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Sample records for cancer drug target

  1. Targeted Drug Delivery in Pancreatic Cancer

    Science.gov (United States)

    Yu, Xianjun; Zhang, Yuqing; Chen, Changyi; Yao, Qizhi; Li, Min

    2009-01-01

    Effective drug delivery in pancreatic cancer treatment remains a major challenge. Because of the high resistance to chemo and radiation therapy, the overall survival rate for pancreatic cancer is extremely low. Recent advances in drug delivery systems hold great promise for improving cancer therapy. Using liposomes, nanoparticles, and carbon nanotubes to deliver cancer drugs and other therapeutic agents such as siRNA, suicide gene, oncolytic virus, small molecule inhibitor and antibody has been a success in recent pre-clinical trials. However, how to improve the specificity and stability of the delivered drug using ligand or antibody directed delivery represent a major problem. Therefore, developing novel, specific, tumor-targeted drug delivery systems is urgently needed for this terrible disease. This review summarizes the current progress on targeted drug delivery in pancreatic cancer, and provides important information on potential therapeutic targets for pancreatic cancer treatment. PMID:19853645

  2. Bioinspired Nanonetworks for Targeted Cancer Drug Delivery.

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    Raz, Nasibeh Rady; Akbarzadeh-T, Mohammad-R; Tafaghodi, Mohsen

    2015-12-01

    A biomimicry approach to nanonetworks is proposed here for targeted cancer drug delivery (TDD). The swarm of bioinspired nanomachines utilizes the blood distribution network and chemotaxis to carry drug through the vascular system to the cancer site, recognized by a high concentration of vascular endothelial growth factor (VEGF). Our approach is multi-scale and includes processes that occur both within cells and with their neighbors. The proposed bionanonetwork takes advantage of several organic processes, some of which already occur within the human body, such as a plate-like structure similar to those of red blood cells for more environmental contact; a berry fruit architecture for its internal multi-foams architecture; the penetrable structure of cancer cells, tissue, as well as the porous structure of the capillaries for drug penetration; state of glycocalyx for ligand-receptor adhesion; as well as changes in pH state of blood and O 2 release for nanomachine communication. For a more appropriate evaluation, we compare our work with a conventional chemotherapy approach using a mathematical model of cancer under actual experimental parameter settings. Simulation results show the merits of the proposed method in targeted cancer therapy by improving the densities of the relevant cancer cell types and VEGF concentration, while following more organic and natural processes. PMID:26529771

  3. Targeting autophagic pathways for cancer drug discovery

    Institute of Scientific and Technical Information of China (English)

    Bo Liu; Jin-Ku Bao; Jin-Ming Yang; Yan Cheng

    2013-01-01

    Autophagy,an evolutionarily conserved lysosomal degradation process,has drawn an increasing amount of attention in recent years for its role in a variety of human diseases,such as cancer.Notably,autophagy plays an important role in regulating several survival and death signaling pathways that determine cell fate in cancer.To date,substantial evidence has demonstrated that some key autophagic mediators,such as autophagy-related genes (ATGs),PI3K,mTOR,p53,and Beclin-1,may play crucial roles in modulating autophagic activity in cancer initiation and progression.Because autophagy-modulating agents such as rapamycin and chloroquine have already been used clinically to treat cancer,it is conceivable that targeting autophagic pathways may provide a new opportunity for discovery and development of more novel cancer therapeutics.With a deeper understanding of the regulatory mechanisms governing autophagy,we will have a better opportunity to facilitate the exploitation of autophagy as a target for therapeutic intervention in cancer.This review discusses the current status of targeting autophagic pathways as a potential cancer therapy.

  4. Killing cancer cells by targeted drug-carrying phage nanomedicines

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    Yacoby Iftach

    2008-04-01

    Full Text Available Abstract Background Systemic administration of chemotherapeutic agents, in addition to its anti-tumor benefits, results in indiscriminate drug distribution and severe toxicity. This shortcoming may be overcome by targeted drug-carrying platforms that ferry the drug to the tumor site while limiting exposure to non-target tissues and organs. Results We present a new form of targeted anti-cancer therapy in the form of targeted drug-carrying phage nanoparticles. Our approach is based on genetically-modified and chemically manipulated filamentous bacteriophages. The genetic manipulation endows the phages with the ability to display a host-specificity-conferring ligand. The phages are loaded with a large payload of a cytotoxic drug by chemical conjugation. In the presented examples we used anti ErbB2 and anti ERGR antibodies as targeting moieties, the drug hygromycin conjugated to the phages by a covalent amide bond, or the drug doxorubicin conjugated to genetically-engineered cathepsin-B sites on the phage coat. We show that targeting of phage nanomedicines via specific antibodies to receptors on cancer cell membranes results in endocytosis, intracellular degradation, and drug release, resulting in growth inhibition of the target cells in vitro with a potentiation factor of >1000 over the corresponding free drugs. Conclusion The results of the proof-of concept study presented here reveal important features regarding the potential of filamentous phages to serve as drug-delivery platform, on the affect of drug solubility or hydrophobicity on the target specificity of the platform and on the effect of drug release mechanism on the potency of the platform. These results define targeted drug-carrying filamentous phage nanoparticles as a unique type of antibody-drug conjugates.

  5. Approaches of targeting Rho GTPases in cancer drug discovery

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    Lin, Yuan; Zheng, Yi

    2016-01-01

    Introduction Rho GTPases are master regulators of actomyosin structure and dynamics and play pivotal roles in a variety of cellular processes including cell morphology, gene transcription, cell cycle progression and cell adhesion. Because aberrant Rho GTPase signaling activities are widely associated with human cancer, key components of Rho GTPase signaling pathways have attracted increasing interest as potential therapeutic targets. Similar to Ras, Rho GTPases themselves were, until recently, deemed “undruggable” because of structure-function considerations. Several approaches to interfere with Rho GTPase signaling have been explored and show promise as new ways for tackling cancer cells. Areas covered This review focuses on the recent progress in targeting the signaling activities of three prototypical Rho GTPases, i.e. RhoA, Rac1, and Cdc42. The authors describe the involvement of these Rho GTPases, their key regulators and effectors in cancer. Furthermore, the authors discuss the current approaches for rationally targeting aberrant Rho GTPases along their signaling cascades, upstream and downstream of Rho GTPases and posttranslational modifications at a molecular level. Expert opinion To date, while no clinically effective drugs targeting Rho GTPase signaling for cancer treatment are available, tool compounds and lead drugs that pharmacologically inhibit Rho GTPase pathways have shown promise. Small molecule inhibitors targeting Rho GTPase signaling may add new treatment options for future precision cancer therapy, particularly in combination with other anti-cancer agents. PMID:26087073

  6. Mitochondrial chaperones may be targets for anti-cancer drugs

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    Scientists at NCI have found that a mitochondrial chaperone protein, TRAP1, may act indirectly as a tumor suppressor as well as a novel target for developing anti-cancer drugs. Chaperone proteins, such as TRAP1, help other proteins adapt to stress, but sc

  7. Salinomycin as a Drug for Targeting Human Cancer Stem Cells

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    Cord Naujokat

    2012-01-01

    Full Text Available Cancer stem cells (CSCs represent a subpopulation of tumor cells that possess self-renewal and tumor initiation capacity and the ability to give rise to the heterogenous lineages of malignant cells that comprise a tumor. CSCs possess multiple intrinsic mechanisms of resistance to chemotherapeutic drugs, novel tumor-targeted drugs, and radiation therapy, allowing them to survive standard cancer therapies and to initiate tumor recurrence and metastasis. Various molecular complexes and pathways that confer resistance and survival of CSCs, including expression of ATP-binding cassette (ABC drug transporters, activation of the Wnt/β-catenin, Hedgehog, Notch and PI3K/Akt/mTOR signaling pathways, and acquisition of epithelial-mesenchymal transition (EMT, have been identified recently. Salinomycin, a polyether ionophore antibiotic isolated from Streptomyces albus, has been shown to kill CSCs in different types of human cancers, most likely by interfering with ABC drug transporters, the Wnt/β-catenin signaling pathway, and other CSC pathways. Promising results from preclinical trials in human xenograft mice and a few clinical pilote studies reveal that salinomycin is able to effectively eliminate CSCs and to induce partial clinical regression of heavily pretreated and therapy-resistant cancers. The ability of salinomycin to kill both CSCs and therapy-resistant cancer cells may define the compound as a novel and an effective anticancer drug.

  8. MITOCHONDRIA: INSIGHT TARGET OF DRUG DEVELOPMENT IN CANCER CELLS

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    Md. Ataur Rahman

    2012-09-01

    Full Text Available Mitochondria are involved in different physiological and pathological processes that are crucial for tumor cell physiology, growth and survival and its dysfunction leads to many human abnormalities, including cardiovascular diseases, neurodegenerative diseases, autoimmune disorders and cancer. The present review is focused on the different experimental and therapeutic cancer strategies addressed to either target mitochondria directly, or use mitochondria as mediators of apoptosis, although its total molecular mechanism has not been elucidated. Therefore, the role of mitochondria in the etiology and progression of several function and explore potential therapeutic benefits of targeting mitochondria in the disease processes. Newly evolving advances in disease diagnostics and therapy will further facilitate future growth in the field of mitochondrian biology, where there is a dire need for sensitive and more affordable diagnostic tools and an urgency to develop effective therapies and identify reliable drug to predict accurately the response to a cancer therapy. These approaches to treat mitochondrial dysfunction rationally could lead to selective protection of cells in different tissues and various disease states. To avoid mitochondrial liabilities, routine screens need to be positioned within the drug-development process as targets of drug-induced cytotoxicity or cancer promotion, as regulators of apoptosis, as sources of cell signalling through reactive oxygen species, and mitochondrial control of specific nuclear responses. However, several novel mitochondrial targets are now emerging, including the potential to manipulate the mitochondrial pool to maintain function via biogenesis and mitophagy. Forthcoming insights into the fine regulation of mitochondrial apoptosis will likely open future perspectives for cancer drug development.

  9. Functional liposomes in the cancer-targeted drug delivery.

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    Tila, Dena; Ghasemi, Saeed; Yazdani-Arazi, Seyedeh Narjes; Ghanbarzadeh, Saeed

    2015-07-01

    Cancer is considered as one of the most severe health problems and is currently the third most common cause of death in the world after heart and infectious diseases. Novel therapies are constantly being discovered, developed and trialed. Many of the current anticancer agents exhibit non-ideal pharmaceutical and pharmacological properties and are distributed non-specifically throughout the body. This results in death of the both normal healthy and malignant cells and substantially leads to accruing a variety of serious toxic side effects. Therefore, the efficient systemic therapy of cancer is almost impossible due to harmful side effects of anticancer agents to the healthy organs and tissues. Furthermore, several problems such as low bioavailability of the drugs, low drug concentrations at the site of action, lack of drug specificity and drug-resistance also cause many restrictions on clinical applications of these drugs in the tumor therapy. Different types of the liposomal formulations have been used in medicine due to their distinctive advantages associated with their structural flexibility in the encapsulation of various agents with different physicochemical properties. They can also mediate delivery of the cargo to the appropriate cell type and subcellular compartment, reducing the effective dosage and possible side effects which are related to high systemic concentrations. Therefore, these novel systems were found very promising and encouraging dosage forms for the treatment of different types of cancer by increasing efficiency and reducing the systemic toxicity due to the specific drug delivery and targeting. PMID:25823898

  10. tcTKB: an integrated cardiovascular toxicity knowledge base for targeted cancer drugs

    OpenAIRE

    Xu, Rong; Wang, QuanQiu

    2015-01-01

    Targeted cancer drugs are often associated with unexpectedly high cardiovascular (CV) adverse events. Systematic approaches to studying CV events associated with targeted anticancer drugs have high potential for elucidating the complex pathways underlying targeted anti-cancer drugs. In this study, we built tcTKB, a comprehensive CV toxicity knowledge base for targeted cancer drugs, by extracting drug-CV pairs from five large-scale and complementary data sources. The data sources include FDA d...

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

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    Liu, Daxing; Auguste, Debra T

    2015-12-10

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

  12. Polymeric nanoparticles for targeted drug delivery system for cancer therapy.

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    Masood, Farha

    2016-03-01

    A targeted delivery system based on the polymeric nanoparticles as a drug carrier represents a marvelous avenue for cancer therapy. The pivotal characteristics of this system include biodegradability, biocompatibility, non-toxicity, prolonged circulation and a wide payload spectrum of a therapeutic agent. Other outstanding features are their distinctive size and shape properties for tissue penetration via an active and passive targeting, specific cellular/subcellular trafficking pathways and facile control of cargo release by sophisticated material engineering. In this review, the current implications of encapsulation of anticancer agents within polyhydroxyalkanoates, poly-(lactic-co-glycolic acid) and cyclodextrin based nanoparticles to precisely target the tumor site, i.e., cell, tissue and organ are highlighted. Furthermore, the promising perspectives in this emerging field are discussed. PMID:26706565

  13. The antihelmintic drug pyrvinium pamoate targets aggressive breast cancer.

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    Wei Xu

    Full Text Available WNT signaling plays a key role in the self-renewal of tumor initiation cells (TICs. In this study, we used pyrvinium pamoate (PP, an FDA-approved antihelmintic drug that inhibits WNT signaling, to test whether pharmacologic inhibition of WNT signaling can specifically target TICs of aggressive breast cancer cells. SUM-149, an inflammatory breast cancer cell line, and SUM-159, a metaplastic basal-type breast cancer cell line, were used in these studies. We found that PP inhibited primary and secondary mammosphere formation of cancer cells at nanomolar concentrations, at least 10 times less than the dose needed to have a toxic effect on cancer cells. A comparable mammosphere formation IC50 dose to that observed in cancer cell lines was obtained using malignant pleural effusion samples from patients with IBC. A decrease in activity of the TIC surrogate aldehyde dehydrogenase was observed in PP-treated cells, and inhibition of WNT signaling by PP was associated with down-regulation of a panel of markers associated with epithelial-mesenchymal transition. In vivo, intratumoral injection was associated with tumor necrosis, and intraperitoneal injection into mice with tumor xenografts caused significant tumor growth delay and a trend toward decreased lung metastasis. In in vitro mammosphere-based and monolayer-based clonogenic assays, we found that PP radiosensitized cells in monolayer culture but not mammosphere culture. These findings suggest WNT signaling inhibition may be a feasible strategy for targeting aggressive breast cancer. Investigation and modification of the bioavailability and toxicity profile of systemic PP are warranted.

  14. Predicting enzyme targets for cancer drugs by profiling human Metabolic reactions in NCI-60 cell lines

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    Ching Wai-Ki

    2010-10-01

    Full Text Available Abstract Background Drugs can influence the whole metabolic system by targeting enzymes which catalyze metabolic reactions. The existence of interactions between drugs and metabolic reactions suggests a potential way to discover drug targets. Results In this paper, we present a computational method to predict new targets for approved anti-cancer drugs by exploring drug-reaction interactions. We construct a Drug-Reaction Network to provide a global view of drug-reaction interactions and drug-pathway interactions. The recent reconstruction of the human metabolic network and development of flux analysis approaches make it possible to predict each metabolic reaction's cell line-specific flux state based on the cell line-specific gene expressions. We first profile each reaction by its flux states in NCI-60 cancer cell lines, and then propose a kernel k-nearest neighbor model to predict related metabolic reactions and enzyme targets for approved cancer drugs. We also integrate the target structure data with reaction flux profiles to predict drug targets and the area under curves can reach 0.92. Conclusions The cross validations using the methods with and without metabolic network indicate that the former method is significantly better than the latter. Further experiments show the synergism of reaction flux profiles and target structure for drug target prediction. It also implies the significant contribution of metabolic network to predict drug targets. Finally, we apply our method to predict new reactions and possible enzyme targets for cancer drugs.

  15. MITOCHONDRIA: INSIGHT TARGET OF DRUG DEVELOPMENT IN CANCER CELLS

    OpenAIRE

    Md. Ataur Rahman

    2012-01-01

    Mitochondria are involved in different physiological and pathological processes that are crucial for tumor cell physiology, growth and survival and its dysfunction leads to many human abnormalities, including cardiovascular diseases, neurodegenerative diseases, autoimmune disorders and cancer. The present review is focused on the different experimental and therapeutic cancer strategies addressed to either target mitochondria directly, or use mitochondria as mediators of apoptosis, although it...

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

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    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.

  17. A smart multifunctional drug delivery nanoplatform for targeting cancer cells

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    Hoop, M.; Mushtaq, F.; Hurter, C.; Chen, X.-Z.; Nelson, B. J.; Pané, S.

    2016-06-01

    Wirelessly guided magnetic nanomachines are promising vectors for targeted drug delivery, which have the potential to minimize the interaction between anticancer agents and healthy tissues. In this work, we propose a smart multifunctional drug delivery nanomachine for targeted drug delivery that incorporates a stimuli-responsive building block. The nanomachine consists of a magnetic nickel (Ni) nanotube that contains a pH-responsive chitosan hydrogel in its inner cavity. The chitosan inside the nanotube serves as a matrix that can selectively release drugs in acidic environments, such as the extracellular space of most tumors. Approximately a 2.5 times higher drug release from Ni nanotubes at pH = 6 is achieved compared to that at pH = 7.4. The outside of the Ni tube is coated with gold. A fluorescein isothiocyanate (FITC) labeled thiol-ssDNA, a biological marker, was conjugated on its surface by thiol-gold click chemistry, which enables traceability. The Ni nanotube allows the propulsion of the device by means of external magnetic fields. As the proposed nanoarchitecture integrates different functional building blocks, our drug delivery nanoplatform can be employed for carrying molecular drug conjugates and for performing targeted combinatorial therapies, which can provide an alternative and supplementary solution to current drug delivery technologies.Wirelessly guided magnetic nanomachines are promising vectors for targeted drug delivery, which have the potential to minimize the interaction between anticancer agents and healthy tissues. In this work, we propose a smart multifunctional drug delivery nanomachine for targeted drug delivery that incorporates a stimuli-responsive building block. The nanomachine consists of a magnetic nickel (Ni) nanotube that contains a pH-responsive chitosan hydrogel in its inner cavity. The chitosan inside the nanotube serves as a matrix that can selectively release drugs in acidic environments, such as the extracellular space of

  18. Neoadjuvant Window Studies of Metformin and Biomarker Development for Drugs Targeting Cancer Metabolism.

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    Lord, Simon R; Patel, Neel; Liu, Dan; Fenwick, John; Gleeson, Fergus; Buffa, Francesca; Harris, Adrian L

    2015-05-01

    There has been growing interest in the potential of the altered metabolic state typical of cancer cells as a drug target. The antidiabetes drug, metformin, is now under intense investigation as a safe method to modify cancer metabolism. Several studies have used window of opportunity in breast cancer patients before neoadjuvant chemotherapy to correlate gene expression analysis, metabolomics, immunohistochemical markers, and metabolic serum markers with those likely to benefit. We review the role metabolite measurement, functional imaging and gene sequencing analysis play in elucidating the effects of metabolically targeted drugs in cancer treatment and determining patient selection. PMID:26063894

  19. From drug response profiling to target addiction scoring in cancer cell models

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    Bhagwan Yadav

    2015-10-01

    Full Text Available Deconvoluting the molecular target signals behind observed drug response phenotypes is an important part of phenotype-based drug discovery and repurposing efforts. We demonstrate here how our network-based deconvolution approach, named target addiction score (TAS, provides insights into the functional importance of druggable protein targets in cell-based drug sensitivity testing experiments. Using cancer cell line profiling data sets, we constructed a functional classification across 107 cancer cell models, based on their common and unique target addiction signatures. The pan-cancer addiction correlations could not be explained by the tissue of origin, and only correlated in part with molecular and genomic signatures of the heterogeneous cancer cells. The TAS-based cancer cell classification was also shown to be robust to drug response data resampling, as well as predictive of the transcriptomic patterns in an independent set of cancer cells that shared similar addiction signatures with the 107 cancers. The critical protein targets identified by the integrated approach were also shown to have clinically relevant mutation frequencies in patients with various cancer subtypes, including not only well-established pan-cancer genes, such as PTEN tumor suppressor, but also a number of targets that are less frequently mutated in specific cancer types, including ABL1 oncoprotein in acute myeloid leukemia. An application to leukemia patient primary cell models demonstrated how the target deconvolution approach offers functional insights into patient-specific addiction patterns, such as those indicative of their receptor-type tyrosine-protein kinase FLT3 internal tandem duplication (FLT3-ITD status and co-addiction partners, which may lead to clinically actionable, personalized drug treatment developments. To promote its application to the future drug testing studies, we have made available an open-source implementation of the TAS calculation in the form

  20. A novel targeted system to deliver chemotherapeutic drugs to EphA2-expressing cancer cells

    OpenAIRE

    Wang, Si; Placzek, William J.; Stebbins, John L.; Mitra, Sayantan; Noberini, Roberta; Koolpe, Mitchell; Zhang, Ziming; Dahl, Russell; Pasquale, Elena B.; Pellecchia, Maurizio

    2012-01-01

    The efficacy of anti-cancer drugs is often limited by their systemic toxicities and adverse side effects. We report that the EphA2 receptor is over-expressed preferentially in several human cancer cell lines compared to normal tissues and that an EphA2 targeting peptide (YSAYPDSVPMMS) can be effective in delivering anti-cancer agents to such tumors. Hence, we report on the synthesis and characterizations of a novel EphA2-targeting agent conjugated with the chemotherapeutic drug paclitaxel. We...

  1. A small molecule nanodrug consisting of amphiphilic targeting ligand-chemotherapy drug conjugate for targeted cancer therapy.

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    Mou, Quanbing; Ma, Yuan; Zhu, Xinyuan; Yan, Deyue

    2016-05-28

    Targeted drug delivery is a broadly applicable approach for cancer therapy. However, the nanocarrier-based targeted delivery system suffers from batch-to-batch variation, quality concerns and carrier-related toxicity issues. Thus, to develop a carrier-free targeted delivery system with nanoscale characteristics is very attractive. Here, a novel targeting small molecule nanodrug self-delivery system consisting of targeting ligand and chemotherapy drug was constructed, which combined the advantages of small molecules and nano-assemblies together and showed excellent targeting ability and long blood circulation time with well-defined structure, high drug loading ratio and on-demand drug release behavior. As a proof-of-concept, lactose (Lac) and doxorubicin (DOX) were chosen as the targeting ligand and chemotherapy drug, respectively. Lac and DOX were conjugated through a pH-responsive hydrazone group. For its intrinsic amphiphilic property, Lac-DOX conjugate could self-assemble into nanoparticles in water. Both in vitro and in vivo assays indicated that Lac-DOX nanoparticles exhibited enhanced anticancer activity and weak side effects. This novel active targeting nanodrug delivery system shows great potential in cancer therapy. PMID:27040815

  2. Emerging Glycolysis Targeting and Drug Discovery from Chinese Medicine in Cancer Therapy

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    Zhiyu Wang

    2012-01-01

    Full Text Available Molecular-targeted therapy has been developed for cancer chemoprevention and treatment. Cancer cells have different metabolic properties from normal cells. Normal cells mostly rely upon the process of mitochondrial oxidative phosphorylation to produce energy whereas cancer cells have developed an altered metabolism that allows them to sustain higher proliferation rates. Cancer cells could predominantly produce energy by glycolysis even in the presence of oxygen. This alternative metabolic characteristic is known as the “Warburg Effect.” Although the exact mechanisms underlying the Warburg effect are unclear, recent progress indicates that glycolytic pathway of cancer cells could be a critical target for drug discovery. With a long history in cancer treatment, traditional Chinese medicine (TCM is recognized as a valuable source for seeking bioactive anticancer compounds. A great progress has been made to identify active compounds from herbal medicine targeting on glycolysis for cancer treatment. Herein, we provide an overall picture of the current understanding of the molecular targets in the cancer glycolytic pathway and reviewed active compounds from Chinese herbal medicine with the potentials to inhibit the metabolic targets for cancer treatment. Combination of TCM with conventional therapies will provide an attractive strategy for improving clinical outcome in cancer treatment.

  3. Polymeric micelles with stimuli-triggering systems for advanced cancer drug targeting.

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    Nakayama, Masamichi; Akimoto, Jun; Okano, Teruo

    2014-08-01

    Since the 1990s, nanoscale drug carriers have played a pivotal role in cancer chemotherapy, acting through passive drug delivery mechanisms and subsequent pharmaceutical action at tumor tissues with reduction of adverse effects. Polymeric micelles, as supramolecular assemblies of amphiphilic polymers, have been considerably developed as promising drug carrier candidates, and a number of clinical studies of anticancer drug-loaded polymeric micelle carriers for cancer chemotherapy applications are now in progress. However, these systems still face several issues; at present, the simultaneous control of target-selective delivery and release of incorporated drugs remains difficult. To resolve these points, the introduction of stimuli-responsive mechanisms to drug carrier systems is believed to be a promising approach to provide better solutions for future tumor drug targeting strategies. As possible trigger signals, biological acidic pH, light, heating/cooling and ultrasound actively play significant roles in signal-triggering drug release and carrier interaction with target cells. This review article summarizes several molecular designs for stimuli-responsive polymeric micelles in response to variation of pH, light and temperature and discusses their potentials as next-generation tumor drug targeting systems.

  4. Fighting cancer with nanomedicine---drug-polyester nanoconjugates for targeted cancer therapy

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    Yin, Qian

    The aim of my Ph. D. research is to develop drug-polyester nanoconjugates (NCs) as a novel translational polymeric drug delivery system that can successfully evade non-specific uptake by reticuloendothelial system (RES) and facilitate targeted cancer diagnosis and therapy. By uniquely integrating well-established chemical reaction-controlled ring opening polymerization (ROP) with nanoprecipitation technique, I successfully developed a polymeric NC system based on poly(lactic acid) and poly(O-carboxyanhydrides) (OCA) that allows for the quantitative loading and controlled release of a variety of anticancer drugs. The developed NC system could be easily modified with parmidronate, one of bisphosphonates commonly used as the treatment for disease characterized by osteolysis, to selectively deliver doxorubicin (Doxo) to the bone tissues and substantially to improve their therapeutic efficiency in inhibiting the growth of osteosarcoma in both murine and canine models. More importantly, the developed NCs could avidly bind to human serum albumin, a ubiquitous protein in the blood, to bypass the endothelium barrier and penetrate into tumor tissues more deeply and efficiently. When compared with PEGylated NCs, these albumin-bound NCs showed significantly reduced accumulation in RES and enhanced tumor accumulation, which consequently contributed to higher their tumor inhibition capabilities. In addition, the developed NC system allows easy incorporation of X-ray computed tomography (CT) contrast agents to largely facilitate personalized therapy by improving diagnosis accuracy and monitoring therapeutic efficacy. Through the synthetic and formulation strategy I developed, a large quantity (grams or larger-scale) of drug-polyester NCs can be easily obtained, which can be used as a model drug delivery system for fundamental studies as well as a real drug delivery system for disease treatment in clinical settings.

  5. Targeting AMPK Signaling Pathway to Overcome Drug Resistance for Cancer Therapy.

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    Wang, Zhiyu; Liu, Pengxi; Chen, Qianjun; Deng, Shigui; Liu, Xiaoyan; Situ, Honglin; Zhong, Shaowen; Hann, Swei; Lin, Yi

    2016-01-01

    Mulitdrug resistance (MDR) is one of critical factorslimiting the efficacy of cancer chemoor radiotherapy. Emerging evidence has indicated that MDR is a complex process regulated by multiple factors, among which stress response molecules are considered as central players. AMP-activated protein kinase (AMPK) is a major regulator balancing energy supply and ultimately protects cells from harmful stresses via coordinating multiple metabolic pathways Notably, AMPK activation was recently shown to mediate the metabolism reprogramming in drug resistant cancer cells including promoting Warburg effects and mitochondrial biogenesis. Furthermore, AMPK activity has also been shown to regulate the self-renewal ability of cancer stem cells that are often refractory to chemotherapy. In addition, AMPK phosphorylation was critical in mediating autophagy induction, a process demonstrated to be effective in chemosensitivity modulation via degrading cellular components to satisfy nutrients requirement under stressful condition. Meanwhile, drug discovery targeting AMPK has been developed to validate the pathological significance of AMPK in cancer prevention and treatment. Although conflicting evidence focusing on the AMPK modulation for cancer treatment is still remained, this might be attributed to differences in AMPK isotypes in specific tissues, off-targets effects, the degree and duration of drug administration and experimental setting of stress conditions. This review will focus on AMPK mediated resistance to cancer therapy and discuss its potential therapeutic implication and targeting drug development. PMID:25777274

  6. For Some Skin Cancers, Targeted Drug Hits the Mark

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    Two studies reported June 7, 2012, in NEJM indicate that the drug vismodegib can elicit responses in people with advanced or metastatic basal cell carcinoma and help shrink or prevent tumors in those with basal cell nevus syndrome.

  7. For Some Skin Cancers, Targeted Drug Hits the Mark

    Science.gov (United States)

    ... 29 new BCCs among those who received a placebo . However, more than half of the patients taking vismodegib discontinued treatment because of side effects. Once patients stopped taking the drug, tumors began ...

  8. Mechanisms of acquired resistance to androgen receptor targeting drugs in castration resistant prostate cancer

    OpenAIRE

    Chism, David D.; De Silva, Dinuka; Whang, Young E.

    2014-01-01

    After initial response to androgen receptor targeting drugs abiraterone or enzalutamide, most patients develop progressive disease and therefore, castration resistant prostate cancer (CRPC) remains a terminal disease. Multiple mechanisms underlying acquired resistance have been postulated. Intratumoral androgen synthesis may resume after abiraterone treatment. A point mutation in the ligand binding domain of androgen receptor may confer resistance to enzalutamide. Emergence of androgen recept...

  9. Targeting anti-cancer drug resistance in mouse models of breast cancer

    NARCIS (Netherlands)

    Jaspers, J.E.

    2013-01-01

    Resistance to anti-cancer drugs is one of the biggest challenges in clinical oncology. In contrast to the success of local therapy (e.g. surgery or radiotherapy), the treatment of disseminated cancers using classical DNA-damaging chemotherapeutic agents and novel specific inhibitors frequently fails

  10. Hyaluronic acid modified mesoporous carbon nanoparticles for targeted drug delivery to CD44-overexpressing cancer cells

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    Wan, Long; Jiao, Jian; Cui, Yu; Guo, Jingwen; Han, Ning; Di, Donghua; Chang, Di; Wang, Pu; Jiang, Tongying; Wang, Siling

    2016-04-01

    In this paper, hyaluronic acid (HA) functionalized uniform mesoporous carbon spheres (UMCS) were synthesized for targeted enzyme responsive drug delivery using a facile electrostatic attraction strategy. This HA modification ensured stable drug encapsulation in mesoporous carbon nanoparticles in an extracellular environment while increasing colloidal stability, biocompatibility, cell-targeting ability, and controlled cargo release. The cellular uptake experiments of fluorescently labeled mesoporous carbon nanoparticles, with or without HA functionalization, demonstrated that HA-UMCS are able to specifically target cancer cells overexpressing CD44 receptors. Moreover, the cargo loaded doxorubicin (DOX) and verapamil (VER) exhibited a dual pH and hyaluronidase-1 responsive release in the tumor microenvironment. In addition, VER/DOX/HA-UMCS exhibited a superior therapeutic effect on an in vivo HCT-116 tumor in BALB/c nude mice. In summary, it is expected that HA-UMCS will offer a new method for targeted co-delivery of drugs to tumors overexpressing CD44 receptors.

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

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    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

  12. Targeted cancer therapies

    Institute of Scientific and Technical Information of China (English)

    Li Yan; Neal Rosen; Carlos Arteaga

    2011-01-01

    With unprecedented understanding of molecular events underlying human cancer in this genomic era, a large number of drugs specifically targeting hypothesized oncogenic drivers to which tumors are potentially addicted to have been developed and continue to be developed. These targeted cancer therapies are being actively tested in clinical trials with mixed successes. This editorial provides an overview on successful targeted cancer drugs on the market and those drugs that are in late clinical development stages. Importantly, the article lays out main challenges in developing molecular targeted therapies and potential path forward to overcome these challenges, as well as opportunities for China in this new era of targeted agents. The editorial serves as an introduction to the Targeted Cancer Therapies serias that will review in depth of major pathways and drugs targeting these pathways to be published in the coming issues of the Chinese Journal of Cancer.

  13. Combining targeted drugs to overcome and prevent resistance of solid cancers with some stem-like cell features

    OpenAIRE

    Jokinen, Elina; Laurila, Niina; Koivunen, Peppi; Koivunen, Jussi P

    2014-01-01

    Treatment resistance significantly inhibits the efficiency of targeted cancer therapies in drug-sensitive genotypes. In the current work, we studied mechanisms for rapidly occurring, adaptive resistance in targeted therapy-sensitive lung, breast, and melanoma cancer cell lines. The results show that in ALK translocated lung cancer lines H3122 and H2228, cells with cancer stem-like cell features characterized by high expression of cancer stem cell markers and/or in vivo tumorigenesis can media...

  14. Novel drugs that target the estrogen-related receptor alpha: their therapeutic potential in breast cancer

    International Nuclear Information System (INIS)

    The incidence of breast cancer continues to rise: 1.7 million women were diagnosed with and 521,000 women died from breast cancer in 2012. This review considers first current treatment options: surgery; radiotherapy; and systemic endocrine, anti-biological, and cytotoxic therapies. Clinical management includes prevention, early detection by screening, treatment with curative intent, management of chronic disease, and palliative control of advanced breast cancer. Next, the potential of novel drugs that target DNA repair, growth factor dependence, intracellular and intercellular signal transduction, and cell cycle are considered. Estrogen-related receptor alpha has attracted attention as a therapeutic target in triple-negative breast cancers with de novo resistance to, and in breast cancers with acquired resistance to, endocrine therapies such as antiestrogens and aromatase inhibitors. Estrogen-related receptor alpha is an orphan receptor and transcription factor. Its activity is regulated by coregulator proteins and posttranslational modification. It is an energy sensor that controls adaptation to energy demand and may facilitate glycolytic metabolism and mitochondrial oxidative respiration in breast cancer cells. Estrogen-related receptor alpha increases breast cancer cell migration, proliferation, and tumor development. It is expressed at high levels in estrogen receptor-negative tumors, and is proposed to activate estrogen-responsive genes in endocrine-resistant tumors. The structures and functions of the ligand-binding domains of estrogen receptor alpha and estrogen-related receptor alpha, their ability to bind estrogens, phytoestrogens, and synthetic ligands, and the effects of ligand agonists, antagonists, and inverse agonists on biological activity, are evaluated. Synthetic ligands of estrogen-related receptor alpha have activity in preclinical models of metabolic disorders, diabetes, osteoporosis, and oncology. The clinical settings in which these novel

  15. 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

  16. Dual-targeting anti-angiogenic cyclic peptides as potential drug leads for cancer therapy

    Science.gov (United States)

    Chan, Lai Yue; Craik, David J.; Daly, Norelle L.

    2016-01-01

    Peptide analogues derived from bioactive hormones such as somatostatin or certain growth factors have great potential as angiogenesis inhibitors for cancer applications. In an attempt to combat emerging drug resistance many FDA-approved anti-angiogenesis therapies are co-administered with cytotoxic drugs as a combination therapy to target multiple signaling pathways of cancers. However, cancer therapies often encounter limiting factors such as high toxicities and side effects. Here, we combined two anti-angiogenic epitopes that act on different pathways of angiogenesis into a single non-toxic cyclic peptide framework, namely MCoTI-II (Momordica cochinchinensis trypsin inhibitor-II), and subsequently assessed the anti-angiogenic activity of the novel compound. We hypothesized that the combination of these two epitopes would elicit a synergistic effect by targeting different angiogenesis pathways and result in improved potency, compared to that of a single epitope. This novel approach has resulted in the development of a potent, non-toxic, stable and cyclic analogue with nanomolar potency inhibition in in vitro endothelial cell migration and in vivo chorioallantoic membrane angiogenesis assays. This is the first report to use the MCoTI-II framework to develop a 2-in-1 anti-angiogenic peptide, which has the potential to be used as a form of combination therapy for targeting a wide range of cancers. PMID:27734947

  17. A comprehensive overview of exosomes as drug delivery vehicles - endogenous nanocarriers for targeted cancer therapy.

    Science.gov (United States)

    Johnsen, Kasper Bendix; Gudbergsson, Johann Mar; Skov, Martin Najbjerg; Pilgaard, Linda; Moos, Torben; Duroux, Meg

    2014-08-01

    Exosomes denote a class of secreted nanoparticles defined by size, surface protein and lipid composition, and the ability to carry RNA and proteins. They are important mediators of intercellular communication and regulators of the cellular niche, and their altered characteristics in many diseases, such as cancer, suggest them to be important both for diagnostic and therapeutic purposes, prompting the idea of using exosomes as drug delivery vehicles, especially for gene therapy. This review covers the current status of evidence presented in the field of exosome-based drug delivery systems. Components for successful exosome-based drug delivery, such as choice of donor cell, therapeutic cargo, use of targeting peptide, loading method and administration route are highlighted and discussed with a general focus pertaining to the results obtained in models of different cancer types. In addition, completed and on-going clinical trials are described, evaluating exosome-based therapies for the treatment of different cancer types. Due to their endogenous origin, exosome-based drug delivery systems may have advantages in the treatment of cancer, but their design needs further refinement to justify their usage on the clinical scale.

  18. 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.

  19. Targeted pancreatic cancer therapy with the small molecule drug conjugate SW IV-134.

    Science.gov (United States)

    Hashim, Yassar M; Spitzer, Dirk; Vangveravong, Suwanna; Hornick, Mary C; Garg, Gunjal; Hornick, John R; Goedegebuure, Peter; Mach, Robert H; Hawkins, William G

    2014-07-01

    Pancreatic adenocarcinoma is highly resistant to conventional therapeutics and has been shown to evade apoptosis by deregulation of the X-linked and cellular inhibitors of apoptosis proteins (XIAP and cIAP). Second mitochondria-derived activator of caspases (Smac) induces and amplifies cell death by reversing the anti-apoptotic activity of IAPs. Thus, Smac-derived peptide analogues (peptidomimetics) have been developed and shown to represent promising cancer therapeutics. Sigma-2 receptors are overexpressed in many proliferating tumor cells including pancreatic cancer. Selected ligands to this receptor are rapidly internalized by cancer cells. These characteristics have made the sigma-2 receptor an attractive target for drug delivery because selective delivery to cancer cells has the potential to increase therapeutic efficacy while minimizing toxicity to normal tissues. Here, we describe the initial characterization of SW IV-134, a chemically linked drug conjugate between the sigma-2 ligand SW43 and the Smac mimetic SW IV-52 as a novel treatment option for pancreatic adenocarcinoma. The tumor killing characteristics of our dual-domain therapeutic SW IV-134 was far greater than either component in isolation or in an equimolar mix and suggests enhanced cellular delivery when chemically linked to the sigma-2 ligand. One of the key findings was that SW IV-134 retained target selectivity of the Smac cargo with the involvement of the NF-κB/TNFα signaling pathway. Importantly, SW IV-134 slowed tumor growth and improved survival in murine models of pancreatic cancer. Our data support further study of this novel therapeutic and this drug delivery strategy because it may eventually benefit patients with pancreatic cancer.

  20. Drug design with Cdc7 kinase: a potential novel cancer therapy target

    Directory of Open Access Journals (Sweden)

    Masaaki Sawa

    2008-11-01

    Full Text Available Masaaki Sawa1, Hisao Masai21Carna Biosciences, Inc., Kobe, Japan; 2Genome Dynamics Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, JapanAbstract: Identification of novel molecular targets is critical in development of new and efficient cancer therapies. Kinases are one of the most common drug targets with a potential for cancer therapy. Cell cycle progression is regulated by a number of kinases, some of which are being developed to treat cancer. Cdc7 is a serine-threonine kinase originally discovered in budding yeast, which has been shown to be necessary to initiate the S phase. Inhibition of Cdc7 in cancer cells retards the progression of the S phase, accumulates DNA damage, and induces p53-independent cell death, but the same treatment in normal cells does not significantly affect viability. Low-molecular-weight compounds that inhibit Cdc7 kinase with an IC50 of less than 10 nM have been identified, and shown to be effective in the inhibition of tumor growth in animal models. Thus Cdc7 kinase can be recognized as a novel molecular target for cancer therapy.Keywords: Cdc7 kinase, cell cycle, replication fork, genome stability, DNA damages, ATP-binding pocket, kinase inhibitor

  1. Multifunctional Nanoprobes for Cancer Cell Targeting, Imaging and Anticancer Drug Delivery

    Science.gov (United States)

    Linkov, Pavel; Laronze-Cochard, Marie; Sapi, Janos; Sidorov, Lev N.; Nabiev, Igor

    The diagnosis and treatment of cancer have been greatly improved with recent developments in bio-nanotechnology, including engineering of multifunctional probes. One of the promising nanoscale tools for cancer imaging is fluorescent quantum dots (QDs), whose small size and unique optical properties allow them to penetrate into cells and ensure highly sensitive optical diagnosis of cancer at the cellular level. Furthermore, novel multi-functional probes have been developed in which QDs are conjugated with one or several functional molecules, including targeting moieties and therapeutic agents. Here, the strategy for engineering novel nanocarriers for controlled nucleus-targeted antitumor drug delivery and real-time imaging by single- or two-photon microscopy is described. A triple multifunctional nanoprobe is being developed that consists of a nitrogen-based heterocyclic derivative, an anticancer agent interacting with a DNA in living cells; a recognized molecule serving as a vector responsible for targeted delivery of the probe into cancer cells; and photoluminescent QDs providing the imaging capability of the probe. Subsequent optimization of the multifunctional nanoprobe will offer new possibilities for cancer diagnosis and treatment.

  2. Biosynthetic Machinery Involved in Aberrant Glycosylation: Promising Targets for Development Drugs Against Cancer

    Directory of Open Access Journals (Sweden)

    Andreia eVasconcelos-dos-Santos

    2015-06-01

    Full Text Available Cancer cells depend on altered metabolism and nutrient uptake to generate and keep the malignant phenotype. The hexosamine biosynthetic pathway (HBP is a branch of glucose metabolism that produces UDP-GlcNAc, and its derivatives, UDP-GalNAc and CMP-Neu5Ac, donor substrates used in the production of glycoproteins and glycolipids. Growing evidence demonstrates that alteration of the pool of activated substrates might lead to different glycosylation and cell signaling. It is already well established that aberrant glycosylation can modulate tumor growth and malignant transformation in different cancer types. Therefore, biosynthetic machinery involved in the assembly of aberrant glycans are becoming prominent targets for anti-tumor drugs. This review describes three classes of glycosylation, O-GlcNAcylation, N-linked and mucin type O-linked glycosylation, involved in tumor progression, their biosynthesis and highlights the available inhibitors as potential anti-tumor drugs.

  3. Hyaluronic acid modified mesoporous silica nanoparticles for targeted drug delivery to CD44-overexpressing cancer cells

    Science.gov (United States)

    Yu, Meihua; Jambhrunkar, Siddharth; Thorn, Peter; Chen, Jiezhong; Gu, Wenyi; Yu, Chengzhong

    2012-12-01

    In this paper, a targeted drug delivery system has been developed based on hyaluronic acid (HA) modified mesoporous silica nanoparticles (MSNs). HA-MSNs possess a specific affinity to CD44 over-expressed on the surface of a specific cancer cell line, HCT-116 (human colon cancer cells). The cellular uptake performance of fluorescently labelled MSNs with and without HA modification has been evaluated by confocal microscopy and fluorescence-activated cell sorter (FACS) analysis. Compared to bare MSNs, HA-MSNs exhibit a higher cellular uptake via HA receptor mediated endocytosis. An anticancer drug, doxorubicin hydrochloride (Dox), has been loaded into MSNs and HA-MSNs as drug delivery vehicles. Dox loaded HA-MSNs show greater cytotoxicity to HCT-116 cells than free Dox and Dox-MSNs due to the enhanced cell internalization behavior of HA-MSNs. It is expected that HA-MSNs have a great potential in targeted delivery of anticancer drugs to CD44 over-expressing tumors.

  4. Multifunctional aptamer-based nanoparticles for targeted drug delivery to circumvent cancer resistance.

    Science.gov (United States)

    Liu, Juan; Wei, Tuo; Zhao, Jing; Huang, Yuanyu; Deng, Hua; Kumar, Anil; Wang, Chenxuan; Liang, Zicai; Ma, Xiaowei; Liang, Xing-Jie

    2016-06-01

    By its unique advantages over traditional medicine, nanomedicine has offered new strategies for cancer treatment. In particular, the development of drug delivery strategies has focused on nanoscale particles to improve bioavailability. However, many of these nanoparticles are unable to overcome tumor resistance to chemotherapeutic agents. Recently, new opportunities for drug delivery have been provided by oligonucleotides that can self-assemble into three-dimensional nanostructures. In this work, we have designed and developed functional DNA nanostructures to deliver the chemotherapy drug doxorubicin (Dox) to resistant cancer cells. These nanostructures have two components. The first component is a DNA aptamer, which forms a dimeric G-quadruplex nanostructure to target cancer cells by binding with nucleolin. The second component is double-stranded DNA (dsDNA), which is rich in -GC- base pairs that can be applied for Dox delivery. We demonstrated that Dox was able to efficiently intercalate into dsDNA and this intercalation did not affect the aptamer's three-dimensional structure. In addition, the Aptamer-dsDNA (ApS) nanoparticle showed good stability and protected the dsDNA from degradation in bovine serum. More importantly, the ApS&Dox nanoparticle efficiently reversed the resistance of human breast cancer cells to Dox. The mechanism circumventing doxorubicin resistance by ApS&Dox nanoparticles may be predominantly by cell cycle arrest in S phase, effectively increased cell uptake and decreased cell efflux of doxorubicin. Furthermore, the ApS&Dox nanoparticles could effectively inhibit tumor growth, while less cardiotoxicity was observed. Overall, this functional DNA nanostructure provides new insights into the design of nanocarriers to overcome multidrug resistance through targeted drug delivery. PMID:26994877

  5. Targeting anticancer drug delivery to pancreatic cancer cells using a fucose-bound nanoparticle approach.

    Science.gov (United States)

    Yoshida, Makoto; Takimoto, Rishu; Murase, Kazuyuki; Sato, Yasushi; Hirakawa, Masahiro; Tamura, Fumito; Sato, Tsutomu; Iyama, Satoshi; Osuga, Takahiro; Miyanishi, Koji; Takada, Kohichi; Hayashi, Tsuyoshi; Kobune, Masayoshi; Kato, Junji

    2012-01-01

    Owing to its aggressiveness and the lack of effective therapies, pancreatic ductal adenocarcinoma has a dismal prognosis. New strategies to improve treatment and survival are therefore urgently required. Numerous fucosylated antigens in sera serve as tumor markers for cancer detection and evaluation of treatment efficacy. Increased expression of fucosyltransferases has also been reported for pancreatic cancer. These enzymes accelerate malignant transformation through fucosylation of sialylated precursors, suggesting a crucial requirement for fucose by pancreatic cancer cells. With this in mind, we developed fucose-bound nanoparticles as vehicles for delivery of anticancer drugs specifically to cancer cells. L-fucose-bound liposomes containing Cy5.5 or Cisplatin were effectively delivered into CA19-9 expressing pancreatic cancer cells. Excess L-fucose decreased the efficiency of Cy5.5 introduction by L-fucose-bound liposomes, suggesting L-fucose-receptor-mediated delivery. Intravenously injected L-fucose-bound liposomes carrying Cisplatin were successfully delivered to pancreatic cancer cells, mediating efficient tumor growth inhibition as well as prolonging survival in mouse xenograft models. This modality represents a new strategy for pancreatic cancer cell-targeting therapy.

  6. IGF-1 receptor targeted nanoparticles for image-guided therapy of stroma-rich and drug resistant human cancer

    Science.gov (United States)

    Zhou, Hongyu; Qian, Weiping; Uckun, Fatih M.; Zhou, Zhiyang; Wang, Liya; Wang, Andrew; Mao, Hui; Yang, Lily

    2016-05-01

    Low drug delivery efficiency and drug resistance from highly heterogeneous cancer cells and tumor microenvironment represent major challenges in clinical oncology. Growth factor receptor, IGF-1R, is overexpressed in both human tumor cells and tumor associated stromal cells. The level of IGF-1R expression is further up-regulated in drug resistant tumor cells. We have developed IGF-1R targeted magnetic iron oxide nanoparticles (IONPs) carrying multiple anticancer drugs into human tumors. This IGF-1R targeted theranostic nanoparticle delivery system has an iron core for non-invasive MR imaging, amphiphilic polymer coating to ensure the biocompatibility as well as for drug loading and conjugation of recombinant human IGF-1 as targeting molecules. Chemotherapy drugs, Doxorubicin (Dox), was encapsulated into the polymer coating and/or conjugated to the IONP surface by coupling with the carboxyl groups. The ability of IGF1R targeted theranostic nanoparticles to penetrate tumor stromal barrier and enhance tumor cell killing has been demonstrated in human pancreatic cancer patient tissue derived xenograft (PDX) models. Repeated systemic administrations of those IGF-1R targeted theranostic IONP carrying Dox led to breaking the tumor stromal barrier and improved therapeutic effect. Near infrared (NIR) optical and MR imaging enabled noninvasive monitoring of nanoparticle-drug delivery and therapeutic responses. Our results demonstrated that IGF-1R targeted nanoparticles carrying multiple drugs are promising combination therapy approaches for image-guided therapy of stroma-rich and drug resistant human cancer, such as pancreatic cancer.

