. Today, more than 50 lamellarins have been inventoried and numerous derivatives synthesized and tested as antiviral or anticancer agents. The lead compound in the family is lamellarin D, characterized as a potent inhibitor of both nuclear and mitochondrial topoisomerase I but also capable of directly interfering with mitochondria to trigger cancer cell death. The pharmacology and chemistry of lamellarins are discussed here and the mechanistic portrait of lamellarin D is detailed. Lamellarins frequently serve as a starting point in the design of anticancer compounds. Extensive efforts have been devoted to create novel structures as well as to improve synthetic methods, leading to lamellarins and related pyrrole-derived marine alkaloids.

  17. Aminoflavone-loaded EGFR-targeted unimolecular micelle nanoparticles exhibit anti-cancer effects in triple negative breast cancer.

    Science.gov (United States)

    Brinkman, Ashley M; Chen, Guojun; Wang, Yidan; Hedman, Curtis J; Sherer, Nathan M; Havighurst, Thomas C; Gong, Shaoqin; Xu, Wei

    2016-09-01

    Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer for which there is no available targeted therapy. TNBC cases contribute disproportionately to breast cancer-related mortality, thus the need for novel and effective therapeutic methods is urgent. We have previously shown that a National Cancer Institute (NCI) investigational drug aminoflavone (AF) exhibits strong growth inhibitory effects in TNBC cells. However, in vivo pulmonary toxicity resulted in withdrawal or termination of several human clinical trials for AF. Herein we report the in vivo efficacy of a nanoformulation of AF that enhances the therapeutic index of AF in TNBC. We engineered a unique unimolecular micelle nanoparticle (NP) loaded with AF and conjugated with GE11, a 12 amino acid peptide targeting epidermal growth factor receptor (EGFR), since EGFR amplification is frequently observed in TNBC tumors. These unimolecular micelles possessed excellent stability and preferentially released drug payload at endosomal pH levels rather than blood pH levels. Use of the GE11 targeting peptide resulted in enhanced cellular uptake and strong growth inhibitory effects in TNBC cells. Further, AF-loaded, GE11-conjugated (targeted) unimolecular micelle NPs significantly inhibit orthotopic TNBC tumor growth in a xenograft model, compared to treatment with AF-loaded, GE11-lacking (non-targeted) unimolecular micelle NPs or free AF. Interestingly, the animals treated with AF-loaded, targeted NPs had the highest plasma and tumor level of AF among different treatment groups yet exhibited no increase in plasma aspartate aminotransferase (AST) activity level or observable tissue damage at the time of sacrifice. Together, these results highlight AF-loaded, EGFR-targeted unimolecular micelle NPs as an effective therapeutic option for EGFR-overexpressing TNBC. PMID:27267625

  18. The lack of target specificity of small molecule anticancer kinase inhibitors is correlated with their ability to damage myocytes in vitro

    International Nuclear Information System (INIS)

    Many new targeted small molecule anticancer kinase inhibitors are actively being developed. However, the clinical use of some kinase inhibitors has been shown to result in cardiotoxicity. In most cases the mechanisms by which they exert their cardiotoxicity are not well understood. We have used large scale profiling data on 8 FDA-approved tyrosine kinase inhibitors and 10 other kinase inhibitors to a panel of 317 kinases in order to correlate binding constants and kinase inhibitor binding selectivity scores with kinase inhibitor-induced damage to neonatal rat cardiac myocytes. The 18 kinase inhibitors that were the subject of this study were: canertinib, dasatinib, dovitinib, erlotinib, flavopiridol, gefitinib, imatinib, lapatinib, midostaurin, motesanib, pazopanib, sorafenib, staurosporine, sunitinib, tandutinib, tozasertib, vandetanib and vatalanib. The combined tyrosine kinase and serine-threonine kinase selectivity scores were highly correlated with the myocyte-damaging effects of the kinase inhibitors. This result suggests that myocyte damage was due to a lack of target selectivity to binding of both tyrosine kinases and serine-threonine kinases, and was not due to binding to either group specifically. Finally, the strength of kinase inhibitor binding for 290 kinases was examined for correlations with myocyte damage. Kinase inhibitor binding was significantly correlated with myocyte damage for 12 kinases. Thus, myocyte damage may be multifactorial in nature with the inhibition of a number of kinases involved in producing kinase inhibitor-induced myocyte damage.

  19. Pegylated folate and peptide-decorated graphene oxide nanovehicle for in vivo targeted delivery of anticancer drugs and therapeutic self-monitoring.

    Science.gov (United States)

    Tian, Jiangwei; Luo, Yingping; Huang, Liwei; Feng, Yaqiang; Ju, Huangxian; Yu, Bo-Yang

    2016-06-15

    This work reports a graphene oxide-based nanovehicle with conjugation of pegylated folate for targeted delivery of anticancer drugs and fluorescein-labeled peptide for therapeutic self-monitoring in vitro and in vivo. The nanovehicle could absorb hydrophobic and aromatic drug molecules with high loading capacity and efficiency of more than 1.7mgmg(-1) and 90%, respectively. MTT and flow cytometric assays demonstrated that the drug-loaded nanovehicle could specifically transport and release the drugs into the folate receptor high-expressed cancer cells, which ensured a high therapeutic efficiency to cancer cells and prevented the injury to normal cells. Moreover, confocal fluorescence imaging confirmed that the drug-induced cancer cell death could be visualized with the light-up fluorescence of fluorescein activated by caspase-3. The targeted delivery of drug and self-evaluation of therapeutic efficacy were further successfully realized by living imaging in tumor-bearing mice, which broaden the applications of this theranostic system in vivo and may offer new opportunities for precise cancer treatment. PMID:26890827

  20. Titanium(IV) targets phosphoesters on nucleotides: implications for the mechanism of action of the anticancer drug titanocene dichloride.

    Science.gov (United States)

    Guo, M; Guo, Z; Sadler, P J

    2001-09-01

    Abstract Reactions between the anticancer drug titanocene dichloride (Cp2TiCl2) and various nucleotides and their constituents in aqueous solution or N,N-dimethylformamide (DMF) have been investigated by 1H and 31P NMR spectroscopy and in the solid state by IR spectroscopy. In aqueous solution over the pH* (pH meter reading in D2O) range 2.3-6.5, CMP forms one new species with Ti(IV) bound only to the phosphate group. In acidic media at pH*TMP approximately AMP > CMP. At pH* > 7.0, hydrolysis of Cp2TiCl2 predominated and little reaction with the nucleotides was observed. Binding of deoxyribose 5'-phosphate and 4-nitrophenyl phosphate to Cp2TiCl2(aq) via their phosphate groups was detected by 31P NMR spectroscopy, but no reaction between Cp2TiCl2(aq) and deoxyguanosine, 9-ethylguanine or deoxy-D-ribose was observed in aqueous solution. The nucleoside phosphodiesters 3',5'-cyclic GMP and 2',3'-cyclic CMP did not react with Cp2TiCl2(aq) in aqueous solution; however, in the less polar solvent DMF, 3',5'-cyclic GMP coordination to [Cp2Ti]2+ via its phosphodiester group was readily observed. Binding of titanocene to the phosphodiester group of the dinucleotide GpC was also observed in DMF by 31P NMR. The nucleoside triphosphates ATP and GTP reacted more extensively with Cp2TiCl2(aq) than their monophosphates; complexes with bound phosphate groups were formed in acidic media and to a lesser extent at neutral pH. Cleavage of phosphate bonds in ATP (and GTP) by Cp2TiCl2(aq) to form inorganic phosphate, AMP (or GMP) and ADP (or GDP) was observed in aqueous solutions. In addition, titanocene binding to ATP was not inhibited by Mg(II), but the ternary complex titanocene-ATP-Mg appeared to form. These reactions contrast markedly with those of the drug cisplatin, which binds predominantly to the base nitrogen atoms of nucleotides and only weakly to the phosphate groups. The high affinity of Ti(IV) for phosphate groups may be important for its biological activity. PMID:11681703

  1. Targeted drug delivery systems 6: Intracellular bioreductive activation, uptake and transport of an anticancer drug delivery system across intestinal Caco-2 cell monolayers.

    Science.gov (United States)

    Gharat, L; Taneja, R; Weerapreeyakul, N; Rege, B; Polli, J; Chikhale, P J

    2001-05-21

    We demonstrate transport across, intracellular accumulation and bioreductive activation of a conformationally constrained, anticancer drug delivery system (the CH(3)-TDDS) using Caco-2 cell monolayers (CCMs) as an in vitro model of the human intestinal mucosa. Reverse-phase High Performance Liquid Chromatography (HPLC) coupled with UV detection was used to detect CH(3)-TDDS, the bioreduction product (lactone) and the released drug (melphalan methyl ester; MME). Upon incubation of the CH(3)-TDDS with the apical (AP) surface of 21-day-old CCM, we observed rapid decrease in the AP concentration of the CH(3)-TDDS (60%/hr) as a result of cellular uptake. Rapid intracellular accumulation of the CH(3)-TDDS was followed by bioreductive activation to deplete the cellular levels of CH(3)-TDDS. The drug part (MME) and lactone, as well as CH(3)-TDDS, were detected in the basolateral (BL) chamber. Intracellular Caco-2 levels of TDDS and lactone were also detectable. Bioreductive activation of the CH(3)-TDDS was additionally confirmed by formation of lactone after incubation of the CH(3)-TDDS in the presence of freshly prepared Caco-2 cell homogenates. During transport studies of melphalan or MME alone (as control), the intact drug was not detected in the intracellular compartment or in the BL chamber. These observations demonstrate that CH(3)-TDDS has potential for improving intestinal delivery of MME. TDDS could be useful in facilitating oral absorption of MME as well as the oral delivery of other agents. PMID:11337161

  2. Nanoparticles Targeted With NGR Motif Deliver c-myc siRNA and Doxorubicin for Anticancer Therapy

    OpenAIRE

    Chen, Yunching; Wu, Jinzi J.; Huang, Leaf

    2010-01-01

    We have designed a PEGylated LPD (liposome-polycation-DNA) nanoparticle for systemic, specific, and efficient delivery of small interfering RNA (siRNA) into solid tumors in mice by modification with NGR (aspargine–glycine–arginine) peptide, targeting aminopeptidase N (CD13) expressed in the tumor cells or tumor vascular endothelium. LPD-PEG-NGR efficiently delivered siRNA to the cytoplasm and downregulated the target gene in the HT-1080 cells but not CD13− HT-29 cells, whereas nanoparticles c...

  3. Glyco-nanoparticles with sheddable saccharide shells: A unique and potent platform for hepatoma-targeting delivery of anticancer drugs

    NARCIS (Netherlands)

    Chen, Wei; Zou, Yan; Meng, Fenghua; Cheng, Ru; Deng, Chao; Feijen, Jan; Zhong, Zhiyuan

    2014-01-01

    Reduction-sensitive shell-sheddable glyco-nanoparticles were designed and developed based on poly(ε-caprolactone)-graft-SS-lactobionic acid (PCL-g-SS-LBA) copolymer for efficient hepatoma-targeting delivery of doxorubicin (DOX). PCL-g-SS-LBA was prepared by ring-opening copolymerization of ε-caprola

  4. Hepatocyte-targeted MR contrast agents. Contrast enhanced detection of liver cancer in diffusely damaged liver

    International Nuclear Information System (INIS)

    The performance of hepatocyte-targeted magnetic resonance (MR) contrast agents in the detection of liver tumor was tested in rats with hepatitis. Hepatocyte-targeted MR contrast agents (paramagnetic hepatobiliary complex [manganese-DPDP] and superparamagnetic iron oxide coated with arabinogalactan [SPIO-AG]) were injected into normal rats and rats with carbon tetrachloride-induced hepatitis. Before and after injection of either contrast agent, ex vivo relaxometry (0.94 T) or in vivo MR imaging (1.0 T) were performed. The obtained liver and tumor T1 and T2 relaxation times, liver and tumor signal-to-noise ratios (SNR), and tumor-liver contrast-to-noise ratios (CNR) of control rats and rats with hepatitis were compared. Both relaxometry and MR imaging showed that MnDPDP and SPIO-AG selectively enhanced liver tissue in controls and in rats with hepatitis to the same degree, and little tumor enhancement was seen in either group. As a result, no significant difference between control rats and rats with hepatitis was observed in the postcontrast tumor-liver CNR. For a MnDPDP-enhanced CNR with spin echo (SE) of 310/15, the results were -10.4±3.6 in control rats vs. -11.5±1.4 in rats with hepatitis; for a SPIO-AG-enhanced CNR with SE 2000/45 and 2000/90, respectively, the results were 30.7±9.2 and 18.7±4.7 in control rats vs. 31.9±7.1 and 17.7±2.4 in rats with hepatitis. These results indicate that hepatocyte-targeted contrast agents effectively enhance liver tissue and enhance liver-tumor image contrast despite hepatocellular dysfunction. (author)

  5. Molecular targets of dietary agents for prevention and therapy of cancer.

    Science.gov (United States)

    Aggarwal, Bharat B; Shishodia, Shishir

    2006-05-14

    While fruits and vegetables are recommended for prevention of cancer and other diseases, their active ingredients (at the molecular level) and their mechanisms of action less well understood. Extensive research during the last half century has identified various molecular targets that can potentially be used not only for the prevention of cancer but also for treatment. However, lack of success with targeted monotherapy resulting from bypass mechanisms has forced researchers to employ either combination therapy or agents that interfere with multiple cell-signaling pathways. In this review, we present evidence that numerous agents identified from fruits and vegetables can interfere with several cell-signaling pathways. The agents include curcumin (turmeric), resveratrol (red grapes, peanuts and berries), genistein (soybean), diallyl sulfide (allium), S-allyl cysteine (allium), allicin (garlic), lycopene (tomato), capsaicin (red chilli), diosgenin (fenugreek), 6-gingerol (ginger), ellagic acid (pomegranate), ursolic acid (apple, pears, prunes), silymarin (milk thistle), anethol (anise, camphor, and fennel), catechins (green tea), eugenol (cloves), indole-3-carbinol (cruciferous vegetables), limonene (citrus fruits), beta carotene (carrots), and dietary fiber. For instance, the cell-signaling pathways inhibited by curcumin alone include NF-kappaB, AP-1, STAT3, Akt, Bcl-2, Bcl-X(L), caspases, PARP, IKK, EGFR, HER2, JNK, MAPK, COX2, and 5-LOX. The active principle identified in fruit and vegetables and the molecular targets modulated may be the basis for how these dietary agents not only prevent but also treat cancer and other diseases. This work reaffirms what Hippocrates said 25 centuries ago, let food be thy medicine and medicine be thy food. PMID:16563357

  6. Targeting and imaging study of paclitaxel-loaded and Herceptin-targeted ultrasound contrast agent with ultrasound in vitro

    International Nuclear Information System (INIS)

    Objective: To further explore the affinity of paclitaxel-loaded and trastuzumab (Herceptin) -targeted poly (lactic-co-glycolic acid, PLGA) -COOH ultrasound contrast agent (Pac-PLGA-HER) for human breast cancer cell line MCF-7 and study their effect on ultrasound imaging in vitro. Methods: Paclitaxel-loaded PLGA-COOH ultrasound contrast agents (Pac-PLGA) were prepared by the double emulsion technique and conjugated with Herceptin monoclonal antibody by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC)/N-hyalroxysuccinimide (NHS). MCF-7 cells were plated in culture dishes for 24 h and divided into 4 groups with 3 dishes in each group, i. e. Pac-PLGA group, Pac-PLGA-HER group, ultrasound + Pac-PLGA-HER group and antibody blocking group. Binding of polymer ultrasound contrast agents to MCF-7 cells was observed by laser scanning confocal microscopy. In vitro experiments were employed to study the effects of Pac-PLGA-HER on the enhancement of ultrasound imaging as compared with Pac-PLGA, the control group. Independent samples t-test was used for statistical analysis with the help of DFY. Results: The average diameter of Pac-PLGA-HER was (596 ± 12) nm. In the in vitro targeting study,a number of Pac-PLGA-HER bound with MCF-7 cells tightly; while, no conjugation was observed in the control group. During in vitro ultrasound imaging,the average sound intensity of Pac-PLGA-HER and Pac-PLGA was (134.50 ± 10.19) and (135.11 ±11.49) dB (t=-0.097, P>0.05) and the average grey scale was 147.83 ± 11.12 and 148.50 ± 12.63 (t=-0.097, P>0.05), respectively. There was no difference between the two. Conclusion: Pac-PLGA-HER could bind to high HER2-expressing MCF-7 cells specifically and effectively and was an effective ultrasound contrast agent in vitro. (authors)

  7. Susceptibility of non-target invertebrates to Brazilian microbial pest control agents.

    Science.gov (United States)

    Oliveira-Filho, Eduardo Cyrino; Muniz, Daphne Heloisa Freitas; Freire, Ingrid Souza; Ramos, Felipe Rosa; Alves, Roberto Teixeira; Jonsson, Claudio Martin; Grisolia, Cesar Koppe; Monnerat, Rose Gomes

    2011-08-01

    Microbial pest control agents or entomopathogens have been considered an interesting alternative to use instead of chemical insecticides. Knowledge of ecotoxicity data is very important to predict the hazard of any product released in the environment and subsidize the regulation of these products by governmental agencies. In the present study four new Brazilian strains of Bacillus and one fungus were tested to evaluate their acute toxicity to the microcrustacean Daphnia similis, the snail Biomphalaria glabrata and the dung beetle Digitonthophagus gazella. The microcrustaceans and the snails were exposed to entomopathogens in synthetic softwater and the beetles were exposed directly in cattle dung. Obtained data reveal low susceptibility of the non-target species to tested microorganisms, with lethal concentrations being observed only at much higher concentrations than that effective against target insects. These results show that the tested strains are selective in their action mode and seem to be non-hazardous to non-target species. PMID:21533653

  8. The feasibility of a targeted ultrasound contrast agent carrying genes and cell-penetrating peptides to hypoxic HUVEC

    International Nuclear Information System (INIS)