  7. Sphaeropsidin A shows promising activity against drug-resistant cancer cells by targeting regulatory volume increase

    Science.gov (United States)

    Mathieu, Véronique; Chantôme, Aurélie; Lefranc, Florence; Cimmino, Alessio; Miklos, Walter; Paulitschke, Verena; Mohr, Thomas; Maddau, Lucia; Kornienko, Alexander; Berger, Walter; Vandier, Christophe; Evidente, Antonio; Delpire, Eric; Kiss, Robert

    2016-01-01

    Despite the recent advances in the treatment of tumors with intrinsic chemotherapy resistance, such as melanoma and renal cancers, their prognosis remains poor and new chemical agents with promising activity against these cancers are urgently needed. Sphaeropsidin A, a fungal metabolite whose anticancer potential had previously received little attention, was isolated from Diplodia cupressi and found to display specific anticancer activity in vitro against melanoma and kidney cancer subpanels in the National Cancer Institute (NCI) 60-cell line screen. The NCI data revealed a mean LC50 of ca. 10 μM and a cellular sensitivity profile that did not match that of any other agent in the 765,000 compound database. Subsequent mechanistic studies in melanoma and other multidrug-resistant in vitro cancer models showed that sphaeropsidin A can overcome apoptosis as well as multidrug resistance by inducing a marked and rapid cellular shrinkage related to the loss of intracellular Cl− and the decreased HCO3− concentration in the culture supernatant. These changes in ion homeostasis and the absence of effects on the plasma membrane potential were attributed to the sphaeropsidin A-induced impairment of regulatory volume increase (RVI). Preliminary results also indicate that depending on the type of cancer, the sphaeropsidin A effects on RVI could be related to Na–K–2Cl electroneutral cotransporter or Cl−/HCO3− anion exchanger(s) targeting. This study underscores the modulation of ion-transporter activity as a promising therapeutic strategy to combat drug-resistant cancers and identifies the fungal metabolite, sphaeropsidin A, as a lead to develop anticancer agents targeting RVI in cancer cells. PMID:25868554

  8. Identification of Potential Drug Targets in Cancer Signaling Pathways using Stochastic Logical Models.

    Science.gov (United States)

    Zhu, Peican; Aliabadi, Hamidreza Montazeri; Uludağ, Hasan; Han, Jie

    2016-03-18

    The investigation of vulnerable components in a signaling pathway can contribute to development of drug therapy addressing aberrations in that pathway. Here, an original signaling pathway is derived from the published literature on breast cancer models. New stochastic logical models are then developed to analyze the vulnerability of the components in multiple signalling sub-pathways involved in this signaling cascade. The computational results are consistent with the experimental results, where the selected proteins were silenced using specific siRNAs and the viability of the cells were analyzed 72 hours after silencing. The genes elF4E and NFkB are found to have nearly no effect on the relative cell viability and the genes JAK2, Stat3, S6K, JUN, FOS, Myc, and Mcl1 are effective candidates to influence the relative cell growth. The vulnerabilities of some targets such as Myc and S6K are found to vary significantly depending on the weights of the sub-pathways; this will be indicative of the chosen target to require customization for therapy. When these targets are utilized, the response of breast cancers from different patients will be highly variable because of the known heterogeneities in signaling pathways among the patients. The targets whose vulnerabilities are invariably high might be more universally acceptable targets.

  9. Magnetic targeted drug delivery

    Directory of Open Access Journals (Sweden)

    Timothy Wiedmann

    2009-10-01

    Full Text Available Lung cancer is the most common cause of death from cancer in both men and women. Treatment by intravenous or oral administration of chemotherapy agents results in serious and often treatment-limiting side effects. Delivery of drugs directly to the lung by inhalation of an aerosol holds the promise of achieving a higher concentration in the lung with lower blood levels. To further enhance the selective lung deposition, it may be possible to target deposition by using external magnetic fields to direct the delivery of drug coupled to magnetic particles. Moreover, alternating magnetic fields can be used to induce particle heating, which in turn controls the drug release rate with the appropriate thermal sensitive material.With this goal, superparamagetic nanoparticles (SPNP were prepared and characterized, and enhanced magnetic deposition was demonstrated in vitro and in vivo. SPNPs were also incorporated into a lipid-based/SPNP aerosol formulation, and drug release was shown to be controlled by thermal activation. Because of the inherent imaging potential of SPNPs, this use of nanotechnology offers the possibility of coupling the diagnosis of lung cancer to drug release, which perhaps will ultimately provide the “magic bullet” that Paul Ehrlich originally sought.

  10. Non-small-cell lung cancer: molecular targeted therapy and personalized medicine – drug resistance, mechanisms, and strategies

    Directory of Open Access Journals (Sweden)

    Sechler M

    2013-04-01

    Full Text Available Marybeth Sechler,1,2 Amber D Cizmic,3 Sreedevi Avasarala,1 Michelle Van Scoyk,1 Christine Brzezinski,1 Nicole Kelley,1 Rama Kamesh Bikkavilli,1 Robert A Winn1–3 1Division of Pulmonary Sciences and Critical Care, 2Program in Cancer Biology, University of Colorado, Aurora, CO, USA; 3Veterans Affairs Medical Center, Denver, CO, USA Abstract: Targeted therapies for cancer bring the hope of specific treatment, providing high efficacy and in some cases lower toxicity than conventional treatment. Although targeted therapeutics have helped immensely in the treatment of several cancers, like chronic myelogenous leukemia, colon cancer, and breast cancer, the benefit of these agents in the treatment of lung cancer remains limited, in part due to the development of drug resistance. In this review, we discuss the mechanisms of drug resistance and the current strategies used to treat lung cancer. A better understanding of these drug-resistance mechanisms could potentially benefit from the development of a more robust personalized medicine approach for the treatment of lung cancer. Keywords: lung cancer, drug targets, personalized medicine, NSCLC

  11. Ephrin receptor A10 is a promising drug target potentially useful for breast cancers including triple negative breast cancers.

    Science.gov (United States)

    Nagano, Kazuya; Maeda, Yuka; Kanasaki, So-Ichiro; Watanabe, Takanobu; Yamashita, Takuya; Inoue, Masaki; Higashisaka, Kazuma; Yoshioka, Yasuo; Abe, Yasuhiro; Mukai, Yohei; Kamada, Haruhiko; Tsutsumi, Yasuo; Tsunoda, Shin-ichi

    2014-09-10

    Ephrin receptor A10 (EphA10) is a relatively uncharacterized protein which is expressed in many breast cancers but not expressed in normal breast tissues. Here, we examined the potential of EphA10 as a drug target in breast cancer. Immunohistochemical staining of clinical tissue sections revealed that EphA10 was expressed in various breast cancer subtypes, including triple negative breast cancers (TNBCs), with no expression observed in normal tissues apart from testis. Ligand-dependent proliferation was observed in EphA10-transfected MDA-MB-435 cells (MDA-MB-435(EphA10)) and native TNBC cells (MDA-MB-436). However, this phenomenon was not observed in parental MDA-MB-435 cells which express a low level of EphA10. Finally, tumor growth was significantly suppressed by administration of an anti-EphA10 monoclonal antibody in a xenograft mouse model. These results suggest that inhibition of EphA10 signaling may be a novel therapeutic option for management of breast cancer, including TNBCs which are currently not treated with molecularly targeted agents. PMID:24946238

  12. Structural Basis for Induction of Peripheral Neuropathy by Microtubule-Targeting Cancer Drugs.

    Science.gov (United States)

    Smith, Jennifer A; Slusher, Barbara S; Wozniak, Krystyna M; Farah, Mohamed H; Smiyun, Gregoriy; Wilson, Leslie; Feinstein, Stuart; Jordan, Mary Ann

    2016-09-01

    Peripheral neuropathy is a serious, dose-limiting side effect of cancer treatment with microtubule-targeting drugs. Symptoms present in a "stocking-glove" distribution, with longest nerves affected most acutely, suggesting a length-dependent component to the toxicity. Axonal transport of ATP-producing mitochondria along neuronal microtubules from cell body to synapse is crucial to neuronal function. We compared the effects of the drugs paclitaxel and ixabepilone that bind along the lengths of microtubules and the drugs eribulin and vincristine that bind at microtubule ends, on mitochondrial trafficking in cultured human neuronal SK-N-SH cells and on axonal transport in mouse sciatic nerves. Antiproliferative concentrations of paclitaxel and ixabepilone significantly inhibited the anterograde transport velocity of mitochondria in neuronal cells, whereas eribulin and vincristine inhibited transport only at significantly higher concentrations. Confirming these observations, anterogradely transported amyloid precursor protein accumulated in ligated sciatic nerves of control and eribulin-treated mice, but not in paclitaxel-treated mice, indicating that paclitaxel inhibited anterograde axonal transport, whereas eribulin did not. Electron microscopy of sciatic nerves of paclitaxel-treated mice showed reduced organelle accumulation proximal to the ligation consistent with inhibition of anterograde (kinesin based) transport by paclitaxel. In contrast, none of the drugs significantly affected retrograde (dynein based) transport in neuronal cells or mouse nerves. Collectively, these results suggest that paclitaxel and ixabepilone, which bind along the lengths and stabilize microtubules, inhibit kinesin-based axonal transport, but not dynein-based transport, whereas the microtubule-destabilizing drugs, eribulin and vincristine, which bind preferentially to microtubule ends, have significantly less effect on all microtubule-based axonal transport. Cancer Res; 76(17); 5115-23.

  13. Inulin-based polymer coated SPIONs as potential drug delivery systems for targeted cancer therapy.

    Science.gov (United States)

    Scialabba, C; Licciardi, M; Mauro, N; Rocco, F; Ceruti, M; Giammona, G

    2014-11-01

    This paper deal with the synthesis and characterization of PEGylated squalene-grafted-inulin amphiphile capable of self-assembling and self-organizing into nanocarriers once placed in aqueous media. It was exploited as coating agent for obtaining doxorubicin loaded superparamagnetic iron oxide nanoparticles (SPIONs) endowed with stealth like behavior and excellent physicochemical stability. Inulin was firstly modified in the side chain with primary amine groups, followed in turn by conjugation with squalenoyl derivatives through common amidic coupling agents and PEGylation by imine linkage. Polymer coated SPIONs were so obtained by spontaneous self-assembling of inulin copolymer onto magnetite surface involving hydrophobic-hydrophobic interactions between the metallic core and the squalene moieties. The system was characterized in terms of hydrodynamic radius, zeta potential, shape and drug loading capacity. On the whole, the stealth-like shell stabilized the suspension in aqueous media, though allowing the release of the doxorubicin loaded in therapeutic range. The cytotoxicity profile on cancer (HCT116) cell line and in vitro drug uptake were evaluated both with and without an external magnetic field used as targeting agent and uptake promoter, displaying that magnetic targeting implies advantageous therapeutic effects, that is amplified drug uptake and increased anticancer activity throughout the tumor mass.

  14. Potential prostate cancer drug target: bioactivation of androstanediol by conversion to dihydrotestosterone.

    Science.gov (United States)

    Mohler, James L; Titus, Mark A; Wilson, Elizabeth M

    2011-09-15

    High-affinity binding of dihydrotestosterone (DHT) to the androgen receptor (AR) initiates androgen-dependent gene activation, required for normal male sex development in utero, and contributes to prostate cancer development and progression in men. Under normal physiologic conditions, DHT is synthesized predominantly by 5α-reduction of testosterone, the major circulating androgen produced by the testis. During androgen deprivation therapy, intratumoral androgen production is sufficient for AR activation and prostate cancer growth, even though circulating testicular androgen levels are low. Recent studies indicate that the metabolism of 5α-androstane-3α, 17β-diol by 17β-hydroxysteroid dehydrogenase 6 in benign prostate and prostate cancer cells is a major biosynthetic pathway for intratumoral synthesis of DHT, which binds AR and initiates transactivation to promote prostate cancer growth during androgen deprivation therapy. Drugs that target the so-called backdoor pathway of DHT synthesis provide an opportunity to enhance clinical response to luteinizing-hormone-releasing hormone (LHRH) agonists or antagonists, AR antagonists, and inhibitors of 5α-reductase enzymes (finasteride or dutasteride), and other steroid metabolism enzyme inhibitors (ketoconazole or the recently available abiraterone acetate). PMID:21705451

  15. Using Gold Nanoparticles as Delivery Vehicles for Targeted Delivery of Chemotherapy Drug Fludarabine Phosphate to Treat Hematological Cancers.

    Science.gov (United States)

    Song, Steven; Hao, Yuzhi; Yang, Xiaoyan; Patra, Prabir; Chen, Jie

    2016-03-01

    Nanotechnology is an emerging paradigm for creating functional nanoscale materials for various biomedical applications. In this study, a new nanotechnology-based drug delivery method was developed using gold nanoparticles (GNPs) as a delivery vehicle to reduce adverse drug side effects. Fludarabine Phosphate is a commercial chemotherapy drug used in cancer treatment, and has ability to kill various cancer cells. KG-1 cell, a type of acute cancer leukemia cell, was selected as a proof-of-concept target in this study. Due to the small size of GNPs, they can help Fludarabine Phosphate enter cancer cells more efficiently and better interfere with DNA synthesis in the cancer cells. To enhance targeting ability, folic acid molecules were also covalently linked to GNPs, resulting in GNP-Fludarabine-folic acid (GNP-F/f). Compared to treatments with GNP-F or drugs on its own (Fludarabine Phosphate), the GNP-F/f achieves much improved cell-killing effects. The UV-Vis spectra results also revealed that the drugs had successfully bonded covalently to the GNPs. The higher cell-killing efficiency of GNP-F/f compared with GNP-Fludarabine (GNP-F) or drugs on their own further validates the effectiveness of both the vectors (GNPs) and folic acid in enhancing the drug delivery to the cancer cells. The MTT viability tests showed that the GNPs had no cytotoxicity.

  16. Chaperone-Targeting Cytotoxin and Endoplasmic Reticulum Stress-Inducing Drug Synergize to Kill Cancer Cells

    Directory of Open Access Journals (Sweden)

    Joseph M. Backer

    2009-11-01

    Full Text Available Diverse physiological and therapeutic insults that increase the amount of unfolded or misfolded proteins in the endoplasmic reticulum (ER induce the unfolded protein response, an evolutionarily conserved protective mechanism that manages ER stress. Glucose-regulated protein 78/immunoglobulin heavy-chain binding protein (GRP78/BiP is an ER-resident protein that plays a central role in the ER stress response and is the only known substrate of the proteolytic A subunit (SubA of a novel bacterial AB5 toxin. Here, we report that an engineered fusion protein, epidermal growth factor (EGF-SubA, combining EGF and SubA, is highly toxic to growing and confluent epidermal growth factor receptor-expressing cancer cells, and its cytotoxicity is mediated by a remarkably rapid cleavage of GRP78/BiP. Systemic delivery of EGF-SubA results in a significant inhibition of human breast and prostate tumor xenografts in mouse models. Furthermore, EGF-SubA dramatically increases the sensitivity of cancer cells to the ER stress-inducing drug thapsigargin, and vice versa, demonstrating the first example of mechanism-based synergism in the action of a cytotoxin and an ER-targeting drug.

  17. Targeted drug delivery nanosystems based on copolymer poly(lactide)-tocopheryl polyethylene glycol succinate for cancer treatment

    Science.gov (United States)

    Thu Ha, Phuong; Nguyen, Hoai Nam; Doan Do, Hai; Thong Phan, Quoc; Nguyet Tran Thi, Minh; Phuc Nguyen, Xuan; Nhung Hoang Thi, My; Huong Le, Mai; Nguyen, Linh Toan; Quang Bui, Thuc; Hieu Phan, Van

    2016-03-01

    Along with the development of nanotechnology, drug delivery nanosystems (DDNSs) have attracted a great deal of concern among scientists over the world, especially in cancer treatment. DDNSs not only improve water solubility of anticancer drugs but also increase therapeutic efficacy and minimize the side effects of treatment methods through targeting mechanisms including passive and active targeting. Passive targeting is based on the nano-size of drug delivery systems while active targeting is based on the specific bindings between targeting ligands attached on the drug delivery systems and the unique receptors on the cancer cell surface. In this article we present some of our results in the synthesis and testing of DDNSs prepared from copolymer poly(lactide)-tocopheryl polyethylene glycol succinate (PLA-TPGS), which carry anticancer drugs including curcumin, paclitaxel and doxorubicin. In order to increase the targeting effect to cancer cells, active targeting ligand folate was attached to the DDNSs. The results showed copolymer PLA-TPGS to be an excellent carrier for loading hydrophobic drugs (curcumin and paclitaxel). The fabricated DDNSs had a very small size (50-100 nm) and enhanced the cellular uptake and cytotoxicity of drugs. Most notably, folate-decorated paclitaxel-loaded copolymer PLA-TPGS nanoparticles (Fol/PTX/PLA-TPGS NPs) were tested on tumor-bearing nude mice. During the treatment time, Fol/PTX/PLA-TPGS NPs always exhibited the best tumor growth inhibition compared to free paclitaxel and paclitaxel-loaded copolymer PLA-TPGS nanoparticles. All results evidenced the promising potential of copolymer PLA-TPGS in fabricating targeted DDNSs for cancer treatment.

  18. Natural product Celastrol destabilizes tubulin heterodimer and facilitates mitotic cell death triggered by microtubule-targeting anti-cancer drugs.

    Directory of Open Access Journals (Sweden)

    Hakryul Jo

    Full Text Available BACKGROUND: Microtubule drugs are effective anti-cancer agents, primarily due to their ability to induce mitotic arrest and subsequent cell death. However, some cancer cells are intrinsically resistant or acquire a resistance. Lack of apoptosis following mitotic arrest is thought to contribute to drug resistance that limits the efficacy of the microtubule-targeting anti-cancer drugs. Genetic or pharmacological agents that selectively facilitate the apoptosis of mitotic arrested cells present opportunities to strengthen the therapeutic efficacy. METHODOLOGY AND PRINCIPAL FINDINGS: We report a natural product Celastrol targets tubulin and facilitates mitotic cell death caused by microtubule drugs. First, in a small molecule screening effort, we identify Celastrol as an inhibitor of neutrophil chemotaxis. Subsequent time-lapse imaging analyses reveal that inhibition of microtubule-mediated cellular processes, including cell migration and mitotic chromosome alignment, is the earliest events affected by Celastrol. Disorganization, not depolymerization, of mitotic spindles appears responsible for mitotic defects. Celastrol directly affects the biochemical properties of tubulin heterodimer in vitro and reduces its protein level in vivo. At the cellular level, Celastrol induces a synergistic apoptosis when combined with conventional microtubule-targeting drugs and manifests an efficacy toward Taxol-resistant cancer cells. Finally, by time-lapse imaging and tracking of microtubule drug-treated cells, we show that Celastrol preferentially induces apoptosis of mitotic arrested cells in a caspase-dependent manner. This selective effect is not due to inhibition of general cell survival pathways or mitotic kinases that have been shown to enhance microtubule drug-induced cell death. CONCLUSIONS AND SIGNIFICANCE: We provide evidence for new cellular pathways that, when perturbed, selectively induce the apoptosis of mitotic arrested cancer cells, identifying a

  19. A Synthetic Aptamer-Drug Adduct for Targeted Liver Cancer Therapy.

    Directory of Open Access Journals (Sweden)

    Thu Le Trinh

    Full Text Available AS1411 (previously known as AGRO100 is a 26 nucleotide guanine-rich DNA aptamer which forms a guanine quadruplex structure. AS1411 has shown promising utility as a treatment for cancers in Phase I and Phase II clinical trials without causing major side-effects. AS1411 inhibits tumor cell growth by binding to nucleolin which is aberrantly expressed on the cell membrane of many tumors. In this study, we utilized a simple technique to conjugate a widely-used chemotherapeutic agent, doxorubicin (Dox, to AS1411 to form a synthetic Drug-DNA Adduct (DDA, termed as AS1411-Dox. We demonstrate the utility of AS1411-Dox in the treatment of hepatocellular carcinoma (HCC by evaluating the targeted delivery of Dox to Huh7 cells in vitro and in a murine xenograft model of HCC.

  20. Comparative evaluation of novel biodegradable nanoparticles for the drug targeting to breast cancer cells.

    Science.gov (United States)

    Mattu, C; Pabari, R M; Boffito, M; Sartori, S; Ciardelli, G; Ramtoola, Z

    2013-11-01

    Nanomedicine formulations such as biodegradable nanoparticles (nps) and liposomes offer several advantages over traditional routes of administration: due to their small size, nanocarriers are able to selectively accumulate inside tumours or inflammatory tissues, resulting in improved drug efficacy and reduced side effects. To further augment targeting ability of nanoparticles towards tumour cells, specific ligands or antibodies that selectively recognise biomarkers over-expressed on cancer cells, can be attached to the surface either by chemical bond or by hydrophilic/hydrophobic interactions. In the present work, Herceptin (HER), a monoclonal antibody (mAb) able to selectively recognise HER-2 over-expressing tumour cells (such as breast and ovarian cancer cells), was absorbed on the surface of nanoparticles through hydrophilic/hydrophobic interactions. Nps were prepared by a modified single emulsion solvent evaporation method with five different polymers: three commercial polyesters (poly(ε-caprolactone) (PCL), poly (D,L-lactide) (PLA) and poly (D,L-lactide-co-.glycolide) (PLGA)) and two novel biodegradable polyesterurethanes (PURs) based on Poly(ε-caprolactone) blocks, synthesised with different chain extenders (1,4-cyclohexane dimethanol (CDM) and N-Boc-serinol). Polyurethanes were introduced as matrix-forming materials for nanoparticles due to their high chemical versatility, which allows tailoring of the materials final properties by properly selecting the reagents. All nps exhibited a small size and negative surface charge, suitable for surface functionalisation with mAb through hydrophilic/hydrophobic interactions. The extent of cellular internalisation was tested on two different cell lines: MCF-7 and SK-BR-3 breast cancer cells showing a normal and a high expression of the HER-2 receptor, respectively. Paclitaxel, a model anti-neoplastic drug, was encapsulated inside all nps, and release profiles and cytotoxicity on SK-BR-3 cells were also assessed

  1. The Metaboloepigenetic Dimension of Cancer Stem Cells: Evaluating the Market Potential for New Metabostemness-Targeting Oncology Drugs.

    Science.gov (United States)

    Menendez, Javier A

    2015-01-01

    The current global portfolio of oncology drugs is unlikely to produce durable disease remission for millions of cancer patients worldwide. This is due, in part, to the existence of so-called cancer stem cells (CSCs), a particularly aggressive type of malignant cell that is capable of indefinite self-replication, is refractory to conventional treatments, and is skilled at spreading and colonizing distant organs. To date, no drugs from big-league Pharma companies are capable of killing CSCs. Why? Quite simply, a classic drug development approach based on mutated genes and pathological protein products cannot efficiently target the plastic, epigenetic proclivity of cancer tissues to generate CSCs. Recent studies have proposed that certain elite metabolites (oncometabolites) and other common metabolites can significantly influence the establishment and maintenance of epigenetic signatures of stemness and cancer. Consequently, cellular metabolism and the core epigenetic codes, DNA methylation and histone modification, can be better viewed as an integrated metaboloepigenetic dimension of CSCs, which we have recently termed cancer metabostemness. By targeting weaknesses in the bridge connecting metabolism and epigenetics, a new generation of metabostemnessspecific drugs can be generated for potent and long-lasting elimination of life-threatening CSCs. Here I evaluate the market potential of re-modeling the oncology drug pipeline by discovering and developing new metabolic approaches able to target the apparently undruggable epigenetic programs that dynamically regulate the plasticity of non-CSC and CSC cellular states.

  2. Acid-mediated Lipinski’s second rule: application to drug design and targeting in cancer

    OpenAIRE

    Omran, Ziad; Rauch, Cyril

    2014-01-01

    With a predicted 382.4 per 100,000 people expected to suffer from some form of malignant neoplasm by 2015, and a current death toll of 1 out of 8 deaths worldwide, improving treatment and/or drug design is an essential focus of cancer research. Multi-drug resistance is the leading cause of chemotherapeutic failure, and delivery of anticancer drugs to the inside of cancerous cells is another major challenge. Fifteen years ago, in a completely different field in which improving drug delivery is...

  3. Targeted anti-cancer prodrug based on carbon nanotube with photodynamic therapeutic effect and pH-triggered drug release

    Energy Technology Data Exchange (ETDEWEB)

    Fan, Jianquan; Zeng, Fang, E-mail: mcfzeng@scut.edu.cn; Xu, Jiangsheng; Wu, Shuizhu, E-mail: shzhwu@scut.edu.cn [South China University of Technology, College of Materials Science and Engineering, State Key Laboratory of Luminescent Materials and Devices (China)

    2013-09-15

    Herein, we describe a multifunctional anti-cancer prodrug system based on water-dispersible carbon nanotube (CNT); this prodrug system features active targeting, pH-triggered drug release, and photodynamic therapeutic properties. For this prodrug system (with the size of {approx}100-300 nm), an anti-cancer drug, doxorubicin (DOX), was incorporated onto CNT via a cleavable hydrazone bond; and a targeting ligand (folic acid) was also coupled onto CNT. This prodrug can preferably enter folate receptor (FR)-positive cancer cells and undergo intracellular release of the drug triggered by the reduced pH. The targeted CNT-based prodrug system can cause lower cell viability toward FR-positive cells compared to the non-targeted ones. Moreover, the CNT carrier exhibits photodynamic therapeutic (PDT) action; and the cell viability of FR-positive cancer cells can be further reduced upon light irradiation. The dual effects of pH-triggered drug release and PDT increase the therapeutic efficacy of the DOX-CNT prodrug. This study may offer some useful insights on designing and improving the applicability of CNT for other drug delivery systems.

  4. Targeting the chromatin remodeling enzyme BRG1 increases the efficacy of chemotherapy drugs in breast cancer cells

    Science.gov (United States)

    Wu, Qiong; Sharma, Soni; Cui, Hang; LeBlanc, Scott E.; Zhang, Hong; Muthuswami, Rohini; Nickerson, Jeffrey A.; Imbalzano, Anthony N.

    2016-01-01

    Brahma related gene product 1 (BRG1) is an ATPase that drives the catalytic activity of a subset of the mammalian SWI/SNF chromatin remodeling enzymes. BRG1 is overexpressed in most human breast cancer tumors without evidence of mutation and is required for breast cancer cell proliferation. We demonstrate that knockdown of BRG1 sensitized triple negative breast cancer cells to chemotherapeutic drugs used to treat breast cancer. An inhibitor of the BRG1 bromodomain had no effect on breast cancer cell viability, but an inhibitory molecule that targets the BRG1 ATPase activity recapitulated the increased drug efficacy observed in the presence of BRG1 knockdown. We further demonstrate that inhibition of BRG1 ATPase activity blocks the induction of ABC transporter genes by these chemotherapeutic drugs and that BRG1 binds to ABC transporter gene promoters. This inhibition increased intracellular concentrations of the drugs, providing a likely mechanism for the increased chemosensitivity. Since ABC transporters and their induction by chemotherapy drugs are a major cause of chemoresistance and treatment failure, these results support the idea that targeting the enzymatic activity of BRG1 would be an effective adjuvant therapy for breast cancer. PMID:27029062

  5. Efficient pH Dependent Drug Delivery to Target Cancer Cells by Gold Nanoparticles Capped with Carboxymethyl Chitosan

    Directory of Open Access Journals (Sweden)

    Alle Madhusudhan

    2014-05-01

    Full Text Available Doxorubicin (DOX was immobilized on gold nanoparticles (AuNPs capped with carboxymethyl chitosan (CMC for effective delivery to cancer cells. The carboxylic group of carboxymethyl chitosan interacts with the amino group of the doxorubicin (DOX forming stable, non-covalent interactions on the surface of AuNPs. The carboxylic group ionizes at acidic pH, thereby releasing the drug effectively at acidic pH suitable to target cancer cells. The DOX loaded gold nanoparticles were effectively absorbed by cervical cancer cells compared to free DOX and their uptake was further increased at acidic conditions induced by nigericin, an ionophore that causes intracellular acidification. These results suggest that DOX loaded AuNPs with pH-triggered drug releasing properties is a novel nanotheraputic approach to overcome drug resistance in cancer.

  6. Efficient pH Dependent Drug Delivery to Target Cancer Cells by Gold Nanoparticles Capped with Carboxymethyl Chitosan

    OpenAIRE

    Alle Madhusudhan; Gangapuram Bhagavanth Reddy; Maragoni Venkatesham; Guttena Veerabhadram; Dudde Anil Kumar; Sumathi Natarajan; Ming-Yeh Yang; Anren Hu; Singh, Surya S.

    2014-01-01

    Doxorubicin (DOX) was immobilized on gold nanoparticles (AuNPs) capped with carboxymethyl chitosan (CMC) for effective delivery to cancer cells. The carboxylic group of carboxymethyl chitosan interacts with the amino group of the doxorubicin (DOX) forming stable, non-covalent interactions on the surface of AuNPs. The carboxylic group ionizes at acidic pH, thereby releasing the drug effectively at acidic pH suitable to target cancer cells. The DOX loaded gold nanoparticles were effectively abs...

  7. A computational strategy to select optimized protein targets for drug development toward the control of cancer diseases.

    Science.gov (United States)

    Carels, Nicolas; Tilli, Tatiana; Tuszynski, Jack A

    2015-01-01

    In this report, we describe a strategy for the optimized selection of protein targets suitable for drug development against neoplastic diseases taking the particular case of breast cancer as an example. We combined human interactome and transcriptome data from malignant and control cell lines because highly connected proteins that are up-regulated in malignant cell lines are expected to be suitable protein targets for chemotherapy with a lower rate of undesirable side effects. We normalized transcriptome data and applied a statistic treatment to objectively extract the sub-networks of down- and up-regulated genes whose proteins effectively interact. We chose the most connected ones that act as protein hubs, most being in the signaling network. We show that the protein targets effectively identified by the combination of protein connectivity and differential expression are known as suitable targets for the successful chemotherapy of breast cancer. Interestingly, we found additional proteins, not generally targeted by drug treatments, which might justify the extension of existing formulation by addition of inhibitors designed against these proteins with the consequence of improving therapeutic outcomes. The molecular alterations observed in breast cancer cell lines represent either driver events and/or driver pathways that are necessary for breast cancer development or progression. However, it is clear that signaling mechanisms of the luminal A, B and triple negative subtypes are different. Furthermore, the up- and down-regulated networks predicted subtype-specific drug targets and possible compensation circuits between up- and down-regulated genes. We believe these results may have significant clinical implications in the personalized treatment of cancer patients allowing an objective approach to the recycling of the arsenal of available drugs to the specific case of each breast cancer given their distinct qualitative and quantitative molecular traits. PMID:25625699

  8. A computational strategy to select optimized protein targets for drug development toward the control of cancer diseases.

    Directory of Open Access Journals (Sweden)

    Nicolas Carels

    Full Text Available In this report, we describe a strategy for the optimized selection of protein targets suitable for drug development against neoplastic diseases taking the particular case of breast cancer as an example. We combined human interactome and transcriptome data from malignant and control cell lines because highly connected proteins that are up-regulated in malignant cell lines are expected to be suitable protein targets for chemotherapy with a lower rate of undesirable side effects. We normalized transcriptome data and applied a statistic treatment to objectively extract the sub-networks of down- and up-regulated genes whose proteins effectively interact. We chose the most connected ones that act as protein hubs, most being in the signaling network. We show that the protein targets effectively identified by the combination of protein connectivity and differential expression are known as suitable targets for the successful chemotherapy of breast cancer. Interestingly, we found additional proteins, not generally targeted by drug treatments, which might justify the extension of existing formulation by addition of inhibitors designed against these proteins with the consequence of improving therapeutic outcomes. The molecular alterations observed in breast cancer cell lines represent either driver events and/or driver pathways that are necessary for breast cancer development or progression. However, it is clear that signaling mechanisms of the luminal A, B and triple negative subtypes are different. Furthermore, the up- and down-regulated networks predicted subtype-specific drug targets and possible compensation circuits between up- and down-regulated genes. We believe these results may have significant clinical implications in the personalized treatment of cancer patients allowing an objective approach to the recycling of the arsenal of available drugs to the specific case of each breast cancer given their distinct qualitative and quantitative molecular

  9. Targeting CD44 by Hyaluronic Acid-Based Nano Drug Delivery Systems May Eradicate Cancer Stem Cells in Human Breast Cancer

    Directory of Open Access Journals (Sweden)

    Rassoul Dinarvand

    2011-01-01

    Full Text Available Despite the significant progress in cancer diagnosis and therapy, still invasion and metastasis of cancer cells, development of drug resistance and cancer recurrence are the main causes of mortality in cancer patients. Recent researches on cancer stem cells (CSCs along with the role of CD44 marker in drug resistance and as the main marker of breast CSCs, highlight the importance of CD44 in cancer targeted therapy. Additionally, co-localization of MDR1 and CD44 in cancer cell population showed that one protein directly influences the expression of the other and disruption of interaction has significant effects on drug resistance, cell migration and in vitro invasion. Based on the above information, using nanotechnology-derived CD44 targeted drug delivery systems will be able to address recurrence of the disease and other major obstacles in cancer chemotherapy. Therefore, we hypotheses that using combination of cytotoxic agents and CSC specific agents anchored in hyaluronic acid (as the endogenous substrate of CD44, have the potential to develop novel drug delivery systems to eradicate breast cancer.

  10. Half-Antibody Functionalized Lipid-Polymer Hybrid Nanoparticles for Targeted Drug Delivery to Carcinoembryonic Antigen (CEA) Presenting Pancreatic Cancer Cells

    Science.gov (United States)

    Hu, Che-Ming Jack; Kaushal, Sharmeela; Tran Cao, Hop S.; Aryal, Santosh; Sartor, Marta; Esener, Sadik; Bouvet, Michael; Zhang, Liangfang

    2010-01-01

    Current chemotherapy regimens against pancreatic cancer are met with little success as poor tumor vascularization significantly limits the delivery of oncological drugs. High-dose targeted drug delivery, through which a drug delivery vehicle releases a large payload upon tumor localization, is thus a promising alternative strategy against this lethal disease. Herein, we synthesize anti-CEA half-antibody conjugated lipid-polymer hybrid nanoparticles and characterize their ligand conjugation yields, physicochemical properties, and targeting ability against pancreatic cancer cells. Under the same drug loading, the half-antibody targeted nanoparticles show enhanced cancer killing effect compared to the corresponding non-targeted nanoparticles. PMID:20394436

  11. Research Progress in the Use of Drugs for Breast Cancer Targeted Therapy

    Institute of Scientific and Technical Information of China (English)

    Shun'e Yang; Bing Zhao

    2008-01-01

    In recent years,many significant advances have been made on molecular target therapy to aim directly at epidermal growth factor receptors and vascular endothelial growth factor in breast cancers.Clinical studies of such agents as trastuzumab,lapatinib,erlotinib and bevacituzumab have been widely conducted.This paper will review the recent research progress related to targeted therapy.

  12. Quercetin and doxorubicin co-encapsulated biotin receptor-targeting nanoparticles for minimizing drug resistance in breast cancer.

    Science.gov (United States)

    Lv, Li; Liu, Chunxia; Chen, Chuxiong; Yu, Xiaoxia; Chen, Guanghui; Shi, Yonghui; Qin, Fengchao; Ou, Jiebin; Qiu, Kaifeng; Li, Guocheng

    2016-05-31

    The combination of a chemotherapeutic drug with a chemosensitizer has emerged as a promising strategy for cancers showing multidrug resistance (MDR). Herein we describe the simultaneous targeted delivery of two drugs to tumor cells by using biotin-decorated poly(ethylene glycol)-b-poly(ε-caprolactone) nanoparticles encapsulating the chemotherapeutic drug doxorubicin and the chemosensitizer quercetin (BNDQ). Next, the potential ability of BNDQ to reverse MDR in vitro and in vivo was investigated. Studies demonstrated that BNDQ was more effectively taken up with less efflux by doxorubicin-resistant MCF-7 breast cancer cells (MCF-7/ADR cells) than by the cells treated with the free drugs, single-drug-loaded nanoparticles, or non-biotin-decorated nanoparticles. BNDQ exhibited clear inhibition of both the activity and expression of P-glycoprotein in MCF-7/ADR cells. More importantly, it caused a significant reduction in doxorubicin resistance in MCF-7/ADR breast cancer cells both in vitro and in vivo, among all the groups. Overall, this study suggests that BNDQ has a potential role in the treatment of drug-resistant breast cancer. PMID:27058756

  13. Synthesis and biological evaluation of novel folic acid receptor-targeted, β-cyclodextrin-based drug complexes for cancer treatment.

    Directory of Open Access Journals (Sweden)

    Juan-Juan Yin

    Full Text Available Drug targeting is an active area of research and nano-scaled drug delivery systems hold tremendous potential for the treatment of neoplasms. In this study, a novel cyclodextrin (CD-based nanoparticle drug delivery system has been assembled and characterized for the therapy of folate receptor-positive [FR(+] cancer. Water-soluble folic acid (FA-conjugated CD carriers (FACDs were successfully synthesized and their structures were confirmed by 1D/2D nuclear magnetic resonance (NMR, matrix-assisted laser desorption ionization time-of-flight mass spectrometer (MALDI-TOF-MS, high performance liquid chromatography (HPLC, Fourier transform infrared spectroscopy (FTIR, and circular dichroism. Drug complexes of adamatane (Ada and cytotoxic doxorubicin (Dox with FACD were readily obtained by mixed solvent precipitation. The average size of FACD-Ada-Dox was 1.5-2.5 nm. The host-guest association constant K a was 1,639 M(-1 as determined by induced circular dichroism and the hydrophilicity of the FACDs was greatly enhanced compared to unmodified CD. Cellular uptake and FR binding competitive experiments demonstrated an efficient and preferentially targeted delivery of Dox into FR-positive tumor cells and a sustained drug release profile was seen in vitro. The delivery of Dox into FR(+ cancer cells via endocytosis was observed by confocal microscopy and drug uptake of the targeted nanoparticles was 8-fold greater than that of non-targeted drug complexes. Our docking results suggest that FA, FACD and FACD-Ada-Dox could bind human hedgehog interacting protein that contains a FR domain. Mouse cardiomyocytes as well as fibroblast treated with FACD-Ada-Dox had significantly lower levels of reactive oxygen species, with increased content of glutathione and glutathione peroxidase activity, indicating a reduced potential for Dox-induced cardiotoxicity. These results indicate that the targeted drug complex possesses high drug association and sustained drug release

  14. Could drugs inhibiting the mevalonate pathway also target cancer stem cells?

    Science.gov (United States)

    Likus, Wirginia; Siemianowicz, Krzysztof; Bieńk, Konrad; Pakuła, Małgorzata; Pathak, Himani; Dutta, Chhanda; Wang, Qiong; Shojaei, Shahla; Assaraf, Yehuda G; Ghavami, Saeid; Cieślar-Pobuda, Artur; Łos, Marek J

    2016-03-01

    Understanding the connection between metabolic pathways and cancer is very important for the development of new therapeutic approaches based on regulatory enzymes in pathways associated with tumorigenesis. The mevalonate cascade and its rate-liming enzyme HMG CoA-reductase has recently drawn the attention of cancer researchers because strong evidences arising mostly from epidemiologic studies, show that it could promote transformation. Hence, these studies pinpoint HMG CoA-reductase as a candidate proto-oncogene. Several recent epidemiological studies, in different populations, have proven that statins are beneficial for the treatment-outcome of various cancers, and may improve common cancer therapy strategies involving alkylating agents, and antimetabolites. Cancer stem cells/cancer initiating cells (CSC) are key to cancer progression and metastasis. Therefore, in the current review we address the different effects of statins on cancer stem cells. The mevalonate cascade is among the most pleiotropic, and highly interconnected signaling pathways. Through G-protein-coupled receptors (GRCP), it integrates extra-, and intracellular signals. The mevalonate pathway is implicated in cell stemness, cell proliferation, and organ size regulation through the Hippo pathway (e.g. Yap/Taz signaling axis). This pathway is a prime preventive target through the administration of statins for the prophylaxis of obesity-related cardiovascular diseases. Its prominent role in regulation of cell growth and stemness also invokes its role in cancer development and progression. The mevalonate pathway affects cancer metastasis in several ways by: (i) affecting epithelial-to-mesenchymal transition (EMT), (ii) affecting remodeling of the cytoskeleton as well as cell motility, (iii) affecting cell polarity (non-canonical Wnt/planar pathway), and (iv) modulation of mesenchymal-to-epithelial transition (MET). Herein we provide an overview of the mevalonate signaling network. We then briefly

  15. Bacillus-shape design of polymer based drug delivery systems with janus-faced function for synergistic targeted drug delivery and more effective cancer therapy.

    Science.gov (United States)

    Cui, Fei; Lin, Jinyan; Li, Yang; Li, Yanxiu; Wu, Hongjie; Yu, Fei; Jia, Mengmeng; Yang, Xiangrui; Wu, Shichao; Xie, Liya; Ye, Shefang; Luo, Fanghong; Hou, Zhenqing

    2015-04-01

    The particle shape of the drug delivery systems had a strong impact on their in vitro and in vivo performance, but there was limited availability of techniques to produce the specific shaped drug carriers. In this article, the novel methotrexate (MTX) decorated MPEG-PLA nanobacillus (MPEG-PLA-MTX NB) was prepared by the self-assembly technique followed by the extrusion through SPG membrane with high N2 pressure for targeted drug delivery, in which Janus-like MTX was not only used as a specific anticancer drug but could also be served as a tumor-targeting ligand. The MPEG-PLA-MTX NBs demonstrated much higher in vitro and in vivo targeting efficiency compared to the MPEG-PLA-MTX nanospheres (MPEG-PLA-MTX NSs) and MPEG-PLA nanospheres (MPEG-PLA NSs). In addition, the MPEG-PLA-MTX NBs also displayed much more excellent in vitro and in vivo antitumor activity than the MPEG-PLA-MTX NSs and free MTX injection. To our knowledge, this work provided the first example of the integration of the shape design (which mediated an early phase tumor accumulation and a late-phase cell internalization) and Janus-faced function (which mediated an early phase active targeting effect and a late-phase anticancer effect) on the basis of nanoscaled drug delivery systems. The highly convergent and cooperative drug delivery strategy opens the door to more drug delivery systems with new shapes and functions for cancer therapy.

  16. Enriched transcription factor signatures in triple negative breast cancer indicates possible targeted therapies with existing drugs

    Directory of Open Access Journals (Sweden)

    Scooter Willis

    2015-06-01

    Conclusion: With the increasing number of large sample size breast cancer cohorts, an exploratory analysis of genes that are consistently enriched in TN sharing common promoter motifs allows for the identification of possible therapeutic targets with extensive validation in patient derived data sets.

  17. Marketed Drugs Can Inhibit Cytochrome P450 27A1, a Potential New Target for Breast Cancer Adjuvant Therapy.

    Science.gov (United States)

    Mast, Natalia; Lin, Joseph B; Pikuleva, Irina A

    2015-09-01

    Cytochrome P450 CYP27A1 is the only enzyme in humans converting cholesterol to 27-hydroxycholesterol, an oxysterol of multiple functions, including tissue-specific modulation of estrogen and liver X receptors. Both receptors seem to mediate adverse effects of 27-hydroxycholesterol in breast cancer when the levels of this oxysterol are elevated. The present work assessed druggability of CYP27A1 as a potential antibreast cancer target. We selected 26 anticancer and noncancer medications, most approved by the Food and Drug Administration, and evaluated them first in vitro for inhibition of purified recombinant CYP27A1 and binding to the enzyme active site. Six strong CYP27A1 inhibitors/binders were identified. These were the two antibreast cancer pharmaceuticals anastrozole and fadrozole, antiprostate cancer drug bicalutamide, sedative dexmedetomidine, and two antifungals ravuconazole and posaconazole. Anastrozole was then tested in vivo on mice, which received subcutaneous drug injections for 1 week. Mouse plasma and hepatic 27-hydroxycholesterol levels were decreased 2.6- and 1.6-fold, respectively, whereas plasma and hepatic cholesterol content remained unchanged. Thus, pharmacologic CYP27A1 inhibition is possible in the whole body and individual organs, but does not negatively affect cholesterol elimination. Our results enhance the potential of CYP27A1 as an antibreast cancer target, could be of importance for the interpretation of Femara versus Anastrozole Clinical Evaluation Trial, and bring attention to posaconazole as a potential complementary anti-breast cancer medication. More medications on the US market may have unanticipated off-target inhibition of CYP27A1, and we propose strategies for their identification.

  18. A New Role for an Old Drug: Metformin Targets MicroRNAs in Treating Diabetes and Cancer.

    Science.gov (United States)

    Zhou, Joseph Yi; Xu, Biao; Li, Lixin

    2015-09-01

    MicroRNAs (miRNAs) are a family of short, noncoding, 19-23 base pair RNA molecules. Due to their unique role in gene regulation in various tissues, miRNAs play important roles in regulating insulin secretion, metabolic disease, and cancer biology. Emerging evidence demonstrates that miRNAs could also be novel diagnostic markers for a variety of disease states. Additionally, miRNAs have been found to function either as oncogenes, or tumor suppressor genes in cerian cancers. An increasing number of studies have been conducted investigating new drugs targeting miRNAs as a potential anticancer therapy. Metformin is the most widely prescribed medication for treating Type 2 diabetes (T2D). Recent clinical data suggests that metformin impacts the miRNA profile in T2D subjects. Most excitingly, studies have found that metformin is protective against cancer. The anticancer activity of metformin is mediated through a direct regulation of miRNAs, which further modulates several downstream genes in metabolic or preoncogenic pathways. These miRNAs are, therefore, prospective therapeutic targets for treating diabetes and cancer which is the topic of this review. Further study on the regulation of miRNAs by metformin could result in novel therapeutic strategies for recurrent or drug-esistant cancer, and as part of combinatorial approaches with conventional anticancer therapies. PMID:26936407

  19. Bispecific antibody complex pre-targeting and targeted delivery of polymer drug conjugates for imaging and therapy in dual human mammary cancer xenografts. Targeted polymer drug conjugates for cancer diagnosis and therapy

    Energy Technology Data Exchange (ETDEWEB)

    Khaw, Ban-An; Gada, Keyur S.; Patil, Vishwesh; Panwar, Rajiv; Mandapati, Savitri [Northeastern University, Department of Pharmaceutical Sciences, Bouve College of Health Sciences, School of Pharmacy, Boston, MA (United States); Hatefi, Arash [Rutgers University, Department of Pharmaceutics, New Brunswick, NJ (United States); Majewski, Stan [West Virginia University, Department of Radiology, Morgantown, WV (United States); Weisenberger, Andrew [Thomas Jefferson National Accelerator Facility, Jefferson Lab, Newport News, VA (United States)

    2014-08-15

    Doxorubicin, a frontline chemotherapeutic agent, limited by its cardiotoxicity and other tissue toxicities, was conjugated to N-terminal DTPA-modified polyglutamic acid (D-Dox-PGA) to produce polymer pro-drug conjugates. D-Dox-PGA or Tc-99 m labeled DTPA-succinyl-polylysine polymers (DSPL) were targeted to HER2-positive human mammary carcinoma (BT-474) in a double xenografted SCID mouse model also hosting HER2-negative human mammary carcinoma (BT-20). After pretargeting with bispecific anti-HER2-affibody-anti-DTPA-Fab complexes (BAAC), anti-DTPA-Fab or only phosphate buffered saline, D-Dox-PGA or Tc-99 m DSPL were administered. Positive therapeutic control mice were injected with Dox alone at maximum tolerated dose (MTD). Only BT-474 lesions were visualized by gamma imaging with Tc-99 m-DSPL; BT-20 lesions were not. Therapeutic efficacy was equivalent in mice pretargeted with BAAC/targeted with D-Dox-PGA to mice treated only with doxorubicin. There was no total body weight (TBW) loss at three times the doxorubicin equivalent MTD with D-Dox-PGA, whereas mice treated with doxorubicin lost 10 % of TBW at 2 weeks and 16 % after the second MTD injection leading to death of all mice. Our cancer imaging and pretargeted therapeutic approaches are highly target specific, delivering very high specific activity reagents that may result in the development of a novel theranostic application. HER/2 neu specific affibody-anti-DTPA-Fab bispecific antibody pretargeting of HER2 positive human mammary xenografts enabled exquisite targeting of polymers loaded with radioisotopes for molecular imaging and doxorubicin for effective therapy without the associating non-tumor normal tissue toxicities. (orig.)

  20. A cell-targeted, size-photocontrollable, nuclear-uptake nanodrug delivery system for drug-resistant cancer therapy.

    Science.gov (United States)

    Qiu, Liping; Chen, Tao; Öçsoy, Ismail; Yasun, Emir; Wu, Cuichen; Zhu, Guizhi; You, Mingxu; Han, Da; Jiang, Jianhui; Yu, Ruqin; Tan, Weihong

    2015-01-14

    The development of multidrug resistance (MDR) has become an increasingly serious problem in cancer therapy. The cell-membrane overexpression of P-glycoprotein (P-gp), which can actively efflux various anticancer drugs from the cell, is a major mechanism of MDR. Nuclear-uptake nanodrug delivery systems, which enable intranuclear release of anticancer drugs, are expected to address this challenge by bypassing P-gp. However, before entering the nucleus, the nanocarrier must pass through the cell membrane, necessitating coordination between intracellular and intranuclear delivery. To accommodate this requirement, we have used DNA self-assembly to develop a nuclear-uptake nanodrug system carried by a cell-targeted near-infrared (NIR)-responsive nanotruck for drug-resistant cancer therapy. Via DNA hybridization, small drug-loaded gold nanoparticles (termed nanodrugs) can self-assemble onto the side face of a silver-gold nanorod (NR, termed nanotruck) whose end faces were modified with a cell type-specific internalizing aptamer. By using this size-photocontrollable nanodrug delivery system, anticancer drugs can be efficiently accumulated in the nuclei to effectively kill the cancer cells. PMID:25479133

  1. FOXD1 promotes breast cancer proliferation and chemotherapeutic drug resistance by targeting p27

    International Nuclear Information System (INIS)

    Highlights: • FOXD1 is up-regulated in breast cancer tissues. • FOXD1 promotes breast cancer cell proliferation and chemoresistance by inducing G1 to S transition. • FOXD1 transcriptionally suppresses p27 expression. - Abstract: Forkhead transcription factors are essential for diverse processes in early embryonic development and organogenesis. As a member of the forkhead family, FOXD1 is required during kidney development and its inactivation results in failure of nephron progenitor cells. However, the role of FOXD1 in carcinogenesis and progression is still limited. Here, we reported that FOXD1 is a potential oncogene in breast cancer. We found that FOXD1 is up-regulated in breast cancer tissues. Depletion of FOXD1 expression decreases the ability of cell proliferation and chemoresistance in MDA-MB-231 cells, whereas overexpression of FOXD1 increases the ability of cell proliferation and chemoresistance in MCF-7 cells. Furthermore, we observed that FOXD1 induces G1 to S phase transition by targeting p27 expression. Our results suggest that FOXD1 may be a potential therapy target for patients with breast cancer

  2. FOXD1 promotes breast cancer proliferation and chemotherapeutic drug resistance by targeting p27

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, Yi-Fan; Zhao, Jing-Yu; Yue, Hong [Department of Anesthesiology, The First Affiliated Hospital of the General Hospital of CPLA, Beijing 100048 (China); Hu, Ke-Shi; Shen, Hao [Department of Anesthesiology, The General Hospital of CPLA, Beijing 100853 (China); Guo, Zheng-Gang, E-mail: gsgzg304@163.com [Department of Anesthesiology, The First Affiliated Hospital of the General Hospital of CPLA, Beijing 100048 (China); Su, Xiao-Jun, E-mail: lucusebibi@163.com [Department of Anesthesiology, The First Affiliated Hospital of the General Hospital of CPLA, Beijing 100048 (China)

    2015-01-02

    Highlights: • FOXD1 is up-regulated in breast cancer tissues. • FOXD1 promotes breast cancer cell proliferation and chemoresistance by inducing G1 to S transition. • FOXD1 transcriptionally suppresses p27 expression. - Abstract: Forkhead transcription factors are essential for diverse processes in early embryonic development and organogenesis. As a member of the forkhead family, FOXD1 is required during kidney development and its inactivation results in failure of nephron progenitor cells. However, the role of FOXD1 in carcinogenesis and progression is still limited. Here, we reported that FOXD1 is a potential oncogene in breast cancer. We found that FOXD1 is up-regulated in breast cancer tissues. Depletion of FOXD1 expression decreases the ability of cell proliferation and chemoresistance in MDA-MB-231 cells, whereas overexpression of FOXD1 increases the ability of cell proliferation and chemoresistance in MCF-7 cells. Furthermore, we observed that FOXD1 induces G1 to S phase transition by targeting p27 expression. Our results suggest that FOXD1 may be a potential therapy target for patients with breast cancer.

  3. 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.

  4. Recursive Random Lasso (RRLasso for Identifying Anti-Cancer Drug Targets.

    Directory of Open Access Journals (Sweden)

    Heewon Park

    Full Text Available Uncovering driver genes is crucial for understanding heterogeneity in cancer. L1-type regularization approaches have been widely used for uncovering cancer driver genes based on genome-scale data. Although the existing methods have been widely applied in the field of bioinformatics, they possess several drawbacks: subset size limitations, erroneous estimation results, multicollinearity, and heavy time consumption. We introduce a novel statistical strategy, called a Recursive Random Lasso (RRLasso, for high dimensional genomic data analysis and investigation of driver genes. For time-effective analysis, we consider a recursive bootstrap procedure in line with the random lasso. Furthermore, we introduce a parametric statistical test for driver gene selection based on bootstrap regression modeling results. The proposed RRLasso is not only rapid but performs well for high dimensional genomic data analysis. Monte Carlo simulations and analysis of the "Sanger Genomics of Drug Sensitivity in Cancer dataset from the Cancer Genome Project" show that the proposed RRLasso is an effective tool for high dimensional genomic data analysis. The proposed methods provide reliable and biologically relevant results for cancer driver gene selection.

  5. Global connectivity of hub residues in Oncoprotein structures encodes genetic factors dictating personalized drug response to targeted Cancer therapy

    Science.gov (United States)

    Soundararajan, Venky; Aravamudan, Murali

    2014-12-01

    The efficacy and mechanisms of therapeutic action are largely described by atomic bonds and interactions local to drug binding sites. Here we introduce global connectivity analysis as a high-throughput computational assay of therapeutic action - inspired by the Google page rank algorithm that unearths most ``globally connected'' websites from the information-dense world wide web (WWW). We execute short timescale (30 ps) molecular dynamics simulations with high sampling frequency (0.01 ps), to identify amino acid residue hubs whose global connectivity dynamics are characteristic of the ligand or mutation associated with the target protein. We find that unexpected allosteric hubs - up to 20Å from the ATP binding site, but within 5Å of the phosphorylation site - encode the Gibbs free energy of inhibition (ΔGinhibition) for select protein kinase-targeted cancer therapeutics. We further find that clinically relevant somatic cancer mutations implicated in both drug resistance and personalized drug sensitivity can be predicted in a high-throughput fashion. Our results establish global connectivity analysis as a potent assay of protein functional modulation. This sets the stage for unearthing disease-causal exome mutations and motivates forecast of clinical drug response on a patient-by-patient basis. We suggest incorporation of structure-guided genetic inference assays into pharmaceutical and healthcare Oncology workflows.

  6. Nanoparticles inhibit cancer cell invasion and enhance antitumor efficiency by targeted drug delivery via cell surface-related GRP78

    Directory of Open Access Journals (Sweden)

    Zhao L

    2014-12-01

    Full Text Available Liang Zhao,1,* Hongdan Li,2,* Yijie Shi,1 Guan Wang,2 Liwei Liu,1 Chang Su,3 Rongjian Su2 1School of Pharmacy, Liaoning Medical University, Jinzhou, People’s Republic of China; 2Central Laboratory of Liaoning Medical University, Jinzhou, People’s Republic of China; 3School of Veterinary Medicine, Liaoning Medical University, Jinzhou, People’s Republic of China *These authors contributed equally to this work Abstract: Nanoparticles (NPs which target specific agents could effectively recognize the target cells and increase the stability of chemical agents by encapsulation. As such, NPs have been widely used in cancer treatment research. Recently, over 90% of treatment failure cases in patients with metastatic cancer were attributed to resistance to chemotherapy. Surface-exposed glucose-regulated protein of 78 kDa (GRP78 is expressed highly on many tumor cell surfaces in many human cancers and is related to the regulation of invasion and metastasis. Herein, we report that NPs conjugated with antibody against GRP78 (mAb GRP78-NPs inhibit the adhesion, invasion, and metastasis of hepatocellular carcinoma (HCC and promote drug delivery of 5-fluorouracil into GRP78 high-expressed human hepatocellular carcinoma cells. Our new findings suggest that mAb GRP78-NPs could enhance drug accumulation by effectively transporting NPs into cell surface GRP78-overexpressed human hepatocellular carcinoma cells and then inhibit cell proliferation and viability and induce cell apoptosis by regulating caspase-3. In brief, mAb GRP78-NPs effectively inhibit cancer cell invasion and enhance antitumor efficiency by targeted drug delivery. Keywords: 5-Fu, apoptosis, HCC, caspase-3

  7. Bcl-2 Targeted Structural Based Computer Aided Drug Design (CAAD For Therapeutic Assessment of Ricin in Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Meghraj Singh Baghel

    2015-03-01

    Full Text Available Cancer is referred as uncontrolled growth of abnormal cell mass. Out of the several types of cancer, prostate cancer (PC has become a major public health problem in men worldwide. Bcl-2 and p27 proteins are important regulatory molecules of cell cycle. Failure of cell cycle regulation leads to uncontrolled cell proliferation and causes cancer. For designing an effective structural based targeted drug, the assessment of protein-protein and protein-ligand interaction is indispensable. Therefore for treatment of PC, we selected a ribosome inactivating protein, Ricin, for assessment of its therapeutic nature. In the present work through CLUSTAL-W phylogenetic analysis, we found that Bcl-2 protein was found more conserved than p27. Further Bcl-2 was selected as target molecule for docking study with Ricin protein and other chemically synthetic inhibitor molecules i.e. 2-difluoromethylornithine (DFMO and Sarcosine, as lead molecule. Through HEX5.1 docking software docking was performed between targeted receptor and lead molecules. Energy maximum (Emax= -93.12 and energy minimum (Emin= -163.07 was observed for docking complex of optimised and energy minimised structure of Bcl-2 receptor with Ricin, which in turn shows that it is highly stable interaction. On the other hand, for synthetic inhibitors, we found energy maximum (DFMO; Emax= -77.17, Emin= -117.83 and Sarcosine; Emax= -72.23, Emin= -103.00 and energy minimum, which are significant more as compared to Ricin docking complex. Due to ricin docking complex having less energies shows stable interaction with Bcl-2. We also observed that Ricin is less toxic (lesser log P value as compared to other molecules by toxicity analysis by ADME/TOX server. These evidences show this Ricin could be better drug for PC. Further results are needed to validate by in vitro and in vivo study to make proper elucidation of drug for better PC treatment.

  8. A lysosome-targeted drug delivery system based on sorbitol backbone towards efficient cancer therapy.

    Science.gov (United States)

    Maniganda, Santhi; Sankar, Vandana; Nair, Jyothi B; Raghu, K G; Maiti, Kaustabh K

    2014-09-14

    A straightforward synthetic approach was adopted for the construction of a lysosome-targeted drug delivery system (TDDS) using sorbitol scaffold (Sor) linked to octa-guanidine and tetrapeptide GLPG, a peptide substrate of lysosomal cysteine protease, cathepsin B. The main objective was to efficiently deliver the potential anticancer drug, doxorubicin to the target sites, thereby minimizing dose-limiting toxicity. Three TDDS vectors were synthesized viz., DDS1: Sor-GLPG-Fl, DDS2: Sor-Fl (control) and DDS3: Sor-GLPGC-SMCC-Dox. Dox release from DDS3 in the presence of cathepsin B was studied by kinetics measurement based on the fluorescent property of Dox. The cytotoxicity of DDS1 was assessed and found to be non-toxic. Cellular internalization and colocalization studies of all the 3 systems were carried out by flow cytometry and confocal microscopy utilizing cathepsin B-expressing HeLa cells. DDS1 and DDS3 revealed significant localization within the lysosomes, in contrast to DDS2 (control). The doxorubicin-conjugated carrier, DDS3, demonstrated significant cytotoxic effect when compared to free Dox by MTT assay and also by flow cytometric analysis. The targeted approach with DDS3 is expected to be promising, because it is indicated to be advantageous over free Dox, which possesses dose-limiting toxicity, posing risk of injury to normal tissues.

  9. Medical treatment of breast cancer bone metastasis: from bisphosphonates to targeted drugs.

    Science.gov (United States)

    Erdogan, Bulent; Cicin, Irfan

    2014-01-01

    Breast cancer bone metastasis causing severe morbidity is commonly encountered in daily clinical practice. It causes pain, pathologic fractures, spinal cord and other nerve compression syndromes and life threatening hypercalcemia. Breast cancer metastasizes to bone through complicated steps in which numerous molecules play roles. Metastatic cells disrupt normal bone turnover and create a vicious cycle to which treatment efforts should be directed. Bisphosphonates have been used safely for more than two decades. As a group they delay time to first skeletal related event and reduce pain, but do not prevent development of bone metastasis in patients with no bone metastasis, and also do not prolong survival. The receptor activator for nuclear factor κB ligand inhibitor denosumab delays time to first skeletal related event and reduces the skeletal morbidity rate. Radionuclides are another treatment option for bone pain. New targeted therapies and radionuclides are still under investigation. In this review we will focus on mechanisms of bone metastasis and its medical treatment in breast cancer patients.

  10. Tumour-selective targeting of drug metabolizing enzymes to treat metastatic cancer.

    Science.gov (United States)

    Wierdl, Monika; Tsurkan, Lyudmila; Hatfield, M Jason; Potter, Philip M

    2016-10-01

    Carboxylesterases (CEs) are ubiquitous enzymes responsible for the detoxification of ester-containing xenobiotics. This hydrolysis reaction results in the formation of the corresponding carboxylic acid and alcohol. Due to their highly plastic active site, CEs can hydrolyze structurally very distinct and complex molecules. Because ester groups significantly increase the water solubility of compounds, they are frequently used in the pharmaceutical industry to make relatively insoluble compounds more bioavailable. By default, this results in CEs playing a major role in the distribution and metabolism of these esterified drugs. However, this can be exploited to selectively improve compound hydrolysis, and using specific in vivo targeting techniques can be employed to generate enhanced drug activity. Here, we seek to detail the human CEs involved in esterified molecule hydrolysis, compare and contrast these with CEs present in small mammals and describe novel methods to improve drug therapy by specific delivery of CEs to cells in vivo. Finally, we will discuss the development of such approaches for their potential application towards malignant disease.

  11. pH sensitive core-shell magnetic nanoparticles for targeted drug delivery in cancer therapy.

    Science.gov (United States)

    Lungu, Iulia Ioana; Rădulescu, Marius; Mogoşanu, George Dan; Grumezescu, Alexandru Mihai

    2016-01-01

    In the last decade, nanobiotechnology has evolved rapidly with an extensive impact on biomedical area. In order to improve bioavailability and minimize adverse effects, drug delivery systems based on magnetic nanocomposites are under development mainly for cancer imaging and antitumor therapy. In this regard, pH sensitive core-shell magnetic nanoparticles (NPs) with accurate controlled size and shape are synthesized by various modern methods, such as homogeneous precipitation, coprecipitation, microemulsion or polyol approaches, high temperature and hydrothermal reactions, sol-gel reactions, aerosol÷vapor processes and sonolysis. Due to their unique combined physico-chemical and biological properties (such as higher dispensability, chemical and thermal stability, biocompatibility), pH responsive core-shell magnetic NPs are widely investigated for controlled release of cytostatic drugs into the tumor site by means of pH change: magnetite@silicon dioxide (Fe3O4@SiO2), Fe3O4@titanium dioxide (TiO2), β-thiopropionate-polyethylene glycol (PEG)-modified Fe3O4@mSiO2, Fe3O4 NPs core coated with SiO2 with an imidazole group modified PEG-polypeptide (mPEG-poly-L-Asparagine), polyacrylic acid (PAA) and folic acid (FA) coating of the iron oxide NP core, methoxy polyethylene glycol-block-polymethacrylic acid-block-polyglycerol monomethacrylate (MPEG-b-PMAA-b-PGMA) attached by a PGMA block to a Fe3O4 core, PEG-modified polyamidoamine (PAMAM) dendrimer shell with Fe3O4 core and mesoporous silica coated on Fe3O4, mostly coated with an anticancer drug. This review paper highlights the modern research directions currently employed to demonstrate the utility of the pH responsive core-shell magnetic NPs in diagnosis and treatment of oncological diseases. PMID:27151685

  12. Risk Assessment of Drug Interaction Potential and Concomitant Dosing Pattern on Targeted Toxicities in Pediatric Cancer Patients

    OpenAIRE

    Barrett, Jeffrey S.; Patel, Dimple; Dombrowsky, Erin; Bajaj, Gaurav; Skolnik, Jeffrey M.

    2013-01-01

    This investigation evaluated the impact of potential drug interactions on the incidence of reported toxicities seen with common dosing patterns in children with cancer, with the intent of being able to screen and reduce the incidence of adverse drug reactions (ADRs) in the future. Toxicity reported in pediatric cancer patients treated at the Children’s Hospital of Philadelphia from 2004 to 2010 were abstracted from a cancer tumor registry and merged with drug order profiles from the medical r...

  13. Differential effects of drugs targeting cancer stem cell (CSC) and non-CSC populations on lung primary tumors and metastasis.

    Science.gov (United States)

    Larzabal, Leyre; El-Nikhely, Nefertiti; Redrado, Miriam; Seeger, Werner; Savai, Rajkumar; Calvo, Alfonso

    2013-01-01

    Cancer stem cells (CSCs) are thought to be responsible for tumor initiation and recurrence after chemotherapy. Targeting CSCs and non-CSCs with specific compounds may be an effective approach to reduce lung cancer growth and metastasis. The aim of this study was to investigate the effect of salinomycin, a selective inhibitor of CSCs, with or without combination with paclitaxel, in a metastatic model. To evaluate the effect of these drugs in metastasis and tumor microenvironment we took advantage of the immunocompetent and highly metastatic LLC mouse model. Aldefluor assays were used to analyze the ALDH+/- populations in murine LLC and human H460 and H1299 lung cancer cells. Salinomycin reduced the proportion of ALDH+ CSCs in LLC cells, whereas paclitaxel increased such population. The same effect was observed for the H460 and H1299 cell lines. Salinomycin reduced the tumorsphere formation capacity of LLC by more than 7-fold, but paclitaxel showed no effect. In in vivo experiments, paclitaxel reduced primary tumor volume but increased the number of metastatic nodules (p<0.05), whereas salinomycin had no effect on primary tumors but reduced lung metastasis (p<0.05). Combination of both drugs did not improve the effect of single therapies. ALDH1A1, SOX2, CXCR4 and SDF-1 mRNA levels were higher in metastatic lesions than in primary tumors, and were significantly elevated in both locations by paclitaxel treatment. On the contrary, such levels were reduced (or in some cases did not change) when mice were administered with salinomycin. The number of F4/80+ and CD11b+ cells was also reduced upon administration of both drugs, but particularly in metastasis. These results show that salinomycin targets ALDH+ lung CSCs, which has important therapeutic effects in vivo by reducing metastatic lesions. In contrast, paclitaxel (although reducing primary tumor growth) promotes the selection of ALDH+ cells that likely modify the lung microenvironment to foster metastasis. PMID

  14. Differential effects of drugs targeting cancer stem cell (CSC and non-CSC populations on lung primary tumors and metastasis.

    Directory of Open Access Journals (Sweden)

    Leyre Larzabal

    Full Text Available Cancer stem cells (CSCs are thought to be responsible for tumor initiation and recurrence after chemotherapy. Targeting CSCs and non-CSCs with specific compounds may be an effective approach to reduce lung cancer growth and metastasis. The aim of this study was to investigate the effect of salinomycin, a selective inhibitor of CSCs, with or without combination with paclitaxel, in a metastatic model. To evaluate the effect of these drugs in metastasis and tumor microenvironment we took advantage of the immunocompetent and highly metastatic LLC mouse model. Aldefluor assays were used to analyze the ALDH+/- populations in murine LLC and human H460 and H1299 lung cancer cells. Salinomycin reduced the proportion of ALDH+ CSCs in LLC cells, whereas paclitaxel increased such population. The same effect was observed for the H460 and H1299 cell lines. Salinomycin reduced the tumorsphere formation capacity of LLC by more than 7-fold, but paclitaxel showed no effect. In in vivo experiments, paclitaxel reduced primary tumor volume but increased the number of metastatic nodules (p<0.05, whereas salinomycin had no effect on primary tumors but reduced lung metastasis (p<0.05. Combination of both drugs did not improve the effect of single therapies. ALDH1A1, SOX2, CXCR4 and SDF-1 mRNA levels were higher in metastatic lesions than in primary tumors, and were significantly elevated in both locations by paclitaxel treatment. On the contrary, such levels were reduced (or in some cases did not change when mice were administered with salinomycin. The number of F4/80+ and CD11b+ cells was also reduced upon administration of both drugs, but particularly in metastasis. These results show that salinomycin targets ALDH+ lung CSCs, which has important therapeutic effects in vivo by reducing metastatic lesions. In contrast, paclitaxel (although reducing primary tumor growth promotes the selection of ALDH+ cells that likely modify the lung microenvironment to foster

  15. Magnetic Fluorescent Nanoformulation for Intracellular Drug Delivery to Human Breast Cancer, Primary Tumors, and Tumor Biopsies: Beyond Targeting Expectations.

    Science.gov (United States)

    El-Boubbou, Kheireddine; Ali, Rizwan; Bahhari, Hassan M; AlSaad, Khaled O; Nehdi, Atef; Boudjelal, Mohamed; AlKushi, Abdulmohsen

    2016-06-15

    We report the development of a chemotherapeutic nanoformulation made of polyvinylpyrrolidone-stabilized magnetofluorescent nanoparticles (Fl-PMNPs) loaded with anticancer drugs as a promising drug carrier homing to human breast cancer cells, primary tumors, and solid tumors. First, nanoparticle uptake and cell death were evaluated in three types of human breast cells: two metastatic cancerous MCF-7 and MDA-MB-231 cells and nontumorigenic MCF-10A cells. While Fl-PMNPs were not toxic to cells even at the highest concentrations used, Dox-loaded Fl-PMNPs showed significant potency, effectively killing the different breast cancer cells, albeit at different affinities. Interestingly and superior to free Dox, Dox-loaded Fl-PMNPs were found to be more effective in killing the metastatic cells (2- to 3-fold enhanced cytotoxicities for MDA-MB-231 compared to MCF-7), compared to the normal noncancerous MCF-10A cells (up to 8-fold), suggesting huge potentials as selective anticancer agents. Electron and live confocal microscopy imaging mechanistically confirmed that the nanoparticles were successfully endocytosed and packaged into vesicles inside the cytoplasm, where Dox is released and then translocated to the nucleus exerting its cytotoxic action and causing apoptotic cell death. Furthermore, commendable and enhanced penetration in 3D multilayered primary tumor cells derived from primary lesions as well as in patient breast tumor biopsies was observed, killing the tumor cells inside. The designed nanocarriers described here can potentially open new opportunities for breast cancer patients, especially in theranostic imaging and hyperthermia. While many prior studies have focused on targeting ligands to specific receptors to improve efficacies, we discovered that even with passive-targeted tailored delivery system enhanced toxic responses can be attained. PMID:27269304

  16. pH-Sensitive ZnO Quantum Dots-Doxorubicin Nanoparticles for Lung Cancer Targeted Drug Delivery.

    Science.gov (United States)

    Cai, Xiaoli; Luo, Yanan; Zhang, Weiying; Du, Dan; Lin, Yuehe

    2016-08-31

    In this paper, we reported a ZnO quantum dots-based pH-responsive drug delivery platform for intracellular controlled release of drugs. Acid-decomposable, luminescent aminated ZnO quantum dots (QDs) were synthesized as nanocarriers with ultrasmall size (∼3 nm). The dicarboxyl-terminated poly(ethylene glycol) (PEG) had been introduced to NH2-ZnO QDs, which rendered it stable under physiological fluid. Moreover, a targeting ligand, hyaluronic acid (HA), was conjugated to ZnO QDs for specifically binding to the overexpressed glycoprotein CD44 by cancer cells. Doxorubicin (DOX) molecules were successfully loaded to PEG functionalized ZnO QDs via formation of metal-DOX complex and covalent interactions. The pH-sensitive ZnO QDs dissolved to Zn(2+) in acidic endosome/lysosome after uptake by cancer cells, which triggered dissociation of the metal-drug complex and a controlled DOX release. As result, a synergistic therapy was achieved due to incorporation of the antitumor effect of Zn(2+) and DOX. PMID:27463610

  17. Adjudin disrupts spermatogenesis by targeting drug transporters: Lesson from the breast cancer resistance protein (BCRP).

    Science.gov (United States)

    Qian, Xiaojing; Cheng, Yan-Ho; Jenardhanan, Pranitha; Mruk, Dolores D; Mathur, Premendu P; Xia, Weiliang; Silvestrini, Bruno; Cheng, C Yan

    2013-04-01

    For non-hormonal male contraceptives that exert their effects in the testis locally instead of via the hypothalamic-pituitary-testicular axis, such as adjudin that disrupts germ cell adhesion, a major hurdle in their development is to improve their bioavailability so that they can be efficiently delivered to the seminiferous epithelium by transporting across the blood-testis barrier (BTB). If this can be done, it would widen the gap between their efficacy and general toxicity. However, Sertoli cells that constitute the BTB, peritubular myoid cells in the tunica propria, germ cells at different stages of their development, as well as endothelial cells that constitute the microvessels in the interstitium are all equipped with multiple drug transporters, most notably efflux drug transporters, such as P-glycoprotein, multidrug resistance-related protein 1 (MRP1) and breast cancer resistance protein (BCRP) that can actively prevent drugs (e.g., adjudin) from entering the seminiferous epithelium to exert their effects. Recent studies have shown that BCRP is highly expressed by endothelial cells of the microvessels in the interstitium in the testis and also peritubular myoid cells in tunica propria even though it is absent from Sertoli cells at the site of the BTB. Furthermore, BCRP is also expressed spatiotemporally by Sertoli cells and step 19 spermatids in the rat testis and stage-specifically, limiting to stage VII‒VIII of the epithelial cycle, and restricted to the apical ectoplasmic specialization [apical ES, a testis-specific F-actin-rich adherens junction (AJ)]. Interestingly, adjudin was recently shown to be capable of downregulating BCRP expression at the apical ES. In this Opinion article, we critically discuss the latest findings on BCRP; in particular, we provide some findings utilizing molecular modeling to define the interacting domains of BCRP with adjudin. Based on this information, it is hoped that the next generation of adjudin analogs to be

  18. The effect of dual ligand-targeted micelles on the delivery and efficacy of poorly soluble drug for cancer therapy.

    Science.gov (United States)

    Sawant, Rupa R; Jhaveri, Aditi M; Koshkaryev, Alexander; Qureshi, Farooq; Torchilin, Vladimir P

    2013-08-01

    We prepared and evaluated transferrin (Tf) and monoclonal antibody (mAb) 2C5-modified dual ligand-targeted poly(ethylene glycol)-phosphatidylethanolamine micelles loaded with a poorly soluble drug, R547 (a selective adenosine triphosphate-competitive cyclin-dependent kinase inhibitor) for enhancement of targeting efficiency and cytotoxicity in vitro and in vivo to A2780 ovarian carcinoma compared to single ligand-targeted micelles. Micellar solubilization significantly improved the solubility of R547 from 1 to 800 μg/mL. The size of modified and non-modified micelles was 13-16 nm. Flow cytometry indicated significantly enhanced cellular association of dual ligand-targeted micelles compared to single ligand-targeted micelles. Confocal microscopy confirmed the Tf receptor-mediated endocytosis of rhodamine-labeled Tf-modified micelles after staining the micelle-treated cells with the endosomal marker Tf-Alexa488. The optimized dual-targeted micelles enhanced cytotoxicity in vitro against A2780 ovarian cancer cells compared to plain and single ligand-targeted micelles. Interestingly, in vivo anti-tumor efficacy was more pronounced for the preparation with a single-targeting ligand (Tf). The specific combination Tf and mAb 2C5 did not yield the expected increase in efficacy as was observed in vitro. This observation suggests that the relationships between targeting ligands in vivo could be more complex than in simplified in vitro systems, and the results of the optimization process should always be verified in vivo. PMID:23594094

  19. Targeted Therapies for Kidney Cancer

    Science.gov (United States)

    ... for kidney cancer Targeted therapies for kidney cancer Biologic therapy (immunotherapy) for kidney cancer Chemotherapy for kidney cancer Pain control for kidney cancer Treatment choices by stage for ...

  20. Target-specific near-IR induced drug release and photothermal therapy with accumulated Au/Ag hollow nanoshells on pulmonary cancer cell membranes.

    Science.gov (United States)

    Noh, Mi Suk; Lee, Somin; Kang, Homan; Yang, Jin-Kyoung; Lee, Hyunmi; Hwang, Doyk; Lee, Jong Woo; Jeong, Sinyoung; Jang, Yoonjeong; Jun, Bong-Hyun; Jeong, Dae Hong; Kim, Seong Keun; Lee, Yoon-Sik; Cho, Myung-Haing

    2015-03-01

    Au/Ag hollow nanoshells (AuHNSs) were developed as multifunctional therapeutic agents for effective, targeted, photothermally induced drug delivery under near-infrared (NIR) light. AuHNSs were synthesized by galvanic replacement reaction. We further conjugated antibodies against the epidermal growth factor receptor (EGFR) to the PEGylated AuHNS, followed by loading with the antitumor drug doxorubicin (AuHNS-EGFR-DOX) for lung cancer treatment. AuHNSs showed similar photothermal efficiency to gold nanorods under optimized NIR laser power. The targeting of AuHNS-EGFR-DOX was confirmed by light-scattering images of A549 cells, and doxorubicin release from the AuHNSs was evaluated under low pH and NIR-irradiated conditions. Multifunctional AuHNS-EGFR-DOX induced photothermal ablation of the targeted lung cancer cells and rapid doxorubicin release following irradiation with NIR laser. Furthermore, we evaluated the effectiveness of AuHNS-EGFR-DOX drug delivery by comparing two drug delivery methods: receptor-mediated endocytosis and cell-surface targeting. Accumulation of the AuHNS-EGFR-DOX on the cell surfaces by targeting EGFR turned out to be more effective for lung cancer treatments than uptake of AuHNS-EGFR-DOX. Taken together, our data suggest a new and optimal method of NIR-induced drug release via the accumulation of targeted AuHNS-EGFR-DOX on cancer cell membranes.

  1. 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.

  2. Dual Targeting of the Insulin-Like Growth Factor and Collateral Pathways in Cancer: Combating Drug Resistance

    Energy Technology Data Exchange (ETDEWEB)

    Ludwig, Joseph A., E-mail: jaludwig@mdanderson.org; Lamhamedi-Cherradi, Salah-Eddine [Departments of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030 (United States); Lee, Ho-Young [Departments of Thoracic Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030 (United States); Naing, Aung [Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030 (United States); Benjamin, Robert [Departments of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030 (United States)

    2011-07-26

    The insulin-like growth factor pathway, regulated by a complex interplay of growth factors, cognate receptors, and binding proteins, is critically important for many of the hallmarks of cancer such as oncogenesis, cell division, growth, and antineoplastic resistance. Naturally, a number of clinical trials have sought to directly abrogate insulin-like growth factor receptor 1 (IGF-1R) function and/or indirectly mitigate its downstream mediators such as mTOR, PI3K, MAPK, and others under the assumption that such therapeutic interventions would provide clinical benefit, demonstrable by impaired tumor growth as well as prolonged progression-free and overall survival for patients. Though a small subset of patients enrolled within phase I or II clinical trials revealed dramatic clinical response to IGF-1R targeted therapies (most using monoclonal antibodies to IGF-1R), in toto, the anticancer effect has been underwhelming and unsustained, as even those with marked clinical responses seem to rapidly acquire resistance to IGF-1R targeted agents when used alone through yet to be identified mechanisms. As the IGF-1R receptor is just one of many that converge upon common intracellular signaling cascades, it is likely that effective IGF-1R targeting must occur in parallel with blockade of redundant signaling paths. Herein, we present the rationale for dual targeting of IGF-1R and other signaling molecules as an effective strategy to combat acquired drug resistance by carcinomas and sarcomas.

  3. Targeted therapy: tailoring cancer treatment

    Institute of Scientific and Technical Information of China (English)

    Min Yan; Quentin Qiang Liu

    2013-01-01

    Targeted therapies include small-molecule inhibitors and monoclonal antibodies,have made treatment more tumor-specific and less toxic,and have opened new possibilities for tailoring cancer treatment.Nevertheless,there remain several challenges to targeted therapies,including molecular identification,drug resistance,and exploring reliable biomarkers.Here,we present several selected signaling pathways and molecular targets involved in human cancers including Aurora kinases,PI3K/mTOR signaling,FOXO-FOXM1 axis,and MDM2/MDM4-p53 interaction.Understanding the molecular mechanisms for tumorigenesis and development of drug resistance will provide new insights into drug discovery and design of therapeutic strategies for targeted therapies.

  4. The Research and Applications of Quantum Dots as Nano-Carriers for Targeted Drug Delivery and Cancer Therapy

    Science.gov (United States)

    Zhao, Mei-Xia; Zhu, Bing-Jie

    2016-04-01

    Quantum dots (QDs), nano-carriers for drugs, can help realize the targeting of drugs, and improve the bioavailability of drugs in biological fields. And, a QD nano-carrier system for drugs has the potential to realize early detection, monitoring, and localized treatments of specific disease sites. In addition, QD nano-carrier systems for drugs can improve stability of drugs, lengthen circulation time in vivo, enhance targeted absorption, and improve the distribution and metabolism process of drugs in organization. So, the development of QD nano-carriers for drugs has become a hotspot in the fields of nano-drug research in recent years. In this paper, we review the advantages and applications of the QD nano-carriers for drugs in biological fields.

  5. The Research and Applications of Quantum Dots as Nano-Carriers for Targeted Drug Delivery and Cancer Therapy.

    Science.gov (United States)

    Zhao, Mei-Xia; Zhu, Bing-Jie

    2016-12-01

    Quantum dots (QDs), nano-carriers for drugs, can help realize the targeting of drugs, and improve the bioavailability of drugs in biological fields. And, a QD nano-carrier system for drugs has the potential to realize early detection, monitoring, and localized treatments of specific disease sites. In addition, QD nano-carrier systems for drugs can improve stability of drugs, lengthen circulation time in vivo, enhance targeted absorption, and improve the distribution and metabolism process of drugs in organization. So, the development of QD nano-carriers for drugs has become a hotspot in the fields of nano-drug research in recent years. In this paper, we review the advantages and applications of the QD nano-carriers for drugs in biological fields. PMID:27090658

  6. A Network-Based Data Integration Approach to Support Drug Repurposing and Multi-Target Therapies in Triple Negative Breast Cancer.

    Science.gov (United States)

    Vitali, Francesca; Cohen, Laurie D; Demartini, Andrea; Amato, Angela; Eterno, Vincenzo; Zambelli, Alberto; Bellazzi, Riccardo

    2016-01-01

    The integration of data and knowledge from heterogeneous sources can be a key success factor in drug design, drug repurposing and multi-target therapies. In this context, biological networks provide a useful instrument to highlight the relationships and to model the phenomena underlying therapeutic action in cancer. In our work, we applied network-based modeling within a novel bioinformatics pipeline to identify promising multi-target drugs. Given a certain tumor type/subtype, we derive a disease-specific Protein-Protein Interaction (PPI) network by combining different data-bases and knowledge repositories. Next, the application of suitable graph-based algorithms allows selecting a set of potentially interesting combinations of drug targets. A list of drug candidates is then extracted by applying a recent data fusion approach based on matrix tri-factorization. Available knowledge about selected drugs mechanisms of action is finally exploited to identify the most promising candidates for planning in vitro studies. We applied this approach to the case of Triple Negative Breast Cancer (TNBC), a subtype of breast cancer whose biology is poorly understood and that lacks of specific molecular targets. Our "in-silico" findings have been confirmed by a number of in vitro experiments, whose results demonstrated the ability of the method to select candidates for drug repurposing. PMID:27632168

  7. Bioinspired fluorescent dipeptide nanoparticles for targeted cancer cell imaging and real-time monitoring of drug release

    Science.gov (United States)

    Fan, Zhen; Sun, Leming; Huang, Yujian; Wang, Yongzhong; Zhang, Mingjun

    2016-04-01

    Peptide nanostructures are biodegradable and are suitable for many biomedical applications. However, to be useful imaging probes, the limited intrinsic optical properties of peptides must be overcome. Here we show the formation of tryptophan-phenylalanine dipeptide nanoparticles (DNPs) that can shift the peptide's intrinsic fluorescent signal from the ultraviolet to the visible range. The visible emission signal allows the DNPs to act as imaging and sensing probes. The peptide design is inspired by the red shift seen in the yellow fluorescent protein that results from π-π stacking and by the enhanced fluorescence intensity seen in the green fluorescent protein mutant, BFPms1, which results from the structure rigidification by Zn(II). We show that DNPs are photostable, biocompatible and have a narrow emission bandwidth and visible fluorescence properties. DNPs functionalized with the MUC1 aptamer and doxorubicin can target cancer cells and can be used to image and monitor drug release in real time.

  8. Bioinspired fluorescent dipeptide nanoparticles for targeted cancer cell imaging and real-time monitoring of drug release

    Science.gov (United States)

    Fan, Zhen; Sun, Leming; Huang, Yujian; Wang, Yongzhong; Zhang, Mingjun

    2016-04-01

    Peptide nanostructures are biodegradable and are suitable for many biomedical applications. However, to be useful imaging probes, the limited intrinsic optical properties of peptides must be overcome. Here we show the formation of tryptophan–phenylalanine dipeptide nanoparticles (DNPs) that can shift the peptide's intrinsic fluorescent signal from the ultraviolet to the visible range. The visible emission signal allows the DNPs to act as imaging and sensing probes. The peptide design is inspired by the red shift seen in the yellow fluorescent protein that results from π–π stacking and by the enhanced fluorescence intensity seen in the green fluorescent protein mutant, BFPms1, which results from the structure rigidification by Zn(II). We show that DNPs are photostable, biocompatible and have a narrow emission bandwidth and visible fluorescence properties. DNPs functionalized with the MUC1 aptamer and doxorubicin can target cancer cells and can be used to image and monitor drug release in real time.

  9. Tumor-targeting, pH-sensitive nanoparticles for docetaxel delivery to drug-resistant cancer cells

    Directory of Open Access Journals (Sweden)

    Tran TH

    2015-08-01

    Full Text Available Tuan Hiep Tran,1 Thiruganesh Ramasamy,1 Ju Yeon Choi,1 Hanh Thuy Nguyen,1 Thanh Tung Pham,1 Jee-Heon Jeong,1 Sae Kwang Ku,2 Han-Gon Choi,3 Chul Soon Yong,1 Jong Oh Kim11College of Pharmacy, Yeungnam University, Dae-Dong, 2College of Korean Medicine, Daegu Haany University, Gyeongsan, 3College of Pharmacy, Hanyang University, Hanyangdaehak-ro, Sangnok-gu, Ansan, South KoreaAbstract: The attachment of polyethylene glycol (PEG increases the circulation time of drug-containing nanoparticles; however, this also negatively affects cellular uptake. To overcome this problem, unique lipid polymer hybrid (LPH nanoparticles were developed with a pH-responsive PEG layer that detached prior to cell uptake. Docetaxel (DTX was incorporated into the lipid core of the nanoparticles, which was then shielded with the pH-responsive block co-polymer polyethylene glycol-b-polyaspartic acid (PEG-b-PAsp using a modified emulsion method. The optimized LPH nanoparticles were ~200 nm and had a narrow size distribution. Drug release from DTX-loaded LPH (DTX-LPH nanoparticles was pH-sensitive, which is beneficial for tumor targeting. More importantly, DTX-LPH nanoparticles were able to effectively induce apoptosis in cancer cells. The negative surface charge and PEG shell of vehicle remarkably enhanced the blood circulation and physiological activity of DTX-LPH nanoparticles compared with that of free DTX. The nanoparticles were also found to reduce the size of tumors in tumor-bearing xenograft mice. The in vivo anticancer effect of DTX-LPH nanoparticles was further confirmed by the elevated levels of caspase-3 and poly ADP ribose polymerase found in the tumors after treatment. Thus, the results suggest that this novel LPH system could be an effective new treatment for cancer.Keywords: docetaxel, polyaspartic acid, drug delivery systems, antitumor, pH-sensitive

  10. Evaluation of activity and combination strategies with the microtubule-targeting drug sagopilone in breast cancer cell lines

    Directory of Open Access Journals (Sweden)

    Julia eEschenbrenner

    2011-11-01

    Full Text Available The molecular heterogeneity of cancer calls for individualized therapies to become the standard of care. The development of new therapeutic agents needs to include integrative translational research as early as possible. Target-specific compounds require specific diagnostic biomarker support. Tailored treatment approaches, such as specific schedules or combinations, can improve the therapeutic outcome of drugs with more general mode of action, i.e. the classical chemotherapy. Results from translational research will allow to define the optimal patient population, to tailor individual treatment and to choose treatment combinations on a rational basis.Sagopilone, a fully synthetic epothilone, is a microtubule-stabilizing agent optimized for high in vitro and in vivo activity against a broad range of tumor models, including those resistant to paclitaxel and other systemic treatments. Sagopilone development was accompanied by translational research studies to evaluate the molecular mode of action, to recognize mechanisms leading to resistance, to identify predictive response biomarkers and to establish a rationale for combination with different therapies.Here, we present an RNAi drug modifier screen interrogating 300 genes in four cancer cell lines. Defects of the spindle assembly checkpoint (SAC were identified to cause resistance against sagopilone-induced mitotic arrest and apoptosis. Potential biomarkers for resistance are SAC-defects like mutations in the SAC-kinase BUB1B and chromosomal heterogeneity and polyploidy since they imply an increased tolerance for aberrant mitosis. The RNAi drug modifier screen identified the enhancement of sagopilone-induced mitotic arrest by inhibition of the mitotic kinesin KIF2C (MCAK as potential combination strategy.These new findings are correlated with results from previous studies. We discuss successes and failures of our integrative preclinical development program and provide recommendations for future

  11. Drugs Approved for Vulvar Cancer

    Science.gov (United States)

    This page lists cancer drugs approved by the Food and Drug Administration (FDA) for vulvar cancer. The list includes generic names and brand names. The drug names link to NCI's Cancer Drug Information summaries.

  12. Drugs Approved for Bone Cancer

    Science.gov (United States)

    This page lists cancer drugs approved by the Food and Drug Administration (FDA) for bone cancer. The list includes generic names and brand names. The drug names link to NCI's Cancer Drug Information summaries.

  13. Drugs Approved for Penile Cancer

    Science.gov (United States)

    This page lists cancer drugs approved by the Food and Drug Administration (FDA) for penile cancer. The list includes generic names and brand names. The drug names link to NCI’s Cancer Drug Information summaries.

  14. Drugs Approved for Endometrial Cancer

    Science.gov (United States)

    This page lists cancer drugs approved by the Food and Drug Administration (FDA) for endometrial cancer. The list includes generic names and brand names. The drug names link to NCI's Cancer Drug Information summaries.

  15. Drugs Approved for Esophageal Cancer

    Science.gov (United States)

    This page lists cancer drugs approved by the Food and Drug Administration (FDA) for esophageal cancer. The list includes generic names and brand names. The drug names link to NCI's Cancer Drug Information summaries.

  16. Drugs Approved for Liver Cancer

    Science.gov (United States)

    This page lists cancer drugs approved by the Food and Drug Administration (FDA) for liver cancer. The list includes generic names and brand names. The drug names link to NCI’s Cancer Drug Information summaries.

  17. Drugs Approved for Skin Cancer

    Science.gov (United States)

    ... Ask about Your Treatment Research Drugs Approved for Skin Cancer This page lists cancer drugs approved by the Food and Drug Administration (FDA) for skin cancer, including drugs for basal cell carcinoma and melanoma. ...

  18. Drugs Approved for Vaginal Cancer

    Science.gov (United States)

    This page lists cancer drugs approved by the Food and Drug Administration (FDA) to prevent vaginal cancer. The list includes generic names and brand names. The drug names link to NCI’s Cancer Drug Information summaries.

  19. Drugs Approved for Skin Cancer

    Science.gov (United States)

    This page lists cancer drugs approved by the Food and Drug Administration (FDA) for skin cancer. The list includes generic names and brand names. The drug names link to NCI's Cancer Drug Information summaries.

  20. Targeting Signal Pathways active in Cancer Stem Cells to Overcome Drug Resistance

    Institute of Scientific and Technical Information of China (English)

    Miaorong SHE; Xilin CHEN

    2009-01-01

    @@ 1 Introduction Over the last several decades, although there have been advances in the treatment of diseases such as children leuke-mia, Hodgkin's disease, and testicular cancer, however, the survival of patients with the most common malignancies such as lung, breast, liver, and colon cancers has not changed signifi-cantly[1-4].

  1. Accelerated killing of cancer cells using a multifunctional single-walled carbon nanotube-based system for targeted drug delivery in combination with photothermal therapy

    Directory of Open Access Journals (Sweden)

    Jeyamohan P

    2013-07-01

    Full Text Available Prashanti Jeyamohan, Takashi Hasumura, Yutaka Nagaoka, Yasuhiko Yoshida, Toru Maekawa, D Sakthi Kumar Bio-Nano Electronics Research Centre, Graduate School of Interdisciplinary New Science, Toyo University, Kawagoe, Japan Abstract: The photothermal effect of single-walled carbon nanotubes (SWCNTs in combination with the anticancer drug doxorubicin (DOX for targeting and accelerated destruction of breast cancer cells is demonstrated in this paper. A targeted drug-delivery system was developed for selective killing of breast cancer cells with polyethylene glycol biofunctionalized and DOX-loaded SWCNTs conjugated with folic acid. In our work, in vitro drug-release studies showed that the drug (DOX binds at physiological pH (pH 7.4 and is released only at a lower pH, ie, lysosomal pH (pH 4.0, which is the characteristic pH of the tumor environment. A sustained release of DOX from the SWCNTs was observed for a period of 3 days. SWCNTs have strong optical absorbance in the near-infrared (NIR region. In this special spectral window, biological systems are highly transparent. Our study reports that under laser irradiation at 800 nm, SWCNTs exhibited strong light–heat transfer characteristics. These optical properties of SWCNTs open the way for selective photothermal ablation in cancer therapy. It was also observed that internalization and uptake of folate-conjugated NTs into cancer cells was achieved by a receptor-mediated endocytosis mechanism. Results of the in vitro experiments show that laser was effective in destroying the cancer cells, while sparing the normal cells. When the above laser effect was combined with DOX-conjugated SWCNTs, we found enhanced and accelerated killing of breast cancer cells. Thus, this nanodrug-delivery system, consisting of laser, drug, and SWCNTs, looks to be a promising selective modality with high treatment efficacy and low side effects for cancer therapy. Keywords: cancer, nanotherapy, SWCNTs, targeted drug delivery

  2. Targeting Anticancer Drug Delivery to Pancreatic Cancer Cells Using a Fucose-Bound Nanoparticle Approach

    OpenAIRE

    Makoto Yoshida; Rishu Takimoto; Kazuyuki Murase; Yasushi Sato; Masahiro Hirakawa; Fumito Tamura; Tsutomu Sato; Satoshi Iyama; Takahiro Osuga; Koji Miyanishi; Kohichi Takada; Tsuyoshi Hayashi; Masayoshi Kobune; Junji Kato

    2012-01-01

    Owing to its aggressiveness and the lack of effective therapies, pancreatic ductal adenocarcinoma has a dismal prognosis. New strategies to improve treatment and survival are therefore urgently required. Numerous fucosylated antigens in sera serve as tumor markers for cancer detection and evaluation of treatment efficacy. Increased expression of fucosyltransferases has also been reported for pancreatic cancer. These enzymes accelerate malignant transformation through fucosylation of sialylate...

  3. Manufacturing Techniques and Surface Engineering of Polymer Based Nanoparticles for Targeted Drug Delivery to Cancer

    Directory of Open Access Journals (Sweden)

    Yichao Wang

    2016-02-01

    Full Text Available The evolution of polymer based nanoparticles as a drug delivery carrier via pharmaceutical nano/microencapsulation has greatly promoted the development of nano- and micro-medicine in the past few decades. Poly(lactide-co-glycolide (PLGA and chitosan, which are biodegradable and biocompatible polymers, have been approved by both the Food & Drug Administration (FDA and European Medicine Agency (EMA, making them ideal biomaterials that can be advanced from laboratory development to clinical oral and parental administrations. PLGA and chitosan encapsulated nanoparticles (NPs have successfully been developed as new oral drug delivery systems with demonstrated high efficacy. This review aims to provide a comprehensive overview of the fabrication of PLGA and chitosan particulate systems using nano/microencapsulation methods, the current progress and the future outlooks of the nanoparticulate drug delivery systems. Especially, we focus on the formulations and nano/micro-encapsulation techniques using top-down techniques. It also addresses how the different phases including the organic and aqueous ones in the emulsion system interact with each other and subsequently influence the properties of the drug delivery system. Besides, surface modification strategies which can effectively engineer intrinsic physicochemical properties are summarised. Finally, future perspectives and potential directions of PLGA and chitosan nano/microencapsulated drug systems are outlined.

  4. Possibility of sandwiched liver surgery with molecular targeting drugs, cetuximab and bevacizumab on colon cancer liver metastases: a case report

    Directory of Open Access Journals (Sweden)

    Toyama Yoichi

    2012-06-01

    Full Text Available Abstract A 31-year-old man with sigmoid colon cancer with concomitant simultaneous multiple liver metastases had received FOLFIRI (leucovorin, fluorouracil and irinotecan and FOLFOX6 (leucovorin, fluorouracil and oxaliplatin after an ordinary sigmoidectomy. However, his serum carcinoembryonic antigen (CEA level increased rapidly during the fifteen months after the operation while he was on FOLFOX6. Abdominal computed tomography revealed expanding multiple liver tumors. As the third line chemotherapy, a combination therapy of cetuximab with irinotecan was given, which markedly reduced his levels of serum CEA, and the size and number of liver tumors. He underwent lateral segmentectomy of the liver and microwave coagulation of the liver metastases in the remnant liver. Thereafter, a good quality of life with tumor dormancy was obtained for 6 months. However, his serum CEA started to rise again in the absence of liver tumors. Therefore, FOLFOX6 with bevacizumab was chosen as the fourth line chemotherapy, and the serum CEA was reduced with tumor dormancy. A good quality of life was obtained again at 3 years after the first surgery. This report indicates the effectiveness of sandwiched liver surgery with the molecular targeting drugs cetuximab and bevacizumab on multiple liver metastases of colon cancer, and suggests the possibility of a regimen consisting of bevacizumab following cetuximab.

  5. Trop-2 is a novel target for solid cancer therapy with sacituzumab govitecan (IMMU-132), an antibody-drug conjugate (ADC)*

    Science.gov (United States)

    Goldenberg, David M.; Cardillo, Thomas M.; Govindan, Serengulam V.; Rossi, Edmund A.; Sharkey, Robert M.

    2015-01-01

    Trop-2 is a novel target for ADC therapy because of its high expression by many solid cancers. The rational development of IMMU-132 represents a paradigm shift as an ADC that binds a well-known moderately-cytotoxic drug, SN-38, to the anti-Trop-2 antibody. In vitro and in vivo studies show enhanced efficacy, while there is a gradual release of SN-38 that contributes to the overall effect. IMMU-132 is most efficacious at a high drug:antibody ratio (DAR) of 7.6:1, which does not affect binding and pharmacokinetics. It targets up to 136-fold more SN-38 to a human cancer xenograft than irinotecan, SN-38′s prodrug. IMMU-132 delivers SN-38 in its most active, non-glucuronidated form, which may explain the lower frequency of severe diarrhea than with irinotecan. Thus, this ADC, carrying a moderately-toxic drug targeting Trop-2 represents a novel cancer therapeutic that is showing promising activity in patients with several metastatic cancer types, including triple-negative breast cancer, non-small-cell and small-cell lung cancers. PMID:26101915

  6. Identification and Characterization of Novel Drug Targets for Personalized Breast Cancer Nanomedicine

    DEFF Research Database (Denmark)

    Block, Ines; Müller, Carolin; Sdogati, Daniel;

    Personalized cancer nanomedicine aims at the design of novel nanodrugs that would match the molecular fingerprint of an individual patient`s tumor. Expression profiling and next generation-sequencing data represent rich resources for discovering new starting points for such approaches. Here, we...... of these may provide starting points for the consecutive design of synthetic lethal screens for personalized nanodrugs....

  7. Energy metabolism targeted drugs synergize with photodynamic therapy to potentiate breast cancer cell death.

    Science.gov (United States)

    Feng, Xiaolan; Zhang, Yi; Wang, Pan; Liu, Quanhong; Wang, Xiaobing

    2014-12-01

    Malignant cells are highly dependent on aerobic glycolysis, which differs significantly from normal cells (the Warburg effect). Interference of this metabolic process has been considered as an innovative method for developing selective cancer therapy. A recent study demonstrated that the glycolysis inhibitor 2-deoxyglucose (2-DG) can potentiate PDT efficacy, whereas the possible mechanisms have not been carefully investigated. This study firstly proved the general potentiation of PDT efficacy by 2-DG and 3-bromopyruvate (3-BP) in human breast cancer MDA-MB-231 cells, and carefully elucidated the underlying mechanism in the process. Our results showed that both 2-DG and 3-BP could significantly promote a PDT-induced cell cytotoxic effect when compared with either monotherapy. Synergistic potentiation of mitochondria- and caspase-dependent cell apoptosis was observed, including a mitochondrial membrane potential (MMP) drop, Bax translocation, and caspase-3 activation. Besides, ROS generation and the expression of oxidative stress related proteins such as P38 MAPK phosphorylation and JNK phosphorylation were notably increased after the combined treatments. Moreover, when pretreated with the ROS scavenger N-acetylcysteine (NAC), the ROS generation, the MMP drop, cell apoptosis and cytotoxicity were differently inhibited, suggesting that ROS was vertical in the pro-apoptotic process induced by 2-DG/3-BP combined with PDT treatment. These results indicate that the combination of glycolytic antagonists and PDT may be a promising therapeutic strategy to effectively kill cancer cells. PMID:25363473

  8. β-Lapachone and Paclitaxel Combination Micelles with Improved Drug Encapsulation and Therapeutic Synergy as Novel Nanotherapeutics for NQO1-Targeted Cancer Therapy.