    Objective: To prepare an anti-P-selectin targeted ultrasound contrast agent carrying genes and cell-penetrating peptides (CPP) and to investigate its feasibility of delivery to hypoxic human umbilical vein endothelial cells (HUVEC). Methods: Anti-P-selectin targeted ultrasound contrast agent carrying a green fluorescent protein gene (pEGFP-N1) and CPP was prepared by mechanical vibration and carbodiimide techniques. The appearance, distribution, concentration and diameter of the ultrasound contrast agent were measured. The gene and CPP distribution on the agent was investigated using confocal laser scanning microscopy (CLSM). The efficiency of the ultrasound contrast agent to carry the gene and CPP was investigated by fluorospectrophotometry. HUVEC were cultured in vitro and hypoxic HUVEC were prepared using hydrogen peroxide (H2O2). Hypoxic HUVEC were randomly assigned targeted ultrasound contrast agents and non-targeted ultrasound contrast agents for transfection. The transfection effect of green fluorescent protein in the two groups was observed using fluorescence microscopy and flow cytometry. T-test and linear correlation analysis were used for statistical analysis. Results: The average diameter of anti-P-selectin targeted ultrasound contrast agents carrying gene and CPP was (2.15 ±0.36) μm and the concentration was (1.58 ± 0.23) × 107/ml.The results of CLSM showed that gene and CPP were distributed on the shell of the agent. The gene encapsulation efficiency was 28% (y=0.932x-0.09, r=0.993, P<0.05), and the CPP encapsulation efficiency was 25% (y=5.875x-0.81, r=0.987, P<0.05). EGFP expression was observed using fluorescence microscopy in targeted ultrasound contrast agents and non-targeted ultrasound contrast agents. The average transfection efficiencies of targeted ultrasound contrast agents and non-targeted ultrasound contrast agents were (18.74 ± 0.47) % and (15.34 ± 0.22) % after 24 h (t=10.923, P<0.001). Conclusions: The in vitro studies showed

  9. Recent insights in nanotechnology-based drugs and formulations designed for effective anti-cancer therapy.

    Science.gov (United States)

    Piktel, Ewelina; Niemirowicz, Katarzyna; Wątek, Marzena; Wollny, Tomasz; Deptuła, Piotr; Bucki, Robert

    2016-01-01

    The rapid development of nanotechnology provides alternative approaches to overcome several limitations of conventional anti-cancer therapy. Drug targeting using functionalized nanoparticles to advance their transport to the dedicated site, became a new standard in novel anti-cancer methods. In effect, the employment of nanoparticles during design of antineoplastic drugs helps to improve pharmacokinetic properties, with subsequent development of high specific, non-toxic and biocompatible anti-cancer agents. However, the physicochemical and biological diversity of nanomaterials and a broad spectrum of unique features influencing their biological action requires continuous research to assess their activity. Among numerous nanosystems designed to eradicate cancer cells, only a limited number of them entered the clinical trials. It is anticipated that progress in development of nanotechnology-based anti-cancer materials will provide modern, individualized anti-cancer therapies assuring decrease in morbidity and mortality from cancer diseases. In this review we discussed the implication of nanomaterials in design of new drugs for effective antineoplastic therapy and describe a variety of mechanisms and challenges for selective tumor targeting. We emphasized the recent advantages in the field of nanotechnology-based strategies to fight cancer and discussed their part in effective anti-cancer therapy and successful drug delivery. PMID:27229857

  10. uPAR as anti-cancer target: evaluation of biomarker potential, histological localization, and antibody-based therapy

    DEFF Research Database (Denmark)

    Lund, Ida K; Illemann, Martin; Sørensen, Tine Thurison; Christensen, Ib J; Hoyer-Hansen, Gunilla

    2011-01-01

    action of several proteolytic systems in generation of a high proteolytic potential required for tissue remodeling processes. uPAR is additionally cleaved by uPA on the cell surface, liberating domain I, resulting in abrogated pericellular proteolysis. The expression of both uPAR and uPA is significantly...... hepatic fibrinolysis using mouse monoclonal antibodies (mAbs) against mouse uPA or uPAR. These reagents will target uPA and uPAR in both stromal cells and cancer cells, and their therapeutic potential can now be assessed in syngenic mouse cancer models....

  11. Molecular Targeted Agents for Gastric Cancer: A Step Forward Towards Personalized Therapy

    Directory of Open Access Journals (Sweden)

    Tom Geldart

    2013-01-01

    Full Text Available Gastric cancer (GC represents a major cancer burden worldwide, and remains the second leading cause of cancer-related death. Due to its insidious nature, presentation is usually late and often carries a poor prognosis. Despite having improved treatment modalities over the last decade, for most patients only modest improvements have been seen in overall survival. Recent progress in understanding the molecular biology of GC and its signaling pathways, offers the hope of clinically significant promising advances for selected groups of patients. Patients with Her-2 overexpression or amplification have experienced benefit from the integration of monoclonal antibodies such as trastuzumab to the standard chemotherapy. Additionally, drugs targeting angiogenesis (bevacizumab, sorafenib, sunitinib are under investigation and other targeted agents such as mTOR inhibitors, anti c-MET, polo-like kinase 1 inhibitors are in preclinical or early clinical development. Patient selection and the development of reliable biomarkers to accurately select patients most likely to benefit from these tailored therapies is now key. Future trials should focus on these advances to optimize the treatment for GC patients. This article will review recent progress and current status of targeted agents in GC.

  12. Enediyne compounds - new promises in anticancer therapy.

    Science.gov (United States)

    Gredicak, Matija; Jerić, Ivanka

    2007-06-01

    Scientists of all kinds have long been intrigued by the nature, action and potential of natural toxins that possess exceptional antibacterial and anticancer activities. These compounds, named enediynes, are among the most effective chemotherapeutic agents known. Often compared with intelligent weapons, due to the unique structure and sophisticated mechanism by which they destroy double-helical DNA, enediyne antibiotics are nowadays the most promising leaders in the anticancer therapy. Apart from their diversity, enediyne compounds share some structural and functional similarities. One fragment of a structure is responsible for the recognition and transport, another part acts as molecular trigger while the third, reactive enediyne unit, undergoes Bergman cycloaromatization and causes DNA breakage. Members of the enediyne family are already in clinical use to treat various cancers, but more general use is limited by their complex structure, which makes them formidable targets for synthetic chemists. There are three main approaches in the design of new enediyne-related compounds: improvement of enediyne >warheadsenediynes, their mode of action and efforts undertaken to design artificial enediyne-related DNA cleaving agents. PMID:17507311

  13. Potential Activity of Basil Plants as a Source of Antioxidants and Anticancer Agents as Affected by Organic and Bio-organic Fertilization

    OpenAIRE

    Hanan Anwar Aly TAIE; Zeinab Abd-EL Rahman SALAMA; Radwan, Samir

    2010-01-01

    Sweet basil (Ocimum basilicum) is a popular culinary herbal crop grown for fresh or dry leaf, essential oil and seed markets. Recently, basil was shown to rank highest among species and herbal crops for phenolic compounds, essential oils which are associated with decreasing risks of cancer and aging diseases. The current study aimed to evaluate the potential activity of phenolic, flavonoids and essential oil of basil as antioxidant and anticancer activities by application organic and bio-orga...

  14. Fucoidan Extract Enhances the Anti-Cancer Activity of Chemotherapeutic Agents in MDA-MB-231 and MCF-7 Breast Cancer Cells

    OpenAIRE

    Zhongyuan Zhang; Kiichiro Teruya; Toshihiro Yoshida; Hiroshi Eto; Sanetaka Shirahata

    2013-01-01

    Fucoidan, a fucose-rich polysaccharide isolated from brown alga, is currently under investigation as a new anti-cancer compound. In the present study, fucoidan extract (FE) from Cladosiphon navae-caledoniae Kylin was prepared by enzymatic digestion. We investigated whether a combination of FE with cisplatin, tamoxifen or paclitaxel had the potential to improve the therapeutic efficacy of cancer treatment. These co-treatments significantly induced cell growth inhibition, apoptosis, as well as ...

  15. A targeted nanoglobular contrast agent from host-guest self-assembly for MR cancer molecular imaging.

    Science.gov (United States)

    Zhou, Zhuxian; Han, Zhen; Lu, Zheng-Rong

    2016-04-01

    The clinical application of nanoparticular Gd(III) based contrast agents for tumor molecular MRI has been hindered by safety concerns associated with prolonged tissue retention, although they can produce strong tumor enhancement. In this study, a targeted well-defined cyclodextrin-based nanoglobular contrast agent was developed through self-assembly driven by host-guest interactions for safe and effective cancer molecular MRI. Multiple β-cyclodextrins attached POSS (polyhedral oligomeric silsesquioxane) nanoglobule was used as host molecule. Adamantane-modified macrocyclic Gd(III) contrast agent, cRGD (cyclic RGDfK peptide) targeting ligand and fluorescent probe was used as guest molecules. The targeted host-guest nanoglobular contrast agent cRGD-POSS-βCD-(DOTA-Gd) specifically bond to αvβ3 integrin in malignant 4T1 breast tumor and provided greater contrast enhancement than the corresponding non-targeted agent. The agent also provided significant fluorescence signal in tumor tissue. The histological analysis of the tumor tissue confirmed its specific and effective targeting to αvβ3 integrin. The targeted imaging agent has a potential for specific cancer molecular MR and fluorescent imaging. PMID:26874280

  16. Testing the Efficacy of Pharmacological Agents in a Pericardial Target Delivery Model in the Swine.

    Science.gov (United States)

    Iles, Tinen L; Howard, Brian; Howard, Stephen; Quallich, Stephen; Rolfes, Christopher; Richardson, Eric; Iaizzo, Hanna R; Iaizzo, Paul A

    2016-01-01

    To date, many pharmacological agents used to treat or prevent arrhythmias in open-heart cases create undesired systemic side effects. For example, antiarrhythmic drugs administered intravenously can produce drops in systemic pressure in the already compromised cardiac patient. While performing open-heart procedures, surgeons will often either create a small port or form a pericardial cradle to create suitable fields for operation. This access yields opportunities for target pharmacological delivery (antiarrhythmic or ischemic preconditioning agents) directly to the myocardial tissue without undesired side effects. We have developed a swine model for testing pharmacological agents for target delivery within the pericardial fluid. While fully anesthetized, each animal was instrumented with a Swan-Ganz catheter as well as left and right ventricle pressure catheters, and pacing leads were placed in the right atrial appendage and the right ventricle. A medial sternotomy was then performed and a pericardial access cradle was created; a plunge pacing lead was placed in the left atrial appendage and a bipolar pacing lead was placed in the left ventricle. Utilizing a programmer and a cardiac mapping system, the refractory period of the atrioventricular node (AVN), atria and ventricles was determined. In addition, atrial fibrillation (AF) induction was produced utilizing a Grass stimulator and time in AF was observed. These measurements were performed prior to treatment, as well as 30 min and 60 min after pericardial treatment. Additional time points were added for selected studies. The heart was then cardiopleged and reanimated in a four chamber working mode. Pressure measurements and function were recorded for 1 hr after reanimation. This treatment strategy model allowed us to observe the effects of pharmacological agents that may decrease the incidence of cardiac arrhythmias and/or ischemic damage, during and after open-heart surgery. PMID:27500319

  17. The Clinical Development of Molecularly Targeted Agents in Combination With Radiation Therapy: A Pharmaceutical Perspective

    International Nuclear Information System (INIS)

    Summary: This paper explores historical and current roles of pharmaceutical industry sponsorship of clinical trials testing radiation therapy combinations with molecularly targeted agents and attempts to identify potential solutions to expediting further combination studies. An analysis of clinical trials involving a combination of radiation therapy and novel cancer therapies was performed. Ongoing and completed trials were identified by searching the (clinicaltrials.gov) Web site, in the first instance, with published trials of drugs of interest identified through American Society of Clinical Oncology, European CanCer Organisation/European Society for Medical Oncology, American Society for Radiation Oncology/European Society for Therapeutic Radiology and Oncology, and PubMed databases and then cross-correlated with (clinicaltrials.gov) protocols. We examined combination trials involving radiation therapy with novel agents and determined their distribution by tumor type, predominant molecular mechanisms examined in combination to date, timing of initiation of trials relative to a novel agent's primary development, and source of sponsorship of such trials. A total of 564 studies of targeted agents in combination with radiation therapy were identified with or without concomitant chemotherapy. Most studies were in phase I/II development, with only 36 trials in phase III. The tumor site most frequently studied was head and neck (26%), followed by non-small cell lung cancer. Pharmaceutical companies were the sponsors of 33% of studies overall and provided support for only 16% of phase III studies. In terms of pharmaceutical sponsorship, Genentech was the most active sponsor of radiation therapy combinations (22%), followed by AstraZeneca (14%). Most radiation therapy combination trials do not appear to be initiated until after drug approval. In phase III studies, the most common (58%) primary endpoint was overall survival. Collectively, this analysis suggests that such

  18. Curcumin binds in silico to anti-cancer drug target enzyme MMP-3 (human stromelysin-1) with affinity comparable to two known inhibitors of the enzyme.

    Science.gov (United States)

    Jerah, Ahmed; Hobani, Yahya; Kumar, B Vinod; Bidwai, Anil

    2015-01-01

    In silico interaction of curcumin with the enzyme MMP-3 (human stromelysin-1) was studied by molecular docking using AutoDock 4.2 as the docking software application. AutoDock 4.2 software serves as a valid and acceptable docking application to study the interactions of small compounds with proteins. Interactions of curcumin with MMP-3 were compared to those of two known inhibitors of the enzyme, PBSA and MPPT. The calculated free energy of binding (ΔG binding) shows that curcumin binds with affinity comparable to or better than the two known inhibitors. Binding interactions of curcumin with active site residues of the enzyme are also predicted. Curcumin appears to bind in an extendended conformation making extensive VDW contacts in the active site of the enzyme. Hydrogen bonding and pi-pi interactions with key active site residues is also observed. Thus, curcumin can be considered as a good lead compound in the development of new inhibitors of MMP-3 which is a potential target of anticancer drugs. The results of these studies can serve as a starting point for further computational and experimental studies. PMID:26420919

  19. Development and evaluation of a novel VEGFR2-targeted nanoscale ultrasound contrast agents

    Science.gov (United States)

    Yu, Houqiang; Li, Chunfang; He, Xiaoling; Zhou, Qibing; Ding, Mingyue

    2016-04-01

    Recent literatures have reported that the targeted nanoscale ultrasound contrast agents are becoming more and more important in medical application, like ultrasound imaging, detection of perfusion, drug delivery and molecular imaging and so on. In this study, we fabricated an uniform nanoscale bubbles (257 nm with the polydispersity index of 0.458) by incorporation of antibody targeted to vascular endothelial growth factor receptor 2 (VEGFR2) into the nanobubbles membrane by using avidin-biotin interaction. Some fundamental characterizations such as nanobubble suspension, surface morphology, particle size distribution and zeta potential were investigated. The concentration and time-intensity curves (TICs) were obtained with a self-made ultrasound experimental setup in vitro evaluation. In addition, in order to evaluate the contrast enhancement ability and the potential tumor-targeted ability in vivo, normal Wistar rats and nude female BALB/c mice were intravascular administration of the nanobubbles via tail vein injection, respectively. Significant contrast enhancement of ultrasound imaging within liver and tumor were visualized. These experiments demonstrated that the targeted nanobubbles is efficient in ultrasound molecular imaging by enhancement of the contrast effect and have potential capacity for targeted tumor diagnosis and therapy in the future.

  20. Research progress in nanoparticles as anticancer drug carrier

    Institute of Scientific and Technical Information of China (English)

    Yingying Sun; Huaqing Lin ; Chuqin Yu; Suna Lin

    2014-01-01

    Nanoparticles drug delivery system has sustained and controled release features as wel as targeted drug deliv-ery, which can change the characteristics of drug distributionin vivo. It can increase the stability of the drug and enhance drug bioavailability. The selective targeting of nanoparticles can be achieved through enhanced permeability and retention efect and a conjugated specific ligand or through the efects of physiological conditions, such as pH and temperature. Nanoparticles can be prepared by using a wide range of materials and can be used to encapsulate chemotherapeutic agents to reduce toxic-ity, which can be used for imaging, therapy, and diagnosis. In this research, recent progress on nanoparticles as a targeted drug delivery system wil be reviewed, including positive-targeting, negative-targeting, and physicochemical-targeting used as anticancer drug carriers.

  1. Cancer metabolic reprogramming:impor tance, main features, and potentials for precise targeted anti-cancer therapies

    Institute of Scientific and Technical Information of China (English)

    Liem Minh Phan; Sai-Ching Jim Yeung; Mong-Hong Lee

    2014-01-01

    Cancer cells are well documented to rewire their metabolism and energy production networks to support and enable rapid proliferation, continuous growth, survival in harsh conditions, invasion, metastasis, and resistance to cancer treatments. Since Dr. Otto Warburg’s discovery about altered cancer cell metabolism in 1930, thousands of studies have shed light on various aspects of cancer metabolism with a common goal to find new ways for effectively eliminating tumor cells by targeting their energy metabolism. hTis review highlights the importance of the main features of cancer metabolism, summarizes recent remarkable advances in this ifeld, and points out the potentials to translate these scientiifc ifndings into life-saving diagnosis and therapies to help cancer patients.

  2. Glyco-nanoparticles with sheddable saccharide shells: a unique and potent platform for hepatoma-targeting delivery of anticancer drugs.

    Science.gov (United States)

    Chen, Wei; Zou, Yan; Meng, Fenghua; Cheng, Ru; Deng, Chao; Feijen, Jan; Zhong, Zhiyuan

    2014-03-10

    Reduction-sensitive shell-sheddable glyco-nanoparticles were designed and developed based on poly(ε-caprolactone)-graft-SS-lactobionic acid (PCL-g-SS-LBA) copolymer for efficient hepatoma-targeting delivery of doxorubicin (DOX). PCL-g-SS-LBA was prepared by ring-opening copolymerization of ε-caprolactone and pyridyl disulfide carbonate followed by postpolymerization modification with thiolated lactobionic acid (LBA-SH) via thiol-disulfide exchange reaction. The dynamic light scattering (DLS) and transmission electron microscopy (TEM) showed that PCL-g-SS-LBA was self-assembled into monodisperse nanoparticles (SS-GNs) with a mean diameter of about 80 nm. SS-GNs while remaining stable under physiological conditions (37 °C, pH 7.4) were prone to rapid shell-shedding and aggregation in the presence of 10 mM dithiothreitol (DTT). DOX was loaded into SS-GNs with a decent loading content of 12.0 wt %. Notably, in vitro release studies revealed that about 80.3% DOX was released from DOX-loaded SS-GNs in 24 h under a reductive condition while low drug release (mechanism and DOX was released into the nuclei of cells following 4 h incubation. MTT assays showed that DOX-loaded SS-GNs exhibited a high antitumor activity toward HepG2 cells, which was comparable to free DOX and about 18-fold higher than their reduction-insensitive counterparts, while blank SS-GNs were nontoxic up to a tested concentration of 1.0 mg/mL. These shell-sheddable glyco-nanoparticles are promising for hepatoma-targeting chemotherapy. PMID:24460130

  3. Development of Platinum(iv) Complexes as Anticancer Prodrugs: the Story so Far

    Science.gov (United States)

    Wong, Daniel Yuan Qiang; Ang, Wee Han

    2012-06-01

    The serendipitous discovery of the antitumor properties of cisplatin by Barnett Rosenberg some forty years ago brought about a paradigm shift in the field of medicinal chemistry and challenged conventional thinking regarding the role of potentially toxic heavy metals in drugs. Platinum(II)-based anticancer drugs have since become some of the most effective and widely-used drugs in a clinician's arsenal and have saved countless lives. However, they are limited by high toxicity, severe side-effects and the incidence of drug resistance. In recent years, attention has shifted to stable platinum(IV) complexes as anticancer prodrugs. By exploiting the unique chemical and structural attributes of their scaffolds, these platinum(IV) prodrugs offer new strategies of targeting and killing cancer cells. This review summarizes the development of anticancer platinum(IV) prodrugs to date and some of the exciting strategies that utilise the platinum(IV) construct as targeted chemotherapeutic agents against cancer.