    Science.gov (United States)

    Zhang, Ling; Chen, Zhen; Yang, Kuan; Liu, Chun; Gao, Jinming; Qian, Feng

    2015-11-01

    β-Lapachone (LPC) is a novel cytotoxic agent that is bioactivated by NADP(H): quinone oxidoreductase 1 (NQO1), an enzyme elevated in a variety of tumors, such as non-small cell lung cancer (NSCLC), pancreatic cancer, liver cancer, and breast cancer. Despite its unique mechanism of action, its clinical evaluation has been largely hindered by low water solubility, short blood half-life, and narrow therapeutic window. Although encapsulation into poly(ethylene glycol)-b-poly(D,L-lactic acid) (PEG-PLA) micelles could modestly improve its solubility and prolong its half-life, the extremely fast intrinsic crystallization tendency of LPC prevents drug loading higher than ∼2 wt %. The physical stability of the LPC-loaded micelles is also far from satisfactory for further development. In this study, we demonstrate that paclitaxel (PTX), a front-line drug for many cancers, can provide two functions when coencapsulated together with LPC in the PEG-PLA micelles; first, as a strong crystallization inhibitor for LPC, thus to significantly increase the LPC encapsulation efficiency in the micelle from 11.7 ± 2.4% to 100.7 ± 2.2%. The total drug loading efficiency of both PTX and LPC in the combination polymeric micelle reached 100.3 ± 3.0%, and the drug loading density reached 33.2 ± 1.0%. Second, the combination of LPC/PTX demonstrates strong synergistic cytotoxicity effect against the NQO1 overexpressing cancer cells, including A549 NSCLC cells, and several pancreatic cancer cells (combination index sodium salicylate, which agrees with the desired dosing sequence of the two drugs to exert synergistic pharmacologic effect at different cell checkpoints. The PEG-PLA micelles coloaded with LPC and PTX offer a novel nanotherapeutic, with high drug loading, sufficient physical stability, and biological synergy to increase drug delivery efficiency and optimize the therapeutic window for NOQ1-targeted therapy of cancer. PMID:26415823

  9. Drugs Approved for Pancreatic Cancer

    Science.gov (United States)

    ... Ask about Your Treatment Research Drugs Approved for Pancreatic Cancer This page lists cancer drugs approved by the ... that are not listed here. Drugs Approved for Pancreatic Cancer Abraxane (Paclitaxel Albumin-stabilized Nanoparticle Formulation) Afinitor (Everolimus) ...

  10. Drugs Approved for Bone Cancer

    Science.gov (United States)

    ... Ask about Your Treatment Research Drugs Approved for Bone Cancer This page lists cancer drugs approved by the ... that are not listed here. Drugs Approved for Bone Cancer Abitrexate (Methotrexate) Cosmegen (Dactinomycin) Dactinomycin Denosumab Doxorubicin Hydrochloride ...

  11. In vitro development of chemotherapy and targeted therapy drug-resistant cancer cell lines: A practical guide with case studies

    Directory of Open Access Journals (Sweden)

    Martina eMcDermott

    2014-03-01

    Full Text Available The development of a drug-resistant cell line can take from 3-18 months. However, little is published on the methodology of this development process. This article will discuss key decisions to be made prior to starting resistant cell line development; the choice of parent cell line, dose of selecting agent, treatment interval and optimising the dose of drug for the parent cell line. Clinically-relevant drug-resistant cell lines are developed by mimicking the conditions cancer patients experience during chemotherapy and cell lines display between 2-8 fold resistance compared to their parental cell line. Doses of drug administered are low, and a pulsed treatment strategy is often used where the cells recover in drug-free media. High-level laboratory models are developed with the aim of understanding potential mechanisms of resistance to chemotherapy agents. Doses of drug are higher and escalated over time. It is common to have difficulty developing stable clinically-relevant drug-resistant cell lines. A comparative selection strategy of multiple cell lines or multiple chemotherapeutic agents mitigates this risk and gives insight into which agents or type of cell line develops resistance easily. Successful selection strategies from our research are presented. Pulsed-selection produced platinum or taxane-resistant large cell lung cancer (H1299, H460 and temozolomide-resistant melanoma (Malme-3M and HT144 cell lines. Continuous selection produced lapatinib-resistant breast cancer cell line (HCC1954. Techniques for maintaining drug-resistant cell lines are outlined including; maintaining cells with chemotherapy, pulse treating with chemotherapy or returning to master drug-resistant stocks. The heterogeneity of drug-resistant models produced from the same parent cell line with the same chemotherapy agent is explored with reference to P-glycoprotein. Heterogeneity in drug-resistant cell lines reflects the heterogeneity that can occur in clinical drug

  12. Evaluation of Three Small Molecular Drugs for Targeted Therapy to Treat Nonsmall Cell Lung Cancer

    Institute of Scientific and Technical Information of China (English)

    Jun Ni; Li Zhang

    2016-01-01

    Objective: To guide the optimal selection among first-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in clinical practice.This review attempted to provide a thorough comparison among three first-generation EGFR-TKIs, namely icotinib,erlotinib, and gefitinib, with regard to their molecular structure, pharmacokinetic parameters, clinical data, adverse reactions, and contraindications.Data Sources: An electronic literature search of the PubMed database and Google Scholar for all the available articles regarding gefitinib,icotinib, and erlotinib in the English language from January 2005 to December 2014 was used.Study Selection: The search terms or keywords included but not limited to "lung cancer", "nonsmall cell lung cancer (NSCLC)","epidemiology", "EGFR", "TKIs", and "optimal selection".Results: As suggested by this review, even though the three first-generation EGFR-TKIs share the quinazoline structure, erlotinib had the strongest apoptosis induction activity because of its use of a different side-chain.The pharmacokinetic parameters indicated that both erlotinib and icotinib are affected by food.The therapeutic window of erlotinib is narrow, and the recommended dosage is close to the maximum tolerable dosage.Icotinib enjoys a wider therapeutic window, and its concentration in the blood is within a safe dosage range even if it is administered with food.Based on multiple large-scale clinical trials, erlotinib is universally applied as the first-line treatment.In marked contrast, icotinib is available only in China as the second-or third-line therapeutic approach for treating advanced lung cancer.In addition, it exhibits a similar efficacy but better safety profile than gefitinib.Conclusions: Although there is a paucity of literature regarding whether icotinib is superior to erlotinib, its superior toxicity profile, noninferior efficacy, and lower cost indicate that it is a better alternative for Chinese patients living with

  13. Bladder Cancer and Urothelial Impairment: The Role of TRPV1 as Potential Drug Target

    Directory of Open Access Journals (Sweden)

    Francesco Mistretta

    2014-01-01

    Full Text Available Urothelium, in addition to its primary function of barrier, is now understood to act as a complex system of cell communication that exhibits specialized sensory properties in the regulation of physiological or pathological stimuli. Furthermore, it has been hypothesized that bladder inflammation and neoplastic cell growth, the two most representative pathological conditions of the lower urinary tract, may arise from a primary defective urothelial lining. Transient receptor potential vanilloid channel 1 (TRPV1, a receptor widely distributed in lower urinary tract structures and involved in the physiological micturition reflex, was described to have a pathophysiological role in inflammatory conditions and in the genesis and development of urothelial cancer. In our opinion new compounds, such as curcumin, the major component of turmeric Curcuma longa, reported to potentiate the effects of the chemotherapeutic agents used in the management of recurrent urothelial cancer in vitro and also identified as one of several compounds to own the vanillyl structure required to work like a TRPV1 agonist, could be thought as complementary in the clinical management of both the recurrences and the inflammatory effects caused by the endoscopic resection or intravesical chemotherapy administration or could be combined with adjuvant agents to potentiate their antitumoral effect.

  14. Targeted nanoparticles for colorectal cancer

    DEFF Research Database (Denmark)

    Cisterna, Bruno A.; Kamaly, Nazila; Choi, Won Il;

    2016-01-01

    Colorectal cancer (CRC) is highly prevalent worldwide, and despite notable progress in treatment still leads to significant morbidity and mortality. The use of nanoparticles as a drug delivery system has become one of the most promising strategies for cancer therapy. Targeted nanoparticles could...... take advantage of differentially expressed molecules on the surface of tumor cells, providing effective release of cytotoxic drugs. Several efforts have recently reported the use of diverse molecules as ligands on the surface of nanoparticles to interact with the tumor cells, enabling the effective...... delivery of antitumor agents. Here, we present recent advances in targeted nanoparticles against CRC and discuss the promising use of ligands and cellular targets in potential strategies for the treatment of CRCs....

  15. Cancer-drug associations: a complex system.

    Directory of Open Access Journals (Sweden)

    Ertugrul Dalkic

    Full Text Available BACKGROUND: Network analysis has been performed on large-scale medical data, capturing the global topology of drugs, targets, and disease relationships. A smaller-scale network is amenable to a more detailed and focused analysis of the individual members and their interactions in a network, which can complement the global topological descriptions of a network system. Analysis of these smaller networks can help address questions, i.e., what governs the pairing of the different cancers and drugs, is it driven by molecular findings or other factors, such as death statistics. METHODOLOGY/PRINCIPAL FINDINGS: We defined global and local lethality values representing death rates relative to other cancers vs. within a cancer. We generated two cancer networks, one of cancer types that share Food and Drug Administration (FDA approved drugs (FDA cancer network, and another of cancer types that share clinical trials of FDA approved drugs (clinical trial cancer network. Breast cancer is the only cancer type with significant weighted degree values in both cancer networks. Lung cancer is significantly connected in the FDA cancer network, whereas ovarian cancer and lymphoma are significantly connected in the clinical trial cancer network. Correlation and linear regression analyses showed that global lethality impacts the drug approval and trial numbers, whereas, local lethality impacts the amount of drug sharing in trials and approvals. However, this effect does not apply to pancreatic, liver, and esophagus cancers as the sharing of drugs for these cancers is very low. We also collected mutation target information to generate cancer type associations which were compared with the cancer type associations derived from the drug target information. The analysis showed a weak overlap between the mutation and drug target based networks. CONCLUSIONS/SIGNIFICANCE: The clinical and FDA cancer networks are differentially connected, with only breast cancer significantly

  16. Drug targeting through pilosebaceous route.

    Science.gov (United States)

    Chourasia, Rashmi; Jain, Sanjay K

    2009-10-01

    Local skin targeting is of interest for the pharmaceutical and the cosmetic industry. A topically applied substance has basically three possibilities to penetrate into the skin: transcellular, intercellular, and follicular. The transfollicular path has been largely ignored because hair follicles constitute only 0.1% of the total skin. The hair follicle is a skin appendage with a complex structure containing many cell types that produce highly specialised proteins. The hair follicle is in a continuous cycle: anagen is the hair growth phase, catagen the involution phase and telogen is the resting phase. Nonetheless, the hair follicle has great potential for skin treatment, owing to its deep extension into the dermis and thus provides much deeper penetration and absorption of compounds beneath the skin than seen with the transdermal route. In the case of skin diseases and of cosmetic products, delivery to sweat glands or to the pilosebaceous unit is essential for the effectiveness of the drug. Increased accumulation in the pilosebaceous unit could treat alopecia, acne and skin cancer more efficiently and improve the effect of cosmetic substances and nutrients. Therefore, we review herein various drug delivery systems, including liposomes, niosomes, microspheres, nanoparticles, nanoemulsions, lipid nanocarriers, gene therapy and discuss the results of recent researches. We also review the drugs which have been investigated for pilosebaceous delivery.

  17. Drug targeting through pilosebaceous route.

    Science.gov (United States)

    Chourasia, Rashmi; Jain, Sanjay K

    2009-10-01

    Local skin targeting is of interest for the pharmaceutical and the cosmetic industry. A topically applied substance has basically three possibilities to penetrate into the skin: transcellular, intercellular, and follicular. The transfollicular path has been largely ignored because hair follicles constitute only 0.1% of the total skin. The hair follicle is a skin appendage with a complex structure containing many cell types that produce highly specialised proteins. The hair follicle is in a continuous cycle: anagen is the hair growth phase, catagen the involution phase and telogen is the resting phase. Nonetheless, the hair follicle has great potential for skin treatment, owing to its deep extension into the dermis and thus provides much deeper penetration and absorption of compounds beneath the skin than seen with the transdermal route. In the case of skin diseases and of cosmetic products, delivery to sweat glands or to the pilosebaceous unit is essential for the effectiveness of the drug. Increased accumulation in the pilosebaceous unit could treat alopecia, acne and skin cancer more efficiently and improve the effect of cosmetic substances and nutrients. Therefore, we review herein various drug delivery systems, including liposomes, niosomes, microspheres, nanoparticles, nanoemulsions, lipid nanocarriers, gene therapy and discuss the results of recent researches. We also review the drugs which have been investigated for pilosebaceous delivery. PMID:19663765

  18. DNA-templated antibody conjugation for targeted drug delivery to cancer cells

    DEFF Research Database (Denmark)

    Liu, Tianqiang

    2016-01-01

    Monoclonal antibodies have been used for the treatment of cancer because of their specificity to tumor markers. However, intact unmodified antibodies used as single agent therapeutics sometimes are not curative. To overcome this, there is a trend to empower them with bioactive payloads (toxins......, chemotherapeutics, radionuclides, cytokines) by means of antibody conjugation. Conventional chemical modification techniques for the conjugation of antibodies result in highly heterogeneous mixtures. This heterogeneity is far from optimal since for therapeutic purpose antibody conjugates are better in homogeneous...... conjugation strategy. Recently, a site-selective antibody conjugation method called “DNA-templated protein conjugation (DTPC)” was developed by our group. The site-selective covalently attachment of single-stranded DNA (ssDNA) to proteins was achieved by using a metal-affinity DNA probe and DNA...

  19. Novel polysaccharide anti-tumour drug delivery system for active targeting and controlled release to breast cancer bone metastases

    OpenAIRE

    Bonzi, Gwénaëlle A.M.

    2014-01-01

    ABSTRACT In the late stage of the disease, breast cancer patients often develop bone metastases, a major cause of cancer-related death among women worldwide. The common treatment currently used clinically includes the anti-neoplastic agent paclitaxel combined with the bisphosphonate alendronate. Paclitaxel is an anti-neoplastic drug which cytotoxic effect is mainly attributed to its ability to promote the assembly of microtubules as well as prevent the depolymerisation of these micro...

  20. A Cell-Targeted, Size-Photocontrollable, Nuclear-Uptake Nanodrug Delivery System for Drug-Resistant Cancer Therapy

    OpenAIRE

    Qiu, Liping; Chen, Tao; Öçsoy, Ismail; Yasun, Emir; Wu, Cuichen; Zhu, Guizhi; You, Mingxu; Han, Da; Jiang, Jianhui; Yu, Ruqin; Tan, Weihong

    2014-01-01

    The development of multidrug resistance (MDR) has become an increasingly serious problem in cancer therapy. The cell-membrane overexpression of P-glycoprotein (P-gp), which can actively efflux various anticancer drugs from the cell, is a major mechanism of MDR. Nuclear-uptake nanodrug delivery systems, which enable intranuclear release of anticancer drugs, are expected to address this challenge by bypassing P-gp. However, before entering the nucleus, the nanocarrier must pass through the cell...

  1. Cancer immunotherapy targeting neoantigens.

    Science.gov (United States)

    Lu, Yong-Chen; Robbins, Paul F

    2016-02-01

    Neoantigens are antigens encoded by tumor-specific mutated genes. Studies in the past few years have suggested a key role for neoantigens in cancer immunotherapy. Here we review the discoveries of neoantigens in the past two decades and the current advances in neoantigen identification. We also discuss the potential benefits and obstacles to the development of effective cancer immunotherapies targeting neoantigens.

  2. Targeted Therapies in Endometrial Cancer

    Directory of Open Access Journals (Sweden)

    Selen Dogan

    2014-04-01

    Full Text Available Endometrial cancer is the most common genital cancer in developed world. It is generally diagnosed in early stage and it has a favorable prognosis. However, advanced staged disease and recurrences are difficult to manage. There are some common genetic alterations related to endometrial carcinogenesis in similar fashion to other cancers. Personalized medicine, which means selection of best suited treatment for an individual, has gain attention in clinical care of patients in recent years. Targeted therapies were developed as a part of personalized or %u201Ctailored%u201D medicine and specifically acts on a target or biologic pathway. There are quite a number of molecular alteration points in endometrial cancer such as PTEN tumor suppressor genes, DNA mismatch repair genes, PI3K/AKT/mTOR pathway and p53 oncogene which all might be potential candidates for tailored targeted therapy. In recent years targeted therapies has clinical application in ovarian cancer patients and in near future with the advent of new agents these %u201Ctailored%u201D drugs will be in market for routine clinical practice in endometrial cancer patients, in primary disease and recurrences as well.

  3. Nelfinavir targets multiple drug resistance mechanisms to increase the efficacy of doxorubicin in MCF-7/Dox breast cancer cells.

    Science.gov (United States)

    Chakravarty, Geetika; Mathur, Aditi; Mallade, Pallavi; Gerlach, Samantha; Willis, Joniece; Datta, Amrita; Srivastav, Sudesh; Abdel-Mageed, Asim B; Mondal, Debasis

    2016-05-01

    Development of multidrug resistance (MDR) remains a significant problem in cancer chemotherapy and underscores the importance of using chemosensitizers. Well known MDR mechanisms include: (i) upregulation of drug-efflux; (ii) increased signaling via AKT; and (iii) decreased apoptosis. Therefore, chemosensitizers should target multiple resistance mechanisms. We investigated the efficacy of nelfinavir (NFV), a clinically approved anti-HIV drug, in increasing doxorubicin (DOX) toxicity in a MDR breast cancer cell line, MCF-7/Dox. As compared to parental MCF-7 cells, the MCF-7/Dox were 15-20 fold more resistant to DOX-induced cytotoxicity at 48 h post-exposure (DOX IC50 = 1.8 μM vs. 32.4 μM). Coexposures to NFV could significantly (p cells. Multiple exposures to physiologic concentrations of NFV (2.25 μM or 6.75 μM) decreased DOX-IC50 by 21-fold and 50-fold, respectively. Interestingly, although single exposure to NFV transiently induced P-glycoprotein (P-gp) levels, multiple treatments with NFV inhibited both P-gp expression and efflux function, which increased intracellular DOX concentrations. Single exposure to NFV augmented the markers of cell-survival (AKT) and autophagy (LC3-II), whereas multiple exposures enabled suppression of both total AKT (t-AKT) and insulin like growth factor-1 (IGF-1)-induced phosphorylated AKT (p-AKT) levels. Multiple exposures to NFV also resulted in increased unfolded protein response (UPR) transducers, e.g. Grp78, p-PERK, p-eIF2α, and ATF-4; and endoplasmic reticulum (ER) stress induced death sensors, e.g. CHOP & TRIB-3. Multiple exposures to NFV also abrogated the mitogenic effects of IGF-1. In mice carrying MCF-7/Dox tumor xenografts, intraperitoneal (i.p.) injection of NFV (20 mg/kg/day) and DOX (2 mg/kg/twice/wk) decreased tumor growth more significantly (p cells and should be tested as an adjunct to chemotherapy. PMID:26844637

  4. Novel Drugs Targeting the Epidermal Growth Factor Receptor and Its Downstream Pathways in the Treatment of Colorectal Cancer: A Systematic Review

    Directory of Open Access Journals (Sweden)

    Amartej Merla

    2012-01-01

    Full Text Available Colorectal cancer is the second most common malignancy among men and women in the United States, and the 5-year survival rate remains poor despite recent advances in chemotherapy and targeted agents. The mainstay of therapy for advanced disease remains the cytotoxic chemotherapy including 5-FU, irinotecan, and oxaliplatin. The USFDA approval and introduction of targeted therapies, including cetuximab and panitumumab (monoclonal antibodies targeting the epidermal growth factor receptor (EGFR and bevacizumab (monoclonal antibody targeting the vascular epithelial growth factor (VEGF, has improved the median survival of patients with metastatic colorectal cancer to around 24 months. Clearly, better and more efficacious drugs are needed, and target-specific agents remain the future of cancer treatment. On this front, rapid advances are being made, which are likely to change the future of the management of metastatic colorectal cancer. However, absence of specific biomarkers for the use of targeted agents, in the subset of population who will benefit from the treatment, remains a major drawback. In this paper, we review agents that are in phases 1 and 2 clinical development, specifically targeting the EGFR and its subsequent downstream pathways.

  5. Risk assessment of drug interaction potential and concomitant dosing pattern on targeted toxicities in pediatric cancer patients.

    Science.gov (United States)

    Barrett, Jeffrey S; Patel, Dimple; Dombrowsky, Erin; Bajaj, Gaurav; Skolnik, Jeffrey M

    2013-07-01

    This investigation evaluated the impact of potential drug interactions on the incidence of reported toxicities seen with common dosing patterns in children with cancer, with the intent of being able to screen and reduce the incidence of adverse drug reactions (ADRs) in the future. Toxicity reported in pediatric cancer patients treated at the Children's Hospital of Philadelphia from 2004 to 2010 were abstracted from a cancer tumor registry and merged with drug order profiles from the medical record system. Analysis datasets were created in SAS and permutation algorithms were used to identify pairwise drug combinations associated with specific toxicity occurrence. Relative risk of toxicity based on dosing pattern was assessed via comparison to control patients. A total of 326 of 1,713 patients (19%) had reportable toxicities. Neutrophil count decreases and alanine aminotransferase increases represented the highest occurring, corresponding to 28.8% and 31.9% prevalence among patients reporting toxicity, respectively. Of coadministered drug pairs, acetaminophen-diphenhydramine occurred most frequently; however, methotrexate-vincristine was the highest occurring pair linked to a single toxicity (hepatotoxicity). Toxicity was highly associated with the diagnoses of leukemia (52.1%) or neuroblastoma (28.5%). Comparison of the dosing interval (≤30 versus >30 min) suggested that risk of toxicity can be associated with the timing of coadministration, with ≤30 min increasing the risk of hepatotoxicity with fentanyl-midazolam and methotrexate-midazolam combinations. Knowledge of drug interactions in children with cancer may help reduce the incidence of ADRs by providing pharmacotherapy options that may reduce the likelihood of toxicity. PMID:23595361

  6. P-glycoprotein targeted nanoscale drug carriers

    KAUST Repository

    Li, Wengang

    2013-02-01

    Multi-drug resistance (MDR) is a trend whereby tumor cells exposed to one cytotoxic agent develop cross-resistance to a range of structurally and functionally unrelated compounds. P -glycoprotein (P -gp) efflux pump is one of the mostly studied drug carrying processes that shuttle the drugs out of tumor cells. Thus, P -gp inhibitors have attracted a lot of attention as they can stop cancer drugs from being pumped out of target cells with the consumption of ATP. Using quantitive structure activity relationship (QSAR), we have successfully synthesized a series of novel P -gp inhibitors. The obtained dihydropyrroloquinoxalines series were fully characterized and then tested against bacterial and tumor assays with over-expressed P -gps. All compounds were bioactive especially compound 1c that had enhanced antibacterial activity. Furthermore, these compounds were utilized as targeting vectors to direct drug delivery vehicles such as silica nanoparticles (SNPs) to cancerous Hela cells with over expressed P -gps. Cell uptake studies showed a successful accumulation of these decorated SNPs in tumor cells compared to undecorated SNPs. The results obtained show that dihydropyrroloquinoxalines constitute a promising drug candidate for targeting cancers with MDR. Copyright © 2013 American Scientific Publishers All rights reserved.

  7. A redox-responsive mesoporous silica nanoparticle capped with amphiphilic peptides by self-assembly for cancer targeting drug delivery

    Science.gov (United States)

    Xiao, Dong; Jia, Hui-Zhen; Ma, Ning; Zhuo, Ren-Xi; Zhang, Xian-Zheng

    2015-05-01

    A redox-responsive mesoporous silica nanoparticle (RRMSN) was developed as a drug nanocarrier by noncovalent functionalization of MSNs with amphiphilic peptides containing the RGD ligand. The alkyl chain stearic acid (C18) with a thiol terminal group was anchored on the surface of MSNs via a disulfide bond, and the amphiphilic peptide (AP) C18-DSDSDSDSRGDS was coated by self-assembly through hydrophobic interactions between the octadecyl groups of MSNs and alkyl chains of AP, which played the role of a gatekeeper collectively. In vitro drug release profiles demonstrated that the anticancer drug (DOX) could be entrapped with nearly no leakage in the absence of dithiothreitol (DTT) or glutathione (GSH). With the addition of DTT or GSH, the entrapped drug released quickly due to the cleavage of the disulfide bond. It was found that after the internalization of MSNs by cancer cells via the receptor-mediated endocytosis, the surface amphiphilic peptides and alkyl chain of RRMSN/DOX were removed to induce rapid drug release intracellularly after the cleavage of the disulfide bond, triggered by GSH secreted in cancer cells. This novel intelligent RRMSN/DOX drug delivery system using self-assembly of amphiphilic peptides around the MSNs provides a facile, but effective strategy for the design and development of smart drug delivery for cancer therapy.A redox-responsive mesoporous silica nanoparticle (RRMSN) was developed as a drug nanocarrier by noncovalent functionalization of MSNs with amphiphilic peptides containing the RGD ligand. The alkyl chain stearic acid (C18) with a thiol terminal group was anchored on the surface of MSNs via a disulfide bond, and the amphiphilic peptide (AP) C18-DSDSDSDSRGDS was coated by self-assembly through hydrophobic interactions between the octadecyl groups of MSNs and alkyl chains of AP, which played the role of a gatekeeper collectively. In vitro drug release profiles demonstrated that the anticancer drug (DOX) could be entrapped with

  8. Mixed PEG-PE/Vitamin E Tumor-Targeted Immunomicelles as Carriers for Poorly Soluble Anti-Cancer Drugs: Improved Drug Solubilization and Enhanced In Vitro Cytotoxicity

    Science.gov (United States)

    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 change it. The solubilization of both drugs by the mixed micelles was more efficient than by micelles made of PEG-PE alone. Solubilization of camptothecin in micelles prevented also the hydrolysis of active lactone form of the drug to inactive carboxylate form. Drug loaded mixed micelles and mAb 2C5-immunomicelles demonstrated significantly higher in vitro cytotoxicity than free drug against various cancer cell lines. PMID:18583114

  9. Aquaporins as potential drug targets

    Institute of Scientific and Technical Information of China (English)

    Fang WANG; Xue-chao FENG; Yong-ming LI; Hong YANG; Tong-hui MA

    2006-01-01

    The aquaporins (AQP) are a family of integral membrane proteins that selectively transport water and,in some cases,small neutral solutes such as glycerol and urea.Thirteen mammalian AQP have been molecularly identified and localized to various epithelial,endothelial and other tissues.Phenotype studies of transgenic mouse models of AQP knockout,mutation,and in some cases humans with AQP mutations have demonstrated essential roles for AQP in mammalian physiology and pathophysiology,including urinary concentrating function,exocrine glandular fluid secretion,brain edema formation,regulation of intracranial and intraocular pressure,skin hydration,fat metabolism,tumor angiogenesis and cell migration.These studies suggest that AQP may be potential drug targets for not only new diuretic reagents for various forms of pathological water retention,but also targets for novel therapy of brain edema,inflammatory disease,glaucoma,obesity,and cancer.However,potent AQP modulators for in vivo application remain to be discovered.

  10. Drugs Approved for Testicular Cancer

    Science.gov (United States)

    This page lists cancer drugs approved by the Food and Drug Administration (FDA) for testicular cancer. The list includes generic names, brand names, and common drug combinations, which are shown in capital letters. The drug names link to NCI's Cancer Drug Information summaries.

  11. Drugs Approved for Cervical Cancer

    Science.gov (United States)

    This page lists cancer drugs approved by the Food and Drug Administration (FDA) for cervical cancer. The list includes generic names, brand names, and common drug combinations, which are shown in capital letters. The drug names link to NCI's Cancer Drug Information summaries.

  12. Targeted Delivery of Protein Drugs by Nanocarriers

    Directory of Open Access Journals (Sweden)

    Antonella Battisti

    2010-03-01

    Full Text Available Recent advances in biotechnology demonstrate that peptides and proteins are the basis of a new generation of drugs. However, the transportation of protein drugs in the body is limited by their high molecular weight, which prevents the crossing of tissue barriers, and by their short lifetime due to immuno response and enzymatic degradation. Moreover, the ability to selectively deliver drugs to target organs, tissues or cells is a major challenge in the treatment of several human diseases, including cancer. Indeed, targeted delivery can be much more efficient than systemic application, while improving bioavailability and limiting undesirable side effects. This review describes how the use of targeted nanocarriers such as nanoparticles and liposomes can improve the pharmacokinetic properties of protein drugs, thus increasing their safety and maximizing the therapeutic effect.

  13. Drugs Approved for Lung Cancer

    Science.gov (United States)

    This page lists cancer drugs approved by the Food and Drug Administration (FDA) for lung cancer. The list includes generic names, brand names, and common drug combinations, which are shown in capital letters.

  14. Drugs Approved for Breast Cancer

    Science.gov (United States)

    This page lists cancer drugs approved by the Food and Drug Administration (FDA) for breast cancer. The list includes generic names, brand names, and common drug combinations, which are shown in capital letters.

  15. Drugs Approved for Pancreatic Cancer

    Science.gov (United States)

    This page lists cancer drugs approved by the Food and Drug Administration (FDA) for pancreatic cancer. The list includes generic names, brand names, and common drug combinations, which are shown in capital letters.

  16. Drugs Approved for Bladder Cancer

    Science.gov (United States)

    This page lists cancer drugs approved by the Food and Drug Administration (FDA) for bladder cancer. The list includes generic names, brand names, and common drug combinations, which are shown in capital letters.

  17. Network systems biology for targeted cancer therapies

    Institute of Scientific and Technical Information of China (English)

    Ting-Ting Zhou

    2012-01-01

    The era of targeted cancer therapies has arrived.However,due to the complexity of biological systems,the current progress is far from enough.From biological network modeling to structural/dynamic network analysis,network systems biology provides unique insight into the potential mechanisms underlying the growth and progression of cancer cells.It has also introduced great changes into the research paradigm of cancer-associated drug discovery and drug resistance.

  18. Clinicopathological significance and potential drug target of CDH1 in breast cancer: a meta-analysis and literature review

    Directory of Open Access Journals (Sweden)

    Huang R

    2015-09-01

    Full Text Available Ruixue Huang,* Ping Ding,* Fei Yang*Department of Occupational and Environmental Health, School of Public Health, Central South University, Changsha, Hunan, People’s Republic of China*All authors contributed equally to this workAbstract: CDH1, as a tumor suppressor gene, contributes sporadic breast cancer (BC progression. However, the association between CDH1 hypermethylation and BC, and its clinicopathological significance remains unclear. We conducted a meta-analysis to investigate the relationship between the CDH1 methylation profile and the major clinicopathological features. A detailed literature was searched through the electronic databases PubMed, Web of Science™, and EMBASE™ for related research publications. The data were extracted and assessed by two reviewers independently. Odds ratios (ORs with corresponding confidence intervals (CIs were calculated and summarized respectively. The frequency of CDH1 methylation was significantly higher in invasive ductal carcinoma than in normal breast tissues (OR =5.83, 95% CI 3.76–9.03, P<0.00001. CDH1 hypermethylation was significantly higher in estrogen receptor (ER-negative BC than in ER-positive BC (OR =0.62, 95% CI 0.43–0.87, P=0.007. In addition, we found that the CDH1 was significantly methylated in HER2-negative BC than in HER2-positive BC (OR =0.26, 95% CI 0.15–0.44, P<0.00001. However, CDH1 methylation frequency was not associated with progesterone receptor (PR status, or with grades, stages, or lymph node metastasis of BC patients. Our results indicate that CDH1 hypermethylation is a potential novel drug target for developing personalized therapy. CDH1 hypermethylation is strongly associated with ER-negative and HER2-negative BC, respectively, suggesting CDH1 methylation status could contribute to the development of novel therapeutic approaches for the treatment of ER-negative or HER2-negative BC with aggressive tumor biology.Keywords: methylation, estrogen receptor, HER2

  19. AS1411 aptamer and folic acid functionalized pH-responsive ATRP fabricated pPEGMA-PCL-pPEGMA polymeric nanoparticles for targeted drug delivery in cancer therapy.

    Science.gov (United States)

    Lale, Shantanu V; R G, Aswathy; Aravind, Athulya; Kumar, D Sakthi; Koul, Veena

    2014-05-12

    Nonspecificity and cardiotoxicity are the primary limitations of current doxorubicin chemotherapy. To minimize side effects and to enhance bioavailability of doxorubicin to cancer cells, a dual-targeted pH-sensitive biocompatible polymeric nanosystem was designed and developed. An ATRP-based biodegradable triblock copolymer, poly(poly(ethylene glycol) methacrylate)-poly(caprolactone)-poly(poly(ethylene glycol) methacrylate) (pPEGMA-PCL-pPEGMA), conjugated with doxorubicin via an acid-labile hydrazone bond was synthesized and characterized. Dual targeting was achieved by attaching folic acid and the AS1411 aptamer through EDC-NHS coupling. Nanoparticles of the functionalized triblock copolymer were prepared using the nanoprecipitation method, resulting in an average particle size of ∼140 nm. The biocompatibility of the nanoparticles was evaluated using MTT cytotoxicity assays, blood compatibility studies, and protein adsorption studies. In vitro drug release studies showed a higher cumulative doxorubicin release at pH 5.0 (∼70%) compared to pH 7.4 (∼25%) owing to the presence of the acid-sensitive hydrazone linkage. Dual targeting with folate and the AS1411 aptamer increased the cancer-targeting efficiency of the nanoparticles, resulting in enhanced cellular uptake (10- and 100-fold increase in uptake compared to single-targeted NPs and non-targeted NPs, respectively) and a higher payload of doxorubicin in epithelial cancer cell lines (MCF-7 and PANC-1), with subsequent higher apoptosis, whereas a normal (noncancerous) cell line (L929) was spared from the adverse effects of doxorubicin. The results indicate that the dual-targeted pH-sensitive biocompatible polymeric nanosystem can act as a potential drug delivery vehicle against various epithelial cancers such as those of the breast, ovary, pancreas, lung, and others. PMID:24689987

  20. Molecular interaction of a kinase inhibitor midostaurin with anticancer drug targets, S100A8 and EGFR: transcriptional profiling and molecular docking study for kidney cancer therapeutics.

    Directory of Open Access Journals (Sweden)

    Zeenat Mirza

    Full Text Available The S100A8 and epidermal growth factor receptor (EGFR proteins are proto-oncogenes that are strongly expressed in a number of cancer types. EGFR promotes cellular proliferation, differentiation, migration and survival by activating molecular pathways. Involvement of proinflammatory S100A8 in tumor cell differentiation and progression is largely unclear and not studied in kidney cancer (KC. S100A8 and EGFR are potential therapeutic biomarkers and anticancer drug targets for KC. In this study, we explored molecular mechanisms of interaction profiles of both molecules with potential anticancer drugs. We undertook transcriptional profiling in Saudi KCs using Affymetrix HuGene 1.0 ST arrays. We identified 1478 significantly expressed genes, including S100A8 and EGFR overexpression, using cut-off p value <0.05 and fold change ≥2. Additionally, we compared and confirmed our findings with expression data available at NCBI's GEO database. A significant number of genes associated with cancer showed involvement in cell cycle progression, DNA repair, tumor morphology, tissue development, and cell survival. Atherosclerosis signaling, leukocyte extravasation signaling, notch signaling, and IL-12 signaling were the most significantly disrupted signaling pathways. The present study provides an initial transcriptional profiling of Saudi KC patients. Our analysis suggests distinct transcriptomic signatures and pathways underlying molecular mechanisms of KC progression. Molecular docking analysis revealed that the kinase inhibitor "midostaurin" has amongst the selected drug targets, the best ligand properties to S100A8 and EGFR, with the implication that its binding inhibits downstream signaling in KC. This is the first structure-based docking study for the selected protein targets and anticancer drug, and the results indicate S100A8 and EGFR as attractive anticancer targets and midostaurin with effective drug properties for therapeutic intervention in KC.

  1. Polymer-Based Prodrugs: Improving Tumor Targeting and the Solubility of Small Molecule Drugs in Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Sonja Dragojevic

    2015-12-01

    Full Text Available The majority of anticancer drugs have poor aqueous solubility, produce adverse effects in healthy tissue, and thus impose major limitations on both clinical efficacy and therapeutic safety of cancer chemotherapy. To help circumvent problems associated with solubility, most cancer drugs are now formulated with co-solubilizers. However, these agents often also introduce severe side effects, thereby restricting effective treatment and patient quality of life. A promising approach to addressing problems in anticancer drug solubility and selectivity is their conjugation with polymeric carriers to form polymer-based prodrugs. These polymer-based prodrugs are macromolecular carriers, designed to increase the aqueous solubility of antitumor drugs, can enhance bioavailability. Additionally, polymer-based prodrugs approach exploits unique features of tumor physiology to passively facilitate intratumoral accumulation, and so improve chemodrug pharmacokinetics and pharmacological properties. This review introduces basic concepts of polymer-based prodrugs, provides an overview of currently emerging synthetic, natural, and genetically engineered polymers that now deliver anticancer drugs in preclinical or clinical trials, and highlights their major anticipated applications in anticancer therapies.

  2. Polymer-Based Prodrugs: Improving Tumor Targeting and the Solubility of Small Molecule Drugs in Cancer Therapy.

    Science.gov (United States)

    Dragojevic, Sonja; Ryu, Jung Su; Raucher, Drazen

    2015-12-04

    The majority of anticancer drugs have poor aqueous solubility, produce adverse effects in healthy tissue, and thus impose major limitations on both clinical efficacy and therapeutic safety of cancer chemotherapy. To help circumvent problems associated with solubility, most cancer drugs are now formulated with co-solubilizers. However, these agents often also introduce severe side effects, thereby restricting effective treatment and patient quality of life. A promising approach to addressing problems in anticancer drug solubility and selectivity is their conjugation with polymeric carriers to form polymer-based prodrugs. These polymer-based prodrugs are macromolecular carriers, designed to increase the aqueous solubility of antitumor drugs, can enhance bioavailability. Additionally, polymer-based prodrugs approach exploits unique features of tumor physiology to passively facilitate intratumoral accumulation, and so improve chemodrug pharmacokinetics and pharmacological properties. This review introduces basic concepts of polymer-based prodrugs, provides an overview of currently emerging synthetic, natural, and genetically engineered polymers that now deliver anticancer drugs in preclinical or clinical trials, and highlights their major anticipated applications in anticancer therapies.

  3. TIMP-1 overexpression does not affect sensitivity to HER2-targeting drugs in the HER2-gene-amplified SK-BR-3 human breast cancer cell line

    DEFF Research Database (Denmark)

    Deng, Xiaohong; Fogh, Louise; Lademann, Ulrik Axel;

    2013-01-01

    and lapatinib was studied in five selected single-cell subclones expressing TIMP-1 protein at various levels plus the parental SK-BR-3 cell line. Both trastuzumab and lapatinib reduced cell viability, as determined by MTT assay, but the sensitivity to the drugs was not associated with the expression level...... affect sensitivity to the HER2-targeting drugs trastuzumab and lapatinib. SK-BR-3 human breast cancer cells were stably transfected with TIMP-1, characterized with regard to TIMP-1 protein expression, proliferation, and functionality of the secreted TIMP-1, and the sensitivity to trastuzumab...

  4. 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

  5. Sugar-decorated mesoporous silica nanoparticles as delivery vehicles for the poorly soluble drug celastrol enables targeted induction of apoptosis in cancer cells.

    Science.gov (United States)

    Niemelä, Erik; Desai, Diti; Nkizinkiko, Yves; Eriksson, John E; Rosenholm, Jessica M

    2015-10-01

    Cancerous cells have a rapid metabolism by which they take up sugars, such as glucose, at significantly higher rates than normal cells. Celastrol is a traditional herbal medicine known for its anti-inflammatory and anti-cancer activities. The poor aqueous solubility and lack of target selectivity of celastrol result in low therapeutic concentration of the drug reaching subcellular compartments of the target tissue, making it an interesting candidate for nanoparticulate delivery. The goal of this study was to utilize glucose as an affinity ligand decorated on mesoporous silica nanoparticles (MSNs), with the aim of delivering these celastrol-loaded MSNs with high specificity to cancer cells and inducing minimal off-target effects in healthy cells. MSNs were thus functionalized with sugar moieties by two different routes, either by conjugation directly to the MSN surface or mediated by a hyperbranched poly(ethylene imine), PEI layer; the latter to increase the cellular uptake by providing an overall positive surface charge as well as to increase the reaction sites for sugar conjugation. The effect of surface functionalization on the target-specific efficacy of the particles was assessed by analyzing the uptake in HeLa and A549 cells as cancer cell models, as compared to mouse embryonic fibroblasts (MEF) as a representative for normal cells. To this end a comprehensive analysis strategy was employed, including flow cytometry, confocal microscopy, and spectrophotometry. When the apoptotic effect of celastrol was evaluated, the anti-cancer activity of celastrol was shown to be significantly enhanced when it was loaded into the specifically designed MSNs. The particles themselves did not induce any toxicity, and normal cells displayed minimal off-target effects. In summary, we show that glucose-functionalized MSNs can be used as efficient carriers for targeted celastrol delivery to achieve specific induction of apoptosis in cancer cells.

  6. The National Cancer Institute's PREVENT Cancer Preclinical Drug Development Program: overview, current projects, animal models, agent development strategies, and molecular targets.

    Science.gov (United States)

    Shoemaker, Robert H; Suen, Chen S; Holmes, Cathy A; Fay, Judith R; Steele, Vernon E

    2016-02-01

    The PREVENT Cancer Preclinical Drug Development Program (PREVENT) is a National Cancer Institute, Division of Cancer Prevention (NCI, DCP)-supported program whose primary goal is to bring new cancer preventive interventions (small molecules and vaccines) and biomarkers through preclinical development towards clinical trials by creating partnerships between the public sector (eg, academia, industry) and DCP. PREVENT has a formalized structure for moving interventions forward in the prevention pipeline using a stage-gate process with go/no go decision points along the critical path for development. This review describes the structure of the program, its focus areas, and provides examples of projects currently in the pipeline.

  7. The National Cancer Institute's PREVENT Cancer Preclinical Drug Development Program: overview, current projects, animal models, agent development strategies, and molecular targets.

    Science.gov (United States)

    Shoemaker, Robert H; Suen, Chen S; Holmes, Cathy A; Fay, Judith R; Steele, Vernon E

    2016-02-01

    The PREVENT Cancer Preclinical Drug Development Program (PREVENT) is a National Cancer Institute, Division of Cancer Prevention (NCI, DCP)-supported program whose primary goal is to bring new cancer preventive interventions (small molecules and vaccines) and biomarkers through preclinical development towards clinical trials by creating partnerships between the public sector (eg, academia, industry) and DCP. PREVENT has a formalized structure for moving interventions forward in the prevention pipeline using a stage-gate process with go/no go decision points along the critical path for development. This review describes the structure of the program, its focus areas, and provides examples of projects currently in the pipeline. PMID:26970137

  8. Therapeutic efficacy and safety of paclitaxel/lonidamine loaded EGFR-targeted nanoparticles for the treatment of multi-drug resistant cancer.

    Science.gov (United States)

    Milane, Lara; Duan, Zhenfeng; Amiji, Mansoor

    2011-01-01

    The treatment of multi-drug resistant (MDR) cancer is a clinical challenge. Many MDR cells over-express epidermal growth factor receptor (EGFR). We exploit this expression through the development of EGFR-targeted, polymer blend nanocarriers for the treatment of MDR cancer using paclitaxel (a common chemotherapeutic agent) and lonidamine (an experimental drug; mitochondrial hexokinase 2 inhibitor). An orthotopic model of MDR human breast cancer was developed in nude mice and used to evaluate the safety and efficacy of nanoparticle treatment. The efficacy parameters included tumor volume measurements from day 0 through 28 days post-treatment, terminal tumor weight measurements, tumor density and morphology assessment through hematoxylin and eosin staining of excised tumors, and immunohistochemistry of tumor sections for MDR protein markers (P-glycoprotein, Hypoxia Inducible Factor, EGFR, Hexokinase 2, and Stem Cell Factor). Toxicity was assessed by tracking changes in animal body weight from day 0 through 28 days post-treatment, by measuring plasma levels of the liver enzymes ALT (Alanine Aminotransferase) and LDH (lactate dehydrogenase), and by white blood cell and platelet counts. In these studies, this nanocarrier system demonstrated superior efficacy relative to combination (paclitaxel/lonidamine) drug solution and single agent treatments in nanoparticle and solution form. The combination nanoparticles were the only treatment group that decreased tumor volume, sustaining this decrease until the 28 day time point. In addition, treatment with the EGFR-targeted lonidamine/paclitaxel nanoparticles decreased tumor density and altered the MDR phenotype of the tumor xenografts. These EGFR-targeted combination nanoparticles were considerably less toxic than solution treatments. Due to the flexible design and simple conjugation chemistry, this nanocarrier system could be used as a platform for the development of other MDR cancer therapies; the use of this system for EGFR-targeted

  9. Therapeutic efficacy and safety of paclitaxel/lonidamine loaded EGFR-targeted nanoparticles for the treatment of multi-drug resistant cancer.

    Directory of Open Access Journals (Sweden)

    Lara Milane

    Full Text Available The treatment of multi-drug resistant (MDR cancer is a clinical challenge. Many MDR cells over-express epidermal growth factor receptor (EGFR. We exploit this expression through the development of EGFR-targeted, polymer blend nanocarriers for the treatment of MDR cancer using paclitaxel (a common chemotherapeutic agent and lonidamine (an experimental drug; mitochondrial hexokinase 2 inhibitor. An orthotopic model of MDR human breast cancer was developed in nude mice and used to evaluate the safety and efficacy of nanoparticle treatment. The efficacy parameters included tumor volume measurements from day 0 through 28 days post-treatment, terminal tumor weight measurements, tumor density and morphology assessment through hematoxylin and eosin staining of excised tumors, and immunohistochemistry of tumor sections for MDR protein markers (P-glycoprotein, Hypoxia Inducible Factor, EGFR, Hexokinase 2, and Stem Cell Factor. Toxicity was assessed by tracking changes in animal body weight from day 0 through 28 days post-treatment, by measuring plasma levels of the liver enzymes ALT (Alanine Aminotransferase and LDH (lactate dehydrogenase, and by white blood cell and platelet counts. In these studies, this nanocarrier system demonstrated superior efficacy relative to combination (paclitaxel/lonidamine drug solution and single agent treatments in nanoparticle and solution form. The combination nanoparticles were the only treatment group that decreased tumor volume, sustaining this decrease until the 28 day time point. In addition, treatment with the EGFR-targeted lonidamine/paclitaxel nanoparticles decreased tumor density and altered the MDR phenotype of the tumor xenografts. These EGFR-targeted combination nanoparticles were considerably less toxic than solution treatments. Due to the flexible design and simple conjugation chemistry, this nanocarrier system could be used as a platform for the development of other MDR cancer therapies; the use of this

  10. Drugs Approved for Lung Cancer

    Science.gov (United States)

    ... Ask about Your Treatment Research Drugs Approved for Lung Cancer This page lists cancer drugs approved by the Food and Drug Administration (FDA) for lung cancer. The list includes generic and brand names. This page also lists common drug combinations used in lung ...

  11. Scaffold Repurposing of Old Drugs Towards New Cancer Drug Discovery.

    Science.gov (United States)

    Chen, Haijun; Wu, Jianlei; Gao, Yu; Chen, Haiying; Zhou, Jia

    2016-01-01

    As commented by the Nobelist James Black that "The most fruitful basis of the discovery of a new drug is to start with an old drug", drug repurposing represents an attractive drug discovery strategy. Despite the success of several repurposed drugs on the market, the ultimate therapeutic potential of a large number of non-cancer drugs is hindered during their repositioning due to various issues including the limited efficacy and intellectual property. With the increasing knowledge about the pharmacological properties and newly identified targets, the scaffolds of the old drugs emerge as a great treasure-trove towards new cancer drug discovery. In this review, we summarize the recent advances in the development of novel small molecules for cancer therapy by scaffold repurposing with highlighted examples. The relevant strategies, advantages, challenges and future research directions associated with this approach are also discussed.

  12. Scaffold Repurposing of Old Drugs Towards New Cancer Drug Discovery.

    Science.gov (United States)

    Chen, Haijun; Wu, Jianlei; Gao, Yu; Chen, Haiying; Zhou, Jia

    2016-01-01

    As commented by the Nobelist James Black that "The most fruitful basis of the discovery of a new drug is to start with an old drug", drug repurposing represents an attractive drug discovery strategy. Despite the success of several repurposed drugs on the market, the ultimate therapeutic potential of a large number of non-cancer drugs is hindered during their repositioning due to various issues including the limited efficacy and intellectual property. With the increasing knowledge about the pharmacological properties and newly identified targets, the scaffolds of the old drugs emerge as a great treasure-trove towards new cancer drug discovery. In this review, we summarize the recent advances in the development of novel small molecules for cancer therapy by scaffold repurposing with highlighted examples. The relevant strategies, advantages, challenges and future research directions associated with this approach are also discussed. PMID:26881709

  13. Design and Fabrication of Multifunctional Sericin Nanoparticles for Tumor Targeting and pH-Responsive Subcellular Delivery of Cancer Chemotherapy Drugs.

    Science.gov (United States)

    Huang, Lei; Tao, Kaixiong; Liu, Jia; Qi, Chao; Xu, Luming; Chang, Panpan; Gao, Jinbo; Shuai, Xiaoming; Wang, Guobin; Wang, Zheng; Wang, Lin

    2016-03-01

    The severe cytotoxicity of cancer chemotherapy drugs limits their clinical applications. Various protein-based nanoparticles with good biocompatibility have been developed for chemotherapy drug delivery in hope of reducing drugs' side effects. Sericin, a natural protein from silk, has no immunogenicity and possesses diverse bioactivities that have prompted sericin's application studies. However, the potential of sericin as a multifunctional nanoscale vehicle for cancer therapy have not been fully explored. Here we report the successful fabrication and characterization of folate-conjugated sericin nanoparticles with cancer-targeting capability for pH-responsive release of doxorubicin (these nanoparticles are termed "FA-SND"). DOX is covalently linked to sericin through pH-sensitive hydrazone bonds that render a pH-triggered release property. The hydrophobicity of DOX and the hydrophilicity of sericin promote the self-assembly of sericin-DOX (SND) nanoconjugates. Folate (FA) is then covalently grafted to SND nanoconjugates as a binding unit for actively targeting cancer cells that overexpress folate receptors. Our characterization study shows that FA-SND nanoparticles exhibit negative surface charges that would reduce nonspecific clearance by circulation. These nanoparticles possess good cytotoxicity and hemocompatibiliy. Acidic environment (pH 5.0) triggers effective DOX release from FA-SND, 5-fold higher than does a neutral condition (pH 7.4). Further, FA-SND nanoparticles specifically target folate-receptor-rich KB cells, and endocytosed into lysosomes, an acidic organelle. The acidic microenvironment of lysosomes promotes a rapid release of DOX to nuclei, producing cancer specific chemo-cytotoxicity. Thus, FA-mediated cancer targeting and lysosomal-acidity promoting DOX release, two sequentially-occurring cellular events triggered by the designed components of FA-SND, form the basis for FA-SND to achieve its localized and intracellular chemo

  14. Drug/Dye-Loaded, Multifunctional PEG-Chitosan-Iron Oxide Nanocomposites for Methotraxate Synergistically Self-Targeted Cancer Therapy and Dual Model Imaging.

    Science.gov (United States)

    Lin, Jinyan; Li, Yang; Li, Yanxiu; Wu, Hongjie; Yu, Fei; Zhou, Shuifan; Xie, Liya; Luo, Fanghong; Lin, Changjian; Hou, Zhenqing

    2015-06-10

    Multifunctional nanocomposites hold great potential to integrate therapeutic and diagnostic functions into a single nanoscale structure. In this paper, we prepared the MTX-PEG-CS-IONPs-Cy5.5 nanocomposites by functionalizing the surface of chitosan-decorated iron oxide nanoparticles (CS-IONPs) with polyethylene glycolated methotraxate (MTX-PEG) and near-infrared fluorescent cyanin dye (Cy5.5). A clinically useful PEGylated anticancer prodrug, MTX-PEG, was also developed as a tumor cell-specific targeting ligand for self-targeted cancer treatment. In such nanocomposites, the advantage was that the orthogonally functionalized, self-targeted MTX-PEG-CS-IONPs-Cy5.5 can synergistically combine an early phase selective tumor-targeting efficacy with a late-phase cancer-killing effect, which was also confirmed by dual model (magnetic resonance and fluorescence) imaging. Furthermore, with the aids of the folate (FA) receptor-mediated endocytosis (able to turn cellular uptake "off" in normal cells and "on" in cancer cells) and pH/intracellular protease-mediated hydrolyzing peptide bonds (able to turn drug release "off" in systemic circulation and "on" inside endo/lysosomes), the MTX-PEG-CS-IONPs-Cy5.5 could deliver MTX to FA receptors-overexpressed cancer cells, showing the improved anticancer activity with the reduced side effects. Together, the MTX-PEG-CS-IONPs-Cy5.5 could act as a highly convergent, flexible, and simplified system for dual model imaging and synergistically self-targeted cancer therapy, holding great promise for versatile biomedical applications in future. PMID:25978458

  15. EGFR-targeted drugs for colorectal cancer: current status and future challenges%EGFR靶向药物在结直肠癌中的研究进展

    Institute of Scientific and Technical Information of China (English)

    王丽; 余英豪

    2011-01-01

    Colorectal cancer is a common gastrointestinal malignancy. The effects of traditional chemotherapy and radiation therapy against colorectal cancer are not satisfactory. The epidermal growth factor receptor (EGFR) signaling pathway plays an important role in tumor proliferation, angiogenesis, invasion, and metastasis in colorectal cancer. EGFR-targeted drugs have been developed and applied to the treatment of colorectal cancer. This paper provides a literature review on the current status and future challenges of EGFR-targeted therapy of colorectal cancer.%结直肠癌是常见的消化系恶性肿瘤,传统的化疗和放疗效果均不甚理想.表皮生长因子受体(EGFR)q%号转导通路在结直肠癌细胞的增殖、血管生成、侵袭、转移等方面有重要作用.因此,针对EGFR的靶向药物已陆续开发,并应用于结直肠癌治疗的临床实践.本文就EGFR靶向药物在结直肠癌中的研究现状及其相关问题进行综述.

  16. Extracellular proteases as targets for drug development

    OpenAIRE

    Cudic, Mare; Fields, Gregg B.

    2009-01-01

    Proteases constitute one of the primary targets in drug discovery. In the present review, we focus on extracellular proteases (ECPs) because of their differential expression in many pathophysiological processes, including cancer, cardiovascular conditions, and inflammatory, pulmonary, and periodontal diseases. Many new ECP inhibitors are currently under clinical investigation and a significant increase in new therapies based on protease inhibition can be expected in the coming years. In addit...

  17. Targeted therapy in lung and breast cancer: a big deal

    OpenAIRE

    Caffarra, Cristina

    2015-01-01

    Great strides have been done in treating cancer. For decades, the hallmark of medical treatment for cancer has been intravenous cytotoxic chemotherapy which targets all dividing cells. In the last ten years the identification of different driver oncogenic mutations has allowed the development of targeted drugs. Targeted cancer therapies are based on the use of drugs that block the growth and spread of cancer by interfering with specific molecules involved in tumor growth and progression. The ...

  18. Sphingosines Derived from Marine Sponge as Potential Multi-Target Drug Related to Disorders in Cancer Development.

    Science.gov (United States)

    Biegelmeyer, Renata; Schröder, Rafael; Rambo, Douglas F; Dresch, Roger R; Carraro, João L F; Mothes, Beatriz; Moreira, José Cláudio F; Junior, Mário L C da Frota; Henriques, Amélia T

    2015-08-25

    Haliclona tubifera, marine sponge species abundant in Brazilian coastline, presents only a few papers published in the literature. Recently, we have reported the isolation of two modified C18 sphingoid bases: (2R,3R,6R,7Z)-2-aminooctadec-7-ene-1,3, 6-triol and and (2R,3R,6R)-2-aminooctadec-1,3,6-triol. In order to continue our research, in this work aimed at the biological investigation of fractions that led to the isolation of these compounds. We evaluated the cytotoxic effect of marine sponge H. tubifera fractions in glioma (U87) and neuroblastoma (SH-SY5Y) human cell lines. In addition, considering the link between cancer, imbalance of reactive oxygen species and coagulation disorders, we also investigated the in vitro effects on blood coagulation and their redox properties. We showed that the ethyl acetate (EtOAc) fraction, rich in sphingoid bases, had important cytotoxic effects in both cancer cell lines with an IC50 < 15 μg/mL and also can inhibit the production of peroxyl radicals. Interestingly, this fraction increased the recalcification time of human blood, showing anticoagulant properties. The present study indicates the sphingosines fraction as a promising source of chemical prototypes, especially multifunctional drugs in cancer therapy.

  19. Biotin-targeted Pluronic(®) P123/F127 mixed micelles delivering niclosamide: A repositioning strategy to treat drug-resistant lung cancer cells.

    Science.gov (United States)

    Russo, Annapina; Pellosi, Diogo Silva; Pagliara, Valentina; Milone, Maria Rita; Pucci, Biagio; Caetano, Wilker; Hioka, Noboru; Budillon, Alfredo; Ungaro, Francesca; Russo, Giulia; Quaglia, Fabiana

    2016-09-10

    With the aim to develop alternative therapeutic tools for the treatment of resistant cancers, here we propose targeted Pluronic(®) P123/F127 mixed micelles (PMM) delivering niclosamide (NCL) as a repositioning strategy to treat multidrug resistant non-small lung cancer cell lines. To build multifunctional PMM for targeting and imaging, Pluronic(®) F127 was conjugated with biotin, while Pluronic(®) P123 was fluorescently tagged with rhodamine B, in both cases at one of the two hydroxyl end groups. This design intended to avoid any interference of rhodamine B on biotin exposition on PMM surface, which is a key fundamental for cell trafficking studies. Biotin-decorated PMM were internalized more efficiently than non-targeted PMM in A549 lung cancer cells, while very low internalization was found in NHI3T3 normal fibroblasts. Biotin-decorated PMM entrapped NCL with good efficiency, displayed sustained drug release in protein-rich media and improved cytotoxicity in A549 cells as compared to free NCL (P<0.01). To go in depth into the actual therapeutic potential of NCL-loaded PMM, a cisplatin-resistant A549 lung cancer cell line (CPr-A549) was developed and its multidrug resistance tested against common chemotherapeutics. Free NCL was able to overcome chemoresistance showing cytotoxic effects in this cell line ascribable to nucleolar stress, which was associated to a significant increase of the ribosomal protein rpL3 and consequent up-regulation of p21. It is noteworthy that biotin-decorated PMM carrying NCL at low doses demonstrated a significantly higher cytotoxicity than free NCL in CPr-A549. These results point at NCL-based regimen with targeted PMM as a possible second-line chemotherapy for lung cancer showing cisplatin or multidrug resistance.

  20. Size-controlled synthesis of biodegradable nanocarriers for targeted and controlled cancer drug delivery using salting out cation

    Indian Academy of Sciences (India)

    Madasamy Hari Balakrishanan; Mariappan Rajan

    2016-02-01

    Research for synthesis of size-controlled carriers is currently challenging one. In this research paper, a method for size-controlled synthesis of biodegradable nanocarriers is proposed and described. Salting out method is suitable for both hydrophilic and hydrophobic drugs for the encapsulation on carriers. This synthetic method is based on polylactic acid (PLA) and non-ionic carboxymethyl cellulose (CMC) composed by CaCl2 as salting out agent. This method permits size-controlled synthesis of particles between 50 and 400 nm simply by varying the concentration of salting out agents. We have prepared cisplatin (CDDP)-loaded PLA-CMC nanocarriers by salting out method, with varying salting out agent (CaCl2) concentrations as 0.05, 0.2, 0.35 and 0.5 M. The nanocarriers were characterized for their size, surface charge and morphology by atomic force microscope, zeta potential analyser and transmission electron microscope, respectively. The encapsulation efficiency and in-vitro drug-releasing behaviour of the nanocarriers were investigated. The cytotoxicity effect of nanocarriers and drug-loaded nanocarriers was tested against MCF-7 breast cancer cell line.

  1. Nucleolin overexpression in breast cancer cell sub-populations with different stem-like phenotype enables targeted intracellular delivery of synergistic drug combination.

    Science.gov (United States)

    Fonseca, Nuno A; Rodrigues, Ana S; Rodrigues-Santos, Paulo; Alves, Vera; Gregório, Ana C; Valério-Fernandes, Ângela; Gomes-da-Silva, Lígia C; Rosa, Manuel Santos; Moura, Vera; Ramalho-Santos, João; Simões, Sérgio; Moreira, João Nuno

    2015-11-01

    Breast cancer stem cells (CSC) are thought responsible for tumor growth and relapse, metastization and active evasion to standard chemotherapy. The recognition that CSC may originate from non-stem cancer cells (non-SCC) through plastic epithelial-to-mesenchymal transition turned these into relevant cell targets. Of crucial importance for successful therapeutic intervention is the identification of surface receptors overexpressed in both CSC and non-SCC. Cell surface nucleolin has been described as overexpressed in cancer cells as well as a tumor angiogenic marker. Herein we have addressed the questions on whether nucleolin was a common receptor among breast CSC and non-SCC and whether it could be exploited for targeting purposes. Liposomes functionalized with the nucleolin-binding F3 peptide, targeted simultaneously, nucleolin-overexpressing putative breast CSC and non-SCC, which was paralleled by OCT4 and NANOG mRNA levels in cells from triple negative breast cancer (TNBC) origin. In murine embryonic stem cells, both nucleolin mRNA levels and F3 peptide-targeted liposomes cellular association were dependent on the stemness status. An in vivo tumorigenic assay suggested that surface nucleolin overexpression per se, could be associated with the identification of highly tumorigenic TNBC cells. This proposed link between nucleolin expression and the stem-like phenotype in TNBC, enabled 100% cell death mediated by F3 peptide-targeted synergistic drug combination, suggesting the potential to abrogate the plasticity and adaptability associated with CSC and non-SCC. Ultimately, nucleolin-specific therapeutic tools capable of simultaneous debulk multiple cellular compartments of the tumor microenvironment may pave the way towards a specific treatment for TNBC patient care. PMID:26283155

  2. Nucleolin overexpression in breast cancer cell sub-populations with different stem-like phenotype enables targeted intracellular delivery of synergistic drug combination.

    Science.gov (United States)

    Fonseca, Nuno A; Rodrigues, Ana S; Rodrigues-Santos, Paulo; Alves, Vera; Gregório, Ana C; Valério-Fernandes, Ângela; Gomes-da-Silva, Lígia C; Rosa, Manuel Santos; Moura, Vera; Ramalho-Santos, João; Simões, Sérgio; Moreira, João Nuno

    2015-11-01

    Breast cancer stem cells (CSC) are thought responsible for tumor growth and relapse, metastization and active evasion to standard chemotherapy. The recognition that CSC may originate from non-stem cancer cells (non-SCC) through plastic epithelial-to-mesenchymal transition turned these into relevant cell targets. Of crucial importance for successful therapeutic intervention is the identification of surface receptors overexpressed in both CSC and non-SCC. Cell surface nucleolin has been described as overexpressed in cancer cells as well as a tumor angiogenic marker. Herein we have addressed the questions on whether nucleolin was a common receptor among breast CSC and non-SCC and whether it could be exploited for targeting purposes. Liposomes functionalized with the nucleolin-binding F3 peptide, targeted simultaneously, nucleolin-overexpressing putative breast CSC and non-SCC, which was paralleled by OCT4 and NANOG mRNA levels in cells from triple negative breast cancer (TNBC) origin. In murine embryonic stem cells, both nucleolin mRNA levels and F3 peptide-targeted liposomes cellular association were dependent on the stemness status. An in vivo tumorigenic assay suggested that surface nucleolin overexpression per se, could be associated with the identification of highly tumorigenic TNBC cells. This proposed link between nucleolin expression and the stem-like phenotype in TNBC, enabled 100% cell death mediated by F3 peptide-targeted synergistic drug combination, suggesting the potential to abrogate the plasticity and adaptability associated with CSC and non-SCC. Ultimately, nucleolin-specific therapeutic tools capable of simultaneous debulk multiple cellular compartments of the tumor microenvironment may pave the way towards a specific treatment for TNBC patient care.

  3. Extracellular proteases as targets for drug development.

    Science.gov (United States)

    Cudic, Mare; Fields, Gregg B

    2009-08-01

    Proteases constitute one of the primary targets in drug discovery. In the present review, we focus on extracellular proteases (ECPs) because of their differential expression in many pathophysiological processes, including cancer, cardiovascular conditions, and inflammatory, pulmonary, and periodontal diseases. Many new ECP inhibitors are currently under clinical investigation and a significant increase in new therapies based on protease inhibition can be expected in the coming years. In addition to directly blocking the activity of a targeted protease, one can take advantage of differential expression in disease states to selectively deliver therapeutic or imaging agents. Recent studies in targeted drug development for the metalloproteases (matrix metalloproteinases, adamalysins, pappalysins, neprilysin, angiotensin-converting enzyme, metallocarboxypeptidases, and glutamate carboxypeptidase II), serine proteases (elastase, coagulation factors, tissue/urokinase plasminogen activator system, kallikreins, tryptase, dipeptidyl peptidase IV) and cysteine proteases (cathepsin B) are discussed herein. PMID:19689354

  4. Photodynamic therapy of a 2-methoxyestradiol tumor-targeting drug delivery system mediated by Asn-Gly-Arg in breast cancer

    Directory of Open Access Journals (Sweden)

    Shi J

    2013-04-01

    Full Text Available Jinjin Shi, Zhenzhen Wang, Lei Wang, Honghong Wang, Lulu Li, Xiaoyuan Yu, Jing Zhang, Rou Ma, Zhenzhong ZhangSchool of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, People's Republic of ChinaAbstract: Fullerene (C60 has shown great potential in drug delivery. In this study we exploited modified fullerene (diadduct malonic acid-fullerene-Asn-Gly-Arg peptide [DMA-C60-NGR] as an antitumor drug carrier in order to build a new tumor-targeting drug delivery system. We also investigated the synergistic enhancement of cancer therapy using photodynamic therapy (PDT induced by DMA-C60-NGR and 2-methoxyestradiol (2ME. Cytotoxicity tests indicated that DMA-C60-NGR had no obvious toxicity, while our drug delivery system (DMA-C60-2ME-NGR had a high inhibition effect on MCF-7 cells compared to free 2ME. The tumor-targeting drug delivery system could efficiently cross cell membranes, and illumination induced the generation of intracellular reactive oxygen species and DNA damage. Furthermore, DMA-C60-2ME-NGR with irradiation had the highest inhibition effect on MCF-7 cells compared to the other groups. DMA-C60-NGR combined with 2ME showed a good synergistic photosensitization effect for inhibiting the growth of MCF-7 cells, demonstrating that DMA-C60-2ME-NGR may be promising for high treatment efficacy with minimal side effects in future therapy.Keywords: fullerene, drug delivery system, photodynamic therapy, tumor targeting

  5. Evaluation and validation of drug targets

    Institute of Scientific and Technical Information of China (English)

    Guan-huaDU

    2004-01-01

    Drug target is one of the key factors for discovering and developing new drugs. To find and validate drug targets is a crucial technique required in drug discovery by the strategy of high throughput screening. Based on the knowledge of molecular biology, human genomics and proteomics, it has been predicted that 5000 to 10000 drug targets exist in human. So, it is important orocedure to evaluate and validate the drug targets.

  6. Thr 163 phosphorylation causes Mcl-1 stabilization when degradation is independent of the adjacent GSK3-targeted phosphodegron, promoting drug resistance in cancer.

    Directory of Open Access Journals (Sweden)

    Shanna K Nifoussi

    Full Text Available The antiapoptotic Bcl-2 family member Mcl-1 is a PEST protein (containing sequences enriched in proline, glutamic acid, serine, and threonine and is subject to rapid degradation via multiple pathways. Impaired degradation leading to the maintenance of Mcl-1 expression is an important determinant of drug resistance in cancer. Phosphorylation at Thr 163 in the PEST region, stimulated by 12-O-tetradecanoylphorbol acetic acid (TPA-induced activation of extracellular signal-regulated kinase (ERK, is associated with Mcl-1 stabilization in BL41-3 Burkitt lymphoma cells. This contrasts with the observation that Thr 163 phosphorylation in normal fibroblasts primes glycogen synthase kinase (GSK3-induced phosphorylation at Ser 159, producing a phosphodegron that targets Mcl-1 for degradation. In the present follow-up studies in BL41-3 cells, Mcl-1 degradation was found to be independent of the GSK3-mediated pathway, providing a parallel to emerging findings showing that Mcl-1 degradation through this pathway is lost in many different types of cancer. Findings in Mcl-1-transfected CHO cells corroborated those in BL41-3 cells in that the GSK3-targeted phosphodegron did not play a major role in Mcl-1 degradation, and a phosphomimetic T163E mutation resulted in marked Mcl-1 stabilization. TPA-treated BL41-3 cells, in addition to exhibiting Thr 163 phosphorylation and Mcl-1 stabilization, exhibited an ∼10-fold increase in resistance to multiple chemotherapeutic agents, including Ara-C, etoposide, vinblastine, or cisplatin. In these cancer cells in which Mcl-1 degradation is not dependent on the GSK3/phosphodegron-targeted pathway, ERK activation and Thr 163 phosphorylation are associated with pronounced Mcl-1 stabilization and drug resistance - effects that can be suppressed by inhibition of ERK activation.

  7. Drugs Approved for Stomach (Gastric) Cancer

    Science.gov (United States)

    This page lists cancer drugs approved by the Food and Drug Administration (FDA) for stomach (gastric) cancer. The list includes generic names and brand names. The drug names link to NCI's Cancer Drug Information summaries.

  8. Drugs Approved for Head and Neck Cancer

    Science.gov (United States)

    This page lists cancer drugs approved by the Food and Drug Administration (FDA) for head and neck cancer. The list includes generic names and brand names. The drug names link to NCI’s Cancer Drug Information summaries.

  9. Profound activity of the anti-cancer drug bortezomib against Echinococcus multilocularis metacestodes identifies the proteasome as a novel drug target for cestodes.

    Directory of Open Access Journals (Sweden)

    Britta Stadelmann

    2014-12-01

    Full Text Available A library of 426 FDA-approved drugs was screened for in vitro activity against E. multilocularis metacestodes employing the phosphoglucose isomerase (PGI assay. Initial screening at 20 µM revealed that 7 drugs induced considerable metacestode damage, and further dose-response studies revealed that bortezomib (BTZ, a proteasome inhibitor developed for the chemotherapy of myeloma, displayed high anti-metacestodal activity with an EC50 of 0.6 µM. BTZ treatment of E. multilocularis metacestodes led to an accumulation of ubiquinated proteins and unequivocally parasite death. In-gel zymography assays using E. multilocularis extracts demonstrated BTZ-mediated inhibition of protease activity in a band of approximately 23 kDa, the same size at which the proteasome subunit beta 5 of E. multilocularis could be detected by Western blot. Balb/c mice experimentally infected with E. multilocularis metacestodes were used to assess BTZ treatment, starting at 6 weeks post-infection by intraperitoneal injection of BTZ. This treatment led to reduced parasite weight, but to a degree that was not statistically significant, and it induced adverse effects such as diarrhea and neurological symptoms. In conclusion, the proteasome was identified as a drug target in E. multilocularis metacestodes that can be efficiently inhibited by BTZ in vitro. However, translation of these findings into in vivo efficacy requires further adjustments of treatment regimens using BTZ, or possibly other proteasome inhibitors.

  10. Anionic clay as the drug delivery vehicle: tumor targeting function of layered double hydroxide-methotrexate nanohybrid in C33A orthotopic cervical cancer model.

    Science.gov (United States)

    Choi, Goeun; Piao, Huiyan; Alothman, Zeid A; Vinu, Ajayan; Yun, Chae-Ok; Choy, Jin-Ho

    2016-01-01

    Methotrexate (MTX), an anticancer agent, was successfully intercalated into the anionic clay, layered double hydroxides to form a new nanohybrid drug. The coprecipitation and subsequent hydrothermal method were used to prepare chemically, structurally, and morphologically well-defined two-dimensional drug-clay nanohybrid. The resulting two-dimensional drug-clay nanohybrid showed excellent colloidal stability not only in deionized water but also in an electrolyte solution of Dulbecco's Modified Eagle's Medium with 10% fetal bovine serum, in which the average particle size in colloid and the polydispersity index were determined to be around 100 and 0.250 nm, respectively. The targeting property of the nanohybrid drug was confirmed by evaluating the tumor-to-blood and tumor-to-liver ratios of the MTX with anionic clay carrier, and these ratios were compared to those of free MTX in the C33A orthotopic cervical cancer model. The biodistribution studies indicated that the mice treated with the former showed 3.5-fold higher tumor-to-liver ratio and fivefold higher tumor-to-blood ratio of MTX than those treated with the latter at 30 minutes postinjection.

  11. Anionic clay as the drug delivery vehicle: tumor targeting function of layered double hydroxide-methotrexate nanohybrid in C33A orthotopic cervical cancer model.

    Science.gov (United States)

    Choi, Goeun; Piao, Huiyan; Alothman, Zeid A; Vinu, Ajayan; Yun, Chae-Ok; Choy, Jin-Ho

    2016-01-01

    Methotrexate (MTX), an anticancer agent, was successfully intercalated into the anionic clay, layered double hydroxides to form a new nanohybrid drug. The coprecipitation and subsequent hydrothermal method were used to prepare chemically, structurally, and morphologically well-defined two-dimensional drug-clay nanohybrid. The resulting two-dimensional drug-clay nanohybrid showed excellent colloidal stability not only in deionized water but also in an electrolyte solution of Dulbecco's Modified Eagle's Medium with 10% fetal bovine serum, in which the average particle size in colloid and the polydispersity index were determined to be around 100 and 0.250 nm, respectively. The targeting property of the nanohybrid drug was confirmed by evaluating the tumor-to-blood and tumor-to-liver ratios of the MTX with anionic clay carrier, and these ratios were compared to those of free MTX in the C33A orthotopic cervical cancer model. The biodistribution studies indicated that the mice treated with the former showed 3.5-fold higher tumor-to-liver ratio and fivefold higher tumor-to-blood ratio of MTX than those treated with the latter at 30 minutes postinjection. PMID:26855572

  12. 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

  13. Drug targeting to the brain.

    Science.gov (United States)

    Pardridge, William M

    2007-09-01

    The goal of brain drug targeting technology is the delivery of therapeutics across the blood-brain barrier (BBB), including the human BBB. This is accomplished by re-engineering pharmaceuticals to cross the BBB via specific endogenous transporters localized within the brain capillary endothelium. Certain endogenous peptides, such as insulin or transferrin, undergo receptor-mediated transport (RMT) across the BBB in vivo. In addition, peptidomimetic monoclonal antibodies (MAb) may also cross the BBB via RMT on the endogenous transporters. The MAb may be used as a molecular Trojan horse to ferry across the BBB large molecule pharmaceuticals, including recombinant proteins, antibodies, RNA interference drugs, or non-viral gene medicines. Fusion proteins of the molecular Trojan horse and either neurotrophins or single chain Fv antibodies have been genetically engineered. The fusion proteins retain bi-functional properties, and both bind the BBB receptor, to trigger transport into brain, and bind the cognate receptor inside brain to induce the pharmacologic effect. Trojan horse liposome technology enables the brain targeting of non-viral plasmid DNA. Molecular Trojan horses may be formulated with fusion protein technology, avidin-biotin technology, or Trojan horse liposomes to target to brain virtually any large molecule pharmaceutical. PMID:17554607

  14. NEW DRUG TARGETING TREATMENT - GLIVEC

    Institute of Scientific and Technical Information of China (English)

    SUN Xue-mei(孙雪梅); BRADY Ben

    2003-01-01

    This review evaluates the role of Glivec in the treatment of chronic myelogenous leukemia and other malignant tumors. Preclinical and clinical evidence showed that Glivec demonstrated a potent and specific inhibition on BCR-ABL positive leukemias and other malignant tumors in which overexpression of c-kit and PDGFR-β played a major role in their pathogenesis. Glivec has induced complete hematologic responses in up to 98% of patients evaluated in clinical trials. It's a very successful drug that supported the idea of targeted therapy through inhibition of tyrosine kinases. Although it's still in the early stages of clinical development and the resistance to Glivec remains to be a problem needed further study, a great deal has been learned from these research and observation. And with the increasing data, molecular targeting therapy will play much more important role in the treatment of malignant tumors. With the better understanding of the pathogenesis of malignant tumors, well-designed drugs targeting the specific molecular abnormalities with higher efficacy and lower side effect will benefit numerous patients with malignant tumors.

  15. Anionic clay as the drug delivery vehicle: tumor targeting function of layered double hydroxide-methotrexate nanohybrid in C33A orthotopic cervical cancer model

    Directory of Open Access Journals (Sweden)

    Choi G

    2016-01-01

    Full Text Available Goeun Choi,1 Huiyan Piao,1 Zeid A Alothman,2 Ajayan Vinu,3 Chae-Ok Yun,4 Jin-Ho Choy1 1Center for Intelligent Nano-Bio Materials, Department of Chemistry and Nano Science, Ewha Womans University, Seoul, Korea; 2Advanced Materials Research Chair, Chemistry Department, College of Science, King Saud University, Riyadh, Saudi Arabia; 3Future Industries Institute, University of South Australia, Mawson Lakes, SA, Australia; 4Department of Bioengineering, College of Engineering, Hanyang University, Seoul, Korea Abstract: Methotrexate (MTX, an anticancer agent, was successfully intercalated into the anionic clay, layered double hydroxides to form a new nanohybrid drug. The coprecipitation and subsequent hydrothermal method were used to prepare chemically, structurally, and morphologically well-defined two-dimensional drug-clay nanohybrid. The resulting two-dimensional drug-clay nanohybrid showed excellent colloidal stability not only in deionized water but also in an electrolyte solution of Dulbecco’s Modified Eagle’s Medium with 10% fetal bovine serum, in which the average particle size in colloid and the polydispersity index were determined to be around 100 and 0.250 nm, respectively. The targeting property of the nanohybrid drug was confirmed by evaluating the tumor-to-blood and tumor-to-liver ratios of the MTX with anionic clay carrier, and these ratios were compared to those of free MTX in the C33A orthotopic cervical cancer model. The biodistribution studies indicated that the mice treated with the former showed 3.5-fold higher tumor-to-liver ratio and fivefold higher tumor-to-blood ratio of MTX than those treated with the latter at 30 minutes postinjection. Keywords: anionic clay, biodistribution, cervical cancer, colloidal stability, layered double hydroxide, methotrexate 

  16. General route to multifunctional uniform yolk/mesoporous silica shell nanocapsules: a platform for simultaneous cancer-targeted imaging and magnetically guided drug delivery.

    Science.gov (United States)

    Zhang, Lingyu; Wang, Tingting; Yang, Lei; Liu, Cong; Wang, Chungang; Liu, Haiyan; Wang, Y Andrew; Su, Zhongmin

    2012-09-24

    Hollow mesoporous SiO(2) (mSiO(2)) nanostructures with movable nanoparticles (NPs) as cores, so-called yolk-shell nanocapsules (NCs), have attracted great research interest. However, a highly efficient, simple and general way to produce yolk-mSiO(2) shell NCs with tunable functional cores and shell compositions is still a great challenge. A facile, general and reproducible strategy has been developed for fabricating discrete, monodisperse and highly uniform yolk-shell NCs under mild conditions, composed of mSiO(2) shells and diverse functional NP cores with different compositions and shapes. These NPs can be Fe(3)O(4) NPs, gold nanorods (GNRs), and rare-earth upconversion NRs, endowing the yolk-mSiO(2) shell NCs with magnetic, plasmonic, and upconversion fluorescent properties. In addition, multifunctional yolk-shell NCs with tunable interior hollow spaces and mSiO(2) shell thickness can be precisely controlled. More importantly, fluorescent-magnetic-biotargeting multifunctional polyethyleneimine (PEI)-modified fluorescent Fe(3)O(4)@mSiO(2) yolk-shell nanobioprobes as an example for simultaneous targeted fluorescence imaging and magnetically guided drug delivery to liver cancer cells is also demonstrated. This synthetic approach can be easily extended to the fabrication of multifunctional yolk@mSiO(2) shell nanostructures that encapsulate various functional movable NP cores, which construct a potential platform for the simultaneous targeted delivery of drug/gene/DNA/siRNA and bio-imaging.

  17. General route to multifunctional uniform yolk/mesoporous silica shell nanocapsules: a platform for simultaneous cancer-targeted imaging and magnetically guided drug delivery.

    Science.gov (United States)

    Zhang, Lingyu; Wang, Tingting; Yang, Lei; Liu, Cong; Wang, Chungang; Liu, Haiyan; Wang, Y Andrew; Su, Zhongmin

    2012-09-24

    Hollow mesoporous SiO(2) (mSiO(2)) nanostructures with movable nanoparticles (NPs) as cores, so-called yolk-shell nanocapsules (NCs), have attracted great research interest. However, a highly efficient, simple and general way to produce yolk-mSiO(2) shell NCs with tunable functional cores and shell compositions is still a great challenge. A facile, general and reproducible strategy has been developed for fabricating discrete, monodisperse and highly uniform yolk-shell NCs under mild conditions, composed of mSiO(2) shells and diverse functional NP cores with different compositions and shapes. These NPs can be Fe(3)O(4) NPs, gold nanorods (GNRs), and rare-earth upconversion NRs, endowing the yolk-mSiO(2) shell NCs with magnetic, plasmonic, and upconversion fluorescent properties. In addition, multifunctional yolk-shell NCs with tunable interior hollow spaces and mSiO(2) shell thickness can be precisely controlled. More importantly, fluorescent-magnetic-biotargeting multifunctional polyethyleneimine (PEI)-modified fluorescent Fe(3)O(4)@mSiO(2) yolk-shell nanobioprobes as an example for simultaneous targeted fluorescence imaging and magnetically guided drug delivery to liver cancer cells is also demonstrated. This synthetic approach can be easily extended to the fabrication of multifunctional yolk@mSiO(2) shell nanostructures that encapsulate various functional movable NP cores, which construct a potential platform for the simultaneous targeted delivery of drug/gene/DNA/siRNA and bio-imaging. PMID:22907903

  18. MAGNETIC MICROSPHERES AS A TARGETED DRUG DELIVERY SYSTEM : A REVIEW

    Directory of Open Access Journals (Sweden)

    TARUN PATEL

    2012-06-01

    Full Text Available The in-vivo targeting of tumors with magnetic microspheres is currently realized through the applicationof external non-uniform magnetic fields generated by rare-earth permanent magnets or electromagnets.This technique can be applied to magnetically targeted cancer therapy, magnetic embolization therapywith magnetic particles that contain anticancer agent, such as chemotherapeutic drugs or therapeuticradioisotopes. Drug targeting is one way of local or regional antitumor treatment. Magneticallycontrolled drug targeting is one of the various possible ways of drug targeting. This technology is basedon binding establish anticancer drug with ferrofluids that concentrate the drug in the area of interest(tumor site by means of magnetic fields. There has been keen interest in the development of amagnetically target drug delivery system. These drug delivery systems aims to deliver the drug at a ratedirected by the needs of the body during the period of treatment, and target the activity entity to the siteof action. This paper gives an overview of current application of magnetic microspheres (ferrofluid inconjunction with magnetic fields as they relate to the latest advances in medical application and inparticular to anticancer therapy and also discuss about mechanism of magnetic targeted delivery, drugrelease rate in-vitro, benefits and drawbacks of magnetic targeting.

  19. Targeting the cancer epigenome for therapy.

    Science.gov (United States)

    Jones, Peter A; Issa, Jean-Pierre J; Baylin, Stephen

    2016-09-15

    Next-generation sequencing has revealed that more than 50% of human cancers harbour mutations in enzymes that are involved in chromatin organization. Tumour cells not only are activated by genetic and epigenetic alterations, but also routinely use epigenetic processes to ensure their escape from chemotherapy and host immune surveillance. Hence, a growing emphasis of recent drug discovery efforts has been on targeting the epigenome, including DNA methylation and histone modifications, with several new drugs being tested and some already approved by the US Food and Drug Administration (FDA). The future will see the increasing success of combining epigenetic drugs with other therapies. As epigenetic drugs target the epigenome as a whole, these true 'genomic medicines' lessen the need for precision approaches to individualized therapies. PMID:27629931

  20. Drugs Approved for Colon and Rectal Cancer

    Science.gov (United States)

    This page lists cancer drugs approved by the Food and Drug Administration (FDA) for use in colon cancer and rectal cancer. The list includes generic names, brand names, and common drug combinations, which are shown in capital letters.

  1. Drugs Approved for Stomach (Gastric) Cancer

    Science.gov (United States)

    ... Ask about Your Treatment Research Drugs Approved for Stomach (Gastric) Cancer This page lists cancer drugs approved ... that are not listed here. Drugs Approved for Stomach (Gastric) Cancer Cyramza (Ramucirumab) Docetaxel Doxorubicin Hydrochloride 5- ...

  2. MicroRNA-133b targets glutathione S-transferase π expression to increase ovarian cancer cell sensitivity to chemotherapy drugs

    Directory of Open Access Journals (Sweden)

    Chen S

    2015-09-01

    Full Text Available Shuo Chen,1 Jin-Wen Jiao,2 Kai-Xuan Sun,1 Zhi-Hong Zong,3 Yang Zhao1 1Department of Gynecology, The First Affiliated Hospital of China Medical University, Shenyang, People’s Republic of China; 2Department of Gynecology, The Affiliated Hospital of Medical College, Qingdao University, Qingdao, People’s Republic of China; 3Department of Biochemistry and Molecular Biology, College of Basic Medicine, China Medical University, Shenyang, People’s Republic of China Background: Accumulating studies reveal that aberrant microRNA (miRNA expression can affect the development of chemotherapy drug resistance by modulating the expression of relevant target proteins. The aim of this study was to investigate the role of miR-133b in the development of drug resistance in ovarian cancer cells. Methods: We examined the levels of miR-133b expression in ovarian carcinoma tissues and the human ovarian carcinoma cell lines (A2780, A2780/DDP and A2780/Taxol, respectively. We determined the cell viability of these cell lines treated with cisplatin or paclitaxel in the presence or absence of miR-133b or anti-miR-133b transfection using the MTT assay. Reverse transcription polymerase chain reaction and Western blotting were used to assess the mRNA and protein expression levels of two drug-resistance-related genes: glutathione S-transferase (GST-π and multidrug resistance protein 1 (MDR1. The dual-luciferase reporter assay was used to detect the promoter activity of GST-π in the presence and absence of miR-133b. Results: The expression of miR-133b was significantly lower in primary resistant ovarian carcinomas than in the chemotherapy-sensitive carcinomas (P<0.05, and the same results were found in primary resistant ovarian cell lines (A2780/Taxol and A2780/DDP compared to the chemotherapy-sensitive cell line (A2780; P<0.05. Following miR-133b transfection, four cell lines showed increased sensitivity to paclitaxel and cisplatin, while anti-miR-133b transfection

  3. Therapeutic strategies for targeting cancer stem cells

    Institute of Scientific and Technical Information of China (English)

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

    2016-01-01

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

  4. Cholinergic Targets in Lung Cancer.

    Science.gov (United States)

    Spindel, Eliot R

    2016-01-01

    Lung cancers express an autocrine cholinergic loop in which secreted acetylcholine can stimulate tumor growth through both nicotinic and muscarinic receptors. Because activation of mAChR and nAChR stimulates growth; tumor growth can be stimulated by both locally synthesized acetylcholine as well as acetylcholine from distal sources and from nicotine in the high percentage of lung cancer patients who are smokers. The stimulation of lung cancer growth by cholinergic agonists offers many potential new targets for lung cancer therapy. Cholinergic signaling can be targeted at the level of choline transport; acetylcholine synthesis, secretion and degradation; and nicotinic and muscarinic receptors. In addition, the newly describe family of ly-6 allosteric modulators of nicotinic signaling such as lynx1 and lynx2 offers yet another new approach to novel lung cancer therapeutics. Each of these targets has their potential advantages and disadvantages for the development of new lung cancer therapies which are discussed in this review. PMID:26818857

  5. Targeting in Cancer Therapies

    Directory of Open Access Journals (Sweden)

    Ramon Mangues

    2016-03-01

    Full Text Available Drug developers recruit and combine principles, procedures and strategies from chemistry, pharmacology, nanotechnology and biotechnology, focusing on the generation of functional vehicles as nano-carriers of drugs for improved stability and enhanced intracellular delivery.[...

  6. Antiepileptic drugs: newer targets and new drugs

    OpenAIRE

    Vihang S. Chawan; Abhishek M. Phatak; Kalpesh V. Gawand; Sagar V. Badwane; Sagar S. Panchal

    2016-01-01

    Epilepsy is a common neurological disorder affecting 0.5-1% of the population in India. Majority of patients respond to currently available antiepileptic drugs (AEDs), but a small percentage of patients have shown poor and inadequate response to AEDs in addition to various side effects and drug interactions while on therapy. Thus there is a need to develop more effective AEDs in drug resistant epilepsy which have a better safety profile with minimal adverse effects. The United States food and...

  7. Emerging drug discovery approaches for selective targeting of “precursor” metastatic breast cancer cells: highlights and perspectives

    OpenAIRE

    AAlaoui-Jamali, Moulay; Bijian, Krikor; Batist, Gerald

    2011-01-01

    Breast cancer is a prevalent disease and a major cause of morbidity and cancer-related deaths among women worldwide. A significant number of patients at the time of primary diagnosis present metastatic disease, at least to locoregional lymph nodes, which results in somewhat unpredictable prognosis that often prompts adjuvant systemic therapies of various kinds. The time course of distant recurrence is also unpredictable with some patients sustaining a recurrence within months after diagnosis,...

  8. Decorating Nanoparticle Surface for Targeted Drug Delivery: Opportunities and Challenges

    OpenAIRE

    Zhiqiang Shen; Mu-Ping Nieh; Ying Li

    2016-01-01

    The size, shape, stiffness (composition) and surface properties of nanoparticles (NPs) have been recognized as key design parameters for NP-mediated drug delivery platforms. Among them, the surface functionalization of NPs is of great significance for targeted drug delivery. For instance, targeting moieties are covalently coated on the surface of NPs to improve their selectively and affinity to cancer cells. However, due to a broad range of possible choices of surface decorating molecules, it...

  9. Targeted biopharmaceuticals for cancer treatment.

    Science.gov (United States)

    Zhou, Lufang; Xu, Ningning; Sun, Yan; Liu, Xiaoguang Margaret

    2014-10-01

    Cancer is a complex invasive genetic disease that causes significant mortality rate worldwide. Protein-based biopharmaceuticals have significantly extended the lives of millions of cancer patients. This article reviews the biological function and application of targeted anticancer biopharmaceuticals. We first discuss the specific antigens and core pathways that are used in the development of targeted cancer therapy. The innovative monoclonal antibodies, non-antibody proteins, and small molecules targeting these antigens or pathways are then reviewed. Finally, the current challenges in anticancer biopharmaceuticals development and the potential solutions to address these challenges are discussed.

  10. Design of Nanoparticle-Based Carriers for Targeted Drug Delivery

    OpenAIRE

    Xiaojiao Yu; Ian Trase; Muqing Ren; Kayla Duval; Xing Guo; Zi Chen

    2016-01-01

    Nanoparticles have shown promise as both drug delivery vehicles and direct antitumor systems, but they must be properly designed in order to maximize efficacy. Computational modeling is often used both to design new nanoparticles and to better understand existing ones. Modeled processes include the release of drugs at the tumor site and the physical interaction between the nanoparticle and cancer cells. In this paper, we provide an overview of three different targeted drug delivery methods (p...

  11. Antiepileptic drugs: newer targets and new drugs

    Directory of Open Access Journals (Sweden)

    Vihang S. Chawan

    2016-06-01

    Full Text Available Epilepsy is a common neurological disorder affecting 0.5-1% of the population in India. Majority of patients respond to currently available antiepileptic drugs (AEDs, but a small percentage of patients have shown poor and inadequate response to AEDs in addition to various side effects and drug interactions while on therapy. Thus there is a need to develop more effective AEDs in drug resistant epilepsy which have a better safety profile with minimal adverse effects. The United States food and drug administration (USFDA has approved eslicarbazepine acetate, ezogabine, perampanel and brivaracetam which have shown a promising future as better AEDs and drugs like ganaxolone, intranasal diazepam, ICA- 105665, valnoctamide, VX-765, naluzotan are in the pipeline. [Int J Basic Clin Pharmacol 2016; 5(3.000: 587-592

  12. Strategically targeting MYC in cancer

    Science.gov (United States)

    Posternak, Valeriya; Cole, Michael D.

    2016-01-01

    MYC is a major driver of cancer cell growth and mediates a transcriptional program spanning cell growth, the cell cycle, metabolism, and cell survival. Many efforts have been made to deliberately target MYC for cancer therapy. A variety of compounds have been generated to inhibit MYC function or stability, either directly or indirectly. The most direct inhibitors target the interaction between MYC and MAX, which is required for DNA binding. Unfortunately, these compounds do not have the desired pharmacokinetics and pharmacodynamics for in vivo application. Recent studies report the indirect inhibition of MYC through the development of two compounds, JQ1 and THZ1, which target factors involved in unique stages of transcription. These compounds appear to have significant therapeutic value for cancers with high levels of MYC, although some effects are MYC-independent. These approaches serve as a foundation for developing novel compounds to pharmacologically target MYC-driven cancers. PMID:27081479

  13. New Paradigm in Treating Cancer: Right on Target.

    Science.gov (United States)

    Sutandyo, Noorwati

    2016-04-01

    Cancer prevalence is increasing every year and now cancer is the third highest cause of death in developing countries. Effective anticancer treatment can prolong life and improve the patient's quality of life. Targeted therapy is a new therapeutic modality which targets specific molecules in the cancer cell and disrupts dysregulated signaling pathways involved in carcinogenesis. Since targeted therapy does not attack normal cells, its side effects are considered low compared to chemotherapy. More than 15 drugs have been approved for treatment in various human cancers. These drugs can largely be grouped into tyrosine kinase inhibitors and monoclonal antibodies. This review will focus on the most common agents within both groups. PMID:27550884

  14. Type of Cancer Treatment: Targeted Therapy

    Science.gov (United States)

    Information about the role that targeted therapies play in cancer treatment. Includes how targeted therapies work against cancer, who receives targeted therapies, common side effects, and what to expect when having targeted therapies.

  15. Radionuclide molecular target therapy for lung cancer

    International Nuclear Information System (INIS)

    Lung cancer harms people's health or even lives severely. Currently, the morbidity and mortality of lung cancer are ascending all over the world. Accounting for 38.08% of malignant tumor caused death in male and 16% in female in cities,ranking top in both sex. Especially, the therapy of non-small cell lung cancer has not been obviously improved for many years. Recently, sodium/iodide transporter gene transfection and the therapy of molecular target drugs mediated radionuclide are being taken into account and become the new research directions in treatment of advanced lung cancer patients with the development of technology and theory for medical molecular biology and the new knowledge of lung cancer's pathogenesis. (authors)

  16. Therapeutic strategies targeting cancer stem cells.

    Science.gov (United States)

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

    2013-04-01

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

  17. Drug delivery system and breast cancer cells

    Science.gov (United States)

    Colone, Marisa; Kaliappan, Subramanian; Calcabrini, Annarica; Tortora, Mariarosaria; Cavalieri, Francesca; Stringaro, Annarita

    2016-06-01

    Recently, nanomedicine has received increasing attention for its ability to improve the efficacy of cancer therapeutics. Nanosized polymer therapeutic agents offer the advantage of prolonged circulation in the blood stream, targeting to specific sites, improved efficacy and reduced side effects. In this way, local, controlled delivery of the drug will be achieved with the advantage of a high concentration of drug release at the target site while keeping the systemic concentration of the drug low, thus reducing side effects due to bioaccumulation. Various drug delivery systems such as nanoparticles, liposomes, microparticles and implants have been demonstrated to significantly enhance the preventive/therapeutic efficacy of many drugs by increasing their bioavailability and targetability. As these carriers significantly increase the therapeutic effect of drugs, their administration would become less cost effective in the near future. The purpose of our research work is to develop a delivery system for breast cancer cells using a microvector of drugs. These results highlight the potential uses of these responsive platforms suited for biomedical and pharmaceutical applications. At the request of all authors of the paper an updated version was published on 12 July 2016. The manuscript was prepared and submitted without Dr. Francesca Cavalieri's contribution and her name was added without her consent. Her name has been removed in the updated and re-published article.

  18. Targeted nanotherapeutics in cancer

    OpenAIRE

    Shiekh FA

    2014-01-01

    Farooq A ShiekhAvalon University School of Medicine, Curaçao, Netherlands AntillesCancer is not one, but many heterogeneous diseases1 with complex genetic and epigenetic alterations2,3 that annually afflict millions of people worldwide. Despite the progress in understanding the molecular mechanics of cancer,4 its treatment has remained essentially unchanged and the death rates almost remain as they were 6 decades ago.5,6 In the past, the outstanding failure to deliver effective tre...

  19. Imaging small human prostate cancer xenografts after pretargeting with bispecific bombesin-antibody complexes and targeting with high specific radioactivity labeled polymer-drug conjugates

    Energy Technology Data Exchange (ETDEWEB)

    Patil, Vishwesh; Gada, Keyur; Panwar, Rajiv; Ferris, Craig; Khaw, Ban-An [Northeastern University, School of Pharmacy, Department of Pharmaceutical Sciences, Boston, MA (United States); Varvarigou, Alexandra [Institute of Radioisotopes and Radiodiagnostics, National Centre for Scientific Research ' ' Demokritos' ' , Athens (Greece); Majewski, Stan [West Virginia University, Department of Radiology, Nuclear Medicine Imaging Instrumentation Program, Center for Advanced Imaging, Morgantown, WV (United States); Weisenberger, Andrew [Jefferson LA, Thomas Jefferson National Accelerator Facility, Newport News, VA (United States); Tekabe, Yared [Columbia University Medical Center, New York, NY (United States)

    2012-05-15

    .21 {+-} 0.36%ID/g) was 5.4 times that in tumors pretargeted with Bom or anti-DTPA alone (0.22 {+-} 0.08, p = 0.001). PC-3 xenografts pretargeted with Bom-bsFCx and targeted with {sup 99m}Tc-DSPL were visualizable by 1-3 h. Exquisite tumor uptake at 24 h (6.54 {+-} 1.58%ID/g) was about 15 times greater than that of Bom pretargeted controls (0.44 {+-} 0.17, p = 0.002). Pretargeting prostate cancer with Bom-bsCx or Bom-bsFCx enabled fast delivery of high specific radioactivity {sup 111}In- or {sup 99m}Tc-labeled polymer-drug conjugates resulting in visualization of lesions smaller than 1-2 mm in diameter within 3 h. (orig.)

  20. Targeting ECM Disrupts Cancer Progression

    DEFF Research Database (Denmark)

    Venning, Freja A; Wullkopf, Lena; Erler, Janine T

    2015-01-01

    Metastatic complications are responsible for more than 90% of cancer-related deaths. The progression from an isolated tumor to disseminated metastatic disease is a multistep process, with each step involving intricate cross talk between the cancer cells and their non-cellular surroundings, the ex...... is summarized. In addition, we highlight the promising (pre-)clinical data showing benefits of targeting these ECM macromolecules to prevent cancer progression.......Metastatic complications are responsible for more than 90% of cancer-related deaths. The progression from an isolated tumor to disseminated metastatic disease is a multistep process, with each step involving intricate cross talk between the cancer cells and their non-cellular surroundings......, the extracellular matrix (ECM). Many ECM proteins are significantly deregulated during the progression of cancer, causing both biochemical and biomechanical changes that together promote the metastatic cascade. In this review, the influence of several ECM proteins on these multiple steps of cancer spread...

  1. Therapeutic Approaches to Target Cancer Stem Cells

    Energy Technology Data Exchange (ETDEWEB)

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

    2011-08-15

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

  2. Formulation of Biologically-Inspired Silk-Based Drug Carriers for Pulmonary Delivery Targeted for Lung Cancer

    OpenAIRE

    Sally Yunsun Kim; Deboki Naskar; Kundu, Subhas C.; Bishop, David P.; Doble, Philip A.; Boddy, Alan V.; Hak-Kim Chan; Ivan B. Wall; Wojciech Chrzanowski

    2015-01-01

    The benefits of using silk fibroin, a major protein in silk, are widely established in many biomedical applications including tissue regeneration, bioactive coating and in vitro tissue models. The properties of silk such as biocompatibility and controlled degradation are utilized in this study to formulate for the first time as carriers for pulmonary drug delivery. Silk fibroin particles are spray dried or spray-freeze-dried to enable the delivery to the airways via dry powder inhalers. The a...

  3. Bioinert Anodic Alumina Nanotubes for Targeting of Endoplasmic Reticulum Stress and Autophagic Signaling: A Combinatorial Nanotube-Based Drug Delivery System for Enhancing Cancer Therapy.