  4. Anticancer chemotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Weller, R.E.

    1991-10-01

    This document examines chemotherapeutic agents for use in veterinary oncology. It lists some of the most common categories of chemotherapeutic drugs, such as alkylating agents and corticosteroids. For each category, the paper lists some example drugs, gives their mode of action, tumors usually susceptible to the drug, and common side effects. A brief discussion of mechanisms of drug resistance is also provided. (MHB)

  5. Hyaluronic acid-functionalized single-walled carbon nanotubes as tumor-targeting MRI contrast agent

    Directory of Open Access Journals (Sweden)

    Hou L

    2015-07-01

    Full Text Available Lin Hou,* Huijuan Zhang,* Yating Wang, Lili Wang, Xiaomin Yang, Zhenzhong ZhangSchool of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, People’s Republic of China*These authors contributed equally to this workAbstract: A tumor-targeting carrier, hyaluronic acid (HA-functionalized single-walled carbon nanotubes (SWCNTs, was explored to deliver magnetic resonance imaging (MRI contrast agents (CAs targeting to the tumor cells specifically. In this system, HA surface modification for SWCNTs was simply accomplished by amidation process and could make this nanomaterial highly hydrophilic. Cellular uptake was performed to evaluate the intracellular transport capabilities of HA-SWCNTs for tumor cells and the uptake rank was HA-SWCNTs> SWCNTs owing to the presence of HA, which was also evidenced by flow cytometry. The safety evaluation of this MRI CAs was investigated in vitro and in vivo. It revealed that HA-SWCNTs could stand as a biocompatible nanocarrier and gadolinium (Gd/HA-SWCNTs demonstrated almost no toxicity compared with free GdCl3. Moreover, GdCl3 bearing HA-SWCNTs could significantly increase the circulation time for MRI. Finally, to investigate the MRI contrast enhancing capabilities of Gd/HA-SWCNTs, T1-weighted MR images of tumor-bearing mice were acquired. The results suggested Gd/HA-SWCNTs had the highest tumor-targeting efficiency and T1-relaxivity enhancement, indicating HA-SWCNTs could be developed as a tumor-targeting carrier to deliver the CAs, GdCl3, for the identifiable diagnosis of tumor.Keywords: gadolinium, magnetic resonance, SWCNTs, hyaluronic acid, contrast agent

  6. Proposal of “cyclic therapy”, a novel treatment strategy with targeted agents for advanced renal cell carcinoma

    OpenAIRE

    Nozawa, Masahiro; Uemura, Hirotsugu

    2013-01-01

    The number of molecular targeted agents for advanced renal cell carcinoma (RCC) has gradually increased, but evidence on the optimal order of selection for such agents has not yet caught up with this trend. In addition, timing of switching molecular targeted drugs may also become an important issue for controlling the disease as types of these drugs grow in number. Based on the fact that the efficacy of a rechallenge of the drug previously used suggests the recovery of the sensitivity, a cycl...

  7. Conventional anticancer therapeutics and telomere maintenance mechanisms.

    Science.gov (United States)

    Uziel, Orit; Lahav, Meir

    2014-01-01

    The telomere-telomerase system has a unique role in the biology of cancer. Telomere maintenance, mostly affected by the up regulation of telomerase activity, is a prerequisite for perpetuation of malignant cells. This fundamental biologic feature defines telomere maintenance as an attractive therapeutic target for most types of cancer. This review summarizes some critical aspects of telomere biology with special emphasis on the connection to anticancer therapy. In particular, the effects on the telomere - telomerase system of conventional anticancer treatments, including various cytotoxic drugs, targeted biological agents and radiotherapy, and their possible combination with telomerase-directed therapy are discussed. Several potential problems, including side effects and complications inherent to perturbations of telomere biology in normal cells, are also highlighted. In spite of significant progress in this field, there are still several issues that have to be addressed and ultimately resolved in order to obtain a better characterization of the pros and cons of telomerase-directed therapies and, consequently, their clinical relevance. PMID:24975606

  8. Gracilaria lemaneiformis polysaccharide as integrin-targeting surface decorator of selenium nanoparticles to achieve enhanced anticancer efficacy.

    Science.gov (United States)

    Jiang, Wenting; Fu, Yuanting; Yang, Fang; Yang, Yufeng; Liu, Ting; Zheng, Wenjie; Zeng, Lilan; Chen, Tianfeng

    2014-08-27

    The poor permeability of glioma parenchyma represents a major limit for antiglioblastoma drug delivery. Gracilaria lemaneiformis polysaccharide (GLP), which has a high binding affinity to αvβ3 integrin overexpressed in glioma cells, was employed in the present study to functionalize selenium nanoparticles (SeNPs) to achieve antiglioblastoma efficacy. GLP-SeNPs showed satisfactory size distribution, high stability, and selectivity between cancer and normal cells. In U87 glioma cell membrane, which has a high integrin expression level, GLP-SeNPs exhibited significantly higher cellular uptake than unmodified SeNPs. As expected, U87 cells exhibited a greater uptake of GLP-SeNPs than C6 cells with low integrin expression level. Furthermore, the internalization of GLP-SeNPs was inhibited by cyclo-(Arg-Gly-Asp-Phe-Lys) peptides, suggesting that cellular uptake into U87 cells and C6 cells occurred via αvβ3 integrin-mediated endocytosis. For U87 cells, the cytotoxicity of SeNPs decorated by GLP was enhanced significantly because of the induction of various apoptosis signaling pathways. Internalized GLP-SeNPs triggered intracellular reactive oxygen species downregulation. Therefore, p53, MAPKs, and AKT pathways were activated to advance cell apoptosis. These findings suggest that surface decoration of nanomaterials with GLP could be an efficient strategy for design and preparation of glioblastoma targeting nanodrugs. PMID:25073123

  9. Direct targeting of MEK1/2 and RSK2 by silybin induces cell cycle arrest and inhibits melanoma cell growth

    OpenAIRE

    Lee, Mee-Hyun; Huang, Zunnan; Kim, Dong Joon; Kim, Sung-Hyun; Kim, Myoung Ok; Lee, Sung-Young; Xie, Hua; Park, Si Jun; Kim, Jae Young; Kundu, Joydeb Kumar; Bode, Ann M.; Surh, Young-Joon; Dong, Zigang

    2013-01-01

    Abnormal functioning of multiple gene products underlies the neoplastic transformation of cells. Thus, chemopreventive and/or chemotherapeutic agents with multigene targets hold promise in the development of effective anticancer drugs. Silybin, a component of milk thistle, is a natural anticancer agent. In the present study, we investigated the effect of silybin on melanoma cell growth and elucidated its molecular targets. Our study revealed that silybin attenuated the growth of melanoma xeno...

  10. A single-dose toxicity study on non-radioactive iodinated hypericin for a targeted anticancer therapy in mice

    Institute of Scientific and Technical Information of China (English)

    Jun-jie LI; Yi-cheng NI; Marlein Miranda CONA; Yuan-bo FENG; Feng CHEN; Guo-zhi ZHANG; Xue-bin FU; Uwe HIMMELREICH; Raymond OYEN; Alfons VERBRUGGEN

    2012-01-01

    Aim: Hypericin (Hyp) and its radio-derivatives have been investigated in animal models with ischemic heart diseases and malignancies for diagnostic and therapeutic purposes.Before radioiodinated Hyp (123I-Hyp or 131I-Hyp) can be considered as a clinically useful drug,vigorous evaluations on its chemotoxicity are necessary.In the present study,we examined the toxicity of a single dose of non-radioactive 127I-Hyp in normal mice for 24 h and 14 d.Methods: Studies were performed on 132 normal mice.127I-Hyp at a clinically relevant dose of 0.1 mg/kg body weight and a 100-times higher dose of 10 mg/kg was intravenously injected into 40 mice.The safety aspects of clinical manifestations,serological biochemistry,and histopathology were assessed.In another 72 mice,127I-Hyp was administered intravenously at assumed values to bracket the value of LD50.The rest 20 mice were used in the control groups.Results: At 24 h and 14 d following the injection of 127I-Hyp at either 0.1 or 10 mg/kg,all mice tolerated well without mortality or any observable treatment-related symptoms.No significant differences were found in blood biochemical parameters between the test and control groups.All organs presented normal appearances upon histopathological inspection.The value of LD50 of 127I-Hyp in mice through intravenous injection was 20.26 mg/kg,with the 95% confidence interval between 18.90 and 21.55 mg/kg.Conclusion: The current study reveals a broad safety range of 127I-Hyp,which not only supports the use of 123I-Hyp or 131I-Hyp in the necrosis targeting theragnostic strategy,but also serves as a valuable reference for exploring other possible applications for iodinated Hyp.

  11. Development of molecularly targeted agents and immunotherapies in small cell lung cancer.

    Science.gov (United States)

    Sharp, Adam; Bhosle, Jaishree; Abdelraouf, Fatma; Popat, Sanjay; O'Brien, Mary; Yap, Timothy A

    2016-06-01

    Small cell lung cancer (SCLC) is a smoking-induced malignancy with multiple toxin-associated mutations, which accounts for 15% of all lung cancers. It remains a clinical challenge with a rapid doubling time, early dissemination and poor prognosis. Despite multiple clinical trials in SCLC, platinum-based chemotherapy remains the mainstay of treatment in the first line advanced disease setting; good initial responses are nevertheless inevitably followed by disease relapse and survival ultimately remains poor. There are currently no molecularly targeted agents licenced for use in SCLC. Advances in sequencing the cancer genome and other high-throughput profiling technologies have identified aberrant pathways and mechanisms implicated in SCLC development and progression. Novel anti-tumour therapeutics that impact these putative targets are now being developed and investigated in SCLC. In this review, we discuss novel anti-tumour agents assessed in SCLC with reference to the complex molecular mechanisms implicated in SCLC development and progression. We focus on novel DNA damage response inhibitors, immune checkpoint modulators and antibody-drug conjugates that have shown promise in SCLC, and which may potentially transform treatment strategies in this disease. Finally, we envision the future management of SCLC and propose a biomarker-driven translational treatment paradigm for SCLC that incorporates next generation sequencing studies with patient tumours, circulating plasma DNA and functional imaging. Such modern strategies have the potential to transform the management and improve patient outcomes in SCLC. PMID:27060747

  12. Transforming a Targeted Porphyrin Theranostic Agent into a PET Imaging Probe for Cancer

    Directory of Open Access Journals (Sweden)

    Jiyun Shi, Tracy W.B. Liu, Juan Chen, David Green, David Jaffray, Brian C. Wilson, Fan Wang, Gang Zheng

    2011-01-01

    Full Text Available Porphyrin based photosensitizers are useful agents for photodynamic therapy (PDT and fluorescence imaging of cancer. Porphyrins are also excellent metal chelators forming highly stable metallo-complexes making them efficient delivery vehicles for radioisotopes. Here we investigated the possibility of incorporating 64Cu into a porphyrin-peptide-folate (PPF probe developed previously as folate receptor (FR targeted fluorescent/PDT agent, and evaluated the potential of turning the resulting 64Cu-PPF into a positron emission tomography (PET probe for cancer imaging. Noninvasive PET imaging followed by radioassay evaluated the tumor accumulation, pharmacokinetics and biodistribution of 64Cu-PPF. 64Cu-PPF uptake in FR-positive tumors was visible on small-animal PET images with high tumor-to-muscle ratio (8.88 ± 3.60 observed after 24 h. Competitive blocking studies confirmed the FR-mediated tracer uptake by the tumor. The ease of efficient 64Cu-radiolabeling of PPF while retaining its favorable biodistribution, pharmacokinetics and selective tumor uptake, provides a robust strategy to transform tumor-targeted porphyrin-based photosensitizers into PET imaging probes.

  13. Identification of agents effective against multiple toxins and viruses by host-oriented cell targeting.

    Science.gov (United States)

    Zilbermintz, Leeor; Leonardi, William; Jeong, Sun-Young; Sjodt, Megan; McComb, Ryan; Ho, Chi-Lee C; Retterer, Cary; Gharaibeh, Dima; Zamani, Rouzbeh; Soloveva, Veronica; Bavari, Sina; Levitin, Anastasia; West, Joel; Bradley, Kenneth A; Clubb, Robert T; Cohen, Stanley N; Gupta, Vivek; Martchenko, Mikhail

    2015-01-01

    A longstanding and still-increasing threat to the effective treatment of infectious diseases is resistance to antimicrobial countermeasures. Potentially, the targeting of host proteins and pathways essential for the detrimental effects of pathogens offers an approach that may discover broad-spectrum anti-pathogen countermeasures and circumvent the effects of pathogen mutations leading to resistance. Here we report implementation of a strategy for discovering broad-spectrum host-oriented therapies against multiple pathogenic agents by multiplex screening of drugs for protection against the detrimental effects of multiple pathogens, identification of host cell pathways inhibited by the drug, and screening for effects of the agent on other pathogens exploiting the same pathway. We show that a clinically used antimalarial drug, Amodiaquine, discovered by this strategy, protects host cells against infection by multiple toxins and viruses by inhibiting host cathepsin B. Our results reveal the practicality of discovering broadly acting anti-pathogen countermeasures that target host proteins exploited by pathogens. PMID:26310922

  14. Pro-oxidant activity of dietary chemopreventive agents: an under-appreciated anti-cancer property [v1; ref status: indexed, http://f1000r.es/15s

    Directory of Open Access Journals (Sweden)

    Asfar S Azmi

    2013-06-01

    Full Text Available “Let food be thy medicine and medicine be thy food” was quoted by Hippocrates more than two thousand years ago and since ancient times the health benefits of different natural agents have been exploited. In modern research, the disease preventive benefits of many such natural agents, particularly dietary compounds and their derivatives, has been attributed to their well recognized activity as the regulators of redox state of the cell. Nevertheless, most of these studies have focused on their antioxidant activity. A large body of evidence indicates that a major fraction of these agents can elicit pro-oxidant (radical generating behavior which has been linked to their anti-cancer effects. This editorial provides an overview of the under-appreciated pro-oxidant activity of natural products, with a special focus on their ability to generate reactive oxygen species in the presence of transition metal ions, and discusses their possible use as cancer chemotherapeutic agents.

  15. Genetic Interactions of STAT3 and Anticancer Drug Development

    Energy Technology Data Exchange (ETDEWEB)

    Fang, Bingliang [Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 (United States)

    2014-03-06

    Signal transducer and activator of transcription 3 (STAT3) plays critical roles in tumorigenesis and malignant evolution and has been intensively studied as a therapeutic target for cancer. A number of STAT3 inhibitors have been evaluated for their antitumor activity in vitro and in vivo in experimental tumor models and several approved therapeutic agents have been reported to function as STAT3 inhibitors. Nevertheless, most STAT3 inhibitors have yet to be translated to clinical evaluation for cancer treatment, presumably because of pharmacokinetic, efficacy, and safety issues. In fact, a major cause of failure of anticancer drug development is lack of efficacy. Genetic interactions among various cancer-related pathways often provide redundant input from parallel and/or cooperative pathways that drives and maintains survival environments for cancer cells, leading to low efficacy of single-target agents. Exploiting genetic interactions of STAT3 with other cancer-related pathways may provide molecular insight into mechanisms of cancer resistance to pathway-targeted therapies and strategies for development of more effective anticancer agents and treatment regimens. This review focuses on functional regulation of STAT3 activity; possible interactions of the STAT3, RAS, epidermal growth factor receptor, and reduction-oxidation pathways; and molecular mechanisms that modulate therapeutic efficacies of STAT3 inhibitors.

  16. Genetic Interactions of STAT3 and Anticancer Drug Development

    International Nuclear Information System (INIS)

    Signal transducer and activator of transcription 3 (STAT3) plays critical roles in tumorigenesis and malignant evolution and has been intensively studied as a therapeutic target for cancer. A number of STAT3 inhibitors have been evaluated for their antitumor activity in vitro and in vivo in experimental tumor models and several approved therapeutic agents have been reported to function as STAT3 inhibitors. Nevertheless, most STAT3 inhibitors have yet to be translated to clinical evaluation for cancer treatment, presumably because of pharmacokinetic, efficacy, and safety issues. In fact, a major cause of failure of anticancer drug development is lack of efficacy. Genetic interactions among various cancer-related pathways often provide redundant input from parallel and/or cooperative pathways that drives and maintains survival environments for cancer cells, leading to low efficacy of single-target agents. Exploiting genetic interactions of STAT3 with other cancer-related pathways may provide molecular insight into mechanisms of cancer resistance to pathway-targeted therapies and strategies for development of more effective anticancer agents and treatment regimens. This review focuses on functional regulation of STAT3 activity; possible interactions of the STAT3, RAS, epidermal growth factor receptor, and reduction-oxidation pathways; and molecular mechanisms that modulate therapeutic efficacies of STAT3 inhibitors

  17. Clearing the Fog of Anticancer Patents from 1993–2013: Through an In-Depth Technology Landscape & Target Analysis from Pioneer Research Institutes and Universities Worldwide

    OpenAIRE

    Dara, Ajay; Sangamwar, Abhay T.