    Science.gov (United States)

    Wang, Ye; Kaur, Gagandeep; Chen, Yuting; Santos, Abel; Losic, Dusan; Evdokiou, Andreas

    2015-12-16

    Although nanoparticle-based targeted delivery systems have gained promising achievements for cancer therapy, the development of sophisticated strategies with effective combinatorial therapies remains an enduring challenge. Herein, we report the fabrication of a novel nanomaterial, so-called anodic alumina nanotubes (AANTs) for proof-of-concept cancer therapy by targeting cell signaling networks. This strategy is to target autophagic and endoplasmic reticulum (ER) stress signaling by using thapsigargin (TG)-loaded AANTs cotreated with an autophagy inhibitor 3-methyladenine (3-MA). We first show that AANTs are nontoxic and can activate autophagy in different cell types including human fibroblast cells (HFF), human monocyte cells (THP-1), and human breast cancer cells (MDA-MB 231-TXSA). Treatment with 3-MA at a nontoxic dose reduced the level of autophagy induced by AANTs, and consequently sensitized breast cancer cells to AANTs-induced cellular stresses. To target autophagic and ER stress signaling networking, breast cancer cells were treated with 3-MA together with AANTs loaded with the prototype ER stress inducer TG. We demonstrated that 3-MA enhanced the cancer cell killing effect of AANTs loaded with TG. This effect was associated with enhanced ER stress signaling due to the combination effect of TG and 3-MA. These findings not only demonstrate the excellent biocompatibility of AANTs as novel biomaterials but also provide new opportunities for developing ER- and autophagy-targeted delivery systems for future clinical cancer therapy.

  4. A Novel Theranostic Platform for Targeted Cancer Therapy and Treatment Monitoring | Division of Cancer Prevention

    Science.gov (United States)

    DESCRIPTION (provided by applicant): Cancer treatment currently relies heavily upon administration of cytotoxic drugs that attack both cancerous and healthy cells due to limited selectivity of drugs. Therapeutic efficacy and systemic toxicity can be improved by employing a multifunctional drug delivery system that allows targeted drug delivery, controlled drug release and therapeutic effect monitoring. The integration of therapeutic and diagnostic treatments has created a new genre in patient care and personalized medicine termed theranostics. |

  5. 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...

  6. Nanoparticles inhibit cancer cell invasion and enhance antitumor efficiency by targeted drug delivery via cell surface-related GRP78

    OpenAIRE

    Zhao L; Li H; Shi Y.; Wang G; Liu L; Su C; Su R

    2014-01-01

    Liang Zhao,1,* Hongdan Li,2,* Yijie Shi,1 Guan Wang,2 Liwei Liu,1 Chang Su,3 Rongjian Su2 1School of Pharmacy, Liaoning Medical University, Jinzhou, People’s Republic of China; 2Central Laboratory of Liaoning Medical University, Jinzhou, People’s Republic of China; 3School of Veterinary Medicine, Liaoning Medical University, Jinzhou, People’s Republic of China *These authors contributed equally to this work Abstract: Nanoparticles (NPs) which target specific a...

  7. Targeted therapies for cancer

    Science.gov (United States)

    ... to be untrue. Possible side effects from targeted therapies include: Diarrhea Liver problems Skin problems such as rash, dry skin, and nail changes Problems with blood clotting and wound healing High blood pressure As with any treatment, you ...

  8. Drugs Approved for Colon and Rectal Cancer

    Science.gov (United States)

    ... Professionals Questions to Ask about Your Treatment Research Drugs Approved for Colon and Rectal Cancer This page ... and rectal cancer that are not listed here. Drugs Approved for Colon Cancer Avastin (Bevacizumab) Bevacizumab Camptosar ( ...

  9. Development of Combination Therapy with Anti-Cancer Drugs

    NARCIS (Netherlands)

    Leijen, S.

    2013-01-01

    This thesis describes early clinical trials with anti-cancer drugs in combination with commonly applied and registered chemotherapy and single agent studies with compounds that are intended for use in combination with registered or other targeted anti-cancer drugs. Gemcitabine is a prodrug that fi

  10. Successes and limitations of targeted cancer therapy in lung cancer.

    Science.gov (United States)

    Suda, Kenichi; Mitsudomi, Tetsuya

    2014-01-01

    Human cancers usually evolve through multistep processes. These processes are driven by the accumulation of abundant genetic and epigenetic abnormalities. However, some lung cancers depend on a single activated oncogene by somatic mutation, termed 'driver oncogenic mutations', for their proliferation and survival. EGFR(epidermal growth factor receptor) mutations and ALK(anaplastic lymphoma kinase) rearrangement are typical examples of such driver oncogenic mutations found in lung adenocarcinomas. EGFR-tyrosine kinase inhibitors (TKIs) or ALK-TKIs significantly improved treatment outcomes compared with conventional cytotoxic chemotherapy in patients with lung cancers harboring EGFR mutations or ALK rearrangement, respectively. Therefore, treatment strategies for lung cancers have dramatically changed from a 'general and empiric' to a 'personalized and evidence-based' approach according to the driver oncogenic mutation. Several novel driver oncogenic mutations, which are candidates as novel targets, such as ERBB2, BRAF, ROS1, and RET, have been discovered. Despite these successes, several limitations have arisen. One example is that some lung cancers do not respond to treatments targeting driver oncogenic mutations, as exemplified in KRAS-mutated lung cancers. Another is resistance to molecular-targeted drugs. Such resistance includes de novo resistance and acquired resistance. A number of molecular mechanisms underlying such resistance have been reported. These mechanisms can be roughly divided into three categories: alteration of the targeted oncogenes themselves by secondary mutations or amplification, activation of an alternative oncogenic signaling track, and conversion of cellular characteristics. Overcoming resistance is a current area of urgent clinical research. PMID:24727987

  11. Targeted treatments for cervical cancer: a review.

    Science.gov (United States)

    Peralta-Zaragoza, Oscar; Bermúdez-Morales, Víctor Hugo; Pérez-Plasencia, Carlos; Salazar-León, Jonathan; Gómez-Cerón, Claudia; Madrid-Marina, Vicente

    2012-01-01

    Cervical cancer is the second most common cause of cancer death in women worldwide and the development of new diagnosis, prognostic, and treatment strategies merits special attention. Although surgery and chemoradiotherapy can cure 80%-95% of women with early stage cancer, the recurrent and metastatic disease remains a major cause of cancer death. Many efforts have been made to design new drugs and develop gene therapies to treat cervical cancer. In recent decades, research on treatment strategies has proposed several options, including the role of HPV E6 and E7 oncogenes, which are retained and expressed in most cervical cancers and whose respective oncoproteins are critical to the induction and maintenance of the malignant phenotype. Other efforts have been focused on antitumor immunotherapy strategies. It is known that during the development of cervical cancer, a cascade of abnormal events is induced, including disruption of cellular cycle control, perturbation of antitumor immune response, alteration of gene expression, and deregulation of microRNA expression. Thus, in this review article we discuss potential targets for the treatment of cervical cancer associated with HPV infection, with special attention to immunotherapy approaches, clinical trials, siRNA molecules, and their implications as gene therapy strategies against cervical cancer development. PMID:23144564

  12. Targeted nanodrugs for cancer therapy: prospects and challenges.

    Science.gov (United States)

    Bottini, Massimo; Sacchetti, Cristiano; Pietroiusti, Antonio; Bellucci, Stefano; Magrini, Andrea; Rosato, Nicola; Bottini, Nunzio

    2014-01-01

    The recent advent of nanomedicine holds potential to revolutionize cancer therapy. This innovative discipline has paved the way for the emergence of a new class of drugs based on nanoengineered particles. These "nanodrugs" are designed to greatly enhance drug therapeutic indices. First-generation nanodrugs consisted of conventional anti-cancer drugs loaded into/onto nanoengineered particles (nanocarriers) devoid of targeting features (non-targeted nanodrugs). Non-targeted nanodrugs have provided the opportunity to carry large amounts of drugs, including poorly water-soluble and/or permeable drugs, to several types of tumors, improving the therapeutic index with respect to comparable free drugs. Although effective, the primary delivery mechanism of non-targeted nanodrugs was through passive tissue accumulation, due to pathophysiological differences between tumor-associated and healthy vessels, and through non-specific targeting of cell subsets, posing the danger of off-target binding and effects. Recently, the therapeutic indices of certain anti-cancer drugs were further improved by attaching targeting ligands to nanodrugs (targeted-nanodrugs). Targeted-nanodrugs selectively bind to cognate receptors expressed on target cells and enter cells more efficiently than non-targeted formulations. Although these advancements have been sufficiently beneficial to place targeted-nanodrugs into clinical development for use in cancer therapy, they also come at a price. The addition of ligands to drug-loaded nanocarriers often leads to additional synthesis steps and costs, and more complex biological performance relative to ligand-devoid nanodrugs. Here, we will discuss the benefits and challenges facing the addition of targeting features to nanodrugs for cancer therapy. PMID:24730253

  13. Targeting metabolism in breast cancer: How far we can go?

    Science.gov (United States)

    Long, Jing-Pei; Li, Xiao-Na; Zhang, Feng

    2016-02-10

    Adjuvant therapies for breast cancer have achieved great success in recent years and early breast cancer is now a curable or chronic disease. Targeted therapies, including endocrine therapy and human epidermal growth factor receptor-2 targeted therapy, marked a new era of breast cancer treatment. However, except for chemotherapy, an efficient drug treatment to improve the overall survival of breast cancer patients is still lacking for triple negative breast cancer. Furthermore, a certain proportion of breast cancer patients present with resistance to drug therapy, making it much more difficult to control the deterioration of the disease. Recently, altered energy metabolism has become one of the hallmarks of cancer, including breast cancer, and it may be linked to drug resistance. Targeting cellular metabolism is becoming a promising strategy to overcome drug resistance in cancer therapy. This review discusses metabolic reprogramming in breast cancer and the possible complex mechanism of modulation. We also summarize the recent advances in metabolic therapy targeted glycolysis, glutaminolysis and fatty acids synthesis in breast cancer. PMID:26862496

  14. Amifostine-conjugated pH-sensitive calcium phosphate-covered magnetic-amphiphilic gelatin nanoparticles for controlled intracellular dual drug release for dual-targeting in HER-2-overexpressing breast cancer.

    Science.gov (United States)

    Li, Wei-Ming; Chiang, Chih-Sheng; Huang, Wei-Chen; Su, Chia-Wei; Chiang, Min-Yu; Chen, Jian-Yi; Chen, San-Yuan

    2015-12-28

    We developed a surfactant-free method utilizing amifostine to stably link a targeting ligand (Herceptin) to amphiphilic gelatin (AG)-iron oxide@calcium phosphate (CaP) nanoparticles with hydrophobic curcumin (CUR) and hydrophilic doxorubicin (DOX) encapsulated in the AG core and CaP shell (AGIO@CaP-CD), respectively. This multi-functional nanoparticle system has a pH-sensitive CaP shell and degradable amphiphilic gelatin (AG) core, which enables controllable sequential release of the two drugs. The dual-targeting system of AGIO@CaP-CD (HER-AGIO@CaP-CD) with a bioligand and magnetic targeting resulted in significantly elevated cellular uptake in HER2-overexpressing SKBr3 cells and more efficacious therapy than delivery of targeting ligand alone due to the synergistic cell multi-drug resistance/apoptosis-inducing effect of the CUR and DOX combination. This nanoparticle combined with Herceptin and iron oxide nanoparticles not only provided a dual-targeting functionality, but also encapsulated CUR and DOX as a dual-drug delivery system for the combination therapy. This study further demonstrated that the therapeutic efficacy of this dual-targeting co-delivery system can be improved by modifying the application duration of magnetic targeting, which makes this combination therapy system a powerful new tool for in vitro/in vivo cancer therapy, especially for HER2-positive cancers. PMID:26478017

  15. Targeted drug induces responses in aggressive lymphomas

    Science.gov (United States)

    Preliminary results from clinical trials in a subtype of lymphoma show that for a number of patients whose disease was not cured by other treatments, the drug ibrutinib can provide significant anti-cancer responses with modest side effects.

  16. Nanogel Carrier Design for Targeted Drug Delivery

    OpenAIRE

    Eckmann, D.M.; Composto, R. J.; Tsourkas, A; Muzykantov, V. R.

    2014-01-01

    Polymer-based nanogel formulations offer features attractive for drug delivery, including ease of synthesis, controllable swelling and viscoelasticity as well as drug loading and release characteristics, passive and active targeting, and the ability to formulate nanogel carriers that can respond to biological stimuli. These unique features and low toxicity make the nanogels a favorable option for vascular drug targeting. In this review, we address key chemical and biological aspects of nanoge...

  17. Cancer Immunotherapy of Targeting Angiogenesis

    Institute of Scientific and Technical Information of China (English)

    Jianmei Hou; Ling Tian; Yuquan Wei

    2004-01-01

    Tumor growth and metastasis are angiogenesis-dependent. Anti-angiogenic therapy may be a useful approach to cancer therapy. This review discussed tumor angiogenesis and immunotherapy of targeting tumor angiogenesis from two main aspects: (1) active vaccination to induce effective anti-angiogenesis immunity; (2) passive immunotherapy with anti-pro-angiogenic molecules relevant antibody. Evidence from the recent years suggested that anti-angiogenic therapy should be one of the most promising approaches to cancer therapy.

  18. Targeting the lysosome in cancer

    OpenAIRE

    Piao, Shengfu; Amaravadi, Ravi K.

    2015-01-01

    Lysosomes are membrane-bound intracellular organelles that receive macromolecules delivered by endocytosis, phagocytosis, and autophagy for degradation and recycling. Over the last decade, advances in lysosome research have established a broad role for the lysosome in the pathophysiology of disease. In this review, we highlight the recent discoveries in lysosome biology, with an emphasis on their implications for cancer therapy. We focus on targeting the lysosome in cancer by exploring lysoso...

  19. Drug transporters in breast cancer

    DEFF Research Database (Denmark)

    Kümler, Iben; Stenvang, Jan; Moreira, José;

    2015-01-01

    Despite the advances that have taken place in the past decade, including the development of novel molecular targeted agents, cytotoxic chemotherapy remains the mainstay of cancer treatment. In breast cancer, anthracyclines and taxanes are the two main chemotherapeutic options used on a routine...

  20. Eukaryotic elongation factor 2 kinase as a drug target in cancer, and in cardiovascular and neurodegenerative diseases.

    Science.gov (United States)

    Liu, Rui; Proud, Christopher G

    2016-03-01

    Eukaryotic elongation factor 2 kinase (eEF2K) is an unusual protein kinase that regulates the elongation stage of protein synthesis by phosphorylating and inhibiting its only known substrate, eEF2. Elongation is a highly energy-consuming process, and eEF2K activity is tightly regulated by several signaling pathways. Regulating translation elongation can modulate the cellular energy demand and may also control the expression of specific proteins. Growing evidence links eEF2K to a range of human diseases, including cardiovascular conditions (atherosclerosis, via macrophage survival) and pulmonary arterial hypertension, as well as solid tumors, where eEF2K appears to play contrasting roles depending on tumor type and stage. eEF2K is also involved in neurological disorders and may be a valuable target in treating depression and certain neurodegenerative diseases. Because eEF2K is not required for mammalian development or cell viability, inhibiting its function may not elicit serious side effects, while the fact that it is an atypical kinase and quite distinct from the vast majority of other mammalian kinases suggests the possibility to develop it into compounds that inhibit eEF2K without affecting other important protein kinases. Further research is needed to explore these possibilities and there is an urgent need to identify and characterize potent and specific small-molecule inhibitors of eEF2K. In this article we review the recent evidence concerning the role of eEF2K in human diseases as well as the progress in developing small-molecule inhibitors of this enzyme. PMID:26806303

  1. Targeted treatments for cervical cancer: a review

    Directory of Open Access Journals (Sweden)

    Peralta-Zaragoza O

    2012-11-01

    Full Text Available Oscar Peralta-Zaragoza,1 Víctor Hugo Bermúdez-Morales,1 Carlos Pérez-Plasencia,2,3 Jonathan Salazar-León,1 Claudia Gómez-Cerón,1 Vicente Madrid-Marina11Direction of Chronic Infections and Cancer, Research Center in Infection Diseases, National Institute of Public Health, Cuernavaca, Morelos, México; 2Oncogenomics Laboratory, National Cancer Institute of Mexico, Tlalpan, México; 3Biomedicine Unit, FES-Iztacala UNAM, México City, MéxicoAbstract: Cervical cancer is the second most common cause of cancer death in women worldwide and the development of new diagnosis, prognostic, and treatment strategies merits special attention. Although surgery and chemoradiotherapy can cure 80%–95% of women with early stage cancer, the recurrent and metastatic disease remains a major cause of cancer death. Many efforts have been made to design new drugs and develop gene therapies to treat cervical cancer. In recent decades, research on treatment strategies has proposed several options, including the role of HPV E6 and E7 oncogenes, which are retained and expressed in most cervical cancers and whose respective oncoproteins are critical to the induction and maintenance of the malignant phenotype. Other efforts have been focused on antitumor immunotherapy strategies. It is known that during the development of cervical cancer, a cascade of abnormal events is induced, including disruption of cellular cycle control, perturbation of antitumor immune response, alteration of gene expression, and deregulation of microRNA expression. Thus, in this review article we discuss potential targets for the treatment of cervical cancer associated with HPV infection, with special attention to immunotherapy approaches, clinical trials, siRNA molecules, and their implications as gene therapy strategies against cervical cancer development.Keywords: Cervical cancer, clinical trials, gene therapy, HPV E6 and E7 oncogenes, siRNAs

  2. Targeting cancer with peptide aptamers

    OpenAIRE

    Seigneuric, Renaud; Gobbo, Jessica; Colas, Pierre; Garrido, Carmen

    2011-01-01

    A major endeavour in cancer chemotherapy is to develop agents that specifically target a biomolecule of interest. There are two main classes of targeting agents: small molecules and biologics. Among biologics (e.g.: antibodies), DNA, RNA but also peptide aptamers are relatively recent agents. Peptide aptamers are seldom described but represent attractive agents that can inhibit a growing panel of oncotargets including Heat Shock Proteins. Potential pitfalls and coming challenges towards succe...

  3. Overcoming acquired drug resistance in colorectal cancer cells by targeted delivery of 5-FU with EGF grafted hollow mesoporous silica nanoparticles

    Science.gov (United States)

    Chen, Lijue; She, Xiaodong; Wang, Tao; He, Li; Shigdar, Sarah; Duan, Wei; Kong, Lingxue

    2015-08-01

    Acquired drug resistance (ADR) can be developed in colorectal cancer cells after 5-fluorouracil (5-FU) treatment and diminish the effectiveness of chemotherapy. In this work, acquired 5-FU resistance in the colorectal cancer cell line SW480 was obtained with the up-regulation of dihydropyrimidine dehydrogenase (DPYD) gene expression which can convert 5-FU to its inactive metabolite. To overcome ADR in colorectal cancer, hollow mesoporous silica nanoparticles (HMSNs) grafted with epidermal growth factor (EGF) were used as nanocarriers to deliver 5-FU to colorectal cancer cells with acquired drug resistance. The effect and mechanism of 5-FU loaded EGF grafted HMSNs (EGF-HMSNs-5-FU) in overcoming acquired drug resistance in SW480/ADR cells were studied. The EGF-HMSNs were demonstrated to be specifically internalized in EGFR overexpressed SW480/ADR cells via a receptor-mediated endocytosis and can escape from endo-lysosomes. The EGF-HMSNs-5-FU exhibited much higher cytotoxicity on SW480/ADR cells than HMSNs-5-FU and free 5-FU while the plain HMSNs did not show significant cytotoxicity. The mechanism of EGF-HMSNs-5-FU in overcoming drug resistance in SW480/ADR cells could be attributed to the specific internalization of EGF-HMSNs-5-FU in EGFR overexpressed cells which can lead to high intracellular drug accumulation and cause cell death through S phase arrest.Acquired drug resistance (ADR) can be developed in colorectal cancer cells after 5-fluorouracil (5-FU) treatment and diminish the effectiveness of chemotherapy. In this work, acquired 5-FU resistance in the colorectal cancer cell line SW480 was obtained with the up-regulation of dihydropyrimidine dehydrogenase (DPYD) gene expression which can convert 5-FU to its inactive metabolite. To overcome ADR in colorectal cancer, hollow mesoporous silica nanoparticles (HMSNs) grafted with epidermal growth factor (EGF) were used as nanocarriers to deliver 5-FU to colorectal cancer cells with acquired drug resistance. The

  4. Targeted therapies in gastroesophageal cancer.

    Science.gov (United States)

    Kasper, Stefan; Schuler, Martin

    2014-05-01

    Gastroesophageal cancers comprising gastric cancer (GC), and cancers of the distal oesophagus and gastroesophageal junction (GEJ) are a global health threat. In Western populations the incidence of GC is declining which has been attributed to effective strategies of eradicating Helicobacter pylori infection. To the contrary, GEJ cancers are on the rise, with obesity and reflux disease being viewed as major risk factors. During the past decade perioperative chemotherapy, pre- or postoperative radio-chemotherapy, and, in Asian populations, adjuvant chemotherapy have been shown to improve the outcome of patients with advanced GC and GEJ cancers suited for surgery. Less progress has been made in the treatment of metastatic disease. The introduction of trastuzumab in combination with platinum/fluoropyrimidine-based chemotherapy for patients with HER2-positive disease has marked a turning point. Recently, several novel agents targeting growth factor receptors, angiogenic pathways, adhesion molecules and mediators of intracellular signal transduction have been clinically explored. Here we summarise the current status and future developments of molecularly targeted therapies in GC and GEJ cancer.

  5. A Computational Drug Repositioning Approach for Targeting Oncogenic Transcription Factors.

    Science.gov (United States)

    Gayvert, Kaitlyn M; Dardenne, Etienne; Cheung, Cynthia; Boland, Mary Regina; Lorberbaum, Tal; Wanjala, Jackline; Chen, Yu; Rubin, Mark A; Tatonetti, Nicholas P; Rickman, David S; Elemento, Olivier

    2016-06-14

    Mutations in transcription factor (TF) genes are frequently observed in tumors, often leading to aberrant transcriptional activity. Unfortunately, TFs are often considered undruggable due to the absence of targetable enzymatic activity. To address this problem, we developed CRAFTT, a computational drug-repositioning approach for targeting TF activity. CRAFTT combines ChIP-seq with drug-induced expression profiling to identify small molecules that can specifically perturb TF activity. Application to ENCODE ChIP-seq datasets revealed known drug-TF interactions, and a global drug-protein network analysis supported these predictions. Application of CRAFTT to ERG, a pro-invasive, frequently overexpressed oncogenic TF, predicted that dexamethasone would inhibit ERG activity. Dexamethasone significantly decreased cell invasion and migration in an ERG-dependent manner. Furthermore, analysis of electronic medical record data indicates a protective role for dexamethasone against prostate cancer. Altogether, our method provides a broadly applicable strategy for identifying drugs that specifically modulate TF activity. PMID:27264179

  6. Splicing regulators: targets and drugs

    OpenAIRE

    Yeo, Gene Wei-Ming

    2005-01-01

    Silencing of splicing regulators by RNA interference, combined with splicing-specific microarrays, has revealed a complex network of distinct alternative splicing events in Drosophila, while a high-throughput screen of more than 6,000 compounds has identified drugs that interfere specifically and directly with one class of splicing regulators in human cells.

  7. Targeted therapy in non-small cell lung cancer

    Institute of Scientific and Technical Information of China (English)

    Shou-Ching Tang

    2004-01-01

    @@ 1 Introduction Recent progress in molecular biology has enabled us to better understand the molecular mechanism underlying pathogenesis of human malignancy including lung cancer. Sequencing of human genome has identified many oncogenes and tumor suppressor genes,giving us a better understanding of the molecular events leading to the formation, progression, metastasis, and the development of drug resistance in human lung cancer. In addition, many signal transduction pathways have been discovered that play important roles in lung cancer. Novel strategy of anti-cancer drug development now involves the identification and development of targeted therapy that interrupts one or more than one pathways or cross-talk among different signal transduction pathways. In addition, efforts are underway that combine the traditional cytotoxic (non-targeted) agents with the biological (targeted) therapy to increase the response rate and survival in patients with lung cancer, especially advanced non-small cell lung cancer (NSCLC).

  8. New approaches to targeted drug delivery to tumour cells

    International Nuclear Information System (INIS)

    Basic approaches to the design of targeted drugs for the treatment of human malignant tumours have been considered. The stages of the development of these approaches have been described in detail and theoretically substantiated, and basic experimental results have been reported. Considerable attention is paid to the general characteristic of nanopharmacological drugs and to the description of mechanisms of cellular interactions with nanodrugs. The potentialities and limitations of application of nanodrugs for cancer therapy and treatment of other diseases have been considered. The use of nanodrugs conjugated with vector molecules seems to be the most promising trend of targeted therapy of malignant tumours. The bibliography includes 122 references

  9. New approaches to targeted drug delivery to tumour cells

    Science.gov (United States)

    Severin, E. S.

    2015-01-01

    Basic approaches to the design of targeted drugs for the treatment of human malignant tumours have been considered. The stages of the development of these approaches have been described in detail and theoretically substantiated, and basic experimental results have been reported. Considerable attention is paid to the general characteristic of nanopharmacological drugs and to the description of mechanisms of cellular interactions with nanodrugs. The potentialities and limitations of application of nanodrugs for cancer therapy and treatment of other diseases have been considered. The use of nanodrugs conjugated with vector molecules seems to be the most promising trend of targeted therapy of malignant tumours. The bibliography includes 122 references.

  10. Targeted Therapy in Nonmelanoma Skin Cancers

    Directory of Open Access Journals (Sweden)

    Giulia Spallone

    2011-05-01

    Full Text Available Nonmelanoma skin cancer (NMSC is the most prevalent cancer in light-skinned populations, and includes mainly Basal Cell Carcinomas (BCC, representing around 75% of NMSC and Squamous Cell Carcinomas (SCC. The incidence of these tumors is continuously growing. It was found that the overall number of procedures for NMSC in US rose by 76%, from 1,158,298 in 1992 to 2,048,517 in 2006. Although mortality from NMSC tends to be very low, clearly the morbidity related to these skin cancers is very high. Treatment options for NMSC include both surgical and nonsurgical interventions. Surgery was considered the gold standard therapy, however, advancements in the knowledge of pathogenic mechanisms of NMSCs led to the identification of key targets for drug intervention and to the consequent development of several targeted therapies. These represent the future in treatment of these common forms of cancer ensuring a high cure rate, preservation of the maximal amount of normal surrounding tissue and optimal cosmetic outcome. Here, we will review recent advancements in NMSC targeted therapies focusing on BCC and SCC.

  11. Targeted Therapy in Nonmelanoma Skin Cancers

    Energy Technology Data Exchange (ETDEWEB)

    Spallone, Giulia; Botti, Elisabetta; Costanzo, Antonio, E-mail: antonio.costanzo@uniroma2.it [Department of Dermatology, University of Rome “Tor Vergata”, Via Montpellier 1, 00199, Rome (Italy)

    2011-05-03

    Nonmelanoma skin cancer (NMSC) is the most prevalent cancer in light-skinned populations, and includes mainly Basal Cell Carcinomas (BCC), representing around 75% of NMSC and Squamous Cell Carcinomas (SCC). The incidence of these tumors is continuously growing. It was found that the overall number of procedures for NMSC in US rose by 76%, from 1,158,298 in 1992 to 2,048,517 in 2006. Although mortality from NMSC tends to be very low, clearly the morbidity related to these skin cancers is very high. Treatment options for NMSC include both surgical and nonsurgical interventions. Surgery was considered the gold standard therapy, however, advancements in the knowledge of pathogenic mechanisms of NMSCs led to the identification of key targets for drug intervention and to the consequent development of several targeted therapies. These represent the future in treatment of these common forms of cancer ensuring a high cure rate, preservation of the maximal amount of normal surrounding tissue and optimal cosmetic outcome. Here, we will review recent advancements in NMSC targeted therapies focusing on BCC and SCC.

  12. Drug targeting using solid lipid nanoparticles.

    Science.gov (United States)

    Rostami, Elham; Kashanian, Soheila; Azandaryani, Abbas H; Faramarzi, Hossain; Dolatabadi, Jafar Ezzati Nazhad; Omidfar, Kobra

    2014-07-01

    The present review aims to show the features of solid lipid nanoparticles (SLNs) which are at the forefront of the rapidly developing field of nanotechnology with several potential applications in drug delivery and research. Because of some unique features of SLNs such as their unique size dependent properties it offers possibility to develop new therapeutics. A common denominator of all these SLN-based platforms is to deliver drugs into specific tissues or cells in a pathological setting with minimal adverse effects on bystander cells. SLNs are capable to incorporate drugs into nanocarriers which lead to a new prototype in drug delivery which maybe used for drug targeting. Hence solid lipid nanoparticles hold great promise for reaching the goal of controlled and site specific drug delivery and hence attracted wide attention of researchers. This review presents a broad treatment of targeted solid lipid nanoparticles discussing their types such as antibody SLN, magnetic SLN, pH sensitive SLN and cationic SLN. PMID:24717692

  13. Aptamers for Targeted Drug Delivery

    Directory of Open Access Journals (Sweden)

    Partha Ray

    2010-05-01

    Full Text Available Aptamers are a class of therapeutic oligonucleotides that form specific three-dimensional structures that are dictated by their sequences. They are typically generated by an iterative screening process of complex nucleic acid libraries employing a process termed Systemic Evolution of Ligands by Exponential Enrichment (SELEX. SELEX has traditionally been performed using purified proteins, and cell surface receptors may be challenging to purify in their properly folded and modified conformations. Therefore, relatively few aptamers have been generated that bind cell surface receptors. However, improvements in recombinant fusion protein technology have increased the availability of receptor extracellular domains as purified protein targets, and the development of cell-based selection techniques has allowed selection against surface proteins in their native configuration on the cell surface. With cell-based selection, a specific protein target is not always chosen, but selection is performed against a target cell type with the goal of letting the aptamer choose the target. Several studies have demonstrated that aptamers that bind cell surface receptors may have functions other than just blocking receptor-ligand interactions. All cell surface proteins cycle intracellularly to some extent, and many surface receptors are actively internalized in response to ligand binding. Therefore, aptamers that bind cell surface receptors have been exploited for the delivery of a variety of cargoes into cells. This review focuses on recent progress and current challenges in the field of aptamer-mediated delivery.

  14. LIVER SPECIFIC DRUG TARGETING STRATEGIES: A REVIEW

    OpenAIRE

    Ramesh S. Gorad*, Satish K. Mandlik and Kishore N. Gujar

    2013-01-01

    Drug delivery to liver is one of the most challenging research areas in pharmaceutical sciences. The some physiological barrier such as opsonization, mechanical entrapment by pulmonary vascular bed, uptake by RES represents an insurmountable obstacle for a large number of proteins and drugs, including antibiotics, antineoplastic agents and antiviral agents to target liver disorders. Therefore, various strategies have been proposed to improve the delivery of different drugs to liver and hepato...

  15. Target Therapy in Lung Cancer.

    Science.gov (United States)

    Cafarotti, Stefano; Lococo, Filippo; Froesh, Patrizia; Zappa, Francesco; Andrè, Dutly

    2016-01-01

    Lung cancer is an extremely heterogeneous disease, with well over 50 different histological variants recognized under the fourth revision of the World Health Organization (WHO) typing system. Because these variants have differing genetic and biological properties correct classification of lung cancer is necessary to assure that lung cancer patients receive optimum management. Due to the recent understanding that histologic typing and EGFR mutation status are important for target the therapy in lung adenocarcinoma patients there was a great need for a new classification that addresses diagnostic issues and strategic management to allow for molecular testing in small biopsy and cytology specimens. For this reason and in order to address advances in lung cancer treatment an international multidisciplinary classification was proposed by the International Association for the Study of Lung Cancer (IASLC), American Thoracic Society (ATS), and European Respiratory Society (ERS), further increasing the histological heterogeneity and improving the existing WHO-classification. Is now the beginning of personalized therapy era that is ideally finalized to treat each individual case of lung cancer in different way. PMID:26667341

  16. Biomarker-guided repurposing of chemotherapeutic drugs for cancer therapy: a novel strategy in drug development

    Directory of Open Access Journals (Sweden)

    Jan eStenvang

    2013-12-01

    Full Text Available Cancer is a leading cause of mortality worldwide and matters are only set to worsen as its incidence continues to rise. Traditional approaches to combat cancer include improved prevention, early diagnosis, optimized surgery, development of novel drugs and honing regimens of existing anti-cancer drugs. Although discovery and development of novel and effective anti-cancer drugs is a major research area, it is well known that oncology drug development is a lengthy process, extremely costly and with high attrition rates. Furthermore, those drugs that do make it through the drug development mill are often quite expensive, laden with severe side-effects and, unfortunately, to date, have only demonstrated minimal increases in overall survival. Therefore, a strong interest has emerged to identify approved non-cancer drugs that possess anti-cancer activity, thus shortcutting the development process. This research strategy is commonly known as drug repurposing or drug repositioning and provides a faster path to the clinics. We have developed and implemented a modification of the standard drug repurposing strategy that we review here; rather than investigating target-promiscuous non-cancer drugs for possible anti-cancer activity, we focus on the discovery of novel cancer indications for already approved chemotherapeutic anti-cancer drugs. Clinical implementation of this strategy is normally commenced at clinical phase II trials and includes pre-treated patients. As the response rates to any non-standard chemotherapeutic drug will be relatively low in such a patient cohort it is a pre-requisite that such testing is based on predictive biomarkers. This review describes our strategy of biomarker-guided repurposing of chemotherapeutic drugs for cancer therapy, taking the repurposing of topoisomerase I inhibitors and topoisomerase I as a potential predictive biomarker as case in point.

  17. Mathematical modelling of magnetically targeted drug delivery

    Energy Technology Data Exchange (ETDEWEB)

    Grief, Andrew D. [Theoretical Mechanics, School of Mathematical Sciences, University of Nottingham, University Park, Nottingham NG7 2RD (United Kingdom)]. E-mail: andrew.grief@nottingham.ac.uk; Richardson, Giles [Theoretical Mechanics, School of Mathematical Sciences, University of Nottingham, University Park, Nottingham NG7 2RD (United Kingdom)]. E-mail: giles.richardson@nottingham.ac.uk

    2005-05-15

    A mathematical model for targeted drug delivery using magnetic particles is developed. This includes a diffusive flux of particles arising from interactions between erythrocytes in the microcirculation. The model is used to track particles in a vessel network. Magnetic field design is discussed and we show that it is impossible to specifically target internal regions using an externally applied field.

  18. Computational design of nanoparticle drug delivery systems for selective targeting.

    Science.gov (United States)

    Duncan, Gregg A; Bevan, Michael A

    2015-10-01

    Ligand-functionalized nanoparticles capable of selectively binding to diseased versus healthy cell populations are attractive for improved efficacy of nanoparticle-based drug and gene therapies. However, nanoparticles functionalized with high affinity targeting ligands may lead to undesired off-target binding to healthy cells. In this work, Monte Carlo simulations were used to quantitatively determine net surface interactions, binding valency, and selectivity between targeted nanoparticles and cell surfaces. Dissociation constant, KD, and target membrane protein density, ρR, are explored over a range representative of healthy and cancerous cell surfaces. Our findings show highly selective binding to diseased cell surfaces can be achieved with multiple, weaker affinity targeting ligands that can be further optimized by varying the targeting ligand density, ρL. Using the approach developed in this work, nanomedicines can be optimally designed for exclusively targeting diseased cells and tissues.

  19. Cytotoxic and targeted therapy for hereditary cancers.

    Science.gov (United States)

    Iyevleva, Aglaya G; Imyanitov, Evgeny N

    2016-01-01

    There is a number of drugs demonstrating specific activity towards hereditary cancers. For example, tumors in BRCA1/2 mutation carriers usually arise via somatic inactivation of the remaining BRCA allele, which makes them particularly sensitive to platinum-based drugs, PARP inhibitors (PARPi), mitomycin C, liposomal doxorubicin, etc. There are several molecular assays for BRCA-ness, which permit to reveal BRCA-like phenocopies among sporadic tumors and thus extend clinical indications for the use of BRCA-specific therapies. Retrospective data on high-dose chemotherapy deserve consideration given some unexpected instances of cure from metastatic disease among BRCA1/2-mutated patients. Hereditary non-polyposis colorectal cancer (HNPCC) is characterized by high-level microsatellite instability (MSI-H), increased antigenicity and elevated expression of immunosuppressive molecules. Recent clinical trial demonstrated tumor responses in HNPCC patients treated by the immune checkpoint inhibitor pembrolizumab. There are successful clinical trials on the use of novel targeted agents for the treatment or rare cancer syndromes, e.g. RET inhibitors for hereditary medullary thyroid cancer, mTOR inhibitors for tumors arising in patients with tuberous sclerosis (TSC), and SMO inhibitors for basal-cell nevus syndrome. Germ-line mutation tests will be increasingly used in the future for the choice of the optimal therapy, therefore turnaround time for these laboratory procedures needs to be significantly reduced to ensure proper treatment planning. PMID:27555886

  20. From microRNA functions to microRNA therapeutics: Novel targets and novel drugs in breast cancer research and treatment

    OpenAIRE

    Piva, Roberta; Spandidos, Demetrios A.; Gambari, Roberto

    2013-01-01

    MicroRNAs (miRNAs or miRs) are a family of small non-coding RNAs that regulate gene expression by the sequence-selective targeting of mRNAs, leading to translational repression or mRNA degradation, depending on the degree of complementarity with target mRNA sequences. miRNAs play a crucial role in cancer. In the case of breast tumors, several studies have demonstrated a correlation between: i) the expression profile of oncogenic miRNAs (oncomiRs) or tumor suppressor miRNAs and ii) the tumorig...

  1. Fluid mechanics aspects of magnetic drug targeting.

    Science.gov (United States)

    Odenbach, Stefan

    2015-10-01

    Experiments and numerical simulations using a flow phantom for magnetic drug targeting have been undertaken. The flow phantom is a half y-branched tube configuration where the main tube represents an artery from which a tumour-supplying artery, which is simulated by the side branch of the flow phantom, branches off. In the experiments a quantification of the amount of magnetic particles targeted towards the branch by a magnetic field applied via a permanent magnet is achieved by impedance measurement using sensor coils. Measuring the targeting efficiency, i.e. the relative amount of particles targeted to the side branch, for different field configurations one obtains targeting maps which combine the targeting efficiency with the magnetic force densities in characteristic points in the flow phantom. It could be shown that targeting efficiency depends strongly on the magnetic field configuration. A corresponding numerical model has been set up, which allows the simulation of targeting efficiency for variable field configuration. With this simulation good agreement of targeting efficiency with experimental data has been found. Thus, the basis has been laid for future calculations of optimal field configurations in clinical applications of magnetic drug targeting. Moreover, the numerical model allows the variation of additional parameters of the drug targeting process and thus an estimation of the influence, e.g. of the fluid properties on the targeting efficiency. Corresponding calculations have shown that the non-Newtonian behaviour of the fluid will significantly influence the targeting process, an aspect which has to be taken into account, especially recalling the fact that the viscosity of magnetic suspensions depends strongly on the magnetic field strength and the mechanical load. PMID:26415215

  2. Targeted Cancer Therapy Using Engineered Salmonella typhimurium

    Science.gov (United States)

    Zheng, Jin Hai

    2016-01-01

    Obligate or facultative anaerobic bacteria such as Bifidobacterium, Clostridium, Salmonella, or Escherichia coli specifically colonize and proliferate inside tumor tissues and inhibit tumor growth. Among them, attenuated Salmonella typhimurium (S. typhimurium) has been widely studied in animal cancer models and Phase I clinical trials in human patients. S. typhimurium genes are easily manipulated; thus diverse attenuated strains of S. typhimurium have been designed and engineered as tumor-targeting therapeutics or drug delivery vehicles that show both an excellent safety profile and therapeutic efficacy in mouse models. An attenuated strain of S. typhimurium, VNP20009, successfully targeted human metastatic melanoma and squamous cell carcinoma in Phase I clinical trials; however, the efficacy requires further refinement. Along with the characteristics of self-targeting, proliferation, and deep tissue penetration, the ease of genetic manipulation allows for the production of more attenuated strains with greater safety profiles and vector systems that deliver designable cargo molecules for cancer diagnosis and/or therapy. Here, we discuss recent progress in the field of Salmonellae-mediated cancer therapy. PMID:27689027

  3. Targeted Cancer Therapy Using Engineered Salmonella typhimurium.

    Science.gov (United States)

    Zheng, Jin Hai; Min, Jung-Joon

    2016-09-01

    Obligate or facultative anaerobic bacteria such as Bifidobacterium, Clostridium, Salmonella, or Escherichia coli specifically colonize and proliferate inside tumor tissues and inhibit tumor growth. Among them, attenuated Salmonella typhimurium (S. typhimurium) has been widely studied in animal cancer models and Phase I clinical trials in human patients. S. typhimurium genes are easily manipulated; thus diverse attenuated strains of S. typhimurium have been designed and engineered as tumor-targeting therapeutics or drug delivery vehicles that show both an excellent safety profile and therapeutic efficacy in mouse models. An attenuated strain of S. typhimurium, VNP20009, successfully targeted human metastatic melanoma and squamous cell carcinoma in Phase I clinical trials; however, the efficacy requires further refinement. Along with the characteristics of self-targeting, proliferation, and deep tissue penetration, the ease of genetic manipulation allows for the production of more attenuated strains with greater safety profiles and vector systems that deliver designable cargo molecules for cancer diagnosis and/or therapy. Here, we discuss recent progress in the field of Salmonellae-mediated cancer therapy. PMID:27689027

  4. Targeted Cancer Therapy Using Engineered Salmonella typhimurium

    Science.gov (United States)

    Zheng, Jin Hai

    2016-01-01

    Obligate or facultative anaerobic bacteria such as Bifidobacterium, Clostridium, Salmonella, or Escherichia coli specifically colonize and proliferate inside tumor tissues and inhibit tumor growth. Among them, attenuated Salmonella typhimurium (S. typhimurium) has been widely studied in animal cancer models and Phase I clinical trials in human patients. S. typhimurium genes are easily manipulated; thus diverse attenuated strains of S. typhimurium have been designed and engineered as tumor-targeting therapeutics or drug delivery vehicles that show both an excellent safety profile and therapeutic efficacy in mouse models. An attenuated strain of S. typhimurium, VNP20009, successfully targeted human metastatic melanoma and squamous cell carcinoma in Phase I clinical trials; however, the efficacy requires further refinement. Along with the characteristics of self-targeting, proliferation, and deep tissue penetration, the ease of genetic manipulation allows for the production of more attenuated strains with greater safety profiles and vector systems that deliver designable cargo molecules for cancer diagnosis and/or therapy. Here, we discuss recent progress in the field of Salmonellae-mediated cancer therapy.

  5. Targeting protein kinases in the malaria parasite: update of an antimalarial drug target.

    Science.gov (United States)

    Zhang, Veronica M; Chavchich, Marina; Waters, Norman C

    2012-01-01

    Millions of deaths each year are attributed to malaria worldwide. Transmitted through the bite of an Anopheles mosquito, infection and subsequent death from the Plasmodium species, most notably P. falciparum, can readily spread through a susceptible population. A malaria vaccine does not exist and resistance to virtually every antimalarial drug predicts that mortality and morbidity associated with this disease will increase. With only a few antimalarial drugs currently in the pipeline, new therapeutic options and novel chemotypes are desperately needed. Hit-to-Lead diversity may successfully provide novel inhibitory scaffolds when essential enzymes are targeted, for example, the plasmodial protein kinases. Throughout the entire life cycle of the malaria parasite, protein kinases are essential for growth and development. Ongoing efforts continue to characterize these kinases, while simultaneously pursuing them as antimalarial drug targets. A collection of structural data, inhibitory profiles and target validation has set the foundation and support for targeting the malarial kinome. Pursuing protein kinases as cancer drug targets has generated a wealth of information on the inhibitory strategies that can be useful for antimalarial drug discovery. In this review, progress on selected protein kinases is described. As the search for novel antimalarials continues, an understanding of the phosphor-regulatory pathways will not only validate protein kinase targets, but also will identify novel chemotypes to thwart malaria drug resistance. PMID:22242850

  6. Membrane Transporters: Structure, Function and Targets for Drug Design

    Science.gov (United States)

    Ravna, Aina W.; Sager, Georg; Dahl, Svein G.; Sylte, Ingebrigt

    Current therapeutic drugs act on four main types of molecular targets: enzymes, receptors, ion channels and transporters, among which a major part (60-70%) are membrane proteins. This review discusses the molecular structures and potential impact of membrane transporter proteins on new drug discovery. The three-dimensional (3D) molecular structure of a protein contains information about the active site and possible ligand binding, and about evolutionary relationships within the protein family. Transporters have a recognition site for a particular substrate, which may be used as a target for drugs inhibiting the transporter or acting as a false substrate. Three groups of transporters have particular interest as drug targets: the major facilitator superfamily, which includes almost 4000 different proteins transporting sugars, polyols, drugs, neurotransmitters, metabolites, amino acids, peptides, organic and inorganic anions and many other substrates; the ATP-binding cassette superfamily, which plays an important role in multidrug resistance in cancer chemotherapy; and the neurotransmitter:sodium symporter family, which includes the molecular targets for some of the most widely used psychotropic drugs. Recent technical advances have increased the number of known 3D structures of membrane transporters, and demonstrated that they form a divergent group of proteins with large conformational flexibility which facilitates transport of the substrate.

  7. Synthesis, characterization and in vitro evaluation of methotrexate conjugated fluorescent carbon nanoparticles as drug delivery system for human lung cancer targeting.

    Science.gov (United States)

    Ajmal, Muhammad; Yunus, Uzma; Matin, Abdul; Haq, Noaman Ul

    2015-12-01

    Nanotechnology based cancer therapeutics have rapidly advanced towards the solution of many limitations associated with other drug delivery agents such as nonspecific distribution within the body, low water solubility and non-biocompatibility. Carbon nanoparticles have demonstrated unique properties that are useful to combat with these issues, including their properties dependent on size, high stability in different solvents, compatible size for drug delivery and ease of surface modifications. Fluorescent carbon nanoparticles with good water solubility were obtained from a carbohydrate source by acid assisted ultrasonic treatment at 35kHz for 4h. This simple and economical method can be used for large scale production. Electron microscopic, spectroscopic and thermo gravimetric analysis techniques were used to characterize these carbon nanoparticles. Functionalized CNPs were further conjugated with anticancer drug-methotrexate and used as fluorescent nano-carriers. In this research work, we determined the in vitro bioactivity of CNPs-methotrexate conjugates by lactate dehydrogenase assay, cell adhesion assay and sulforhodamine B assay in human lung carcinoma cell line (H157). The CNPs showed promising biocompatibility and CNPs-MTX conjugates demonstrated potent cytotoxic effects and high anticancer activities in human lung cancer cell line.

  8. NIOSOMES IN TARGETED DRUG DELIVERY : A REVIEW

    Directory of Open Access Journals (Sweden)

    PRAGNA GADHIYA

    2012-05-01

    Full Text Available Over the past several years, treatment of infectious diseases and immunization has undergone aparadigm shift. Stemming from the nanobiotechnology research, not only a large number of diseasespecificbiologicals have been developed, but also enormous efforts have been made to effectivelydeliver these biologicals. Non-ionic surfactant vesicles (or niosomes are now widely studied asalternates to liposomes. Different novel approaches used for delivering these drugs include liposomes,Microspheres, nanotechnology, micro emulsions, antibody-loaded drug delivery, magneticMicrocapsules, implantable pumps and niosomes. Niosomes and liposomes are equiactive In drugdelivery potential and both increase drug efficacy as compared with that of free Drug. Niosomes arepreferred over liposomes because the former exhibit high chemical Stability and economy. Niosomes areself assembled vesicles composed primarily of synthetic surfactants and cholesterol. They are analogousin structure to the more widely studied liposomes formed from biologically derived phospholipids.Niosomes represent an emerging class of novel vesicular systems. Niosome formation requires thepresence of a particular class of amphiphile and aqueous solvent. In recent years a comprehensiveresearch carried over niosome as a drug carrier. Various drugs are enlisted and tried in niosomesurfactant vesicles. Niosome appears to be a Well preferred drug delivery system over liposome asniosome being stable and economic. Also niosomes have great drug delivery potential for targeteddelivery of anti-cancer, Anti-infective agents. Drug delivery potential of niosome can enhance by usingnovel Concepts like proniosomes, discomes and aspasome. Niosomes also serve better aid in diagnosticimaging and as a vaccine adjuvant.

  9. Functional and mechanistic analysis of telomerase: An antitumor drug target.

    Science.gov (United States)

    Chen, Yinnan; Zhang, Yanmin

    2016-07-01

    The current research on anticancer drugs focuses on exploiting particular traits or hallmarks unique to cancer cells. Telomerase, a special reverse transcriptase, has been recognized as a common factor in most tumor cells, and in turn a distinctive characteristic with respect to non-malignant cells. This feature has made telomerase a preferred target for anticancer drug development and cancer therapy. This review aims to analyze the pharmacological function and mechanism and role of telomerase in oncogenesis; to provide fundamental knowledge for research on the structure, function, and working mechanism of telomerase; to expound the role that telomerase plays in the initiation and development of tumor and its relationship with tumor cell growth, proliferation, apoptosis, and related pathway molecules; and to display potential targets of antitumor drug for inhibiting the expression, reconstitution, and trafficking of the enzyme. We therefore summarize recent advances in potential telomerase inhibitors for antitumor including natural products, synthetic small molecules, peptides and proteins, which indicate that optimizing the delivery method and drug combination could be of help in a combinatorial drug treatment for tumor. More extensive understanding of the structure, biogenesis, and mechanism of telomerase will provide invaluable information for increasing the efficiency of rational antitumor drug design. PMID:27118336

  10. 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...

  11. Dual responsive PNIPAM–chitosan targeted magnetic nanopolymers for targeted drug delivery

    Energy Technology Data Exchange (ETDEWEB)

    Yadavalli, Tejabhiram, E-mail: tejabhiram@gmail.com [Nanotechnology Research Centre, SRM University, Chennai 603203 (India); Ramasamy, Shivaraman [Nanotechnology Research Centre, SRM University, Chennai 603203 (India); School of Physics, The University of Western Australia, 35 Stirling Hwy, Crawley, WA 6009 (Australia); Chandrasekaran, Gopalakrishnan; Michael, Isaac; Therese, Helen Annal [Nanotechnology Research Centre, SRM University, Chennai 603203 (India); Chennakesavulu, Ramasamy [Department of Pharmacy practice, SRM College of Pharmacy, Chennai 603203 (India)

    2015-04-15

    A dual stimuli sensitive magnetic hyperthermia based drug delivery system has been developed for targeted cancer treatment. Thermosensitive amine terminated poly-N-isopropylacrylamide complexed with pH sensitive chitosan nanoparticles was prepared as the drug carrier. Folic acid and fluorescein were tagged to the nanopolymer complex via N-hydroxysuccinimide and ethyl-3-(3-dimethylaminopropyl)carbodiimide reaction to form a fluorescent and cancer targeting magnetic carrier system. The formation of the polymer complex was confirmed using infrared spectroscopy. Gadolinium doped nickel ferrite nanoparticles prepared by a hydrothermal method were encapsulated in the polymer complex to form a magnetic drug carrier system. The proton relaxation studies on the magnetic carrier system revealed a 200% increase in the T1 proton relaxation rate. These magnetic carriers were loaded with curcumin using solvent evaporation method with a drug loading efficiency of 86%. Drug loaded nanoparticles were tested for their targeting and anticancer properties on four cancer cell lines with the help of MTT assay. The results indicated apoptosis of cancer cell lines within 3 h of incubation. - Highlights: • The use of gadolinium doped nickel ferrite with the suggested doping level. • The use of PNIPMA–chitosan polymer with folic acid and fluorescein as a drug carrier complex. • Magnetic hyperthermia studies of gadolinium doped nickel ferrites are being reported for the first time. • Proton relaxivity studies which indicate the MRI contrasting properties on the reported system are new. • Use of curcumin, a hydrophobic Indian spice as a cancer killing agent inside the reported magnetic polymer complex.

  12. Dual responsive PNIPAM–chitosan targeted magnetic nanopolymers for targeted drug delivery

    International Nuclear Information System (INIS)

    A dual stimuli sensitive magnetic hyperthermia based drug delivery system has been developed for targeted cancer treatment. Thermosensitive amine terminated poly-N-isopropylacrylamide complexed with pH sensitive chitosan nanoparticles was prepared as the drug carrier. Folic acid and fluorescein were tagged to the nanopolymer complex via N-hydroxysuccinimide and ethyl-3-(3-dimethylaminopropyl)carbodiimide reaction to form a fluorescent and cancer targeting magnetic carrier system. The formation of the polymer complex was confirmed using infrared spectroscopy. Gadolinium doped nickel ferrite nanoparticles prepared by a hydrothermal method were encapsulated in the polymer complex to form a magnetic drug carrier system. The proton relaxation studies on the magnetic carrier system revealed a 200% increase in the T1 proton relaxation rate. These magnetic carriers were loaded with curcumin using solvent evaporation method with a drug loading efficiency of 86%. Drug loaded nanoparticles were tested for their targeting and anticancer properties on four cancer cell lines with the help of MTT assay. The results indicated apoptosis of cancer cell lines within 3 h of incubation. - Highlights: • The use of gadolinium doped nickel ferrite with the suggested doping level. • The use of PNIPMA–chitosan polymer with folic acid and fluorescein as a drug carrier complex. • Magnetic hyperthermia studies of gadolinium doped nickel ferrites are being reported for the first time. • Proton relaxivity studies which indicate the MRI contrasting properties on the reported system are new. • Use of curcumin, a hydrophobic Indian spice as a cancer killing agent inside the reported magnetic polymer complex

  13. Nanoscale Quantifying the Effects of Targeted Drug on Chemotherapy in Lymphoma Treatment Using Atomic Force Microscopy.

    Science.gov (United States)

    Li, Mi; Xiao, Xiubin; Liu, Lianqing; Xi, Ning; Wang, Yuechao

    2016-10-01

    The applications of targeted drugs in treating cancers have significantly improved the survival rates of patients. However, in the clinical practice, targeted drugs are commonly combined with chemotherapy drugs, causing that the exact contribution of targeted drugs to the clinical outcome is difficult to evaluate. Quantitatively investigating the effects of targeted drugs on chemotherapy drugs on cancer cells is useful for us to understand drug actions and design better drugs. The advent of atomic force microscopy (AFM) provides a powerful tool for probing the nanoscale physiological activities of single live cells. In this paper, the detailed changes in cell morphology and mechanical properties were quantified on single lymphoma cells during the actions of rituximab (a monoclonal antibody targeted drug) and two chemotherapy drugs (cisplatin and cytarabine) by AFM. AFM imaging revealed the distinct changes of cellular ultramicrostructures induced by the drugs. The changes of cellular mechanical properties after the drug stimulations were measured by AFM indenting. The statistical histograms of cellular surface roughness and mechanical properties quantitatively showed that rituximab could remarkably strengthen the killing effects of chemotherapy drugs. The study offers a new way to quantify the synergistic interactions between targeted drugs and chemotherapy drugs at the nanoscale, which will have potential impacts on predicting the efficacies of drug combinations before clinical treatments.

  14. Prediction of drug-target interactions and drug repositioning via network-based inference.

    Directory of Open Access Journals (Sweden)

    Feixiong Cheng

    Full Text Available Drug-target interaction (DTI is the basis of drug discovery and design. It is time consuming and costly to determine DTI experimentally. Hence, it is necessary to develop computational methods for the prediction of potential DTI. Based on complex network theory, three supervised inference methods were developed here to predict DTI and used for drug repositioning, namely drug-based similarity inference (DBSI, target-based similarity inference (TBSI and network-based inference (NBI. Among them, NBI performed best on four benchmark data sets. Then a drug-target network was created with NBI based on 12,483 FDA-approved and experimental drug-target binary links, and some new DTIs were further predicted. In vitro assays confirmed that five old drugs, namely montelukast, diclofenac, simvastatin, ketoconazole, and itraconazole, showed polypharmacological features on estrogen receptors or dipeptidyl peptidase-IV with half maximal inhibitory or effective concentration ranged from 0.2 to 10 µM. Moreover, simvastatin and ketoconazole showed potent antiproliferative activities on human MDA-MB-231 breast cancer cell line in MTT assays. The results indicated that these methods could be powerful tools in prediction of DTIs and drug repositioning.

  15. LIVER SPECIFIC DRUG TARGETING STRATEGIES: A REVIEW

    Directory of Open Access Journals (Sweden)

    Ramesh S. Gorad*, Satish K. Mandlik and Kishore N. Gujar

    2013-11-01

    Full Text Available Drug delivery to liver is one of the most challenging research areas in pharmaceutical sciences. The some physiological barrier such as opsonization, mechanical entrapment by pulmonary vascular bed, uptake by RES represents an insurmountable obstacle for a large number of proteins and drugs, including antibiotics, antineoplastic agents and antiviral agents to target liver disorders. Therefore, various strategies have been proposed to improve the delivery of different drugs to liver and hepatocytes which includes passive accumulation of nanoparticle therapeutics and active targeting by surface modifications of nanoparticles with specific ligands such as carbohydrates, peptides, proteins and antibodies. The present review enlightens about different pathologies of liver and targeting strategies employed in relation to liver anatomy and disease etiologies.

  16. Targeting Selectins and Their Ligands in Cancer.

    Science.gov (United States)

    Natoni, Alessandro; Macauley, Matthew S; O'Dwyer, Michael E

    2016-01-01

    Aberrant glycosylation is a hallmark of cancer cells with increased evidence pointing to a role in tumor progression. In particular, aberrant sialylation of glycoproteins and glycolipids has been linked to increased immune cell evasion, drug evasion, drug resistance, tumor invasiveness, and vascular dissemination, leading to metastases. Hypersialylation of cancer cells is largely the result of overexpression of sialyltransferases (STs). Differentially, humans express twenty different STs in a tissue-specific manner, each of which catalyzes the attachment of sialic acids via different glycosidic linkages (α2-3, α2-6, or α2-8) to the underlying glycan chain. One important mechanism whereby overexpression of STs contributes to an enhanced metastatic phenotype is via the generation of selectin ligands. Selectin ligand function requires the expression of sialyl-Lewis X and its structural isomer sialyl-Lewis A, which are synthesized by the combined action of alpha α1-3-fucosyltransferases, α2-3-sialyltransferases, β1-4-galactosyltranferases, and N-acetyl-β-glucosaminyltransferases. The α2-3-sialyltransferases ST3Gal4 and ST3Gal6 are critical to the generation of functional E- and P-selectin ligands and overexpression of these STs have been linked to increased risk of metastatic disease in solid tumors and poor outcome in multiple myeloma. Thus, targeting selectins and their ligands as well as the enzymes involved in their generation, in particular STs, could be beneficial to many cancer patients. Potential strategies include ST inhibition and the use of selectin antagonists, such as glycomimetic drugs and antibodies. Here, we review ongoing efforts to optimize the potency and selectivity of ST inhibitors, including the potential for targeted delivery approaches, as well as evaluate the potential utility of selectin inhibitors, which are now in early clinical development. PMID:27148485

  17. Targeting Selectins and Their Ligands in Cancer

    Directory of Open Access Journals (Sweden)

    Alessandro eNatoni

    2016-04-01

    Full Text Available Aberrant glycosylation is a hallmark of cancer cells with increased evidence pointing to a role in tumor progression. In particular, aberrant sialylation of glycoproteins and glycolipids have been linked to increased immune cell evasion, drug evasion, drug resistance, tumor invasiveness, and vascular dissemination leading to metastases. Hypersialylation of cancer cells is largely the result of overexpression of sialyltransferases. Humans differentially express twenty different sialyltransferases in a tissue-specific manner, each of which catalyze the attachment of sialic acids via different glycosidic linkages (2-3; 2-6 or 2-8 to the underlying glycan chain. One important mechanism whereby overexpression of sialyltransferases contributes to an enhanced metastatic phenotype is via the generation of selectin ligands. Selectin ligand function requires the expression of sialyl-Lewis X and its structural-isomer sialyl-Lewis A, which are synthesized by the combined action of alpha 1-3-fucosyltransferases, 2-3-sialyltransferases, 1-4-galactosyltranferases, and N-acetyl--glucosaminyltransferases. The α2-3-sialyltransferases ST3Gal4 and ST3Gal6 are critical to the generation of functional E- and P-selectin ligands and overexpression of these sialyltransferases have been linked to increased risk of metastatic disease in solid tumors and poor outcome in multiple myeloma. Thus, targeting selectins and their ligands as well as the enzymes involved in their generation, in particular sialyltransferases, could be beneficial to many cancer patients. Potential strategies include sialyltransferase inhibition and the use of selectin antagonists, such as glycomimetic drugs and antibodies. Here, we review ongoing efforts to optimize the potency and selectivity of sialyltransferase inhibitors, including the potential for targeted delivery approaches, as well as evaluate the potential utility of selectin inhibitors, which are now in early clinical

  18. Target inhibition networks: predicting selective combinations of druggable targets to block cancer survival pathways.

    Directory of Open Access Journals (Sweden)

    Jing Tang

    Full Text Available A recent trend in drug development is to identify drug combinations or multi-target agents that effectively modify multiple nodes of disease-associated networks. Such polypharmacological effects may reduce the risk of emerging drug resistance by means of attacking the disease networks through synergistic and synthetic lethal interactions. However, due to the exponentially increasing number of potential drug and target combinations, systematic approaches are needed for prioritizing the most potent multi-target alternatives on a global network level. We took a functional systems pharmacology approach toward the identification of selective target combinations for specific cancer cells by combining large-scale screening data on drug treatment efficacies and drug-target binding affinities. Our model-based prediction approach, named TIMMA, takes advantage of the polypharmacological effects of drugs and infers combinatorial drug efficacies through system-level target inhibition networks. Case studies in MCF-7 and MDA-MB-231 breast cancer and BxPC-3 pancreatic cancer cells demonstrated how the target inhibition modeling allows systematic exploration of functional interactions between drugs and their targets to maximally inhibit multiple survival pathways in a given cancer type. The TIMMA prediction results were experimentally validated by means of systematic siRNA-mediated silencing of the selected targets and their pairwise combinations, showing increased ability to identify not only such druggable kinase targets that are essential for cancer survival either individually or in combination, but also synergistic interactions indicative of non-additive drug efficacies. These system-level analyses were enabled by a novel model construction method utilizing maximization and minimization rules, as well as a model selection algorithm based on sequential forward floating search. Compared with an existing computational solution, TIMMA showed both enhanced

  19. Targeted Liposomal Drug Delivery to Monocytes and Macrophages

    Directory of Open Access Journals (Sweden)

    Ciara Kelly

    2011-01-01

    Full Text Available As the role of monocytes and macrophages in a range of diseases is better understood, strategies to target these cell types are of growing importance both scientifically and therapeutically. As particulate carriers, liposomes naturally target cells of the mononuclear phagocytic system (MPS, particularly macrophages. Loading drugs into liposomes can therefore offer an efficient means of drug targeting to MPS cells. Physicochemical properties including size, charge and lipid composition can have a very significant effect on the efficiency with which liposomes target MPS cells. MPS cells express a range of receptors including scavenger receptors, integrins, mannose receptors and Fc-receptors that can be targeted by the addition of ligands to liposome surfaces. These ligands include peptides, antibodies and lectins and have the advantages of increasing target specificity and avoiding the need for cationic lipids to trigger intracellular delivery. The goal for targeting monocytes/macrophages using liposomes includes not only drug delivery but also potentially a role in cell ablation and cell activation for the treatment of conditions including cancer, atherosclerosis, HIV, and chronic inflammation.

  20. Targeting molecular networks for drug research

    Directory of Open Access Journals (Sweden)

    José Pedro Pinto

    2014-06-01

    Full Text Available The study of molecular networks has recently moved into the limelight of biomedical research. While it has certainly provided us with plenty of new insights into cellular mechanisms, the challenge now is how to modify or even restructure these networks. This is especially true for human diseases, which can be regarded as manifestations of distorted states of molecular networks. Of the possible interventions for altering networks, the use of drugs is presently the most feasible. In this mini-review, we present and discuss some exemplary approaches of how analysis of molecular interaction networks can contribute to pharmacology (e.g., by identifying new drug targets or prediction of drug side effects, as well as listing pointers to relevant resources and software to guide future research. We also outline recent progress in the use of drugs for in vitro reprogramming of cells, which constitutes an example par excellence for altering molecular interaction networks with drugs.

  1. Nanoparticle-based targeted gene therapy for lung cancer

    Science.gov (United States)

    Lee, Hung-Yen; Mohammed, Kamal A; Nasreen, Najmunnisa

    2016-01-01

    Despite striking insights on lung cancer progression, and cutting-edge therapeutic approaches the survival of patients with lung cancer, remains poor. In recent years, targeted gene therapy with nanoparticles is one of the most rapidly evolving and extensive areas of research for lung cancer. The major goal of targeted gene therapy is to bring forward a safe and efficient treatment to cancer patients via specifically targeting and deterring cancer cells in the body. To achieve high therapeutic efficacy of gene delivery, various carriers have been engineered and developed to provide protection to the genetic materials and efficient delivery to targeted cancer cells. Nanoparticles play an important role in the area of drug delivery and have been widely applied in cancer treatments for the purposes of controlled release and cancer cell targeting. Nanoparticles composed of artificial polymers, proteins, polysaccharides and lipids have been developed for the delivery of therapeutic deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) sequences to target cancer. In addition, the effectiveness of cancer targeting has been enhanced by surface modification or conjugation with biomolecules on the surface of nanoparticles. In this review article we provide an overview on the latest developments in nanoparticle-based targeted gene therapy for lung cancers. Firstly, we outline the conventional therapies and discuss strategies for targeted gene therapy using nanoparticles. Secondly, we provide the most representative and recent researches in lung cancers including malignant pleural mesothelioma, mainly focusing on the application of Polymeric, Lipid-based, and Metal-based nanoparticles. Finally, we discuss current achievements and future challenges. PMID:27294004

  2. Therapies targeting cancer stem cells: Current trends and future challenges

    Institute of Scientific and Technical Information of China (English)

    Denisa; L; Dragu; Laura; G; Necula; Coralia; Bleotu; Carmen; C; Diaconu; Mihaela; Chivu-Economescu

    2015-01-01

    Traditional therapies against cancer, chemo- and radiotherapy, have multiple limitations that lead to treatment failure and cancer recurrence. These limitations are related to systemic and local toxicity, while treatment failure and cancer relapse are due to drug resistance and self-renewal, properties of a small population of tumor cells called cancer stem cells(CSCs). These cells are involved in cancer initiation, maintenance, metastasis and recurrence. Therefore, in order to develop efficient treatments that can induce a longlasting clinical response preventing tumor relapse it is important to develop drugs that can specifically target and eliminate CSCs. Recent identification of surface markers and understanding of molecular feature associated with CSC phenotype helped with the design of effective treatments. In this review we discuss targeting surface biomarkers, signaling pathways that regulate CSCs self-renewal and differentiation, drug-efflux pumps involved in apoptosis resistance, microenvironmental signals that sustain CSCs growth, manipulation of mi RNA expression, and induction of CSCs apoptosis and differentiation, with specific aim to hamper CSCs regeneration and cancer relapse. Some of these agents are under evaluation in preclinical and clinical studies, most of them for using in combination with traditional therapies. The combined therapy using conventional anticancer drugs with CSCs-targeting agents, may offer a promising strategy for management and eradication of different types of cancers.

  3. Drug Repositioning for Cancer Therapy Based on Large-Scale Drug-Induced Transcriptional Signatures.

    Directory of Open Access Journals (Sweden)

    Haeseung Lee

    Full Text Available An in silico chemical genomics approach is developed to predict drug repositioning (DR candidates for three types of cancer: glioblastoma, lung cancer, and breast cancer. It is based on a recent large-scale dataset of ~20,000 drug-induced expression profiles in multiple cancer cell lines, which provides i a global impact of transcriptional perturbation of both known targets and unknown off-targets, and ii rich information on drug's mode-of-action. First, the drug-induced expression profile is shown more effective than other information, such as the drug structure or known target, using multiple HTS datasets as unbiased benchmarks. Particularly, the utility of our method was robustly demonstrated in identifying novel DR candidates. Second, we predicted 14 high-scoring DR candidates solely based on expression signatures. Eight of the fourteen drugs showed significant anti-proliferative activity against glioblastoma; i.e., ivermectin, trifluridine, astemizole, amlodipine, maprotiline, apomorphine, mometasone, and nortriptyline. Our DR score strongly correlated with that of cell-based experimental results; the top seven DR candidates were positive, corresponding to an approximately 20-fold enrichment compared with conventional HTS. Despite diverse original indications and known targets, the perturbed pathways of active DR candidates show five distinct patterns that form tight clusters together with one or more known cancer drugs, suggesting common transcriptome-level mechanisms of anti-proliferative activity.

  4. Drug Repositioning for Cancer Therapy Based on Large-Scale Drug-Induced Transcriptional Signatures.

    Science.gov (United States)

    Lee, Haeseung; Kang, Seungmin; Kim, Wankyu

    2016-01-01

    An in silico chemical genomics approach is developed to predict drug repositioning (DR) candidates for three types of cancer: glioblastoma, lung cancer, and breast cancer. It is based on a recent large-scale dataset of ~20,000 drug-induced expression profiles in multiple cancer cell lines, which provides i) a global impact of transcriptional perturbation of both known targets and unknown off-targets, and ii) rich information on drug's mode-of-action. First, the drug-induced expression profile is shown more effective than other information, such as the drug structure or known target, using multiple HTS datasets as unbiased benchmarks. Particularly, the utility of our method was robustly demonstrated in identifying novel DR candidates. Second, we predicted 14 high-scoring DR candidates solely based on expression signatures. Eight of the fourteen drugs showed significant anti-proliferative activity against glioblastoma; i.e., ivermectin, trifluridine, astemizole, amlodipine, maprotiline, apomorphine, mometasone, and nortriptyline. Our DR score strongly correlated with that of cell-based experimental results; the top seven DR candidates were positive, corresponding to an approximately 20-fold enrichment compared with conventional HTS. Despite diverse original indications and known targets, the perturbed pathways of active DR candidates show five distinct patterns that form tight clusters together with one or more known cancer drugs, suggesting common transcriptome-level mechanisms of anti-proliferative activity. PMID:26954019

  5. Target Nanoparticles for Therapy - SANS and DLS of Drug Carrier Liposomes and Polymer Nanoparticles

    Science.gov (United States)

    Nawroth, T.; Johnson, R.; Krebs, L.; Khoshakhlagh, P.; Langguth, P.; Hellmann, N.; Goerigk, G.; Boesecke, P.; Bravin, A.; Le Duc, G.; Szekely, N.; Schweins, R.

    2016-09-01

    T arget Nano-Pharmaceutics shall improve therapy and diagnosis of severe diseases, e.g. cancer, by individual targeting of drug-loaded nano-pharmaceuticals towards cancer cells, and drug uptake receptors in other diseases. Specific ligands, proteins or cofactors, which are recognized by the diseased cells or cells of food and drug uptake, are bound to the nanoparticle surface, and thus capable of directing the drug carriers. The strategy has two branches: a) for parenteral cancer medicine a ligand set (2-5 different, surface-linked) are selected according to the biopsy analysis of the patient tissue e.g. from tumor.; b) in the oral drug delivery part the drug transport is enforced by excipients/ detergents in combination with targeting materials for cellular receptors resulting in an induced drug uptake. Both targeting nanomaterials are characterized by a combination of SANS + DLS and SAXS or ASAXS in a feedback process during development by synthesis, nanoparticle assembly and formulation.

  6. Antiangiogenic cancer drug using the zebrafish model.

    Science.gov (United States)

    Santoro, Massimo M

    2014-09-01

    The process of de novo vessel formation, called angiogenesis, is essential for tumor progression and spreading. Targeting of molecular pathways involved in such tumor angiogenetic processes by using specific drugs or inhibitors is important for developing new anticancer therapies. Drug discovery remains to be the main focus for biomedical research and represents the essence of antiangiogenesis cancer research. To pursue these molecular and pharmacological goals, researchers need to use animal models that facilitate the elucidation of tumor angiogenesis mechanisms and the testing of antiangiogenic therapies. The past few years have seen the zebrafish system emerge as a valid model organism to study developmental angiogenesis and, more recently, as an alternative vertebrate model for cancer research. In this review, we will discuss why the zebrafish model system has the advantage of being a vertebrate model equipped with easy and powerful transgenesis as well as imaging tools to investigate not only physiological angiogenesis but also tumor angiogenesis. We will also highlight the potential of zebrafish for identifying antitumor angiogenesis drugs to block tumor development and progression. We foresee the zebrafish model as an important system that can possibly complement well-established mouse models in cancer research to generate novel insights into the molecular mechanism of the tumor angiogenesis. PMID:24903092

  7. A conceptual framework for the identification of candidate drugs and drug targets in acute promyelocytic leukemia

    DEFF Research Database (Denmark)

    Marstrand, T T; Borup, R; Willer, A;

    2010-01-01

    regulation, and (ii) the identification of candidate drugs and drug targets for therapeutic interventions. Significantly, our study provides a conceptual framework that can be applied to any subtype of AML and cancer in general to uncover novel information from published microarray data sets at low cost......Chromosomal translocations of transcription factors generating fusion proteins with aberrant transcriptional activity are common in acute leukemia. In acute promyelocytic leukemia (APL), the promyelocytic leukemia-retinoic-acid receptor alpha (PML-RARA) fusion protein, which emerges....... In a broader perspective, our study provides strong evidence that genomic strategies might be used in a clinical setting to prospectively identify candidate drugs that subsequently are validated in vitro to define the most effective drug combination for individual cancer patients on a rational basis....

  8. Computational design of nanoparticle drug delivery systems for selective targeting

    Science.gov (United States)

    Duncan, Gregg A.; Bevan, Michael A.

    2015-09-01

    Ligand-functionalized nanoparticles capable of selectively binding to diseased versus healthy cell populations are attractive for improved efficacy of nanoparticle-based drug and gene therapies. However, nanoparticles functionalized with high affinity targeting ligands may lead to undesired off-target binding to healthy cells. In this work, Monte Carlo simulations were used to quantitatively determine net surface interactions, binding valency, and selectivity between targeted nanoparticles and cell surfaces. Dissociation constant, KD, and target membrane protein density, ρR, are explored over a range representative of healthy and cancerous cell surfaces. Our findings show highly selective binding to diseased cell surfaces can be achieved with multiple, weaker affinity targeting ligands that can be further optimized by varying the targeting ligand density, ρL. Using the approach developed in this work, nanomedicines can be optimally designed for exclusively targeting diseased cells and tissues.Ligand-functionalized nanoparticles capable of selectively binding to diseased versus healthy cell populations are attractive for improved efficacy of nanoparticle-based drug and gene therapies. However, nanoparticles functionalized with high affinity targeting ligands may lead to undesired off-target binding to healthy cells. In this work, Monte Carlo simulations were used to quantitatively determine net surface interactions, binding valency, and selectivity between targeted nanoparticles and cell surfaces. Dissociation constant, KD, and target membrane protein density, ρR, are explored over a range representative of healthy and cancerous cell surfaces. Our findings show highly selective binding to diseased cell surfaces can be achieved with multiple, weaker affinity targeting ligands that can be further optimized by varying the targeting ligand density, ρL. Using the approach developed in this work, nanomedicines can be optimally designed for exclusively targeting

  9. Novel targeted bladder drug-delivery systems: a review

    Directory of Open Access Journals (Sweden)

    Zacchè MM

    2015-11-01

    Full Text Available Martino Maria Zacchè, Sushma Srikrishna, Linda Cardozo Department of Urogynaecology, King's College Hospital, London, UK Abstract: The objective of pharmaceutics is the development of drugs with increased efficacy and reduced side effects. Prolonged exposure of the diseased tissue to the drug is of crucial importance. Drug-delivery systems (DDSs have been introduced to control rate, time, and place of release. Drugs can easily reach the bladder through a catheter, while systemically administered agents may undergo extensive metabolism. Continuous urine filling and subsequent washout hinder intravesical drug delivery (IDD. Moreover, the low permeability of the urothelium, also described as the bladder permeability barrier, poses a major challenge in the development of the IDD. DDSs increase bioavailability of drugs, therefore improving therapeutic effect and patient compliance. This review focuses on novel DDSs to treat bladder conditions such as overactive bladder, interstitial cystitis, bladder cancer, and recurrent urinary tract infections. The rationale and strategies for both systemic and local delivery methods are discussed, with emphasis on new formulations of well-known drugs (oxybutynin, nanocarriers, polymeric hydrogels, intravesical devices, encapsulated DDSs, and gene therapy. We give an overview of current and future prospects of DDSs for bladder disorders, including nanotechnology and gene therapy. Keywords: drug targeting, drug-delivery system, bladder disorders

  10. Molecular markers as therapeutic targets in lung cancer

    Institute of Scientific and Technical Information of China (English)

    Hsin-Hui Tseng; Biao He

    2013-01-01

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

  11. Mystery unraveled about antifungal drug targets

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    @@ A long-standing mystery about the functional roles of the N-terminal region of protein N-myristoyltransferase, an ideal target for antifungal drugs, was recently decoded, thanks to the threeyear joint efforts of researchers from the CAS Key Laboratory of Molecular Biology and their US colleagues at the DuPont Stine Haskell Research Center.

  12. Drug-induced regulation of target expression

    DEFF Research Database (Denmark)

    Iskar, Murat; Campillos, Monica; Kuhn, Michael;

    2010-01-01

    further newly identified drug-induced differential regulation of Lanosterol 14-alpha demethylase, Endoplasmin, DNA topoisomerase 2-alpha and Calmodulin 1. The feedback regulation in these and other targets is likely to be relevant for the success or failure of the molecular intervention....

  13. Advances of anti-EGFR family targeted drugs in the treatment of gastric cancer%抗EGFR家族靶向药物在胃癌治疗中的研究进展∗

    Institute of Scientific and Technical Information of China (English)

    秦军伟; 韩宇; 白玉贤

    2014-01-01

    Incidence of gastric cancer accounted for the fourth in global cancer incidence, and the mortality accounted for the second. Most patients bearing gastric cancer are already advanced and unresectable at the time of diagnosis. Chemotherapy and molecu⁃lar targeted therapy have been more and more emphasised on clinical research and practice as an effective means of treatment of gastric cancer. In recent years, the targeted therapy of epidermal growth factor receptor(EGFR) family has achieved fruitful results in the treatment of gastric cancer. This article summarizes the signal transduction mechanisms of EGFR family and associated targeted drugs in the treatment of gastric cancer.%胃癌发病率占全球癌症发病率的第4位,死亡率占第2位。大多数胃癌患者就诊时已属中晚期,失去手术机会,化疗及分子靶向治疗作为胃癌治疗的有效手段,越来越受到临床研究及实践的重视。近年来,抗表皮生长因子受体( EGFR)家族靶向治疗在胃癌治疗中取得了丰硕的成果。本文总结了EGFR家族信号转导机制及相关靶向药物在胃癌治疗中的研究进展。

  14. Targeting the nucleolus for cancer intervention.

    Science.gov (United States)

    Quin, Jaclyn E; Devlin, Jennifer R; Cameron, Donald; Hannan, Kate M; Pearson, Richard B; Hannan, Ross D

    2014-06-01

    The contribution of the nucleolus to cancer is well established with respect to its traditional role in facilitating ribosome biogenesis and proliferative capacity. More contemporary studies however, infer that nucleoli contribute a much broader role in malignant transformation. Specifically, extra-ribosomal functions of the nucleolus position it as a central integrator of cellular proliferation and stress signaling, and are emerging as important mechanisms for modulating how oncogenes and tumor suppressors operate in normal and malignant cells. The dependence of certain tumor cells to co-opt nucleolar processes to maintain their cancer phenotypes has now clearly been demonstrated by the application of small molecule inhibitors of RNA Polymerase I to block ribosomal DNA transcription and disrupt nucleolar function (Bywater et al., 2012 [1]). These drugs, which selectively kill tumor cells in vivo while sparing normal cells, have now progressed to clinical trials. It is likely that we have only just begun to scratch the surface of the potential of the nucleolus as a new target for cancer therapy, with "suppression of nucleolar stress" representing an emerging "hallmark" of cancer. This article is part of a Special Issue entitled: Role of the Nucleolus in Human Disease.

  15. Improving cancer immunotherapy by targeting the STATe of MDSCs

    Science.gov (United States)

    de Haas, Nienke; de Koning, Coco; Spilgies, Lisanne; de Vries, I. Jolanda M.; Hato, Stanleyson V.

    2016-01-01

    ABSTRACT Cancer immunotherapy is a promising therapeutic avenue; however, in practice its efficacy is hampered by an immunosuppressive tumor microenvironment that consists of suppressive cell types like myeloid-derived suppressor cells (MDSCs). Eradication or reprogramming of MDSCs could therefore enhance clinical responses to immunotherapy. Here, we review clinically available drugs that target MDSCs, often through inhibition of STAT signaling, which is essential for MDSC accumulation and suppressive functions. Interestingly, several drugs used for non-cancerous indications and natural compounds similarly inhibit MDSCs by STAT inhibition, but have fewer side effects than anticancer drugs. Therefore, they show great potential for combination strategies with immunotherapy.

  16. Targeted delivery and pH-responsive release of stereoisomeric anti-cancer drugs using β-cyclodextrin assemblied Fe3O4 nanoparticles

    Science.gov (United States)

    Wang, Congli; Huang, Lizhen; Song, Shengmei; Saif, Bassam; Zhou, Yehong; Dong, Chuan; Shuang, Shaomin

    2015-12-01

    The β-cyclodextrin assemblied magnetic Fe3O4 nanoparticles (β-CD-MNPs) were successfully fabricated via a layer-by-layer method. Possessing an average size 14 nm, good stability and super-paramagnetic response (Ms 64 emu/g), the resultant nanocomposites could be served as a versatile biocompatible platform for selective loading, targeted delivery and pH-responsive release of stereoisomeric doxorubicin (DOX) and epirubicin (EPI). 1H-nuclear magnetic resonance (1H NMR) and the computer simulation further give the evidence that partial anthracene ring of drug molecule is included by β-CD. In addition, non-toxic β-CD-MNPs have excellent biocompatibility on MCF-7 cells, and cellular uptake indicate that different amounts of DOX or EPI can be transported to targeting site and released from the internalized carriers. The results demonstrate that as-prepared β-CD-MNPs could be a very promising vehicle for DOX and EPI.

  17. Targeted proteins for diabetes drug design

    Science.gov (United States)

    Doan Trang Nguyen, Ngoc; Thi Le, Ly

    2012-03-01

    Type 2 diabetes mellitus is a common metabolism disorder characterized by high glucose in the bloodstream, especially in the case of insulin resistance and relative insulin deficiency. Nowadays, it is very common in middle-aged people and involves such dangerous symptoms as increasing risk of stroke, obesity and heart failure. In Vietnam, besides the common treatment of insulin injection, some herbal medication is used but no unified optimum remedy for the disease yet exists and there is no production of antidiabetic drugs in the domestic market yet. In the development of nanomedicine at the present time, drug design is considered as an innovative tool for researchers to study the mechanisms of diseases at the molecular level. The aim of this article is to review some common protein targets involved in type 2 diabetes, offering a new idea for designing new drug candidates to produce antidiabetic drugs against type 2 diabetes for Vietnamese people.

  18. Targeted therapies in upper gastrointestinal cancer

    NARCIS (Netherlands)

    S. Kordes

    2016-01-01

    Upper gastrointestinal (GI) cancers, as esophageal, gastric and pancreatic cancer, are still highly lethal diseases, in spite of advances in surgery, radiotherapy, chemotherapy and specific targeted therapy. Especially when patients are diagnosed with locally advanced or metastasized disease, upper

  19. Targeted therapies in epithelial ovarian cancer: Molecular mechanisms of action

    Institute of Scientific and Technical Information of China (English)

    Hiroaki; Itamochi

    2010-01-01

    Ovarian cancer is the leading cause of death in women with gynecological cancer. Most patients are diagnosed at an advanced stage and have a poor prognosis.Currently, surgical tumor debulking, followed by platinum- and taxane-based chemotherapy is the standard treatment for advanced ovarian cancer. However, these patients are at great risk of recurrence and emerging drug resistance. Therefore, novel treatment strategies are required to improve outcomes for women with advanced ovarian cancer. A variety of molecular targeted agents, the majority of which are monoclonal antibodies and small-molecule protein-kinase inhibitors, have been explored in the management of ovarian cancer. The targets of these agents include angiogenesis, the human epidermal growth factor receptor family, ubiquitinproteasome pathway, epigenetic modulators, poly(ADPribose) polymerase (PARP), and mammalian target of rapamycin (mTOR) signaling pathway, which are aberrant in tumor tissue. The antiangiogenic agent, bevacizumab, has been reported as the most effective targeted agent and should be included in the standard chemotherapeutic regimen for advanced ovarian cancer. PARP inhibitors, which are mainly used in breast and ovarian cancer susceptibility gene-mutated patients, and mTOR inhibitors are also attractive treatment strategies, either alone or combination with chemotherapy, for ovarian cancer. Understanding the tumor molecular biology and identification of predictive biomarkers are essential steps for selection of the best treatment strategies. This article reviews the molecular mechanisms of the most promising targeted agents that are under early phase clinical evaluation for ovarian cancer.

  20. An efficient targeted drug delivery through apotransferrin loaded nanoparticles.

    Directory of Open Access Journals (Sweden)

    Athuluri Divakar Sai Krishna

    Full Text Available BACKGROUND: Cancerous state is a highly stimulated environment of metabolically active cells. The cells under these conditions over express selective receptors for assimilation of factors essential for growth and transformation. Such receptors would serve as potential targets for the specific ligand mediated transport of pharmaceutically active molecules. The present study demonstrates the specificity and efficacy of protein nanoparticle of apotransferrin for targeted delivery of doxorubicin. METHODOLOGY/PRINCIPAL FINDINGS: Apotransferrin nanoparticles were developed by sol-oil chemistry. A comparative analysis of efficiency of drug delivery in conjugated and non-conjugated forms of doxorubicin to apotransferrin nanoparticle is presented. The spherical shaped apotransferrin nanoparticles (nano have diameters of 25-50 etam, which increase to 60-80 etam upon direct loading of drug (direct-nano, and showed further increase in dimension (75-95 etam in conjugated nanoparticles (conj-nano. The competitive experiments with the transferrin receptor specific antibody showed the entry of both conj-nano and direct-nano into the cells through transferrin receptor mediated endocytosis. Results of various studies conducted clearly establish the superiority of the direct-nano over conj-nano viz. (a localization studies showed complete release of drug very early, even as early as 30 min after treatment, with the drug localizing in the target organelle (nucleus (b pharmacokinetic studies showed enhanced drug concentrations, in circulation with sustainable half-life (c the studies also demonstrated efficient drug delivery, and an enhanced inhibition of proliferation in cancer cells. Tissue distribution analysis showed intravenous administration of direct nano lead to higher drug localization in liver, and blood as compared to relatively lesser localization in heart, kidney and spleen. Experiments using rat cancer model confirmed the efficacy of the formulation in

  1. 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

  2. Injectable nanomaterials for drug delivery: carriers, targeting moieties, and therapeutics.

    Science.gov (United States)

    Webster, David M; Sundaram, Padma; Byrne, Mark E

    2013-05-01

    Therapeutics such as nucleic acids, proteins/peptides, vaccines, anti-cancer, and other drugs have disadvantages of low bio-availability, rapid clearance, and high toxicity. Thus, there is a significant need for the development of efficient delivery methods and carriers. Injectable nanocarriers have received much attention due to their vast range of structures and ability to contain multiple functional groups, both within the bulk material and on the surface of the particles. Nanocarriers may be tailored to control drug release and/or increase selective cell targeting, cellular uptake, drug solubility, and circulation time, all of which lead to a more efficacious delivery and action of therapeutics. The focus of this review is injectable, targeted nanoparticle drug delivery carriers highlighting the diversity of nanoparticle materials and structures as well as highlighting current therapeutics and targeting moieties. Structures and materials discussed include liposomes, polymersomes, dendrimers, cyclodextrin-containing polymers (CDPs), carbon nanotubes (CNTs), and gold nanoparticles. Additionally, current clinical trial information and details such as trial phase, treatment, active drug, carrier sponsor, and clinical trial identifier for different materials and structures are presented and discussed.

  3. Strategies to improve intracellular drug delivery by targeted liposomes

    NARCIS (Netherlands)

    Fretz, M.M.

    2007-01-01

    Biotechnological advances increased the number of novel macromolecular drugs and new drug targets. The latter are mostly found intracellular. Unfortunately, most of the new macromolecular drugs rely on drug delivery tools for their intracellular delivery because their unfavourable physicochemical pr

  4. Folate targeted polymeric 'green' nanotherapy for cancer

    Energy Technology Data Exchange (ETDEWEB)

    Narayanan, Sreeja; Binulal, N S; Mony, Ullas; Manzoor, Koyakutty; Nair, Shantikumar; Menon, Deepthy, E-mail: deepthymenon@aims.amrita.edu [Amrita Center for Nanosciences and Molecular Medicine, Amrita Vishwa Vidyapeetham, Kochi-682 041, Kerala (India)

    2010-07-16

    The concept of 'green' chemotherapy by employing targeted nanoparticle mediated delivery to enhance the efficacy of phytomedicines is reported. Poly (lactide-co-glycolide) (PLGA) nanoparticles encapsulating a well known nutraceutical namely, grape seed extract (GSE)-'NanoGSE'-was prepared by a nanoprecipitation technique. The drug-loaded nanoparticles of size {approx} 100 nm exhibited high colloidal stability at physiological pH. Molecular receptor targeting of this nanophytomedicine against folate receptor over-expressing cancers was demonstrated in vitro by conjugation with a potential cancer targeting ligand, folic acid (FA). Fluorescence microscopy and flow cytometry data showed highly specific cellular uptake of FA conjugated NanoGSE on folate receptor positive cancer cells. Studies were also conducted to investigate the efficiency of targeted (FA conjugated) versus non-targeted (non-FA conjugated) nanoformulations in causing cancer cell death. The IC{sub 50} values were lowered by a factor of {approx} 3 for FA-NanoGSE compared to the free drug, indicating substantially enhanced bioavailability to the tumor cells, sparing the normal ones. Receptor targeting of FA-NanoGSE resulted in a significant increase in apoptotic index, which was also quantified by flow cytometry and fluorescence microscopy. This in vitro study provides a basis for the use of nanoparticle mediated delivery of anticancer nutraceuticals to enhance bioavailability and effectively target cancer by a 'green' approach.

  5. Tumor targeting using liposomal antineoplastic drugs

    Directory of Open Access Journals (Sweden)

    Jörg Huwyler

    2008-03-01

    Full Text Available Jörg Huwyler1, Jürgen Drewe2, Stephan Krähenbühl21University of Applied Sciences Northwestern Switzerland, Institute of Pharma Technology, Muttenz, Switzerland; 2Department of Research and Division of Clinical Pharmacology, University Hospital Basel, Basel, SwitzerlandAbstract: During the last years, liposomes (microparticulate phospholipid vesicles have beenused with growing success as pharmaceutical carriers for antineoplastic drugs. Fields of application include lipid-based formulations to enhance the solubility of poorly soluble antitumordrugs, the use of pegylated liposomes for passive targeting of solid tumors as well as vector-conjugated liposomal carriers for active targeting of tumor tissue. Such formulation and drug targeting strategies enhance the effectiveness of anticancer chemotherapy and reduce at the same time the risk of toxic side-effects. The present article reviews the principles of different liposomal technologies and discusses current trends in this field of research.Keywords: tumor targeting, antineoplastic drugs, liposomes, pegylation, steric stabilization, immunoliposomes

  6. Mining metabolic networks for optimal drug targets.

    Science.gov (United States)

    Sridhar, Padmavati; Song, Bin; Kahveci, Tamer; Ranka, Sanjay

    2008-01-01

    Recent advances in bioinformatics promote drug-design methods that aim to reduce side-effects. Efficient computational methods are required to identify the optimal enzyme-combination (i.e., drug targets) whose inhibition, will achieve the required effect of eliminating a given target set of compounds, while incurring minimal side-effects. We formulate the optimal enzyme-combination identification problem as an optimization problem on metabolic networks. We define a graph based computational damage model that encapsulates the impact of enzymes onto compounds in metabolic networks. We develop a branch-and-bound algorithm, named OPMET, to explore the search space dynamically. We also develop two filtering strategies to prune the search space while still guaranteeing an optimal solution. They compute an upper bound to the number of target compounds eliminated and a lower bound to the side-effect respectively. Our experiments on the human metabolic network demonstrate that the proposed algorithm can accurately identify the target enzymes for known successful drugs in the literature. Our experiments also show that OPMET can reduce the total search time by several orders of magnitude as compared to the exhaustive search. PMID:18229694

  7. Low density lipoproteins mediated nanoplatforms for cancer targeting

    Energy Technology Data Exchange (ETDEWEB)

    Jain, Anupriya; Jain, Keerti; Kesharwani, Prashant, E-mail: prashant_pharmacy04@rediffmail.com; Jain, Narendra K., E-mail: jnarendr@yahoo.co.in [Dr. H. S. Gour University, Pharmaceutics Research Laboratory, Department of Pharmaceutical Sciences (India)

    2013-09-15

    Chemotherapy is a foremost remedial approach for the treatment of localized and metastasized tumors. In order to explore new treatment modalities for cancer, it is important to identify qualitative or quantitative differences in metabolic processes between normal and malignant cells. One such difference may be that of increased receptor-mediated cellular uptake of low density lipoproteins (LDLs) by cancer cells. Lipoproteins in general and specifically LDL are ideal candidates for loading and delivering cancer therapeutic and diagnostic agents due to their biocompatibility. By mimicking the endogenous shape and structure of lipoproteins, the reconstituted lipoproteins can remain in circulation for an extended period of time, while largely evading the reticuloendothelial cells in the body's defenses. In this account, we review the field of low density inspired nanoparticles in relation to the delivery of cancer imaging and therapeutic agents. LDL has instinctive cancer targeting potential and has been used to incorporate various lipophillic molecules to transport them to tumors. Nature's method of rerouting LDL provides a strategy to extend the cancer targeting potential of lipoproteins far off its constricted purview. In this review, we have discussed the various aspects of LDL including its role in cancer imaging and chemotherapy in retrospect and prospect and current efforts aimed to further improve the delivery efficacy of LDL-drug complexes with reduced chances of drug resistance leading to optimal drug delivery. This review provides a strong support for the concept of using LDL as a drug carrier.

  8. Challenges of drug resistance in the management of pancreatic cancer.

    LENUS (Irish Health Repository)

    Sheikh, Rizwan

    2012-02-01

    The current treatment of choice for metastatic pancreatic cancer involves single-agent gemcitabine or a combination of gemcitabine with capecitabine or erlotinib (a tyrosine kinase inhibitor). Only 25–30% of patients respond to this treatment and patients who do respond initially ultimately exhibit disease progression. Median survival for pancreatic cancer patients has reached a plateau due to inherent and acquired resistance to these agents. Key molecular factors implicated in this resistance include: deficiencies in drug uptake, alteration of drug targets, activation of DNA repair pathways, resistance to apoptosis and the contribution of the tumor microenvironment. Moreover, for newer agents including tyrosine kinase inhibitors, overexpression of signaling proteins, mutations in kinase domains, activation of alternative pathways, mutations of genes downstream of the target and\\/or amplification of the target represent key challenges for treatment efficacy. Here we will review the contribution of known mechanisms and markers of resistance to key pancreatic cancer drug treatments.

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

    Institute of Scientific and Technical Information of China (English)

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

    2012-01-01

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

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

    OpenAIRE

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

    2012-01-01

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

  11. Cancer Phenotype Diagnosis and Drug Efficacy within Japanese Health Care

    Directory of Open Access Journals (Sweden)

    Toshihide Nishimura

    2012-01-01

    Full Text Available An overview on targeted personalized medicine is given describing the developments in Japan of lung cancer patients. These new targeted therapies with novel personalized medicine drugs require new implementations, in order to follow and monitor drug efficacy and outcome. Examples from IRESSA (Gefitinib and TARCEVA (Erlotinib treatments used in medication of lung cancer patients are presented. Lung cancer is one of the most common causes of cancer mortality in the world. The importance of both the quantification of disease progression, where diagnostic-related biomarkers are being implemented, in addition to the actual measurement of disease-specific mechanisms relating to pathway signalling activation of disease-progressive protein targets is summarised. An outline is also presented, describing changes and adaptations in Japan, meeting the rising costs and challenges. Today, urgent implementation of programs to address these needs has led to a rebuilding of the entire approach of medical evaluation and clinical care.

  12. Therapeutic Implications of Targeting Energy Metabolism in Breast Cancer

    Directory of Open Access Journals (Sweden)

    Meena K. Sakharkar

    2013-01-01

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

  13. Chemical signatures and new drug targets for gametocytocidal drug development

    Science.gov (United States)

    Sun, Wei; Tanaka, Takeshi Q.; Magle, Crystal T.; Huang, Wenwei; Southall, Noel; Huang, Ruili; Dehdashti, Seameen J.; McKew, John C.; Williamson, Kim C.; Zheng, Wei

    2014-01-01

    Control of parasite transmission is critical for the eradication of malaria. However, most antimalarial drugs are not active against P. falciparum gametocytes, responsible for the spread of malaria. Consequently, patients can remain infectious for weeks after the clearance of asexual parasites and clinical symptoms. Here we report the identification of 27 potent gametocytocidal compounds (IC50 oocyst formation in a mouse model of transmission. These results provide critical new leads and potential targets to expand the repertoire of malaria transmission-blocking reagents.

  14. Autophagy modulation as a target for anticancer drug discovery

    Institute of Scientific and Technical Information of China (English)

    Xin LI; Huai-long XU; Yong-xi LIU; Na AN; Si ZHAO; Jin-ku BAO

    2013-01-01

    Autophagy,an evolutionarily conserved catabolic process involving the engulfment and degradation of non-essential or abnormal cellular organelles and proteins,is crucial for homeostatic maintenance in living cells.This highly regulated,multi-step process has been implicated in diverse diseases including cancer.Autophagy can function as either a promoter or a suppressor of cancer,which makes it a promising and challenging therapeutic target.Herein,we overview the regulatory mechanisms and dual roles of autophagy in cancer.We also describe some of the representative agents that exert their anticancer effects by regulating autophagy.Additionally,some emerging strategies aimed at modulating autophagy are discussed as having the potential for future anticancer drug discovery.In summary,these findings will provide valuable information to better utilize autophagy in the future development of anticancer therapeutics that meet clinical requirements.

  15. Targeting of antileishmanial drugs produced by nanotechnologies

    OpenAIRE

    Pujals Naranjo, Georgina

    2007-01-01

    The aim of this work is to develop an effective new MGA delivery system by means of nanotechnology for the treatment of leishmaniosis which could be administered by parenteral or oral route in a future. Moreover, for ensuring the effectiveness of the formulations developed, their in vitro activities will be assessed against L. infantum. The intention is to prepare a target drug delivery system by means of different technological strategies like micro-nanoparticles by spray drying. These formu...

  16. Nanoparticle Based Combination Treatments for Targeting Multiple Hallmarks of Cancer

    Science.gov (United States)

    VanDyke, D; Kyriacopulos, P; Yassini, B; Wright, A; Burkhart, E; Jacek, S; Pratt, M; Peterson, CR; Rai, P

    2016-01-01

    Treatment of cancer remains one of the most challenging tasks facing the healthcare system. Cancer affects the lives of millions of people and is often fatal. Current treatment methods include surgery, chemotherapy, radiation therapies or some combinations of these. However, recurrence is a major problem. These treatments can be invasive with severe side effects. Inefficacies in treatments are a result of the complex and variable biology of cancerous cells. Malignant tumor cells and normal functioning cells share many of the same biological characteristics but the main difference is that in cancer cells there is in an overuse and over expression of these biological characteristics. These pertinent characteristics can be grouped into eight hallmarks, as illustrated by Hanahan and Weinberg. These characteristics include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, reprogramming energy metabolism, and evading immune destruction. In order to provide a noninvasive, effective treatment, delivery methods must be explored in order to transport cytotoxic agents used for targeting the hallmarks of cancer in a safer and more effective fashion. The use of nanoparticles as drug delivery carriers provides an effective method in which multiple cytotoxic agents can be safely delivered to cancer tissue to simultaneously target multiple hallmarks. By targeting multiple hallmarks of cancer at once, the efficacy of cancer treatments could be improved drastically. This review explores the uses and efficacy of combination therapies using nanoparticles that can simultaneously target multiple hallmarks of cancer. PMID:27547592

  17. Prediction of potential drug targets based on simple sequence properties

    Directory of Open Access Journals (Sweden)

    Lai Luhua

    2007-09-01

    Full Text Available Abstract Background During the past decades, research and development in drug discovery have attracted much attention and efforts. However, only 324 drug targets are known for clinical drugs up to now. Identifying potential drug targets is the first step in the process of modern drug discovery for developing novel therapeutic agents. Therefore, the identification and validation of new and effective drug targets are of great value for drug discovery in both academia and pharmaceutical industry. If a protein can be predicted in advance for its potential application as a drug target, the drug discovery process targeting this protein will be greatly speeded up. In the current study, based on the properties of known drug targets, we have developed a sequence-based drug target prediction method for fast identification of novel drug targets. Results Based on simple physicochemical properties extracted from protein sequences of known drug targets, several support vector machine models have been constructed in this study. The best model can distinguish currently known drug targets from non drug targets at an accuracy of 84%. Using this model, potential protein drug targets of human origin from Swiss-Prot were predicted, some of which have already attracted much attention as potential drug targets in pharmaceutical research. Conclusion We have developed a drug target prediction method based solely on protein sequence information without the knowledge of family/domain annotation, or the protein 3D structure. This method can be applied in novel drug target identification and validation, as well as genome scale drug target predictions.