    2014-01-01

    Background In a search for an effective anticancer therapy the R&D units from leading universities and institutes reveal numerous technologies in the form of patent documents. The article addressed comparative anticancer patent landscape and technology assessment of Council of Scientific and Industrial Research (CSIR): India’s largest R&D organisation with top twenty international public funded universities and institutes from eight different countries. Methodology/Principal Findings The meth...

  18. Autophagy as a target for cancer therapy: new developments

    International Nuclear Information System (INIS)

    Autophagy is an evolutionarily conserved lysosomal degradation pathway that eliminates cytosolic proteins, macromolecules, organelles, and protein aggregates. Activation of autophagy may function as a tumor suppressor by degrading defective organelles and other cellular components. However, this pathway may also be exploited by cancer cells to generate nutrients and energy during periods of starvation, hypoxia, and stress induced by chemotherapy. Therefore, induction of autophagy has emerged as a drug resistance mechanism that promotes cancer cell survival via self-digestion. Numerous preclinical studies have demonstrated that inhibition of autophagy enhances the activity of a broad array of anticancer agents. Thus, targeting autophagy may be a global anticancer strategy that may improve the efficacy of many standard of care agents. These results have led to multiple clinical trials to evaluate autophagy inhibition in combination with conventional chemotherapy. In this review, we summarize the anticancer agents that have been reported to modulate autophagy and discuss new developments in autophagy inhibition as an anticancer strategy

  19. Sorafenib is the first targeted agent to treat metastatic kidney cancer

    Directory of Open Access Journals (Sweden)

    V. B. Matveev

    2015-01-01

    Full Text Available Sorafenib is the first registered new-generation targeted drug for the treatment of metastatic renal cell carcinoma (RCC. As of today, there have been as many as 7 medications used for targeted therapy for disseminated RCC. This has provided a possibility to choose a drug and raised a number questions also remaining relevant at this moment: Which drug treatment should be started? Which criterion should be used to evaluate the efficiency of treatment? Is there any optimal sequence of drugs? The given review attempts to systemize the currently available data to answer the asked questions. According to the results of recently completed trials, sorafenib ranks below other agents for first-line therapy for metastatic RCC in progression- free survival (PFS, which fails to translate into overall survival (OS rates. In contrast, due to its properties, the multikinase inhibitor sorafenib ensures better OS rates, by achieving disease control in the larger proportion of cases (the number of objective replies + stabilization, and has an admissible toxicity profile; at the same time the probability of treatment discontinuation because of intolerability of the drug is not greater than 10 %. Thus, by taking into account of the possible sequence of targeted drugs, one should try to achieve the highest OS sooner than to use PFS as an efficiency criterion. The clinical findings have served as the basis for including sorafenib as an agent for first- and next-line therapy for RCC in the leading Russian (RUSSCO, Russian Society of Oncologists and foreign (ESMO, NCCN clinical guidelines. 

  20. Potential Activity of Basil Plants as a Source of Antioxidants and Anticancer Agents as Affected by Organic and Bio-organic Fertilization

    Directory of Open Access Journals (Sweden)

    Hanan Anwar Aly TAIE

    2010-06-01

    Full Text Available Sweet basil (Ocimum basilicum is a popular culinary herbal crop grown for fresh or dry leaf, essential oil and seed markets. Recently, basil was shown to rank highest among species and herbal crops for phenolic compounds, essential oils which are associated with decreasing risks of cancer and aging diseases. The current study aimed to evaluate the potential activity of phenolic, flavonoids and essential oil of basil as antioxidant and anticancer activities by application organic and bio-organic fertilization. A pot experiment was conducted. Basil seeds were grown, with three levels of organic fertilizers (compost in presence or absence of biofertilizer. Growth parameters, pigments content, total phenolics, total flavonoids and antioxidant activity of methanolic plant extract were examined. Application of 50% compost and 50% sand in the presence of biofertilizer resulted in enhancement fresh and dry weights, total phenolics, total flavonoids and pigment content as compared with compost alone. The constituents of essential oils extracted by hydrodistilation of basil leaves were identified by GLC. Eleven components of essential oils were identified. The highest value of antioxidant and anticancer activities were obtained in basil plants grown in 50% and 75% compost treatments in the presence of biofertilizer. These results emphasized the important of bioorganic fertilizers for enhancement the antioxidant activity of phenolics, flavonoids, and essential oils of basil plant extract.

  1. Cinnamomum verum Component 2-Methoxycinnamaldehyde: A Novel Anticancer Agent with Both Anti-Topoisomerase I and II Activities in Human Lung Adenocarcinoma A549 Cells In Vitro and In Vivo.

    Science.gov (United States)

    Wong, Ho-Yiu; Tsai, Kuen-daw; Liu, Yi-Heng; Yang, Shu-mei; Chen, Ta-Wei; Cherng, Jonathan; Chou, Kuo-Shen; Chang, Chen-Mei; Yao, Belen T; Cherng, Jaw-Ming

    2016-02-01

    Cinnamomum verum is used to make the spice cinnamon and has been used as a traditional Chinese herbal medicine. We evaluated the anticancer effect of 2-methoxycinnamaldehyde (2-MCA), a constituent of the bark of the plant, and its underlying molecular biomarkers associated with carcinogenesis in human lung adenocarcinoma A549 cells. The results show that 2-MCA suppressed proliferation and induced apoptosis as indicated by an upregulation of pro-apoptotic Bax and Bak genes and downregulation of anti-apoptotic Bcl-2 and Bcl-XL genes, mitochondrial membrane potential loss, cytochrome c release, activation of caspase-3 and -9, and morphological characteristics of apoptosis, including plasma membrane blebbing and long comet tail. In addition, 2-MCA also induced lysosomal vacuolation with increased volume of acidic compartment (VAC) and suppressions of nuclear transcription factors nuclear factor-κB (NF-κB) and both topoisomerase I and II activities. Further study reveals that the growth-inhibitory effect of 2-MCA was also evident in a nude mice model. Taken together, the data suggest that the growth-inhibitory effect of 2-MCA against A549 cells is accompanied by downregulations of NF-κB binding activity and proliferative control involving apoptosis and both topoisomerase I and II activities, together with an upregulation of lysosomal vacuolation and VAC. Our data suggest that 2-MCA could be a potential agent for anticancer therapy. PMID:26676220

  2. Simultaneous determination of the novel thiosemicarbazone anti-cancer agent, Bp4eT, and its main phase I metabolites in plasma: application to a pilot pharmacokinetic study in rats.

    Science.gov (United States)

    Stariat, Ján; Suprunová, Vlasta; Roh, Jaroslav; Šesták, Vít; Eisner, Tomáš; Filipský, Tomáš; Mladěnka, Přemysl; Nobilis, Milan; Šimůnek, Tomáš; Klimeš, Jiří; Kalinowski, Danuta S; Richardson, Des R; Kovaříková, Petra

    2014-05-01

    Novel thiosemicarbazone metal chelators are extensively studied anti-cancer agents with marked and selective activity against a wide variety of cancer cells, as well as human tumor xenografts in mice. This study describes the first validated LC-MS/MS method for the simultaneous quantification of 2-benzoylpyridine 4-ethyl-3-thiosemicarbazone (Bp4eT) and its main metabolites (E/Z isomers of the semicarbazone structure, M1-E and M1-Z, and the amidrazone metabolite, M2) in plasma. Separation was achieved using a C18 column with ammonium formate/acetonitrile mixture as the mobile phase. Plasma samples were treated using solid-phase extraction on 96-well plates. This method was validated over the concentration range of 0.18-2.80 μM for Bp4eT, 0.02-0.37 μM for both M1-E and M1-Z, and 0.10-1.60 μM for M2. This methodology was applied to the analysis of samples from in vivo experiments, allowing for the concentration-time profile to be simultaneously assessed for the parent drug and its metabolites. The current study addresses the lack of knowledge regarding the quantitative analysis of thiosemicarbazone anti-cancer drugs and their metabolites in plasma and provides the first pharmacokinetic data on a lead compound of this class. PMID:24254882

  3. Trackable and Targeted Phage as Positron Emission Tomography (PET Agent for Cancer Imaging

    Directory of Open Access Journals (Sweden)

    Zibo Li, Qiaoling Jin, Chiunwei Huang, Siva Dasa, Liaohai Chen, Li-peng Yap, Shuanglong Liu, Hancheng Cai, Ryan Park, Peter S Conti

    2011-01-01

    partially blocked at 1 h time point. Phage-RGD particle was also used as the competitive ligand. In this case, the tumor uptake was significantly reduced and the value was kept at low level consistently. Conclusion: In this report, we constructed a PET trackable nanoplatform based on phage particle and demonstrated the imaging capability of these targeted agents. We also demonstrated that the choice of chelator could have significant impact on imaging results of nano-agents. The method established in this research may be applicable to other receptor/ligand systems for theranostic agent construction, which could have an immediate and profound impact on the field of imaging/therapy and lay the foundation for the construction of next generation cancer specific theranostic agents.

  4. Classification of current anticancer immunotherapies

    Science.gov (United States)

    Vacchelli, Erika; Pedro, José-Manuel Bravo-San; Buqué, Aitziber; Senovilla, Laura; Baracco, Elisa Elena; Bloy, Norma; Castoldi, Francesca; Abastado, Jean-Pierre; Agostinis, Patrizia; Apte, Ron N.; Aranda, Fernando; Ayyoub, Maha; Beckhove, Philipp; Blay, Jean-Yves; Bracci, Laura; Caignard, Anne; Castelli, Chiara; Cavallo, Federica; Celis, Estaban; Cerundolo, Vincenzo; Clayton, Aled; Colombo, Mario P.; Coussens, Lisa; Dhodapkar, Madhav V.; Eggermont, Alexander M.; Fearon, Douglas T.; Fridman, Wolf H.; Fučíková, Jitka; Gabrilovich, Dmitry I.; Galon, Jérôme; Garg, Abhishek; Ghiringhelli, François; Giaccone, Giuseppe; Gilboa, Eli; Gnjatic, Sacha; Hoos, Axel; Hosmalin, Anne; Jäger, Dirk; Kalinski, Pawel; Kärre, Klas; Kepp, Oliver; Kiessling, Rolf; Kirkwood, John M.; Klein, Eva; Knuth, Alexander; Lewis, Claire E.; Liblau, Roland; Lotze, Michael T.; Lugli, Enrico; Mach, Jean-Pierre; Mattei, Fabrizio; Mavilio, Domenico; Melero, Ignacio; Melief, Cornelis J.; Mittendorf, Elizabeth A.; Moretta, Lorenzo; Odunsi, Adekunke; Okada, Hideho; Palucka, Anna Karolina; Peter, Marcus E.; Pienta, Kenneth J.; Porgador, Angel; Prendergast, George C.; Rabinovich, Gabriel A.; Restifo, Nicholas P.; Rizvi, Naiyer; Sautès-Fridman, Catherine; Schreiber, Hans; Seliger, Barbara; Shiku, Hiroshi; Silva-Santos, Bruno; Smyth, Mark J.; Speiser, Daniel E.; Spisek, Radek; Srivastava, Pramod K.; Talmadge, James E.; Tartour, Eric; Van Der Burg, Sjoerd H.; Van Den Eynde, Benoît J.; Vile, Richard; Wagner, Hermann; Weber, Jeffrey S.; Whiteside, Theresa L.; Wolchok, Jedd D.; Zitvogel, Laurence; Zou, Weiping

    2014-01-01

    During the past decades, anticancer immunotherapy has evolved from a promising therapeutic option to a robust clinical reality. Many immunotherapeutic regimens are now approved by the US Food and Drug Administration and the European Medicines Agency for use in cancer patients, and many others are being investigated as standalone therapeutic interventions or combined with conventional treatments in clinical studies. Immunotherapies may be subdivided into “passive” and “active” based on their ability to engage the host immune system against cancer. Since the anticancer activity of most passive immunotherapeutics (including tumor-targeting monoclonal antibodies) also relies on the host immune system, this classification does not properly reflect the complexity of the drug-host-tumor interaction. Alternatively, anticancer immunotherapeutics can be classified according to their antigen specificity. While some immunotherapies specifically target one (or a few) defined tumor-associated antigen(s), others operate in a relatively non-specific manner and boost natural or therapy-elicited anticancer immune responses of unknown and often broad specificity. Here, we propose a critical, integrated classification of anticancer immunotherapies and discuss the clinical relevance of these approaches. PMID:25537519

  5. Synthesis and in vitro evaluation of (R), (S) and (R/S)-2-hexyne-1,4-diol, a natural product produced by fungus Clitocybe catinus, and related analogs as potential anticancer agents.

    Science.gov (United States)

    Princival, Iza Mirela R G; Ferreira, Jeiely G; Silva, Teresinha G; Aguiar, Jaciana S; Princival, Jefferson L

    2016-06-15

    The search for natural products and related analogs as potential anticancer agents has seen a significant growth worldwide. Since small sized propargylic diols can be found in nature and chemically synthesized, their evaluation against cancer cells has been of great interest, being a topic of relevance to be investigated. For this purpose, a scalable approach aiming at the synthesis of several propargylic diols and their bioactivity against seven tumor cell lines were evaluated. Interestingly, when the compound 1a, a natural product produced by fungus Clitocybe catinus, was tested in its racemic mixture a more effective activity was observed if compared when enantiopure R-1a or S-1a were tested separately. PMID:27142752

  6. Exploring the relation between bullying and homophobic verbal content: the homophobic content agent target (HCAT) scale.

    Science.gov (United States)

    Poteat, V Paul; Espelage, Dorothy L

    2005-10-01

    This investigation quantitatively examines the association among homophobic content, bullying, victimization, empathy, and several psychosocial outcomes of these constructs. The 2-factor Homophobic Content Agent Target (HCAT) scale was developed and validated among 191 middle school students to assess the extent to which students both use and are called various epithets in reference to sexual orientation. Cronbach reliability coefficients of alpha = .85 were obtained for both factors. Convergent validity was demonstrated with scales measuring bullying, fighting, victimization, relational aggression and victimization, anxiety and depression, and delinquency. Discriminant validity was demonstrated in comparison with school sense of belonging, empathy, and perspective-taking. Discriminative validity was demonstrated through sex differences on several scales. Results strongly suggest that homophobic content is prevalent in various forms of aggression and victimization, and that future research should examine the role of homophobia in bullying and victimization in schools. PMID:16248488

  7. Structure-Guided Development of Efficacious Antifungal Agents Targeting Candida Glabrata Dihydrofolate Reductase

    Energy Technology Data Exchange (ETDEWEB)

    Liu, J.; Bolstad, D; Smith, A; Priestley, N; Wright, D; Anderson, A

    2008-01-01

    Candida glabrata is a lethal fungal pathogen resistant to many antifungal agents and has emerged as a critical target for drug discovery. Over the past several years, we have been developing a class of propargyl-linked antifolates as antimicrobials and hypothesized that these compounds could be effective inhibitors of dihydrofolate reductase (DHFR) from C. glabrata. We initially screened a small collection of these inhibitors and found modest levels of potency. Subsequently, we determined the crystal structure of C. glabrata DHFR bound to a representative inhibitor with data to 1.6 A resolution. Using this structure, we designed and synthesized second-generation inhibitors. These inhibitors bind the C. glabrata DHFR enzyme with subnanomolar potency, display greater than 2000-fold levels of selectivity over the human enzyme, and inhibit the growth of C. glabrata at levels observed with clinically employed therapeutics.

  8. Gadolinium-labeled dendronized gold nanoparticles as new targeted MRI contrast agent

    Science.gov (United States)

    Pan, Hongmu; Daniel, Marie-Christine

    2010-04-01

    Early diagnosis is critical for positive outcome of cancer treatments. In many cases, lives would be saved if the tumor could be detected at a very early stage. Nanoparticles have the property of passively targeting tumor sites due to their enhanced permeation and retention (EPR) effect. Thus they can play a critical role in improving the ability to find cancer in its earliest and most treatable stages. Furthermore magnetic resonance imaging is one of the most precise techniques for cancer screening since it can show 3D images of the tumors. For a better enhancement of the sensitivity of this method, MRI contrast agent (DOTA)Gd was attached to poly(propylene imine) dendrons of third generation and the obtained dendrons were used for modification of gold nanoparticles.

  9. Cutaneous T-Cell Lymphoma: A Review with a Focus on Targeted Agents.

    Science.gov (United States)

    Devata, Sumana; Wilcox, Ryan A

    2016-06-01

    Cutaneous T-cell lymphomas (CTCLs) are a heterogeneous group of extranodal lymphomas involving the skin. Diagnosis of the two main subtypes of CTCL-mycosis fungoides (MF) and Sézary syndrome (SS)-is based on the International Society for Cutaneous Lymphomas/European Organization for Research and Treatment of Cancer (ISCL/EORTC) classification system, which utilizes clinical, histopathological, molecular biologic, and immunopathologic features. Risk stratification, based on TNMB (tumor, node, metastasis, and blood) staging, provides prognostic information, with limited-stage disease conferring the longest median overall survival. Skin-directed therapies are preferred in the management of limited-stage disease, whereas advanced-stage disease requires systemic therapies. As the mechanisms of CTCL pathogenesis are increasingly understood, new monoclonal antibodies, checkpoint inhibitors, immunomodulatory agents, and small molecules are under investigation and may provide additional therapeutic options for those with advanced CTCL. This review examines the current landscape of targeted therapies in the treatment of CTCLs. PMID:26923912

  10. F-18 Polyethyleneglycol stilbenes as PET imaging agents targeting Aβ aggregates in the brain

    International Nuclear Information System (INIS)

    This paper describes a novel series of 18F-labeled polyethyleneglycol (PEG)-stilbene derivatives as potential β-amyloid (Aβ) plaque-specific imaging agents for positron emission tomography (PET). In these series of compounds, 18F is linked to the stilbene through a PEG chain, of which the number of ethoxy groups ranges from 2 to 5. The purpose of adding PEG groups is to lower the lipophilicity and improve bioavailability. The syntheses of the 'cold' compounds and the 18F-labeled PEG stilbene derivatives are successfully achieved. All of the fluorinated stilbenes displayed high binding affinities in an assay using postmortem AD brain homogenates (K i=2.9-6.7 nM). Labeling was successfully performed by a substitution of the mesylate group of 10a-d by [18F]fluoride giving the target compounds [18F]12a-d (EOS, specific activity, 900-1500 Ci/mmol; radiochemical purity >99%). In vivo biodistribution of these novel 18F ligands in normal mice exhibited excellent brain penetrations and rapid washouts after an intravenous injection (6.6-8.1 and 1.2-2.6% dose/g at 2 and 60 min, respectively). Autoradiography of postmortem AD brain sections of [18F]12a-d confirmed the specific binding related to the presence of Aβ plaques. In addition, in vivo plaque labeling can be clearly demonstrated with these 18F-labeled agents in transgenic mice (Tg2576), a useful animal model for Alzheimer's disease. In conclusion, the preliminary results strongly suggest these fluorinated PEG stilbene derivatives are suitable candidates as Aβ plaque imaging agents for studying patients with Alzheimer's disease

  11. H2O2-responsive molecularly engineered polymer nanoparticles as ischemia/reperfusion-targeted nanotherapeutic agents

    Science.gov (United States)

    Lee, Dongwon; Bae, Soochan; Hong, Donghyun; Lim, Hyungsuk; Yoon, Joo Heung; Hwang, On; Park, Seunggyu; Ke, Qingen; Khang, Gilson; Kang, Peter M.

    2013-07-01

    The main culprit in the pathogenesis of ischemia/reperfusion (I/R) injury is the overproduction of reactive oxygen species (ROS). Hydrogen peroxide (H2O2), the most abundant form of ROS produced during I/R, causes inflammation, apoptosis and subsequent tissue damages. Here, we report H2O2-responsive antioxidant nanoparticles formulated from copolyoxalate containing vanillyl alcohol (VA) (PVAX) as a novel I/R-targeted nanotherapeutic agent. PVAX was designed to incorporate VA and H2O2-responsive peroxalate ester linkages covalently in its backbone. PVAX nanoparticles therefore degrade and release VA, which is able to reduce the generation of ROS, and exert anti-inflammatory and anti-apoptotic activity. In hind-limb I/R and liver I/R models in mice, PVAX nanoparticles specifically reacted with overproduced H2O2 and exerted highly potent anti-inflammatory and anti-apoptotic activities that reduced cellular damages. Therefore, PVAX nanoparticles have tremendous potential as nanotherapeutic agents for I/R injury and H2O2-associated diseases.

  12. DNA Repair and Cancer Therapy: Targeting APE1/Ref-1 Using Dietary Agents

    Directory of Open Access Journals (Sweden)

    Julian J. Raffoul

    2012-01-01

    Full Text Available Epidemiological studies have demonstrated the cancer protective effects of dietary agents and other natural compounds isolated from fruits, soybeans, and vegetables on neoplasia. Studies have also revealed the potential for these natural products to be combined with chemotherapy or radiotherapy for the more effective treatment of cancer. In this paper we discuss the potential for targeting the DNA base excision repair enzyme APE1/Ref-1 using dietary agents such as soy isoflavones, resveratrol, curcumin, and the vitamins ascorbate and α-tocopherol. We also discuss the potential role of soy isoflavones in sensitizing cancer cells to the effects of radiotherapy. A comprehensive review of the dual nature of APE1/Ref-1 in DNA repair and redox activation of cellular transcription factors, NF-κB and HIF-1α, is also discussed. Further research efforts dedicated to delineating the role of APE1/Ref-1 DNA repair versus redox activity in sensitizing cancer cells to conventional treatment are warranted.

  13. Cell-based phenotypic screening of mast cell degranulation unveils kinetic perturbations of agents targeting phosphorylation

    Science.gov (United States)

    Qin, Shenlu; Wang, Xumeng; Wu, Huanwen; Xiao, Peng; Cheng, Hongqiang; Zhang, Xue; Ke, Yuehai

    2016-01-01

    Mast cells play an essential role in initiating allergic diseases. The activation of mast cells are controlled by a complicated signal network of reversible phosphorylation, and finding the key regulators involved in this network has been the focus of the pharmaceutical industry. In this work, we used a method named Time-dependent cell responding profile (TCRP) to track the process of mast cell degranulation under various perturbations caused by agents targeting phosphorylation. To test the feasibility of this high-throughput cell-based phenotypic screening method, a variety of biological techniques were used. We further screened 145 inhibitors and clustered them based on the similarities of their TCRPs. Stat3 phosphorylation has been widely reported as a key step in mast cell degranulation. Interestingly, our TCRP results showed that a Stat3 inhibitor JSI124 did not inhibit degranulation like other Stat3 inhibitors, such as Stattic, clearly inhibited degranulation. Regular endpoint assays demonstrated that the distinctive TCRP of JSI124 potentially correlated with the ability to induce apoptosis. Consequently, different agents possibly have disparate functions, which can be conveniently detected by TCRP. From this perspective, our TCRP screening method is reliable and sensitive when it comes to discovering and selecting novel compounds for new drug developments. PMID:27502076

  14. Design and synthesis of novel 5,6-disubstituted pyridine-2,3-dione-3-thiosemicarbazone derivatives as potential anticancer agents.

    Science.gov (United States)

    Xie, Wenlin; Xie, Shimin; Zhou, Ying; Tang, Xufu; Liu, Jian; Yang, Wenqian; Qiu, Minghua

    2014-06-23

    A series of 5,6-disubstituted pyridine-2,3-dione-3-thiosemicarbazone derivatives(2a-2n) and 5,6-disubstituted pyridine-2,3-dione S-benzyl-3-thiosemicarbazones(3a-3g) were synthesized starting from 2,3-dihydroxypyridine via oxidation-Michael additions, condensations and nucleophilic substitutions. The structures of the compounds were established by IR, (1)H NMR, (13)C NMR, and HRMS. All newly synthesized compounds were screened for their anticancer activity against Breast cancer (MCF-7), Colon cancer (HCT-116) and hepatocellular cancer (BEL7402) cell lines. Bioassay results indicated that most of the prepared compounds exhibited cytotoxicity against various cancer cells in vitro. Some of the compounds exhibited promising antiproliferative activity, which were comparable to the positive control (5-fluorouracil). The structure-activity relationship was discussed. PMID:24819956

  15. Synthesis of novel triazole/isoxazole functionalized 7-(trifluoromethyl)pyrido[2,3-d]pyrimidine derivatives as promising anticancer and antibacterial agents.

    Science.gov (United States)

    Naresh Kumar, R; Jitender Dev, G; Ravikumar, N; Krishna Swaroop, D; Debanjan, B; Bharath, G; Narsaiah, B; Nishant Jain, S; Gangagni Rao, A

    2016-06-15

    A series of novel 1,2,3-triazole/isoxazole functionalized pyrido[2,3-d]pyrimidine derivatives 6a-c, 7a-h and 8a-e were prepared in series of synthetic steps. All the compounds screened for the anticancer activity against four human cancer cell lines using Nocodazole as standard. Compounds 7d and 7h showed highest activity against PANC-1 (pancreatic cancer) and A549 (lung cancer) cell lines respectively and more than standard. All the compounds also screened for antibacterial activity using Rifampicin and Ciprofloxacin as standards and identified promising compounds further evaluated for minimum inhibitory concentration to validate the data. PMID:27130357

  16. Novel Marine Compounds: Anticancer or Genotoxic?

    Directory of Open Access Journals (Sweden)

    Arif Jamal M.

    2004-01-01

    Full Text Available In the past several decades, marine organisms have generously gifted to the pharmaceutical industries numerous naturally bioactive compounds with antiviral, antibacterial, antimalarial, anti-inflammatory, antioxidant, and anticancer potentials. But till date only few anticancer drugs (cytarabine, vidarabine have been commercially developed from marine compounds while several others are currently in different clinical trials. Majority of these compounds were tested in the tumor xenograft models, however, lack of anticancer potential data in the chemical- and/or oncogene-induced pre-initiation animal carcinogenesis models might have cost some of the marine anticancer compounds an early exit from the clinical trials. This review critically discusses importance of preclinical evaluation, failure of human clinical trials with certain potential anticancer agents, the screening tests used, and choice of biomarkers.

  17. 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...

  18. Bio-synthesis of silver nanoparticles using Potentilla fulgens Wall. ex Hook. and its therapeutic evaluation as anticancer and antimicrobial agent

    International Nuclear Information System (INIS)

    The present study aims to develop an easy and eco-friendly method for the synthesis of silver nanoparticles using extracts from the medicinal plant, Potentilla fulgens and evaluation of its anticancer and antimicrobial properties. The various parts of P. fulgens were screened and the root extract was found to have the highest potential for the synthesis of nanoparticles. The root extracts were able to quickly reduce Ag+ to Ag0 and stabilized the nanoparticles. The synthesis of nanoparticles was confirmed by UV–Visible spectrophotometry and further characterized using Zeta sizer, Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), transmission electron microscope (TEM) and X-ray diffraction (XRD). Electron microscopic study showed that the size of the nanoparticle was in the range of 10 to 15 nm and spherical in shape. The studies of phytochemical analysis of nanoparticles indicated that the adsorbed components on the surface of nanoparticles were mainly flavonoid in nature. Furthermore, nanoparticles were evaluated as cytotoxic against various cancer cell lines and 0.2 to 12 μg/mL nanoparticles showed good toxicity. The IC50 value of nanoparticles was found to be 4.91 and 8.23 μg/mL against MCF-7 and U-87 cell lines, respectively. Additionally, the apoptotic effect of synthesized nanoparticles on normal and cancer cells was studied using trypan blue assay and flow-cytometric analysis. The results indicate the synthesized nanoparticle ability to kill cancer cells compared to normal cells. The nanoparticles also exhibited comparable antimicrobial activity against both Gram-positive and Gram-negative bacteria. - Highlights: • Bio-synthesis of AgNPs using a medicinal plant Potentilla fulgens Wall. ex Hook. • Optimization of NP synthesis and its characterization using various techniques • Determination of therapeutic potential in terms of anticancer and antimicrobial properties • To know the mechanistic apoptosis effect of AgNPs

  19. Bio-synthesis of silver nanoparticles using Potentilla fulgens Wall. ex Hook. and its therapeutic evaluation as anticancer and antimicrobial agent

    Energy Technology Data Exchange (ETDEWEB)

    Mittal, Amit Kumar [Department of Pharmaceutical Technology Biotechnology, National Institute of Pharmaceutical Education and Research, Sector-67, S.A.S. Nagar, 160062 Punjab (India); Tripathy, Debabrata [Department of Biotechnology and Bioinformatics, North Eastern Hill University, Shillong, 793002 Meghalaya (India); Choudhary, Alka [Department of Natural Products, National Institute of Pharmaceutical Education and Research, Sector-67, S.A.S. Nagar, 160062 Punjab (India); Aili, Pavan Kumar [Department of Pharmaceutical Technology Biotechnology, National Institute of Pharmaceutical Education and Research, Sector-67, S.A.S. Nagar, 160062 Punjab (India); Chatterjee, Anupam [Department of Biotechnology and Bioinformatics, North Eastern Hill University, Shillong, 793002 Meghalaya (India); Singh, Inder Pal [Department of Natural Products, National Institute of Pharmaceutical Education and Research, Sector-67, S.A.S. Nagar, 160062 Punjab (India); Banerjee, Uttam Chand, E-mail: ucbanerjee@niper.ac.in [Department of Pharmaceutical Technology Biotechnology, National Institute of Pharmaceutical Education and Research, Sector-67, S.A.S. Nagar, 160062 Punjab (India)

    2015-08-01

    The present study aims to develop an easy and eco-friendly method for the synthesis of silver nanoparticles using extracts from the medicinal plant, Potentilla fulgens and evaluation of its anticancer and antimicrobial properties. The various parts of P. fulgens were screened and the root extract was found to have the highest potential for the synthesis of nanoparticles. The root extracts were able to quickly reduce Ag{sup +} to Ag{sup 0} and stabilized the nanoparticles. The synthesis of nanoparticles was confirmed by UV–Visible spectrophotometry and further characterized using Zeta sizer, Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), transmission electron microscope (TEM) and X-ray diffraction (XRD). Electron microscopic study showed that the size of the nanoparticle was in the range of 10 to 15 nm and spherical in shape. The studies of phytochemical analysis of nanoparticles indicated that the adsorbed components on the surface of nanoparticles were mainly flavonoid in nature. Furthermore, nanoparticles were evaluated as cytotoxic against various cancer cell lines and 0.2 to 12 μg/mL nanoparticles showed good toxicity. The IC{sub 50} value of nanoparticles was found to be 4.91 and 8.23 μg/mL against MCF-7 and U-87 cell lines, respectively. Additionally, the apoptotic effect of synthesized nanoparticles on normal and cancer cells was studied using trypan blue assay and flow-cytometric analysis. The results indicate the synthesized nanoparticle ability to kill cancer cells compared to normal cells. The nanoparticles also exhibited comparable antimicrobial activity against both Gram-positive and Gram-negative bacteria. - Highlights: • Bio-synthesis of AgNPs using a medicinal plant Potentilla fulgens Wall. ex Hook. • Optimization of NP synthesis and its characterization using various techniques • Determination of therapeutic potential in terms of anticancer and antimicrobial properties • To know the mechanistic

  20. Deep sea as a source of novel-anticancer drugs

    OpenAIRE

    Russo, Patrizia; Del Bufalo, Alessandra; Fini, Massimo

    2015-01-01

    The deep-sea habitat is a source of very potent marine-derived agents that may inhibit the growth of human cancer cells “in vitro” and “in vivo”. Salinosporamide-A, Marizomib, by Salinispora species is a proteasome inhibitor with promising anticancer activity (Phase I/II trials). Different deep-sea-derived drugs are under preclinical evaluation. Cancer is a complex disease that may be represented by network medicine. A simple consequence is the change of the concept of target entity from a si...

  1. Host-targeting agents for prevention and treatment of chronic hepatitis C - perspectives and challenges.

    Science.gov (United States)

    Zeisel, Mirjam B; Lupberger, Joachim; Fofana, Isabel; Baumert, Thomas F

    2013-02-01

    Hepatitis C virus (HCV) infection is a major cause of chronic liver disease and hepatocellular carcinoma worldwide. Furthermore, HCV-induced liver disease is a major indication of liver transplantation. In the past years, direct-acting antivirals (DAAs) targeting HCV enzymes have been developed. DAAs increase the virologic response to anti-HCV therapy but may lead to selection of drug-resistant variants and treatment failure. To date, strategies to prevent HCV infection are still lacking and antiviral therapy in immunocompromised patients, patients with advanced liver disease and HIV/HCV-co-infection remains limited. Alternative or complementary approaches addressing the limitations of current antiviral therapies are to boost the host's innate immunity or interfere with host factors required for pathogenesis. Host-targeting agents (HTAs) provide an interesting perspective for novel antiviral strategies against viral hepatitis since they have (i) a high genetic barrier to resistance, (ii) a pan-genotypic antiviral activity, and (iii) complementary mechanisms of action to DAAs and might therefore act in a synergistic manner with current standard of care or DAAs in clinical development. This review highlights HTAs against HCV infection that have potential as novel antivirals and are in preclinical or clinical development. PMID:23041307

  2. Human DDX3 protein is a valuable target to develop broad spectrum antiviral agents.

    Science.gov (United States)

    Brai, Annalaura; Fazi, Roberta; Tintori, Cristina; Zamperini, Claudio; Bugli, Francesca; Sanguinetti, Maurizio; Stigliano, Egidio; Esté, José; Badia, Roger; Franco, Sandra; Martinez, Miguel A; Martinez, Javier P; Meyerhans, Andreas; Saladini, Francesco; Zazzi, Maurizio; Garbelli, Anna; Maga, Giovanni; Botta, Maurizio

    2016-05-10

    Targeting a host factor essential for the replication of different viruses but not for the cells offers a higher genetic barrier to the development of resistance, may simplify therapy regimens for coinfections, and facilitates management of emerging viral diseases. DEAD-box polypeptide 3 (DDX3) is a human host factor required for the replication of several DNA and RNA viruses, including some of the most challenging human pathogens currently circulating, such as HIV-1, Hepatitis C virus, Dengue virus, and West Nile virus. Herein, we showed for the first time, to our knowledge, that the inhibition of DDX3 by a small molecule could be successfully exploited for the development of a broad spectrum antiviral agent. In addition to the multiple antiviral activities, hit compound 16d retained full activity against drug-resistant HIV-1 strains in the absence of cellular toxicity. Pharmacokinetics and toxicity studies in rats confirmed a good safety profile and bioavailability of 16d. Thus, DDX3 is here validated as a valuable therapeutic target. PMID:27118832

  3. 2001 ASPET Otto Krayer Award Lecture. Molecular targets for antiviral agents.

    Science.gov (United States)

    De Clercq, E

    2001-04-01

    There are a number of virus-specific processes within the virus replicative cycle or virus-infected cell that have proven to be attractive targets for chemotherapeutic intervention, i.e., virus adsorption and entry into the cells, reverse (RNA --> DNA) transcription, viral DNA polymerization, and cellular enzymatic reactions that are associated with viral DNA and RNA synthesis and viral mRNA maturation (i.e., methylation). A variety of chemotherapeutic agents, both nucleoside (and nucleotide) and non-nucleoside entities, have been identified that specifically interact with these viral targets, that selectively inhibit virus replication, and that are either used or considered for clinical use in the treatment of virus infections in humans. Their indications encompass virtually all major human viral pathogens, including human immunodeficiency virus (HIV), hepatitis B virus (HBV), herpes simplex virus (HSV), varicella-zoster virus (VZV), cytomegalovirus (CMV), human papilloma virus (HPV), orthomyxoviruses (influenza A and B), paramyxoviruses [e.g., respiratory syncytial virus (RSV)] and hemorrhagic fever viruses (such as Ebola virus). PMID:11259521

  4. Curcumin: A multi-target disease-modifying agent for late-stage transthyretin amyloidosis.

    Science.gov (United States)

    Ferreira, Nelson; Gonçalves, Nádia P; Saraiva, Maria J; Almeida, Maria R

    2016-01-01

    Transthyretin amyloidoses encompass a variety of acquired and hereditary diseases triggered by systemic extracellular accumulation of toxic transthyretin aggregates and fibrils, particularly in the peripheral nervous system. Since transthyretin amyloidoses are typically complex progressive disorders, therapeutic approaches aiming multiple molecular targets simultaneously, might improve therapy efficacy and treatment outcome. In this study, we evaluate the protective effect of physiologically achievable doses of curcumin on the cytotoxicity induced by transthyretin oligomers in vitro by showing reduction of caspase-3 activity and the levels of endoplasmic reticulum-resident chaperone binding immunoglobulin protein. When given to an aged Familial Amyloidotic Polyneuropathy mouse model, curcumin not only reduced transthyretin aggregates deposition and toxicity in both gastrointestinal tract and dorsal root ganglia but also remodeled congophilic amyloid material in tissues. In addition, curcumin enhanced internalization, intracellular transport and degradation of transthyretin oligomers by primary macrophages from aged Familial Amyloidotic Polyneuropathy transgenic mice, suggesting an impaired activation of naïve phagocytic cells exposed to transthyretin toxic intermediate species. Overall, our results clearly support curcumin or optimized derivatives as promising multi-target disease-modifying agent for late-stage transthyretin amyloidosis. PMID:27197872

  5. Injectable actarit-loaded solid lipid nanoparticles as passive targeting therapeutic agents for rheumatoid arthritis.

    Science.gov (United States)

    Ye, Jiesheng; Wang, Qun; Zhou, Xuefeng; Zhang, Na

    2008-03-20

    This work systematically studied the intravenous injection formulation of solid lipid nanoparticles (SLNs) loaded with actarit, a poor water soluble anti-rheumatic drug. The goal of this study was to design passive targeting nanoparticles which could improve therapeutic efficacy and reduce side-effects such as nephrotoxicity and gastrointestinal disorders commonly associated with oral formulations of actarit. Based on the optimized results of single-factor and orthogonal design, actarit-loaded SLNs were prepared by a modified solvent diffusion-evaporation method. The formulated SLNs were found to be relatively uniform in size (241+/-23 nm) with a negative zeta potential (-17.14+/-1.6 mV). The average drug entrapment efficiency and loading were (50.87+/-0.25)% and (8.48+/-0.14)%, respectively. The actarit-loaded SLNs exhibited a longer mean retention time in vivo (t(1/2(beta)), 9.373 h; MRT, 13.53 h) compared with the actarit 50% propylene glycol solution (t(1/2(ke)), 0.917 h; MRT, 1.323 h) after intravenous injection to New Zealand rabbits. The area under curve of plasma concentration-time (AUC) of actarit-loaded SLNs was 1.88 times greater than that of the actarit in 50% propylene glycol solution. The overall targeting efficiency (TE(C)) of the actarit-loaded SLNs was enhanced from 6.31% to 16.29% in spleen while the renal distribution of actarit was significantly reduced as compared to that of the actarit solution after intravenous administration to mice. These results indicated that injectable actarit-loaded solid lipid nanoparticles were promising passive targeting therapeutic agents for rheumatoid arthritis. PMID:18054182

  6. Preparation and imaging study of tumor-targeting MRI contrast agent based on Fe3O4 nanoparticles

    International Nuclear Information System (INIS)

    The detection and diagnosis of early hypoxic tumor is the key for successful cancer therapy, which remains a challenge for radiologists because contrast agents could hardly reach it. Herein, a tumor-targeting MRI contrast agent was prepared by conjugating the small-molecule inhibitor of carbonic anhydrase (CA IX) that is overexpressed in hypoxic tumor, mafenide, onto the surface of Fe3O4 magnetic nanoparticles (MNPs) to improve the sensitivity of MRI for early tumor diagnosis. The tumor-targeting MNP (Fe3O4-SO2NH2) showed enhanced MRI contrasting performance both in vitro and in vivo in comparison with the non-targeting control, which made it a promising contrast agent for the detection and diagnosis of early hypoxic tumor. (author)

  7. Analyzing the multiple-target-multiple-agent scenario using optimal assignment algorithms

    International Nuclear Information System (INIS)

    This work considers the problem of maximum utilization of a set of mobile robots with limited sensor-range capabilities and limited travel distances. The robots are initially in random positions. A set of robots properly guards or covers a region if every point within the region is within the effective sensor range of at least one vehicle. The authors wish to move the vehicles into surveillance positions so as to guard or cover a region, while minimizing the maximum distance traveled by any vehicle. This problem can be formulated as an assignment problem, in which they must optimally decide which robot to assign to which slot of a desired matrix of grid points. The cost function is the maximum distance traveled by any robot. Assignment problems can be solved very efficiently. Solutions times for one hundred robots took only seconds on a Silicon Graphics Crimson workstation. The initial positions of all the robots can be sampled by a central base station and their newly assigned positions communicated back to the robots. Alternatively, the robots can establish their own coordinate system with the origin fixed at one of the robots and orientation determined by the compass bearing of another robot relative to this robot. This paper presents example solutions to the multiple-target-multiple-agent scenario using a matching algorithm. Two separate cases with one hundred agents in each were analyzed using this method. They have found these mobile robot problems to be a very interesting application of network optimization methods, and they expect this to be a fruitful area for future research

  8. Solubilization of Poorly Soluble PDT Agent, Meso-tetraphenylporphin, in Plain or Immunotargeted PEG-PE Micelles Results in Dramatically Improved Cancer Cell Killing in Vitro

    OpenAIRE

    Roby, Aruna; Erdogan, Suna; Torchilin, Vladimir P.

    2005-01-01

    Poorly soluble photodynamic therapy (PDT) agent, meso-tetratphenylporphine (TPP), was effectively solubilized using non-targeted and tumor-targeted polymeric micelles prepared of polyethylene glycol/phosphatidyl ethanolamine conjugate (PEG-PE). Encapsulation of TPP into PEG-PE-based micelles and immunomicelles (bearing an anti-cancer monoclonal 2C5 antibody) resulted in significantly improved anticancer effects of the drug at PDT conditions against murine (LLC, B16) and human (MCF-7, BT20) ca...

  9. Synthesis, characterization of some novel 1,3,4-oxadiazole compounds containing 8-hydroxy quinolone moiety as potential antibacterial and anticancer agents

    Directory of Open Access Journals (Sweden)

    Vinayak Mahadev Adimule

    2014-12-01

    Full Text Available In the present work a series of novel derivatives of 8-hydroxy quinolone substituted 1,3,4-oxadiazole compounds were synthesized by convergent synthetic method and studied for their antibacterial and anticancer properties. The cell lines used for cytotoxic evaluation were HeLa, Caco-2 and MCF7. The synthetic chemistry involved conversion of various substituted aromatic acids into ethyl ester 2a-e. The ethyl ester was converted into corresponding carbohydrazide 3a-e. Carbohydrazides are reacted with chloroacetic acid, phosphorous oxytrichloride and irradiated with microwave in order to obtain the various key intermediates 2-(chloromethyl-5-(substituted phenyl-1,3,4-oxadiazole 4a-e. The 2-(chloromethyl-5-(substituted phenyl-1,3,4-oxadiazole was reacted with 8-hydroxy quinolone in presence of sodium hydride and obtained a series of 8-hydroxy quinoline substituted 1,3,4-oxadiazoles 5a-e. Among the synthesised compounds, the cytotoxicity of the compound 5b i.e. 8-{[5-(2,4-dichlorophenyl-1,3,4-oxadiazol-2-yl]methoxy}quinoline against MCF7 with IC50 of 5.3µM and the compound 5e i.e. 8-{[5-(4-bromophenyl-1,3,4-oxadiazol-2-yl]methoxy}quinoline showed MIC of < 6.25µg/mL against Staphylococcus aureus which is comparable with the known standards. The standards used for cytotoxic evaluation was 5-fluorouracil and for antibacterial was nitrofurazone

  10. Fucoidan Extract Enhances the Anti-Cancer Activity of Chemotherapeutic Agents in MDA-MB-231 and MCF-7 Breast Cancer Cells

    Directory of Open Access Journals (Sweden)

    Zhongyuan Zhang

    2013-01-01

    Full Text Available Fucoidan, a fucose-rich polysaccharide isolated from brown alga, is currently under investigation as a new anti-cancer compound. In the present study, fucoidan extract (FE from Cladosiphon navae-caledoniae Kylin was prepared by enzymatic digestion. We investigated whether a combination of FE with cisplatin, tamoxifen or paclitaxel had the potential to improve the therapeutic efficacy of cancer treatment. These co-treatments significantly induced cell growth inhibition, apoptosis, as well as cell cycle modifications in MDA-MB-231 and MCF-7 cells. FE enhanced apoptosis in cancer cells that responded to treatment with three chemotherapeutic drugs with downregulation of the anti-apoptotic proteins Bcl-xL and Mcl-1. The combination treatments led to an obvious decrease in the phosphorylation of ERK and Akt in MDA-MB-231 cells, but increased the phosphorylation of ERK in MCF-7 cells. In addition, we observed that combination treatments enhanced intracellular ROS levels and reduced glutathione (GSH levels in breast cancer cells, suggesting that induction of oxidative stress was an important event in the cell death induced by the combination treatments.

  11. Synthesis and characterization of mixed-ligand diimine-piperonal thiosemicarbazone complexes of ruthenium(II): Biophysical investigations and biological evaluation as anticancer and antibacterial agents

    Science.gov (United States)

    Beckford, Floyd A.; Thessing, Jeffrey; Shaloski, Michael, Jr.; Canisius Mbarushimana, P.; Brock, Alyssa; Didion, Jacob; Woods, Jason; Gonzalez-Sarrías, Antonio; Seeram, Navindra P.

    2011-04-01

    We have used a novel microwave-assisted method developed in our laboratories to synthesize a series of ruthenium-thiosemicarbazone complexes. The new thiosemicarbazone ligands are derived from benzo[ d][1,3]dioxole-5-carbaldehyde (piperonal) and the complexes are formulated as [(diimine) 2Ru(TSC)](PF 6) 2 (where the TSC is the bidentate thiosemicarbazone ligand). The diimine in the complexes is either 2,2'-bipyridine or 1,10-phenanthroline. The complexes have been characterized by spectroscopic means (NMR, IR and UV-Vis) as well as by elemental analysis. We have studied the biophysical characteristics of the complexes by investigating their anti-oxidant ability as well as their ability to disrupt the function of the human topoisomerase II enzyme. The complexes are moderately strong binders of DNA with binding constants of 10 4 M -1. They are also strong binders of human serum albumin having binding constants on the order of 10 4 M -1. The complexes show good in vitro anticancer activity against human colon cancer cells, Caco-2 and HCT-116 and indeed show some cytotoxic selectivity for cancer cells. The IC 50 values range from 7 to 159 μM (after 72 h drug incubation). They also have antibacterial activity against Gram-positive strains of pathogenic bacteria with IC 50 values as low as 10 μM; little activity was seen against Gram-negative strains. It has been established that all the compounds are catalytic inhibitors of human topoisomerase II.

  12. Design, synthesis and molecular modeling studies of few chalcone analogues of benzimidazole for epidermal growth factor receptor inhibitor in search of useful anticancer agent.

    Science.gov (United States)

    Chhajed, Santosh S; Sonawane, Sandeep S; Upasani, Chandrashekhar D; Kshirsagar, Sanjay J; Gupta, Pramodkumar P

    2016-04-01

    In the present investigation, few 3-(substitutedphenyl)-1-[2-(1-hydroxy-ethyl)]-1H-benzimidazol-1-yl)prop-2-en-1-ones are EGFR antagonist are designed, by molecular docking analysis. The synthesized compounds were tested for their in vitro anticancer activity by propidium iodide fluorescent assay and Trypan blue viability assay against colorectal cancer cell lines (HCT116) and non-small cell lung cancer cell lines (H460). Human Epithelial Kidney cell lines (HEK) are used as normal cell lines for studying effect of drug on non-cancerous cells within human body. Evaluation of cytotoxic studies of synthesized compounds CHL(1-8) reveal that compound CHL1 [IC50=7.31 and 10.16 μM against HCT116 and H460 cell lines respectively, by PI assay] and CHL8 [IC50=12.52 and 6.83 against HCT116 and H460μM cell lines respectively] possess promising cytotoxic activity. PMID:26878127

  13. Design and synthesis of C3-pyrazole/chalcone-linked beta-carboline hybrids: antitopoisomerase I, DNA-interactive, and apoptosis-inducing anticancer agents.

    Science.gov (United States)

    Kamal, Ahmed; Srinivasulu, Vunnam; Nayak, V Lakshma; Sathish, Manda; Shankaraiah, Nagula; Bagul, Chandrakant; Reddy, N V Subba; Rangaraj, Nandini; Nagesh, Narayana

    2014-09-01

    A series of β-carboline hybrids bearing a substituted phenyl and a chalcone/(N-acetyl)-pyrazole moiety at the C1 and C3 positions, respectively, was designed, synthesized, and evaluated for anticancer activity. These new hybrid molecules showed significant cytotoxic activity, with IC50 values ranging from indol-3-yl)prop-2-en-1-one (7 d) and 1-(3-(furan-2-yl)-5-(1-(4-(trifluoromethyl)phenyl)-9H-pyrido[3,4-b]indol-3-yl)-4,5-dihydro-1H-pyrazol-1-yl)ethanone (8 d) could effectively cleave pBR322 plasmid DNA upon irradiation with UV light. Active hybrid 8 d inhibited DNA topoisomerase I activity efficiently and preserved DNA in the supercoiled form. To further corroborate the biological activities, as well as to understand the nature of the interaction of these hybrids with DNA, spectroscopic studies were also performed. Unlike simple β-carboline alkaloids, the binding mode of these new hybrid molecules with DNA was not similar, and both biophysical as well as molecular docking studies speculated a combilexin-type of interaction with DNA. Further, an in silico study of these β-carboline hybrids revealed their drug-like properties. PMID:24470122

  14. Study on the thermodynamics of the binding of iminium and alkanolamine forms of the anticancer agent sanguinarine to human serum albumin

    International Nuclear Information System (INIS)

    Highlights: ► Energetics of sanguinarine–human serum albumin has been elucidated. ► The alkanolamine binds stronger than iminium. ► Enthalpy driven binding for iminium was revealed. ► Alkanolamine form binding was favored by negative enthalpy and entropy changes. ► Spectroscopic results support calorimetry data. - Abstract: Sanguinarine is an anticancer plant alkaloid that can exist in the charged iminium and neutral alkanolamine forms. The thermodynamics of the interaction of the two forms with human serum albumin was investigated using calorimetric techniques, and the data supplemented with circular dichroism and spectrofluorimetric studies. The thermodynamic results show that there is only one class of binding for sanguinarine on HSA. The equilibrium constant was four times higher for the alkanolamine (Ka = 2.18 · 105 M−1) than for iminium (Ka = 5.97 · 104 M−1). The binding was enthalpy driven for iminium and favoured by both a negative enthalpy and a stronger favourable entropy contribution for the alkanolamine. Temperature dependent calorimetric data yielded values of ΔCp∘ that are consistent with the involvement of different molecular forces in the complexation of the two forms of sanguinarine to HSA. The fluorescence quenching data suggest a static quenching mechanism. Synchronous fluorescence and circular dichroic data are consistent with a conformational change in the protein on binding that was also higher for the alkanolamine form.

  15. Improved tumor-targeting MRI contrast agents: Gd(DOTA) conjugates of a cycloalkane-based RGD peptide

    Energy Technology Data Exchange (ETDEWEB)

    Park, Ji-Ae, E-mail: jpark@kirams.re.kr [Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Lee, Yong Jin; Ko, In Ok [Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Kim, Tae-Jeong; Chang, Yongmin [Institute of Biomedical Engineering, Kyungpook National University, Daegu (Korea, Republic of); Lim, Sang Moo [Department of Nuclear Medicine, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Kim, Kyeong Min [Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Kim, Jung Young, E-mail: jykim@kirams.re.kr [Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)

    2014-12-12

    Highlights: • Development of improved tumor-targeting MRI contrast agents. • To increase the targeting ability of RGD, we developed cycloalkane-based RGD peptides. • Gd(DOTA) conjugates of cycloalkane-based RGD peptide show improved tumor signal enhancement in vivo MR images. - Abstract: Two new MRI contrast agents, Gd-DOTA-c(RGD-ACP-K) (1) and Gd-DOTA-c(RGD-ACH-K) (2), which were designed by incorporating aminocyclopentane (ACP)- or aminocyclohexane (ACH)-carboxylic acid into Gd-DOTA (gadolinium-tetraazacyclo dodecanetetraacetic acid) and cyclic RGDK peptides, were synthesized and evaluated for tumor-targeting ability in vitro and in vivo. Binding affinity studies showed that both 1 and 2 exhibited higher affinity for integrin receptors than cyclic RGDyK peptides, which were used as a reference. These complexes showed high relaxivity and good stability in human serum and have the potential to improve target-specific signal enhancement in vivo MR images.

  16. Improved tumor-targeting MRI contrast agents: Gd(DOTA) conjugates of a cycloalkane-based RGD peptide

    International Nuclear Information System (INIS)

    Highlights: • Development of improved tumor-targeting MRI contrast agents. • To increase the targeting ability of RGD, we developed cycloalkane-based RGD peptides. • Gd(DOTA) conjugates of cycloalkane-based RGD peptide show improved tumor signal enhancement in vivo MR images. - Abstract: Two new MRI contrast agents, Gd-DOTA-c(RGD-ACP-K) (1) and Gd-DOTA-c(RGD-ACH-K) (2), which were designed by incorporating aminocyclopentane (ACP)- or aminocyclohexane (ACH)-carboxylic acid into Gd-DOTA (gadolinium-tetraazacyclo dodecanetetraacetic acid) and cyclic RGDK peptides, were synthesized and evaluated for tumor-targeting ability in vitro and in vivo. Binding affinity studies showed that both 1 and 2 exhibited higher affinity for integrin receptors than cyclic RGDyK peptides, which were used as a reference. These complexes showed high relaxivity and good stability in human serum and have the potential to improve target-specific signal enhancement in vivo MR images

  17. Discovery of a novel anticancer agent with both anti-topoisomerase I and II activities in hepatocellular carcinoma SK-Hep-1 cells in vitro and in vivo: Cinnamomum verum component 2-methoxycinnamaldehyde

    Directory of Open Access Journals (Sweden)

    Perng DS

    2016-01-01

    proliferative control involving apoptosis, both topoisomerase I and II activities, together with an upregulation of lysosomal vacuolation and volume of acidic compartments. Similar effects (including all of the above-mentioned effects were found in other tested cell lines, including human hepatocellular carcinoma Hep 3B, lung adenocarcinoma A549, squamous cell carcinoma NCI-H520, colorectal adenocarcinoma COLO 205, and T-lymphoblastic MOLT-3 (results not shown. Our data ­suggest that 2-MCA could be a potential agent for anticancer therapy. Keywords: 2-methoxycinnamaldehyde, anticancer, SK-Hep-1 cells, topoisomerase I, topoisomerase II

  18. Discovery of a novel anticancer agent with both anti-topoisomerase I and II activities in hepatocellular carcinoma SK-Hep-1 cells in vitro and in vivo: Cinnamomum verum component 2-methoxycinnamaldehyde.

    Science.gov (United States)

    Perng, Daw-Shyong; Tsai, Yu-Hsin; Cherng, Jonathan; Wang, Jeng-Shing; Chou, Kuo-Shen; Shih, Chia-Wen; Cherng, Jaw-Ming

    2016-01-01

    Cinnamomum verum is used to make the spice cinnamon and has been used as a traditional Chinese herbal medicine for various applications. We evaluated the anticancer effect of 2-methoxycinnamaldehyde (2-MCA), a constituent of the bark of the plant, and its underlying molecular biomarkers associated with carcinogenesis in human hepatocellular carcinoma SK-Hep-1 cell line. The results show that 2-MCA suppressed proliferation and induced apoptosis as indicated by mitochondrial membrane potential loss, activation of caspase-3 and caspase-9, increase in the DNA content in sub-G1, and morphological characteristics of apoptosis, including blebbing of plasma membrane, nuclear condensation, fragmentation, apoptotic body formation, and long comet tail. In addition, 2-MCA also induced lysosomal vacuolation with increased volume of acidic compartments, suppressions of nuclear transcription factors NF-κB, cyclooxygenase-2, prostaglandin E2 (PGE2), and both topoisomerase I and II activities in a dose-dependent manner. Further study reveals the growth-inhibitory effect of 2-MCA was also evident in a nude mice model. Taken together, the data suggest that the growth-inhibitory effect of 2-MCA against SK-Hep-1 cells is accompanied by downregulations of NF-κB-binding activity, inflammatory responses involving cyclooxygenase-2 and PGE2, and proliferative control involving apoptosis, both topoisomerase I and II activities, together with an upregulation of lysosomal vacuolation and volume of acidic compartments. Similar effects (including all of the above-mentioned effects) were found in other tested cell lines, including human hepatocellular carcinoma Hep 3B, lung adenocarcinoma A549, squamous cell carcinoma NCI-H520, colorectal adenocarcinoma COLO 205, and T-lymphoblastic MOLT-3 (results not shown). Our data suggest that 2-MCA could be a potential agent for anticancer therapy. PMID:26792981

  19. Systemic coagulation parameters in mice after treatment with vascular targeting agents

    Directory of Open Access Journals (Sweden)

    Gottstein Claudia

    2005-12-01

    Full Text Available Abstract Background Vascular targeting of malignant tumors has become a clinically validated new treatment approach with clear patient benefit. However clinical studies have also revealed that some types of vascular targeting agents (VTAs are prone to coagulation system side effects. It is therefore essential to predetermine coagulation parameters in preclinical studies. As of to date, this has rarely been done, predominantly due to technical issues. The goal of this study was to establish and apply a standardized process, whereby systemic coagulation activation can be routinely measured in mice. Results We have evaluated a number of sampling techniques and coagulation tests regarding their suitability for this purpose. We were able to adapt two assays measuring soluble fibrin, a marker for a prethrombotic status. Thus, soluble fibrin could be measured for the first time in mice. All assays were validated in a positive control model for systemic coagulation activation, i.e. lipopolysaccharide-induced endotoxemia. Based on our results, we selected a panel of coagulation tests, which are both feasable and informative for preclinical testing of VTAs: soluble fibrin, thrombin-antithrombin complexes, free antithrombin III, white blood cell counts and platelet counts. The effect of tumor transplants on coagulation parameters was evaluated using this panel. We then applied this set of assays in treatment studies with a VTA developed in our laboratory to investigate a potential systemic coagulation activation. Conclusion We have established a standardized panel of assays that can be used to test murine blood samples for coagulation activation in preclinical studies. All tests are feasible to perform in any research laboratory without specialized equipment. In addition, this is the first report to measure soluble fibrin, an early marker of systemic coagulation activation, in mice. The panel was applied on tumor bearing mice and mice treated with a VTA

  20. Magnetically Targeted Delivery of Therapeutic Agents to Injured Blood Vessels for Prevention of In-Stent Stenosis

    OpenAIRE

    Chorny, Michael; Fishbein, Ilia; Adamo, Richard F.; Forbes, Scott P.; Folchman-Wagner, Zoë; Alferiev, Ivan S.

    2012-01-01

    Magnetic guidance is a physical targeting strategy with the potential to improve the safety and efficacy of a variety of therapeutic agents — including small-molecule pharmaceuticals, proteins, gene vectors, and cells — by enabling their site-specific delivery. The application of magnetic targeting for in-stent restenosis can address the need for safer and more efficient treatment strategies. However, its translation to humans may not be possible without revising the traditional magnetic targ...

  1. Drug delivery system for an anticancer agent, chlorogenate-Zn/Al-layered double hydroxide nanohybrid synthesised using direct co-precipitation and ion exchange methods

    Science.gov (United States)

    Barahuie, Farahnaz; Hussein, Mohd Zobir; Arulselvan, Palanisamy; Fakurazi, Sharida; Zainal, Zulkarnain

    2014-09-01

    A nano-structured drug-inorganic clay hybrid involving an active anticancer compound, which is chlorogenic acid (CA) intercalated into Zn/Al-layered double hydroxide, has been assembled via ion-exchange and co-precipitation methods to form a nanohybrid CZAE (a chlorogenic acid-Zn/Al nanohybrid synthesised using an ion-exchange method) and CZAC (a chlorogenic acid-Zn/Al nanohybrid synthesised using a direct method), respectively. The X-ray diffraction (XRD) results confirmed that the CA-LDH had a hybrid structure in which the anionic chlorogenate is arranged between the interlayers as a horizontal monolayer at 90 and 20° angles from the x axis for CZAE and CZAC, respectively. Both nanohybrids have the properties of mesoporous materials. The high loading percentage of chlorogenic acid (approximately 43.2% for CZAE and 45.3% for CZAC) with basal spacings of 11.7 and 12.6 Å for CZAE and CZAC, respectively, corroborates the successful intercalation of chlorogenic acid into the interlayer gallery of layered double hydroxides. Free chlorogenic acid and the synthesised nanocomposites (CZAE, CZAC) were assessed for their cytotoxicity against various cancer cells. The Fourier transform infrared data supported the formation of both nanohybrids, and a thermal analysis showed that the nanohybrids are more thermally stable than their counterparts. The chlorogenate shows a sustained release, and the release rate of chlorogenate from CZAE and CZAC nanohybrids at pH 7.4 is remarkably lower than that at pH 4.8 due to their different release mechanisms. The release rate of chlorogenate from both nanohybrids can be described as pseudo-second order. The present investigation revealed the potential of the nanohybrids to enhance the in vitro anti-tumour effect of chlorogenic acid in liver and lung cancer cells in vitro.

  2. Bio-synthesis of silver nanoparticles using Potentilla fulgens Wall. ex Hook. and its therapeutic evaluation as anticancer and antimicrobial agent.

    Science.gov (United States)

    Mittal, Amit Kumar; Tripathy, Debabrata; Choudhary, Alka; Aili, Pavan Kumar; Chatterjee, Anupam; Singh, Inder Pal; Banerjee, Uttam Chand

    2015-08-01

    The present study aims to develop an easy and eco-friendly method for the synthesis of silver nanoparticles using extracts from the medicinal plant, Potentilla fulgens and evaluation of its anticancer and antimicrobial properties. The various parts of P. fulgens were screened and the root extract was found to have the highest potential for the synthesis of nanoparticles. The root extracts were able to quickly reduce Ag(+) to Ag(0) and stabilized the nanoparticles. The synthesis of nanoparticles was confirmed by UV-Visible spectrophotometry and further characterized using Zeta sizer, Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), transmission electron microscope (TEM) and X-ray diffraction (XRD). Electron microscopic study showed that the size of the nanoparticle was in the range of 10 to 15 nm and spherical in shape. The studies of phytochemical analysis of nanoparticles indicated that the adsorbed components on the surface of nanoparticles were mainly flavonoid in nature. Furthermore, nanoparticles were evaluated as cytotoxic against various cancer cell lines and 0.2 to 12 μg/mL nanoparticles showed good toxicity. The IC50 value of nanoparticles was found to be 4.91 and 8.23 μg/mL against MCF-7 and U-87 cell lines, respectively. Additionally, the apoptotic effect of synthesized nanoparticles on normal and cancer cells was studied using trypan blue assay and flow-cytometric analysis. The results indicate the synthesized nanoparticle ability to kill cancer cells compared to normal cells. The nanoparticles also exhibited comparable antimicrobial activity against both Gram-positive and Gram-negative bacteria. PMID:26042698

  3. Optimizing the radiosensitive liquid-core microcapsules for the targeting of chemotherapeutic agents

    Energy Technology Data Exchange (ETDEWEB)

    Harada, S. [Department of Radiology, Iwate Medical University, 19-1 Uchimaru, Morioka, Iwate 020-8505 (Japan)]. E-mail: sharada@iwate-med.ac.jp; Ehara, S. [Department of Radiology, Iwate Medical University, 19-1 Uchimaru, Morioka, Iwate 020-8505 (Japan); Ishii, K. [Department of Quantum Science and Energy Engineering, Tohoku University, Sendai, Miyagi (Japan); Yamazaki, H. [Department of Quantum Science and Energy Engineering, Tohoku University, Sendai, Miyagi (Japan); Matsuyama, S. [Department of Quantum Science and Energy Engineering, Tohoku University, Sendai, Miyagi (Japan); Kamiya, T. [Takasaki Institute of the Radiation Chemistry Research Establishment, Japan Atomic Energy Research Institute, Takasaki, Gunma (Japan); Sakai, T. [Takasaki Institute of the Radiation Chemistry Research Establishment, Japan Atomic Energy Research Institute, Takasaki, Gunma (Japan); Arakawa, K. [Takasaki Institute of the Radiation Chemistry Research Establishment, Japan Atomic Energy Research Institute, Takasaki, Gunma (Japan); Sato, T. [Takasaki Institute of the Radiation Chemistry Research Establishment, Japan Atomic Energy Research Institute, Takasaki, Gunma (Japan); Oikawa, S. [Takasaki Institute of the Radiation Chemistry Research Establishment, Japan Atomic Energy Research Institute, Takasaki, Gunma (Japan)

    2007-07-15

    Microcapsules consisting of alginate and hyaluronic acid that can be decomposed by radiation are currently under development. In this study, the composition of the microcapsule material was optimized by changing the amounts of alginate and hyaluronic acid. Solutions of 0.025%, 0.05%, 0.1%, 0.2%, or 0.4% (wt./vol.) hyaluronic acid were mixed into a 0.2% alginate solution. To these mixtures, carboplatin (0.2 mmol) was added and the resulting material was used for the capsule preparation. The capsules were prepared by spraying the material into a CaCl{sub 2} solution (0.34 mol/l) using a microatomizer. These capsules were irradiated by a single dose of 2, 5, or 10 Gy {sup 60}Co {gamma}-ray radiation. Immediately after irradiation, the releasing of core content of microcapsule was determined, using a micro particle induced X-ray emission (PIXE) camera. The average diameter of the microcapsules was 22.3 {+-} 3.3 {mu}m, and that of the liquid core was 10.2 {+-} 4.3 {mu}m. The maximum radiation-induced content release was observed with liquid-core microcapsules containing 0.1% hyaluronic acid and 0.2% alginate. Our liquid-core microcapsules suggest a new potential use for radiation: the targeted delivery of the chemotherapeutic agents or radiosensitizers. This offers the prospect of increased combined effectiveness of radiation with chemotherapy or radiosensitization and decreased adverse side effects.

  4. Detection and delineation of oral cancer with a PARP1 targeted optical imaging agent

    Science.gov (United States)

    Kossatz, Susanne; Brand, Christian; Gutiontov, Stanley; Liu, Jonathan T. C.; Lee, Nancy Y.; Gönen, Mithat; Weber, Wolfgang A.; Reiner, Thomas

    2016-01-01

    Earlier and more accurate detection of oral squamous cell carcinoma (OSCC) is essential to improve the prognosis of patients and to reduce the morbidity of surgical therapy. Here, we demonstrate that the nuclear enzyme Poly(ADP-ribose)Polymerase 1 (PARP1) is a promising target for optical imaging of OSCC with the fluorescent dye PARPi-FL. In patient-derived OSCC specimens, PARP1 expression was increased 7.8 ± 2.6-fold when compared to normal tissue. Intravenous injection of PARPi-FL allowed for high contrast in vivo imaging of human OSCC models in mice with a surgical fluorescence stereoscope and high-resolution imaging systems. The emitted signal was specific for PARP1 expression and, most importantly, PARPi-FL can be used as a topical imaging agent, spatially resolving the orthotopic tongue tumors in vivo. Collectively, our results suggest that PARP1 imaging with PARPi-FL can enhance the detection of oral cancer, serve as a screening tool and help to guide surgical resections. PMID:26900125

  5. Comparison of Folate Receptor Targeted Optical Contrast Agents for Intraoperative Molecular Imaging

    Directory of Open Access Journals (Sweden)

    Elizabeth De Jesus

    2015-01-01

    Full Text Available Background. Intraoperative imaging can identify cancer cells in order to improve resection; thus fluorescent contrast agents have emerged. Our objective was to do a preclinical comparison of two fluorescent dyes, EC17 and OTL38, which both target folate receptor but have different fluorochromes. Materials. HeLa and KB cells lines were used for in vitro and in vivo comparisons of EC17 and OTL38 brightness, sensitivity, pharmacokinetics, and biodistribution. In vivo experiments were then performed in mice. Results. The peak excitation and emission wavelengths of EC17 and OTL38 were 470/520 nm and 774/794 nm, respectively. In vitro, OTL38 required increased incubation time compared to EC17 for maximum fluorescence; however, peak signal-to-background ratio (SBR was 1.4-fold higher compared to EC17 within 60 minutes (p<0.001. Additionally, the SBR for detecting smaller quantity of cells was improved with OTL38. In vivo, the mean improvement in SBR of tumors visualized using OTL38 compared to EC17 was 3.3 fold (range 1.48–5.43. Neither dye caused noticeable toxicity in animal studies. Conclusions. In preclinical testing, OTL38 appears to have superior sensitivity and brightness compared to EC17. This coincides with the accepted belief that near infrared (NIR dyes tend to have less autofluorescence and scattering issues than visible wavelength fluorochromes.

  6. Polyphenols: a diverse class of multi-target anti-HIV-1 agents.

    Science.gov (United States)

    Andrae-Marobela, Kerstin; Ghislain, Fotso Wabo; Okatch, Harriet; Majinda, Runner R T

    2013-05-01

    Polyphenols are a versatile class of compounds that represent secondary metabolites from higher plants and which are abundantly present in the human diet. Epidemiological data suggest protective effects of polyhenols in relation to cancer, cardiovascular diseases, diabetes, infectious diseases and age-related conditions. HIV/AIDS remains prevalent in many parts of the world as acute infection and as anti-retroviral drug (ARV)-managed chronic disease. Due to the nature of the human immune deficiency virus (HIV) and an increased use of ARVs many drug-resistant HIV strains have emerged and continue to do so. This makes it impossible to rely on one standard drug treatment regime. This review summarizes anti- HIV activities of polyphenols. It highlights the diversity of modes of action by which polyphenols - according to their respective compound classes - exert their activities. Additionally, this review discusses polyphenols as multi-target anti-HIV agents and provides the context of in-vivo and clinical data. Based on the presented data, a three-pronged approach for further anti-HIV drug discovery is suggested applying methods of combinatorial medicinal chemistry on the diverse and sometimes unique scaffolds of polyphenols. The latter being selected according to the approach of 'reverse pharmacology' as a creative way to place safety and other clinical consideration at the beginning of the drug discovery- and development process. PMID:23330927

  7. Detection and delineation of oral cancer with a PARP1 targeted optical imaging agent.

    Science.gov (United States)

    Kossatz, Susanne; Brand, Christian; Gutiontov, Stanley; Liu, Jonathan T C; Lee, Nancy Y; Gönen, Mithat; Weber, Wolfgang A; Reiner, Thomas

    2016-01-01

    Earlier and more accurate detection of oral squamous cell carcinoma (OSCC) is essential to improve the prognosis of patients and to reduce the morbidity of surgical therapy. Here, we demonstrate that the nuclear enzyme Poly(ADP-ribose)Polymerase 1 (PARP1) is a promising target for optical imaging of OSCC with the fluorescent dye PARPi-FL. In patient-derived OSCC specimens, PARP1 expression was increased 7.8 ± 2.6-fold when compared to normal tissue. Intravenous injection of PARPi-FL allowed for high contrast in vivo imaging of human OSCC models in mice with a surgical fluorescence stereoscope and high-resolution imaging systems. The emitted signal was specific for PARP1 expression and, most importantly, PARPi-FL can be used as a topical imaging agent, spatially resolving the orthotopic tongue tumors in vivo. Collectively, our results suggest that PARP1 imaging with PARPi-FL can enhance the detection of oral cancer, serve as a screening tool and help to guide surgical resections. PMID:26900125

  8. Mitochondria-targeted agents: Future perspectives of mitochondrial pharmaceutics in cardiovascular diseases

    Institute of Scientific and Technical Information of China (English)

    Thekkuttuparambil; Ananthanarayanan; Ajith; Thankamani; Gopinathan; Jayakumar

    2014-01-01

    Mitochondria are one of the major sites for the genera-tion of reactive oxygen species(ROS) as an undesirable side product of oxidative energy metabolism. Damaged mitochondria can augment the generation of ROS. Dys-function of mitochondria increase the risk for a large number of human diseases, including cardiovascular diseases(CVDs). Heart failure(HF) following ischemic heart disease, infantile cardiomyopathy and cardiac hypertrophy associated with left ventricular dilations are some of the CVDs in which the role of mitochon-drial oxidative stress has been reported. Advances in mitochondrial research during the last decade focused on the preservation of its function in the myocardium, which is vital for the cellular energy production. Expe-rimental and clinical trials have been conducted using mitochondria-targeted molecules like: MnSOD mimetics, such as EUK-8, EUK-134 and MitoSOD; choline esters of glutathione and N-acetyl-L-cysteine; triphenylphospho-nium ligated vitamin E, lipoic acid, plastoquinone andmitoCoQ10; and Szeto-Schiller(SS)- peptides(SS-02 and SS-31). Although many results are inconclusive, some of the findings, especially on CoQ10, are worthwhile. This review summarizes the role of mitochondria-tar-geted delivery of agents and their consequences in the control of HF.

  9. 177Lu-DOTA-lanreotide: a novel tracer as a targeted agent for tumor therapy

    International Nuclear Information System (INIS)

    177Lu of specific activity ∼100-110 TBq/g and radionuclidic purity of ∼100% was obtained by irradiation of enriched Lu2O3 (60.6% 176Lu) target for 7 days at a thermal neutron flux of 3x1013n/cm2/sec. The 177Lu labeling of a macrocyclic bifunctional chelating agent viz. 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) has been extensively studied. Lanreotide, [β-naphthyl-Ala-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2] a disulfide-linked cyclic octapeptide and a somatostatin analog, reported to bind with a wide variety of tumors expressing somatostatin receptors, was conjugated with DOTA. The peptide-BFCA conjugate was characterized with the help of high-resolution two-dimensional proton NMR spectroscopy. The 177Lu labeling of the DOTA-lanreotide conjugate has been standardized to give a radiolabeling yield of 85%. The tracer showed specific binding with A-431 human epidermoid carcinoma and IMR-32 human brain neuroblastoma cells

  10. Mixed PEG-PE/Vitamin E Tumor-Targeted Immunomicelles as Carriers for Poorly Soluble Anti-Cancer Drugs: Improved Drug Solubilization and Enhanced In Vitro Cytotoxicity

    OpenAIRE

    Sawant, Rupa R.; Sawant, Rishikesh M.; Torchilin, Vladimir P.

    2008-01-01

    Two poorly soluble, potent anticancer drugs, paclitaxel and camptothecin, were successfully solubilized by mixed micelles of polyethylene glycol-phosphatidyl ethanolamine (PEG-PE) and vitamin E. Drug containing micelles were additionally modified with anti-nucleosome monoclonal antibody 2C5 (mAb 2C5), which can specifically bring micelles to tumor cells in vitro. The optimized micelles had an average size of about 13-to-22 nm and the immuno-modification of micelles did not significantly chang...

  11. Synergistic effect of pH-responsive folate-functionalized poloxamer 407-TPGS-mixed micelles on targeted delivery of anticancer drugs

    OpenAIRE

    Butt AM; Mohd Amin MC; Katas H

    2015-01-01

    Adeel Masood Butt, Mohd Cairul Iqbal Mohd Amin, Haliza Katas Centre for Drug Delivery Research, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia Background: Doxorubicin (DOX), an anthracycline anticancer antibiotic, is used for treating various types of cancers. However, its use is associated with toxicity to normal cells and development of resistance due to overexpression of drug efflux pumps. Poloxamer 407 (P407) and vitamin E TPGS (d-α-tocopheryl poly...

  12. Investigation of the effect of physical parameters on the design of tumour targeting agents

    Science.gov (United States)

    Casey, Joanne Lois

    Tumour targeting using radiolabelled antibodies for radioimmunodetection (RAID) and radioimmunotherapy (RIT) has been studied for many years. The main factors that have limited clinical success are low tumour uptake, immunogenicity and poor therapeutic ratios. This thesis has applied current technology to make advances in this area of research. The effect of physical parameters (antibody size, valency, affinity and charge) on the design of tumour targeting agents was studied by constructing divalent (DFM) and trivalent (TFM) forms of the murine anti-CEA antibody A5B7 Fab' by chemical cross-linking. This involves partial reduction of the hinge disulphides to expose thiol (-SH) groups and subsequent reaction with a maleimide cross-linker to form a thioether bond at the hinge region. Previous studies have suggested that the stability of thioether bonds is superior to naturally occurring disulphide bonds present at the hinge region of IgG and F(ab')2. The aim was to compare the functional affinities and in vivo tumour targeting in nude mice bearing human tumour xenografts of DFM and TFM to similar sized parent IgG and F(ab')2. Radiolabelling with 131I and 90Y was also compared with a view to determine which combination would be optimal for RIT. Results clearly demonstrated a significantly faster on-rate of DFM compared to all other antibody forms and estimated dosimetry analysis suggested that DFM would be the most suitable antibody form radiolabelled with 131I for RIT. Both F(ab')2 and DFM showed high kidney uptake levels on labelling with which is unacceptable for RIT. Despite the improved tumour: blood ratios for TFM, the increased estimated dose to normal tissues and lower therapeutic effect in RIT studies suggests that the most promising combination with the radionuclide appears to be IgG. A humanised version of A5B7 hFab' has been constructed previously in order to reduce its immunogenicity in man. The in vivo stability of hDFM proved to be superior to hF(ab')2

  13. Drug delivery system for an anticancer agent, chlorogenate-Zn/Al-layered double hydroxide nanohybrid synthesised using direct co-precipitation and ion exchange methods

    Energy Technology Data Exchange (ETDEWEB)

    Barahuie, Farahnaz [Materials Synthesis and Characterization Laboratory, Institute of Advanced Technology (ITMA), Universiti Putra Malaysia, 43400 UPM Serdang, Selangor (Malaysia); Hussein, Mohd Zobir, E-mail: mzobir@putra.upm.edu.my [Materials Synthesis and Characterization Laboratory, Institute of Advanced Technology (ITMA), Universiti Putra Malaysia, 43400 UPM Serdang, Selangor (Malaysia); Arulselvan, Palanisamy [Laboratory of Vaccines and Immunotherapeutics, Institute of Bioscience, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor (Malaysia); Fakurazi, Sharida [Laboratory of Vaccines and Immunotherapeutics, Institute of Bioscience, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor (Malaysia); Department of Human Anatomy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor (Malaysia); Zainal, Zulkarnain [Materials Synthesis and Characterization Laboratory, Institute of Advanced Technology (ITMA), Universiti Putra Malaysia, 43400 UPM Serdang, Selangor (Malaysia)

    2014-09-15

    A nano-structured drug-inorganic clay hybrid involving an active anticancer compound, which is chlorogenic acid (CA) intercalated into Zn/Al-layered double hydroxide, has been assembled via ion-exchange and co-precipitation methods to form a nanohybrid CZAE (a chlorogenic acid-Zn/Al nanohybrid synthesised using an ion-exchange method) and CZAC (a chlorogenic acid-Zn/Al nanohybrid synthesised using a direct method), respectively. The X-ray diffraction (XRD) results confirmed that the CA-LDH had a hybrid structure in which the anionic chlorogenate is arranged between the interlayers as a horizontal monolayer at 90 and 20° angles from the x axis for CZAE and CZAC, respectively. Both nanohybrids have the properties of mesoporous materials. The high loading percentage of chlorogenic acid (approximately 43.2% for CZAE and 45.3% for CZAC) with basal spacings of 11.7 and 12.6 Å for CZAE and CZAC, respectively, corroborates the successful intercalation of chlorogenic acid into the interlayer gallery of layered double hydroxides. Free chlorogenic acid and the synthesised nanocomposites (CZAE, CZAC) were assessed for their cytotoxicity against various cancer cells. The Fourier transform infrared data supported the formation of both nanohybrids, and a thermal analysis showed that the nanohybrids are more thermally stable than their counterparts. The chlorogenate shows a sustained release, and the release rate of chlorogenate from CZAE and CZAC nanohybrids at pH 7.4 is remarkably lower than that at pH 4.8 due to their different release mechanisms. The release rate of chlorogenate from both nanohybrids can be described as pseudo-second order. The present investigation revealed the potential of the nanohybrids to enhance the in vitro anti-tumour effect of chlorogenic acid in liver and lung cancer cells in vitro. - Highlights: • We intercalated chlorogenic into Zn/Al-layered double hydroxide by ion-exchange and coprecipitation methods. • The two methods gave nanocomposites

  14. Drug delivery system for an anticancer agent, chlorogenate-Zn/Al-layered double hydroxide nanohybrid synthesised using direct co-precipitation and ion exchange methods

    International Nuclear Information System (INIS)

    A nano-structured drug-inorganic clay hybrid involving an active anticancer compound, which is chlorogenic acid (CA) intercalated into Zn/Al-layered double hydroxide, has been assembled via ion-exchange and co-precipitation methods to form a nanohybrid CZAE (a chlorogenic acid-Zn/Al nanohybrid synthesised using an ion-exchange method) and CZAC (a chlorogenic acid-Zn/Al nanohybrid synthesised using a direct method), respectively. The X-ray diffraction (XRD) results confirmed that the CA-LDH had a hybrid structure in which the anionic chlorogenate is arranged between the interlayers as a horizontal monolayer at 90 and 20° angles from the x axis for CZAE and CZAC, respectively. Both nanohybrids have the properties of mesoporous materials. The high loading percentage of chlorogenic acid (approximately 43.2% for CZAE and 45.3% for CZAC) with basal spacings of 11.7 and 12.6 Å for CZAE and CZAC, respectively, corroborates the successful intercalation of chlorogenic acid into the interlayer gallery of layered double hydroxides. Free chlorogenic acid and the synthesised nanocomposites (CZAE, CZAC) were assessed for their cytotoxicity against various cancer cells. The Fourier transform infrared data supported the formation of both nanohybrids, and a thermal analysis showed that the nanohybrids are more thermally stable than their counterparts. The chlorogenate shows a sustained release, and the release rate of chlorogenate from CZAE and CZAC nanohybrids at pH 7.4 is remarkably lower than that at pH 4.8 due to their different release mechanisms. The release rate of chlorogenate from both nanohybrids can be described as pseudo-second order. The present investigation revealed the potential of the nanohybrids to enhance the in vitro anti-tumour effect of chlorogenic acid in liver and lung cancer cells in vitro. - Highlights: • We intercalated chlorogenic into Zn/Al-layered double hydroxide by ion-exchange and coprecipitation methods. • The two methods gave nanocomposites

  15. The Next Generation of Platinum Drugs: Targeted Pt(II) Agents, Nanoparticle Delivery, and Pt(IV) Prodrugs

    Science.gov (United States)

    Johnstone, Timothy C.; Suntharalingam, Kogularamanan; Lippard, Stephen J.

    2016-01-01

    The platinum drugs, cisplatin, carboplatin, and oxaliplatin, prevail in the treatment of cancer,, but new platinum agents have been very slow to enter the clinic. Recently, however, there has been a surge of activity, based on a great deal of mechanistic information, aimed at developing non-classical platinum complexes that operate via mechanisms of action distinct from those of the approved drugs. The use of nanodelivery devices has also grown and many different strategies have been explored to incorporate platinum warheads into nanomedicine constructs. In this review, we discuss these efforts to create the next generation of platinum anticancer drugs. The introduction provides the reader with a brief overview of the use, development, and mechanism of action of the approved platinum drugs to provide the context in which more recent research has flourished. We then describe approaches that explore non-classical platinum(II) complexes with trans geometry and with a monofunctional coordination mode, polynuclear platinum(II) compounds, platinum(IV) prodrugs, dual-treat agents, and photoactivatable platinum(IV) complexes. Nanodelivery particles designed to deliver platinum(IV) complexes will also be discussed, including carbon nanotubes, carbon nanoparticles, gold nanoparticles, quantum dots, upconversion nanoparticles, and polymeric micelles. Additional nanoformulations including supramolecular self-assembled structures, proteins, peptides, metal-organic frameworks, and coordination polymers will then be described. Finally, the significant clinical progress made by nanoparticle formulations of platinum(II) agents will be reviewed. We anticipate that such a synthesis of disparate research efforts will not only help to generate new drug development ideas and strategies, but also reflect our optimism that the next generation of platinum cancer drugs is about to arrive. PMID:26865551

  16. The Next Generation of Platinum Drugs: Targeted Pt(II) Agents, Nanoparticle Delivery, and Pt(IV) Prodrugs.

    Science.gov (United States)

    Johnstone, Timothy C; Suntharalingam, Kogularamanan; Lippard, Stephen J

    2016-03-01

    The platinum drugs, cisplatin, carboplatin, and oxaliplatin, prevail in the treatment of cancer, but new platinum agents have been very slow to enter the clinic. Recently, however, there has been a surge of activity, based on a great deal of mechanistic information, aimed at developing nonclassical platinum complexes that operate via mechanisms of action distinct from those of the approved drugs. The use of nanodelivery devices has also grown, and many different strategies have been explored to incorporate platinum warheads into nanomedicine constructs. In this Review, we discuss these efforts to create the next generation of platinum anticancer drugs. The introduction provides the reader with a brief overview of the use, development, and mechanism of action of the approved platinum drugs to provide the context in which more recent research has flourished. We then describe approaches that explore nonclassical platinum(II) complexes with trans geometry or with a monofunctional coordination mode, polynuclear platinum(II) compounds, platinum(IV) prodrugs, dual-threat agents, and photoactivatable platinum(IV) complexes. Nanoparticles designed to deliver platinum(IV) complexes will also be discussed, including carbon nanotubes, carbon nanoparticles, gold nanoparticles, quantum dots, upconversion nanoparticles, and polymeric micelles. Additional nanoformulations, including supramolecular self-assembled structures, proteins, peptides, metal-organic frameworks, and coordination polymers, will then be described. Finally, the significant clinical progress made by nanoparticle formulations of platinum(II) agents will be reviewed. We anticipate that such a synthesis of disparate research efforts will not only help to generate new drug development ideas and strategies, but also will reflect our optimism that the next generation of approved platinum cancer drugs is about to arrive. PMID:26865551

  17. Anti-cancer Effects of Novel Flavonoid Vicenin-2 as a Single Agent and in Synergistic Combination with Docetaxel in Prostate Cancer

    OpenAIRE

    Nagaprashantha, Lokesh Dalasanur; Vatsyayan, Rit; Singhal, Jyotsana; Fast, Spence; Roby, Rhonda; Awasthi, Sanjay; SINGHAL, SHARAD S.

    2011-01-01

    The present study was conducted to determine the efficacy of novel flavonoid vicenin-2 (VCN-2), an active constituent of the medicinal herb Ocimum Sanctum Linn or Tulsi, as a single agent and in combination with docetaxel (DTL) in carcinoma of prostate (CaP). VCN-2 effectively induced anti-proliferative, anti-angiogenic and pro-apoptotic effect in CaP cells (PC-3, DU-145 and LNCaP) irrespective of their androgen responsiveness or p53 status. VCN-2 inhibited EGFR/Akt/mTOR/ p70S6K pathway along...

  18. Mechanism of the induction of endoplasmic reticulum stress by the anti-cancer agent, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT): Activation of PERK/eIF2α, IRE1α, ATF6 and calmodulin kinase.

    Science.gov (United States)

    Merlot, Angelica M; Shafie, Nurul H; Yu, Yu; Richardson, Vera; Jansson, Patric J; Sahni, Sumit; Lane, Darius J R; Kovacevic, Zaklina; Kalinowski, Danuta S; Richardson, Des R

    2016-06-01

    The endoplasmic reticulum (ER) plays a major role in the synthesis, maturation and folding of proteins and is a critical calcium (Ca(2+)) reservoir. Cellular stresses lead to an overwhelming accumulation of misfolded proteins in the ER, leading to ER stress and the activation of the unfolded protein response (UPR). In the stressful tumor microenvironment, the UPR maintains ER homeostasis and enables tumor survival. Thus, a novel strategy for cancer therapeutics is to overcome chronically activated ER stress by triggering pro-apoptotic pathways of the UPR. Considering this, the mechanisms by which the novel anti-cancer agent, Dp44mT, can target the ER stress response pathways were investigated in multiple cell-types. Our results demonstrate that the cytotoxic chelator, Dp44mT, which forms redox-active metal complexes, significantly: (1) increased ER stress-associated pro-apoptotic signaling molecules (i.e., p-eIF2α, ATF4, CHOP); (2) increased IRE1α phosphorylation (p-IRE1α) and XBP1 mRNA splicing; (3) reduced expression of ER stress-associated cell survival signaling molecules (e.g., XBP1s and p58(IPK)); (4) increased cleavage of the transcription factor, ATF6, which enhances expression of its downstream targets (i.e., CHOP and BiP); and (5) increased phosphorylation of CaMKII that induces apoptosis. In contrast to Dp44mT, the iron chelator, DFO, which forms redox-inactive iron complexes, did not affect BiP, p-IRE1α, XBP1 or p58(IPK) levels. This study highlights the ability of a novel cancer therapeutic (i.e., Dp44mT) to target the pro-apoptotic functions of the UPR via cellular metal sequestration and redox stress. Assessment of ER stress-mediated apoptosis is fundamental to the understanding of the pharmacology of chelation for cancer treatment. PMID:27059255

  19. Peptidomimetics and metalloprotease inhibitors as anticancer drugs

    Institute of Scientific and Technical Information of China (English)

    SU Li; XU WenFang

    2009-01-01

    Peptidomimetics with three types, as the structural or functional mimetica of natural active peptides, can preserve the bioactivity and improve the bioavailability and the specificity towards the targets of the lead peptides. Peptidomimetica of high bioectivity can be designed through various ways including conformation restriction, modification and non-peptide design. Recently the concentration on the de-velopment of cancer chemotherapeutic drugs was transferred from cytotoxic drugs to target-baeed drugs, and many proteasee and peptidases that play key roles in the process of tumor genesis and development was discovered, which means that peptidomimetice as potential cancer chemotherapeu-tic drugs should be paid close attention to. Our laboratory has focused on the development of small-molecule peplldomimetic inhibitora of APN, MMPs and HDACs as target-based anticancer agents. These three zinc-dependent metalloproteinaees play very important roles in the process of tumor genesis, invasion, metastasis, angiogenesis and matrix degradation, so small-molecule peptidomimetic inhibitora based on them would be quite potential in the development of chemotherapeutic drugs with high selectivity.

  20. Peptidomimetics and metalloprotease inhibitors as anticancer drugs

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    Peptidomimetics with three types, as the structural or functional mimetics of natural active peptides, can preserve the bioactivity and improve the bioavailability and the specificity towards the targets of the lead peptides. Peptidomimetics of high bioactivity can be designed through various ways including conformation restriction, modification and non-peptide design. Recently the concentration on the de-velopment of cancer chemotherapeutic drugs was transferred from cytotoxic drugs to target-based drugs, and many proteases and peptidases that play key roles in the process of tumor genesis and development was discovered, which means that peptidomimetics as potential cancer chemotherapeu-tic drugs should be paid close attention to. Our laboratory has focused on the development of small-molecule peptidomimetic inhibitors of APN, MMPs and HDACs as target-based anticancer agents. These three zinc-dependent metalloproteinases play very important roles in the process of tumor genesis, invasion, metastasis, angiogenesis and matrix degradation, so small-molecule peptidomimetic inhibitors based on them would be quite potential in the development of chemotherapeutic drugs with high selectivity.