  18. VNP: Interactive Visual Network Pharmacology of Diseases, Targets, and Drugs

    OpenAIRE

    Hu, Q-N; Deng, Z.; Tu, W; X. Yang; Meng, Z-B; Deng, Z-X; Liu, J

    2014-01-01

    In drug discovery, promiscuous targets, multifactorial diseases, and “dirty” drugs construct complex network relationships. Network pharmacology description and analysis not only give a systems-level understanding of drug action and disease complexity but can also help to improve the efficiency of target selection and drug design. Visual network pharmacology (VNP) is developed to visualize network pharmacology of targets, diseases, and drugs with a graph network by using disease, target or dr...

  19. Developing EZH2-Targeted Therapy for Lung Cancer.

    Science.gov (United States)

    Frankel, Arthur E; Liu, Xin; Minna, John D

    2016-09-01

    Epigenetic targets are exciting new avenues for cancer drug discovery. Zhang and colleagues have designed the open-source EZH2 inhibitor JQEZ5 and shown antitumor efficacy in vitro and in vivo in preclinical studies in murine and human lung adenocarcinoma models expressing high levels of EZH2. Cancer Discov; 6(9); 949-52. ©2016 AACRSee related article by Zhang and colleagues, p. 1006. PMID:27587466

  20. Current issues in the targeted therapy of advanced colorectal cancer.

    NARCIS (Netherlands)

    Knijn, N.; Tol, J.; Punt, C.J.A.

    2010-01-01

    Currently used cytotoxic drugs in the treatment of advanced colorectal cancer (ACC) are primarily the fluoropyrimidines, irinotecan, and oxaliplatin. The introduction of targeted therapy has increased the therapeutic arsenal. Two classes of monoclonal antibodies have been approved for clinical use i

  1. 针对HER2靶点的抗体药物研究与肿瘤靶向治疗%Development of antibody drugs targeting against HER2 for cancer therapy

    Institute of Scientific and Technical Information of China (English)

    汤沁; 丁倩; 林莉; 张珍珍; 代争; 詹金彪

    2012-01-01

    Human epidermal growth factor receptor 2 (HER2) belongs to the transmembrane glycoprotein receptor family. Overexpression of HER2 could directly lead to tumorigenesis and metastasis. This phenomenon could be observed in the breast cancer, ovarian cancer, gastric cancer, lung cancer and prostate cancer. Compared with the conventional chemotherapy, the targeted treatment of antibody is more specific and has lower side effects. This review describes the current status of monotherapy and combination therapies of anti-HER2 antibodies, trastuzumab and pertuzumab, with chemotherapeutic drugs. The development trends of new formats of anti-HER2 antibody drugs such as bispecific antibody, immunotoxin are also discussed.%人类表皮生长因子受体2(HER2)属于跨膜酪氨酸激酶受体家族的成员,在肿瘤细胞中存在过表达.研究显示在乳腺癌、卵巢癌、胃癌、肺癌、前列腺癌中均存在不同程度的HER2过表达.抗体靶向治疗与传统化疗相比,特异性强,毒副作用小.本文介绍了曲妥珠单抗和帕妥珠单抗的单药治疗效果和与化疗药物、激素治疗、疫苗的联合治疗效果,以及偶联药物策略,阐述了其他新型抗HER2抗体药物,特别是双特异抗体、免疫毒素以及抗体融合蛋白等研究近况,为相应的HER2抗体药物开发和临床应用提供参考.

  2. Metastatic gastric cancer – focus on targeted therapies

    Directory of Open Access Journals (Sweden)

    Meza-Junco J

    2012-06-01

    Full Text Available Judith Meza-Junco, Michael B SawyerDepartment of Oncology, Cross Cancer Institute, Edmonton, Alberta, CanadaAbstract: Gastric cancer (GC is currently the second leading cause of cancer death worldwide; unfortunately, most patients will present with locally advanced or metastatic disease. Despite recent progress in diagnosis, surgery, chemotherapy, and radiotherapy, prognosis remains poor. A better understanding of GC biology and signaling pathways is expected to improve GC therapy, and the integration of targeted therapies has recently become possible and appears to be promising. This article focuses on anti-Her-2 therapy, specifically trastuzumab, as well as other epidermal growth factor receptor antagonists such as cetuximab, panitumub, matuzumab, nimotzumab, gefitinib, and erlotinib. Additionally, drugs that target angiogenesis pathways are also under investigation, particulary bevacizumab, ramucirumab, sorafenib, sunitinib, and cediranib. Other targeted agents in preclinical or early clinical development include mTOR inhibitors, anti c-MET, polo-like kinase 1 inhibitors, anti-insulin-like growth factor, anti-heat shock proteins, and small molecules targeting Hedgehog signaling.Keywords: gastric cancer, targeted therapy, antiangiogenesis drugs, anti-EGFR drugs

  3. Exploiting novel molecular targets in gastrointestinal cancers

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Novel molecular targets are being discovered as we learn more about the aberrant processes underlying various cancers. Efforts to translate this knowledge are starting to impact on the care of patients with gastrointestinal cancers. The epidermal growth factor receptor (EGFR) pathway and angiogenesis have been targeted successfully in colorectal cancer with cetuximab, panitunumab and bevacizumab. Similarly, EGFR-targeting with erlotinib yielded significant survival benefit in pancreatic cancer when combined with gemcitabine. The multi-targeting approach with sorafenib has made it the first agent to achieve significant survival benefit in hepatocellular carcinoma. Efforts to exploit the dysregulated Akt/mTOR pathway in GI cancer therapy are ongoing. These molecular targets can be disrupted by various approaches, including the use of monoclonal antibody to intercept extracellular ligands and disrupt receptor-ligand binding, and small molecule inhibitors that interrupt the activation of intracellular kinases.

  4. Exploring a structural protein-drug interactome for new therapeutics in lung cancer.

    Science.gov (United States)

    Peng, Xiaodong; Wang, Fang; Li, Liwei; Bum-Erdene, Khuchtumur; Xu, David; Wang, Bo; Sinn, Anthony A; Pollok, Karen E; Sandusky, George E; Li, Lang; Turchi, John J; Jalal, Shadia I; Meroueh, Samy O

    2014-03-01

    The pharmacology of drugs is often defined by more than one protein target. This property can be exploited to use approved drugs to uncover new targets and signaling pathways in cancer. Towards enabling a rational approach to uncover new targets, we expand a structural protein-ligand interactome () by scoring the interaction among 1000 FDA-approved drugs docked to 2500 pockets on protein structures of the human genome. This afforded a drug-target network whose properties compared favorably with previous networks constructed using experimental data. Among drugs with the highest degree and betweenness two are cancer drugs and one is currently used for treatment of lung cancer. Comparison of predicted cancer and non-cancer targets reveals that the most cancer-specific compounds were also the most selective compounds. Analysis of compound flexibility, hydrophobicity, and size showed that the most selective compounds were low molecular weight fragment-like heterocycles. We use a previously-developed screening approach using the cancer drug erlotinib as a template to screen other approved drugs that mimic its properties. Among the top 12 ranking candidates, four are cancer drugs, two of them kinase inhibitors (like erlotinib). Cellular studies using non-small cell lung cancer (NSCLC) cells revealed that several drugs inhibited lung cancer cell proliferation. We mined patient records at the Regenstrief Medical Record System to explore the possible association of exposure to three of these drugs with occurrence of lung cancer. Preliminary in vivo studies using the non-small cell lung cancer (NCLSC) xenograft model showed that losartan- and astemizole-treated mice had tumors that weighed 50 (p < 0.01) and 15 (p < 0.01) percent less than the treated controls. These results set the stage for further exploration of these drugs and to uncover new drugs for lung cancer therapy. PMID:24402119

  5. Targeted Therapies in Epithelial Ovarian Cancer

    OpenAIRE

    Jurjees Hasan; Loaie El-Helw; Emma Dean

    2010-01-01

    Molecularly targeted therapy is relatively new to ovarian cancer despite the unquestionable success with these agents in other solid tumours such as breast and colorectal cancer. Advanced ovarian cancer is chemosensitive and patients can survive several years on treatment. However chemotherapy diminishes in efficacy over time whilst toxicities persist. Newer biological agents that target explicit molecular pathways and lack specific chemotherapy toxicities such as myelosuppression offer the a...

  6. The potential therapeutic targets for cervical cancer

    Directory of Open Access Journals (Sweden)

    L Priyanka Dwarampudi

    2013-01-01

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

  7. Cancer Stem Cells: Biological Functions and Therapeutically Targeting

    Directory of Open Access Journals (Sweden)

    Marius Eugen Ciurea

    2014-05-01

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

  8. Aptamers: Active Targeting Ligands for Cancer Diagnosis and Therapy

    OpenAIRE

    Wu, Xu; Chen, Jiao; Wu, Min; Zhao, Julia Xiaojun

    2015-01-01

    Aptamers, including DNA, RNA and peptide aptamers, are a group of promising recognition units that can specifically bind to target molecules and cells. Due to their excellent specificity and high affinity to targets, aptamers have attracted great attention in various fields in which selective recognition units are required. They have been used in biosensing, drug delivery, disease diagnosis and therapy (especially for cancer treatment). In this review, we summarized recent applications of DNA...

  9. Drug-therapy networks and the predictions of novel drug targets

    OpenAIRE

    Spiro, Zoltan; Kovacs, Istvan A.; Csermely, Peter

    2008-01-01

    Recently, a number of drug-therapy, disease, drug, and drug-target networks have been introduced. Here we suggest novel methods for network-based prediction of novel drug targets and for improvement of drug efficiency by analysing the effects of drugs on the robustness of cellular networks.

  10. Cooperative assembly in targeted drug delivery

    Science.gov (United States)

    Auguste, Debra

    2012-02-01

    Described as cell analogues, liposomes are self-assembled lipid bilayer spheres that encapsulate aqueous volumes. Liposomes offer several drug delivery advantages due to their structural versatility related to size, composition, bilayer fluidity, and ability to encapsulate a large variety of compounds non-covalently. However, liposomes lack the structural information embedded within cell membranes. Partitioning of unsaturated and saturated lipids into liquid crystalline (Lα) and gel phase (Lβ) domains, respectively, affects local molecular diffusion and elasticity. Liposome microdomains may be used to pattern molecules, such as antibodies, on the liposome surface to create concentrated, segregated binding regions. We have synthesized, characterized, and evaluated a series of homogeneous and heterogeneous liposomal vehicles that target inflamed endothelium. These drug delivery vehicles are designed to complement the heterogeneous presentation of lipids and receptors on endothelial cells (ECs). EC surfaces are dynamic; they segregate receptors within saturated lipid microdomains on the cell surface to regulate binding and signaling events. We have demonstrated that cooperative binding of two antibodies enhances targeting by multiple fold. Further, we have shown that organization of these antibodies on the surface can further enhance cell uptake. The data suggest that EC targeting may be enhanced by designing liposomes that mirror the segregated structure of lipid and receptor molecules involved in neutrophil-EC adhesion. This strategy is employed in an atherosclerotic mouse model in vivo.

  11. New Prostate Cancer Treatment Target

    Science.gov (United States)

    Researchers have identified a potential alternative approach to blocking a key molecular driver of an advanced form of prostate cancer, called androgen-independent or castration-resistant prostate cancer.

  12. Emerging migraine treatments and drug targets

    DEFF Research Database (Denmark)

    Olesen, Jes; Ashina, Messoud

    2011-01-01

    Migraine has a 1-year prevalence of 10% and high socioeconomic costs. Despite recent drug developments, there is a huge unmet need for better pharmacotherapy. In this review we discuss promising anti-migraine strategies such as calcitonin gene-related peptide (CGRP) receptor antagonists and 5......-hydroxytrypamine (5-HT)(1F) receptor agonists, which are in late-stage development. Nitric oxide antagonists are also in development. New forms of administration of sumatriptan might improve efficacy and reduce side effects. Botulinum toxin A has recently been approved for the prophylaxis of chronic migraine....... Tonabersat, a cortical spreading depression inhibitor, has shown efficacy in the prophylaxis of migraine with aura. Several new drug targets such as nitric oxide synthase, the 5-HT(1D) receptor, the prostanoid receptors EP(2) and EP(4), and the pituitary adenylate cyclase receptor PAC1 await development. The...

  13. New drugs and treatment targets in psoriasis.

    Science.gov (United States)

    Kofoed, Kristian; Skov, Lone; Zachariae, Claus

    2015-02-01

    In recent years, the increased understanding of the pathophysiology of psoriasis has resulted in several new treatments. The success of ustekinumab proved the importance of the IL-23/T helper cell 17 axis in psoriatic diseases. Several new biologics targeting this axis will reach the clinic in the next years. Biologics are costly, require injections, and some patients experience tacaphylaxis, thus, the development of orally available, small-molecule inhibitors is desirable. Among small-molecules under investigation are A3 adenosine receptor agonists, Janus kinase inhibitors, and phosphodiesterase inhibitors. We review published clinical trials, and conference abstracts presented during the last years, concerned with new drugs under development for the treatment of psoriasis. In conclusion, our psoriasis armamentarium will be filled with several new effective therapeutic options the coming years. We need to be aware of the limitations of drug safety data when selecting new novel treatments. Monitoring and clinical registries are still important tools.

  14. New Drugs and Treatment Targets in Psoriasis

    DEFF Research Database (Denmark)

    Kofoed, Kristian; Skov, Lone; Zachariae, Claus

    2015-01-01

    In recent years, the increased understanding of the pathophysiology of psoriasis has resulted in several new treatments. The success of ustekinumab proved the importance of the IL-23/T helper cell 17 axis in psoriatic diseases. Several new biologics targeting this axis will reach the clinic......, and phosphodiesterase inhibitors. We review published clinical trials, and conference abstracts presented during the last years, concerned with new drugs under development for the treatment of psoriasis. In conclusion, our psoriasis armamentarium will be filled with several new effective therapeutic options the coming...... years. We need to be aware of the limitations of drug safety data when selecting new novel treatments. Monitoring and clinical registries are still important tools....

  15. Emerging migraine treatments and drug targets

    DEFF Research Database (Denmark)

    Olesen, Jes; Ashina, Messoud

    2011-01-01

    Migraine has a 1-year prevalence of 10% and high socioeconomic costs. Despite recent drug developments, there is a huge unmet need for better pharmacotherapy. In this review we discuss promising anti-migraine strategies such as calcitonin gene-related peptide (CGRP) receptor antagonists and 5......-hydroxytrypamine (5-HT)(1F) receptor agonists, which are in late-stage development. Nitric oxide antagonists are also in development. New forms of administration of sumatriptan might improve efficacy and reduce side effects. Botulinum toxin A has recently been approved for the prophylaxis of chronic migraine....... Tonabersat, a cortical spreading depression inhibitor, has shown efficacy in the prophylaxis of migraine with aura. Several new drug targets such as nitric oxide synthase, the 5-HT(1D) receptor, the prostanoid receptors EP(2) and EP(4), and the pituitary adenylate cyclase receptor PAC1 await development...

  16. RNA Editing and Drug Discovery for Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Wei-Hsuan Huang

    2013-01-01

    Full Text Available RNA editing is vital to provide the RNA and protein complexity to regulate the gene expression. Correct RNA editing maintains the cell function and organism development. Imbalance of the RNA editing machinery may lead to diseases and cancers. Recently, RNA editing has been recognized as a target for drug discovery although few studies targeting RNA editing for disease and cancer therapy were reported in the field of natural products. Therefore, RNA editing may be a potential target for therapeutic natural products. In this review, we provide a literature overview of the biological functions of RNA editing on gene expression, diseases, cancers, and drugs. The bioinformatics resources of RNA editing were also summarized.

  17. Targeted Therapies in Epithelial Ovarian Cancer

    Directory of Open Access Journals (Sweden)

    Jurjees Hasan

    2010-02-01

    Full Text Available Molecularly targeted therapy is relatively new to ovarian cancer despite the unquestionable success with these agents in other solid tumours such as breast and colorectal cancer. Advanced ovarian cancer is chemosensitive and patients can survive several years on treatment. However chemotherapy diminishes in efficacy over time whilst toxicities persist. Newer biological agents that target explicit molecular pathways and lack specific chemotherapy toxicities such as myelosuppression offer the advantage of long-term therapy with a manageable toxicity profile enabling patients to enjoy a good quality of life. In this review we appraise the emerging data on novel targeted therapies in ovarian cancer. We discuss the role of these compounds in the front-line treatment of ovarian cancer and in relapsed disease; and describe how the development of predictive clinical, molecular and imaging biomarkers will define the role of biological agents in the treatment of ovarian cancer.

  18. Targeted Therapies in Epithelial Ovarian Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Dean, Emma; El-Helw, Loaie; Hasan, Jurjees, E-mail: jurjees.hasan@christie.nhs.uk [Christie Hospital NHS Foundation Trust / Wilmslow Road, Manchester, M20 4BX (United Kingdom)

    2010-02-23

    Molecularly targeted therapy is relatively new to ovarian cancer despite the unquestionable success with these agents in other solid tumours such as breast and colorectal cancer. Advanced ovarian cancer is chemosensitive and patients can survive several years on treatment. However chemotherapy diminishes in efficacy over time whilst toxicities persist. Newer biological agents that target explicit molecular pathways and lack specific chemotherapy toxicities such as myelosuppression offer the advantage of long-term therapy with a manageable toxicity profile enabling patients to enjoy a good quality of life. In this review we appraise the emerging data on novel targeted therapies in ovarian cancer. We discuss the role of these compounds in the front-line treatment of ovarian cancer and in relapsed disease; and describe how the development of predictive clinical, molecular and imaging biomarkers will define the role of biological agents in the treatment of ovarian cancer.

  19. Meningococcal disease and future drug targets

    DEFF Research Database (Denmark)

    Colding, Hanne; Hartzen, S H; Penkowa, Milena;

    2011-01-01

    recent data and current knowledge on molecular mechanisms of meningococcal disease and explains how host immune responses ultimately may aggravate neuropathology and the clinical prognosis. Within this context, particular importance is paid to the endotoxic components that provide potential drug targets......Neisseria meningitidis (N. meningitidis) causes sepsis, epidemic meningitis, and sometimes also meningoencephalitis. Despite early antibiotic treatment, mortality and morbidity remain significant. We present recent studies on meningococcal disease with focus on the pathophysiology caused......-host interactions are key determinants of the clinical course and risk of fatal outcome. Accordingly, successful treatment of severe meningococcal disease requires not only antibiotics but also adjuvants targeting the released endotoxins and the host immune/inflammatory responses. This review highlights the most...

  20. Janus "nano-bullets" for magnetic targeting liver cancer chemotherapy.

    Science.gov (United States)

    Shao, Dan; Li, Jing; Zheng, Xiao; Pan, Yue; Wang, Zheng; Zhang, Ming; Chen, Qi-Xian; Dong, Wen-Fei; Chen, Li

    2016-09-01

    Tumor-targeted delivery of anti-cancer drugs with controlled drug release function has been recognized as a promising strategy for pursuit of increased chemotherapeutic efficacy and reduced adverse effects. Development of magnetic nanoparticulates as delivery carriers to accommodate cytotoxic drugs for liver cancer treatment has evoked immense interest with respect to their convenience in biomedical application. Herein, we engineered multifunctional Janus nanocomposites, characterized by a head of magnetic Fe3O4 and a body of mesoporous SiO2 containing doxorubicin (DOX) as "nano-bullets" (M-MSNs-DOX). This nanodrug formulation possessed nanosize with controlled aspect-ratio, defined abundance in pore structures, and superior magnetic properties. M-MSN-DOX was determined to induce selective growth inhibition to the cancer cell under magnetic field rather than human normal cells due to its preferable endocytosis by the tumor cells and pH-promoted DOX release in the interior of cancer cells. Ultimately, both subcutaneous and orthotropic liver tumor models in mice have demonstrated that the proposed Janus nano-bullets imposed remarkable suppression of the tumor growth and significantly reduced systematic toxicity. Taken together, this study demonstrates an intriguing targeting strategy for liver cancer treatment based on a novel Janus nano-bullet, aiming for utilization of nanotechnology to obtain safe and efficient treatment of liver cancer.

  1. Janus "nano-bullets" for magnetic targeting liver cancer chemotherapy.

    Science.gov (United States)

    Shao, Dan; Li, Jing; Zheng, Xiao; Pan, Yue; Wang, Zheng; Zhang, Ming; Chen, Qi-Xian; Dong, Wen-Fei; Chen, Li

    2016-09-01

    Tumor-targeted delivery of anti-cancer drugs with controlled drug release function has been recognized as a promising strategy for pursuit of increased chemotherapeutic efficacy and reduced adverse effects. Development of magnetic nanoparticulates as delivery carriers to accommodate cytotoxic drugs for liver cancer treatment has evoked immense interest with respect to their convenience in biomedical application. Herein, we engineered multifunctional Janus nanocomposites, characterized by a head of magnetic Fe3O4 and a body of mesoporous SiO2 containing doxorubicin (DOX) as "nano-bullets" (M-MSNs-DOX). This nanodrug formulation possessed nanosize with controlled aspect-ratio, defined abundance in pore structures, and superior magnetic properties. M-MSN-DOX was determined to induce selective growth inhibition to the cancer cell under magnetic field rather than human normal cells due to its preferable endocytosis by the tumor cells and pH-promoted DOX release in the interior of cancer cells. Ultimately, both subcutaneous and orthotropic liver tumor models in mice have demonstrated that the proposed Janus nano-bullets imposed remarkable suppression of the tumor growth and significantly reduced systematic toxicity. Taken together, this study demonstrates an intriguing targeting strategy for liver cancer treatment based on a novel Janus nano-bullet, aiming for utilization of nanotechnology to obtain safe and efficient treatment of liver cancer. PMID:27258482

  2. Drug delivery with carbon nanotubes for in vivo cancer treatment

    OpenAIRE

    Liu, Zhuang; Chen, Kai; Davis, Corrine; Sherlock, Sarah; Cao, Qizhen; Chen, Xiaoyuan; Dai, Hongjie

    2008-01-01

    Chemically functionalized single-walled carbon nanotubes (SWNTs) have shown promise in tumor targeted accumulation in mice and exhibit biocompatibility, excretion and little toxicity. Here, we demonstrate in-vivo SWNT drug delivery for tumor suppression in mice. We conjugate paclitaxel (PTX), a widely used cancer chemotherapy drug to branched polyethylene-glycol (PEG) chains on SWNTs via a cleavable ester bond to obtain a water soluble SWNT-paclitaxel conjugate (SWNT-PTX). SWNT-PTX affords hi...

  3. Reactive Oxygen Species and Targeted Therapy for Pancreatic Cancer

    Directory of Open Access Journals (Sweden)

    Lun Zhang

    2016-01-01

    Full Text Available Pancreatic cancer is the fourth leading cause of cancer-related death in the United States. Reactive oxygen species (ROS are generally increased in pancreatic cancer cells compared with normal cells. ROS plays a vital role in various cellular biological activities including proliferation, growth, apoptosis, and invasion. Besides, ROS participates in tumor microenvironment orchestration. The role of ROS is a doubled-edged sword in pancreatic cancer. The dual roles of ROS depend on the concentration. ROS facilitates carcinogenesis and cancer progression with mild-to-moderate elevated levels, while excessive ROS damages cancer cells dramatically and leads to cell death. Based on the recent knowledge, either promoting ROS generation to increase the concentration of ROS with extremely high levels or enhancing ROS scavenging ability to decrease ROS levels may benefit the treatment of pancreatic cancer. However, when faced with oxidative stress, the antioxidant programs of cancer cells have been activated to help cancer cells to survive in the adverse condition. Furthermore, ROS signaling and antioxidant programs play the vital roles in the progression of pancreatic cancer and in the response to cancer treatment. Eventually, it may be the novel target for various strategies and drugs to modulate ROS levels in pancreatic cancer therapy.

  4. Self-Assembling Peptide Amphiphiles for Targeted Drug Delivery

    Science.gov (United States)

    Moyer, Tyson

    The systemic delivery of therapeutics is currently limited by off-target side effects and poor drug uptake into the cells that need to be treated. One way to circumvent these issues is to target the delivery and release of therapeutics to the desired location while limiting systemic toxicity. Using self-assembling peptide amphiphiles (PAs), this work has investigated supramolecular nanostructures for the development of targeted therapies. Specifically, the research has focused on the interrelationships between presentation of targeting moeities and the control of nanostructure morphology in the context of systemic delivery for targeting cancer and vascular injuries. The self-assembly region of the PA was systematically altered to achieve control of nanostructure widths, from 100 nm to 10 nm, by the addition of valine-glutamic acid dimers into the chemical structure, subsequently increasing the degree of nanostructure twist. For the targeting of tumors, a homing PA was synthesized to include a dimeric, cyclic peptide sequence known to target the cancer-specific, death receptor 5 (DR5) and initiate apoptosis through the oligomerization of DR5. This PA presented a multivalent display of DR5-binding peptides, resulting in improved binding affinity measured by surface plasmon resonance. The DR5-targeting PA also showed enhanced efficacy in both in vitro and in vivo tumor models relative to non-targeted controls. Alternative modifications to the PA-based antitumor therapies included the use of a cytotoxic, membrane-lytic PA coassembled with a pegylated PA, which showed enhanced biodistribution and in vivo activity after coassembly. The functionalization of the hydrophobic core was also accomplished through the encapsulation of the chemotherapy camptothecin, which was shown to be an effective treatment in vivo. Additionally, a targeted PA nanostructure was designed to bind to the site of vascular intervention by targeting collagen IV. Following balloon angioplasty

  5. 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

  6. Stereotactic radiosurgery: a "targeted" therapy for cancer

    Institute of Scientific and Technical Information of China (English)

    Ming Zeng; Liang-Fu Han

    2012-01-01

    The developments of medicine always follow innovations in science and technology.In the past decade,such innovations have made cancer-related targeted therapies possible.In general,the term "targeted therapy" has been used in reference to cellular and molecular level oriented therapies.However,improvements in the delivery and planning of traditional radiation therapy have also provided cancer patients more options for "targeted" treatment,notably stereotactic radiosurgery (SRS) and stereotactic body radiotherapy (SBRT).In this review,the progress and controversies of SRS and SBRT are discussed to show the role of stereotactic radiation therapy in the ever evolving multidisciplinary care of cancer patients.

  7. Molecular markers and targets for colorectal cancer prevention

    Institute of Scientific and Technical Information of China (English)

    Naveena B JANAKIRAM; Chinthalapally V RAO

    2008-01-01

    Colorectal cancer is the third most prevalent cancer in the world. If detected at an early stage, treatment often might lead to cure. As prevention is better than cure, epidemiological studies reveal that having a healthy diet often protects from pro-moting/developing cancer. An important consideration in evaluating new drugs and devices is determining whether a product can effectively treat a targeted disease. There are quite a number of biomarkers making their way into clinical trials and few are awaiting the preclinical efficacy and safety results to enter into clinical trials. Researchers are facing challenges in modifying trial design and defining the right control population, validating biomarker assays from the bio-logical and analytical perspective and using biomarker data as a guideline for decision making. In spite of following all guidelines, the results are disappointing from many of the large clinical trials. To avoid these disappointments, selection of biomarkers and its target drug needs to be evaluated in appropriate animal models for its toxicities and efficacies. The focus of this review is on the few of the potential molecular targets and their biomarkers in colorectal cancers. Strengths and limitations of biomarkers/surrogate endpoints are also discussed. Various pathways involved in tumor cells and the specific agents to target the altered molecular biomarkerin biomolecular pathwayare elucidated. Importance of emerging new platforms siRNAs and miRNAs technology for colorectal cancer therapeutics is reviewed.

  8. Decorating Nanoparticle Surface for Targeted Drug Delivery: Opportunities and Challenges

    Directory of Open Access Journals (Sweden)

    Zhiqiang Shen

    2016-03-01

    Full Text Available The size, shape, stiffness (composition and surface properties of nanoparticles (NPs have been recognized as key design parameters for NP-mediated drug delivery platforms. Among them, the surface functionalization of NPs is of great significance for targeted drug delivery. For instance, targeting moieties are covalently coated on the surface of NPs to improve their selectively and affinity to cancer cells. However, due to a broad range of possible choices of surface decorating molecules, it is difficult to choose the proper one for targeted functions. In this work, we will review several representative experimental and computational studies in selecting the proper surface functional groups. Experimental studies reveal that: (1 the NPs with surface decorated amphiphilic polymers can enter the cell interior through penetrating pathway; (2 the NPs with tunable stiffness and identical surface chemistry can be selectively accepted by the diseased cells according to their stiffness; and (3 the NPs grafted with pH-responsive polymers can be accepted or rejected by the cells due to the local pH environment. In addition, we show that computer simulations could be useful to understand the detailed physical mechanisms behind these phenomena and guide the design of next-generation NP-based drug carriers with high selectivity, affinity, and low toxicity. For example, the detailed free energy analysis and molecular dynamics simulation reveals that amphiphilic polymer-decorated NPs can penetrate into the cell membrane through the “snorkeling” mechanism, by maximizing the interaction energy between the hydrophobic ligands and lipid tails. We anticipate that this work will inspire future studies in the design of environment-responsive NPs for targeted drug delivery.

  9. Targeted Tumor Therapy with "Magnetic Drug Targeting": Therapeutic Efficacy of Ferrofluid Bound Mitoxantrone

    Science.gov (United States)

    Alexiou, Ch.; Schmid, R.; Jurgons, R.; Bergemann, Ch.; Arnold, W.; Parak, F.G.

    The difference between success or failure of chemotherapy depends not only on the drug itself but also on how it is delivered to its target. Biocompatible ferrofluids (FF) are paramagnetic nanoparticles, that may be used as a delivery system for anticancer agents in locoregional tumor therapy, called "magnetic drug targeting". Bound to medical drugs, such magnetic nanoparticles can be enriched in a desired body compartment (tumor) using an external magnetic field, which is focused on the area of the tumor. Through this form of target directed drug application, one attempts to concentrate a pharmacological agent at its site of action in order to minimize unwanted side effects in the organism and to increase its locoregional effectiveness. Tumor bearing rabbits (VX2 squamous cell carcinoma) in the area of the hind limb, were treated by a single intra-arterial injection (A. femoralis) of mitoxantrone bound ferrofluids (FF-MTX), while focusing an external magnetic field (1.7 Tesla) onto the tumor for 60 minutes. Complete tumor remissions could be achieved in these animals in a dose related manner (20% and 50% of the systemic dose of mitoxantrone), without any negative side effects, like e.g. leucocytopenia, alopecia or gastrointestinal disorders. The strong and specific therapeutic efficacy in tumor treatment with mitoxantrone bound ferrofluids may indicate that this system could be used as a delivery system for anticancer agents, like radionuclids, cancer-specific antibodies, anti-angiogenetic factors, genes etc.

  10. Targeting the Checkpoint to Kill Cancer Cells

    Directory of Open Access Journals (Sweden)

    Jan Benada

    2015-08-01

    Full Text Available Cancer treatments such as radiotherapy and most of the chemotherapies act by damaging DNA of cancer cells. Upon DNA damage, cells stop proliferation at cell cycle checkpoints, which provides them time for DNA repair. Inhibiting the checkpoint allows entry to mitosis despite the presence of DNA damage and can lead to cell death. Importantly, as cancer cells exhibit increased levels of endogenous DNA damage due to an excessive replication stress, inhibiting the checkpoint kinases alone could act as a directed anti-cancer therapy. Here, we review the current status of inhibitors targeted towards the checkpoint effectors and discuss mechanisms of their actions in killing of cancer cells.

  11. Challenges and limitations of targeting cancer stem cells and/or the tumour microenvironment

    Directory of Open Access Journals (Sweden)

    Juan Sebastian Yakisich

    2012-05-01

    Full Text Available The existence of cancer cells with stem cell properties (Cancer Stem Cells, CSCs and their association with tumor resistance and relapse has led to the search for active compounds to eliminate these cells or modulate their stemness in the hope of curing cancer. So far, three classes of drugs that target cancer stemness (Stemness Modulator Drugs have been identified: i drugs that selectively eliminate CSCs (stem cell targeting drugs; ii drugs that decrease stemness (stemness inhibitor drugs; and iii drugs that promote stemness (stemness promoting drugs. In addition, microenvironment modulating drugs aimed at selectively targeting the stem cell niche are being investigated and may represent an important class of drug for cancer therapy. This article will briefly review the current use of these substances and discuss the potential outcomes, challenges and limitations of treatment modalities using these classes of drugs for cancer treatment. Finally, a modular tumor model will be proposed as a guide to integrate our knowledge on the biology of cancer stem cell with that of the tumor microenvironment to promote a more rational development of anticancer therapy.

  12. The hydrogenosome as a drug target.

    Science.gov (United States)

    Benchimol, Marlene

    2008-01-01

    Hydrogenosomes are spherical or slightly elongated organelles found in non-mitochondrial organisms. In Trichomonas hydrogenosomes measure between 200 to 500 nm, but under drug treatment they can reach 2 microm. Like mitochondria hydrogenosomes: (1) are surrounded by two closely apposed membranes and present a granular matrix: (2) divide in three different ways: segmentation, partition and the heart form; (3) they may divide at any phase of the cell cycle; (4) produce ATP; (5) participate in the metabolism of pyruvate formed during glycolysis; (6) are the site of molecular hydrogen formation; (7) present a relationship with the endoplasmic reticulum; (8) incorporate calcium; (9) import proteins post-translationally; (10) present cardiolipin. However, there are differences, such as: (1) absence of genetic material, at least in trichomonas; (2) lack a respiratory chain and cytochromes; (3) absence of the F(0)-F(1) ATPase; (4) absence of the tricarboxylic acid cycle; (5) lack of oxidative phosphorylation; (6) presence of peripheral vesicles. Hydrogenosomes are considered an excellent drug target since their metabolic pathway is distinct from those found in mitochondria and thus medicines directed to these organelles will probably not affect the host-cell. The main drug used against trichomonads is metronidazole, although other drugs such as beta-Lapachone, colchicine, Taxol, nocodazole, griseofulvin, cytochalasins, hydroxyurea, among others, have been used in trichomonad studies, showing: (1) flagella internalization forming pseudocyst; (2) dysfunctional hydrogenosomes; (3) hydrogenosomes with abnormal sizes and shapes and with an electron dense deposit called nucleoid; (4) intense autophagy in which hydrogenosomes are removed and further digested in lysosomes. PMID:18473836

  13. Targeting Radiotherapy to Cancer by Gene Transfer

    OpenAIRE

    R. J. Mairs; Boyd, M.

    2003-01-01

    Targeted radionuclide therapy is an alternative method of radiation treatment which uses a tumor-seeking agent carrying a radioactive atom to deposits of tumor, wherever in the body they may be located. Recent experimental data signifies promise for the amalgamation of gene transfer with radionuclide targeting. This review encompasses aspects of the integration of gene manipulation and targeted radiotherapy, highlighting the possibilities of gene transfer to assist the targeting of cancer ...

  14. Drug target mining and analysis of the Chinese tree shrew for pharmacological testing.

    Directory of Open Access Journals (Sweden)

    Feng Zhao

    Full Text Available The discovery of new drugs requires the development of improved animal models for drug testing. The Chinese tree shrew is considered to be a realistic candidate model. To assess the potential of the Chinese tree shrew for pharmacological testing, we performed drug target prediction and analysis on genomic and transcriptomic scales. Using our pipeline, 3,482 proteins were predicted to be drug targets. Of these predicted targets, 446 and 1,049 proteins with the highest rank and total scores, respectively, included homologs of targets for cancer chemotherapy, depression, age-related decline and cardiovascular disease. Based on comparative analyses, more than half of drug target proteins identified from the tree shrew genome were shown to be higher similarity to human targets than in the mouse. Target validation also demonstrated that the constitutive expression of the proteinase-activated receptors of tree shrew platelets is similar to that of human platelets but differs from that of mouse platelets. We developed an effective pipeline and search strategy for drug target prediction and the evaluation of model-based target identification for drug testing. This work provides useful information for future studies of the Chinese tree shrew as a source of novel targets for drug discovery research.

  15. UK partnership targets lung cancer.

    Science.gov (United States)

    2014-07-01

    Cancer Research UK has joined with two major pharmaceutical companies to launch a large multiarm clinical trial, dubbed the National Lung Matrix trial, to test the effectiveness of promising experimental therapies in treating rare forms of advanced lung cancer. PMID:25002593

  16. Targeted treatment of advanced and metastatic breast cancer with lapatinib

    Directory of Open Access Journals (Sweden)

    Brendan Corkery

    2008-09-01

    Full Text Available Brendan Corkery1,2, Norma O’Donovan2, John Crown1,21St. Vincent’s University Hospital, Dublin, Ireland; 2National Institute for Cellular Biotechnology, Dublin City University, Dublin, IrelandAbstract: Improved molecular understanding of breast cancer in recent years has led to the discovery of important drug targets such as HER-2 and EGFR. Lapatinib is a potent dual inhibitor of HER-2 and EGFR. Preclinical and phase I studies have shown activity with lapatinib in a number of cancers, including breast cancer, and the drug is well tolerated. The main known drug interactions are with paclitaxel and irinotecan. The most significant side-effects of lapatinib are diarrhea and adverse skin events. Rates of cardiotoxicity compare favorably with trastuzumab, a monoclonal antibody against HER-2. This paper focuses on lapatinib in advanced and metastatic breast cancer, which remains an important therapeutic challenge. Phase II and III studies show activity as monotherapy, and in combination with chemotherapy or hormonal agents. Results from these studies suggest that the main benefit from lapatinib is in the HER-2 positive breast cancer population. Combinations of lapatinib and trastuzumab are also being studied and show encouraging results, particularly in trastuzumab-refractory metastatic breast cancer. Lapatinib may have a specific role in treating HER-2 positive CNS metastases. The role of lapatinib as neoadjuvant therapy and in early breast cancer is also being evaluated.Keywords: HER-2, EGFR, erbB, lapatinib, Tykerb®, tyrosine kinase

  17. Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission

    OpenAIRE

    Hirsch, Heather A; Iliopoulos, Dimitrios; Tsichlis, Philip N.; Struhl, Kevin

    2009-01-01

    The cancer stem cell hypothesis suggests that, unlike most cancer cells within a tumor, cancer stem cells resist chemotherapeutic drugs and can regenerate the various cell types in the tumor, thereby causing relapse of the disease. Thus, drugs that selectively target cancer stem cells offer great promise for cancer treatment, particularly in combination with chemotherapy. Here, we show that low doses of metformin, a standard drug for diabetes, inhibits cellular transformation and selectively ...

  18. Combining chemotherapy and targeted therapies in metastatic colorectal cancer

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Colorectal cancer remains one of the major causes of cancer death worldwide. During the past years, the development of new effective treatment options has led to a considerable improvement in the outcome of this disease. The advent of agents such as capecitabine, irinotecan, oxaliplatin, cetuximab and bevacizumab has translated into median survival times in the range of 2 years. Intense efforts have focused on identifying novel agents targeting specific growth factor receptors, critical signal transduction pathways or mediators of angiogenesis. In addition, several clinical trials have suggested that some of these molecularly targeted drugs can be safely and effectively used in combination with conventional chemotherapy. In this article we review various treatment options combining cytotoxic and targeted therapies currently available for patients with metastatic colorectal cancer.

  19. Application of phage display technology in targeted therapy of breast cancer

    Institute of Scientific and Technical Information of China (English)

    Mian Kong; Junye Wang; Baojiang Li

    2013-01-01

    Phage display is a technology of gene expression and screening, it is widely used in the fields of defining antigenepitopes, signal transduction, genetic treatment, parasites research and tumor targeted therapy. Breast cancer is the mostcommon cancer in women, we can obtain peptides specially associated with breast cancer by using phage display technology,and this method has great potential in early diagnosis of breast cancer and development new targeted drugs.

  20. Multi-Target Drugs: The Trend of Drug Research and Development

    OpenAIRE

    Jin-Jian Lu; Wei Pan; Yuan-Jia Hu; Yi-Tao Wang

    2012-01-01

    Summarizing the status of drugs in the market and examining the trend of drug research and development is important in drug discovery. In this study, we compared the drug targets and the market sales of the new molecular entities approved by the U.S. Food and Drug Administration from January 2000 to December 2009. Two networks, namely, the target-target and drug-drug networks, have been set up using the network analysis tools. The multi-target drugs have much more potential, as shown by the n...

  1. [Development of molecular targeted therapies in lung cancers].

    Science.gov (United States)

    Suda, Kenichi; Mitsudomi, Tetsuya

    2014-05-01

    Human cancers usually possess cumulative genetic aberrations. However, recent studies have revealed that the proliferation and survival of specific subsets of lung cancer depend on a few somatic mutation(s), so-called driver mutations. Representative driver mutations include the EGFR mutation and ALK translocation identified in about 40% and 3% of lung adenocarcinomas in Japan, respectively. These tumors are extremely sensitive to the respective tyrosine kinase inhibitors. This sensitivity has encouraged researchers and clinicians to explore novel driver mutations in lung cancers as future molecular targets. Driver mutations reported so far include the HER2 mutation, BRAF mutation, ROS1 translocation, RET translocation, and NTRK translocation in lung adenocarcinomas, and FGFR1 amplification, DDR2 mutation, and FGFR3 translocation in lung squamous cell carcinomas. However, despite initial dramatic responses, the acquisition of resistance to molecular targeted drugs is almost inevitable. Overcoming resistance to molecular targeted drugs, the key drugs at this time, is an urgent issue to improve the outcomes of lung cancer patients. PMID:24946519

  2. Improving the pH-response of pHLIP insertion at tumor acidity for targeted drug delivery against cancer: Biophysical studies in model membranes and evaluations in cells

    Science.gov (United States)

    Onyango, Joab Otieno

    pH (Low) Insertion Peptide (pHLIP) possesses unique qualities that can be applied in cancer biology. It is a peptide that lives in three worlds: In State I, pHLIP exists as an unstructured monomer in solution at neutral pH; In State II, pHLIP partitions to the surface of a lipid bilayer at neutral pH; In State III, pHLIP inserts across the lipid bilayer by forming a transmembrane (TM) alpha helix under slightly acidic conditions (pH 6). These properties allow pHLIP to target acidosis (pH 6.5-7.0), a ubiquitous feature of solid tumors. Although pHLIP shows promise as a drug delivery vehicle, insertion properties such as pH50 (i.e. the pH at which 50% of pHLIP are inserted) and Hill coefficient must be tuned to improve tumor targeting and drug delivery in vivo. When TM region D14 and D25 residues were replaced with two glutamic acid residues as well as noncanonical amino acids such as alpha amino adipic acid (Aad) and gamma carboxyglutamic acid (Gla), we discovered pHLIP variants that possess a pH50 that can match tumor extracellular pH. pHLIP variants D25EE, Asp25Aad, and Asp14Gla/Asp25Aad, insert with pH50 of 6.60, 6.74, and 6.79, respectively. We also tuned pH-response (cooperativity of insertion) and we found that the Asp14Gla variant can insert into membrane with the sharpest transition observed so far for a pHLIP (i.e. over half pH unit vs. one pH unit for WT). Furthermore, we used turn-on fluorescence to evaluate the new variants in cancer cells. The most promising Asp25Aad pHLIP gave near theoretical maximum level of dequenching in cancerous A549 cells at pH 6.2 and 6.4, indicating a high level of plasma-membrane insertion. Under the same conditions, the `WT' and D25E pHLIP variants have low levels of plasma-membrane insertion in cells. Dequenching levels were low in non-cancerous HK2 cell line.

  3. 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...

  4. The drug target genes show higher evolutionary conservation than non-target genes.

    Science.gov (United States)

    Lv, Wenhua; Xu, Yongdeng; Guo, Yiying; Yu, Ziqi; Feng, Guanglong; Liu, Panpan; Luan, Meiwei; Zhu, Hongjie; Liu, Guiyou; Zhang, Mingming; Lv, Hongchao; Duan, Lian; Shang, Zhenwei; Li, Jin; Jiang, Yongshuai; Zhang, Ruijie

    2016-01-26

    Although evidence indicates that drug target genes share some common evolutionary features, there have been few studies analyzing evolutionary features of drug targets from an overall level. Therefore, we conducted an analysis which aimed to investigate the evolutionary characteristics of drug target genes. We compared the evolutionary conservation between human drug target genes and non-target genes by combining both the evolutionary features and network topological properties in human protein-protein interaction network. The evolution rate, conservation score and the percentage of orthologous genes of 21 species were included in our study. Meanwhile, four topological features including the average shortest path length, betweenness centrality, clustering coefficient and degree were considered for comparison analysis. Then we got four results as following: compared with non-drug target genes, 1) drug target genes had lower evolutionary rates; 2) drug target genes had higher conservation scores; 3) drug target genes had higher percentages of orthologous genes and 4) drug target genes had a tighter network structure including higher degrees, betweenness centrality, clustering coefficients and lower average shortest path lengths. These results demonstrate that drug target genes are more evolutionarily conserved than non-drug target genes. We hope that our study will provide valuable information for other researchers who are interested in evolutionary conservation of drug targets.

  5. Aptamer conjugated paclitaxel and magnetic fluid loaded fluorescently tagged PLGA nanoparticles for targeted cancer therapy

    Energy Technology Data Exchange (ETDEWEB)

    Aravind, Athulya; Nair, Remya; Raveendran, Sreejith; Veeranarayanan, Srivani; Nagaoka, Yutaka; Fukuda, Takahiro; Hasumura, Takahashi; Morimoto, Hisao; Yoshida, Yasuhiko; Maekawa, Toru; Sakthi Kumar, D., E-mail: sakthi@toyo.jp

    2013-10-15

    Controlled and targeted drug delivery is an essential criterion in cancer therapy to reduce the side effects caused by non-specific drug release and toxicity. Targeted chemotherapy, sustained drug release and optical imaging have been achieved using a multifunctional nanocarrier constructed from poly (D, L-lactide-co-glycolide) nanoparticles (PLGA NPs), an anticancer drug paclitaxel (PTX), a fluorescent dye Nile red (NR), magnetic fluid (MF) and aptamers (Apt, AS1411, anti-nucleolin aptamer). The magnetic fluid and paclitaxel loaded fluorescently labeled PLGA NPs (MF-PTX-NR-PLGA NPs) were synthesized by a single-emulsion technique/solvent evaporation method using a chemical cross linker bis (sulfosuccinimidyl) suberate (BS3) to enable binding of aptamer on to the surface of the nanoparticles. Targeting aptamers were then introduced to the particles through the reaction with the cross linker to target the nucleolin receptors over expressed on the cancer cell surface. Specific binding and uptake of the aptamer conjugated magnetic fluid loaded fluorescently tagged PLGA NPs (Apt-MF-NR-PLGA NPs) to the target cancer cells induced by aptamers was observed using confocal microscopy. Cytotoxicity assay conducted in two cell lines (L929 and MCF-7) confirmed that targeted MCF-7 cancer cells were killed while control cells were unharmed. In addition, aptamer mediated delivery resulting in enhanced binding and uptake to the target cancer cells exhibited increased therapeutic effect of the drug. Moreover, these aptamer conjugated magnetic polymer vehicles apart from actively transporting drugs into specifically targeted tumor regions can also be used to induce hyperthermia or for facilitating magnetic guiding of particles to the tumor regions. - Highlights: • Aptamer escorted, theranostic biodegradable PLGA carriers were developed. • Can target cancer cells, control drug release, image and magnetically guide. • Highly specific to the targeted cancer cells thus delivering

  6. Context Sensitive Modeling of Cancer Drug Sensitivity

    Science.gov (United States)

    Chen, Bo-Juen; Litvin, Oren; Ungar, Lyle; Pe’er, Dana

    2015-01-01

    Recent screening of drug sensitivity in large panels of cancer cell lines provides a valuable resource towards developing algorithms that predict drug response. Since more samples provide increased statistical power, most approaches to prediction of drug sensitivity pool multiple cancer types together without distinction. However, pan-cancer results can be misleading due to the confounding effects of tissues or cancer subtypes. On the other hand, independent analysis for each cancer-type is hampered by small sample size. To balance this trade-off, we present CHER (Contextual Heterogeneity Enabled Regression), an algorithm that builds predictive models for drug sensitivity by selecting predictive genomic features and deciding which ones should—and should not—be shared across different cancers, tissues and drugs. CHER provides significantly more accurate models of drug sensitivity than comparable elastic-net-based models. Moreover, CHER provides better insight into the underlying biological processes by finding a sparse set of shared and type-specific genomic features. PMID:26274927

  7. Context Sensitive Modeling of Cancer Drug Sensitivity.

    Directory of Open Access Journals (Sweden)

    Bo-Juen Chen

    Full Text Available Recent screening of drug sensitivity in large panels of cancer cell lines provides a valuable resource towards developing algorithms that predict drug response. Since more samples provide increased statistical power, most approaches to prediction of drug sensitivity pool multiple cancer types together without distinction. However, pan-cancer results can be misleading due to the confounding effects of tissues or cancer subtypes. On the other hand, independent analysis for each cancer-type is hampered by small sample size. To balance this trade-off, we present CHER (Contextual Heterogeneity Enabled Regression, an algorithm that builds predictive models for drug sensitivity by selecting predictive genomic features and deciding which ones should-and should not-be shared across different cancers, tissues and drugs. CHER provides significantly more accurate models of drug sensitivity than comparable elastic-net-based models. Moreover, CHER provides better insight into the underlying biological processes by finding a sparse set of shared and type-specific genomic features.

  8. A RNA-DNA Hybrid Aptamer for Nanoparticle-Based Prostate Tumor Targeted Drug Delivery

    Directory of Open Access Journals (Sweden)

    John C. Leach

    2016-03-01

    Full Text Available The side effects of radio- and chemo-therapy pose long-term challenges on a cancer patient’s health. It is, therefore, highly desirable to develop more effective therapies that can specifically target carcinoma cells without damaging normal and healthy cells. Tremendous efforts have been made in the past to develop targeted drug delivery systems for solid cancer treatment. In this study, a new aptamer, A10-3-J1, which recognizes the extracellular domain of the prostate specific membrane antigen (PSMA, was designed. A super paramagnetic iron oxide nanoparticle-aptamer-doxorubicin (SPIO-Apt-Dox was fabricated and employed as a targeted drug delivery platform for cancer therapy. This DNA RNA hybridized aptamer antitumor agent was able to enhance the cytotoxicity of targeted cells while minimizing collateral damage to non-targeted cells. This SPIO-Apt-Dox nanoparticle has specificity to PSMA+ prostate cancer cells. Aptamer inhibited nonspecific uptake of membrane-permeable doxorubic to the non-target cells, leading to reduced untargeted cytotoxicity and endocytic uptake while enhancing targeted cytotoxicity and endocytic uptake. The experimental results indicate that the drug delivery platform can yield statistically significant effectiveness being more cytotoxic to the targeted cells as opposed to the non-targeted cells.

  9. A RNA-DNA Hybrid Aptamer for Nanoparticle-Based Prostate Tumor Targeted Drug Delivery

    Science.gov (United States)

    Leach, John C.; Wang, Andrew; Ye, Kaiming; Jin, Sha

    2016-01-01

    The side effects of radio- and chemo-therapy pose long-term challenges on a cancer patient’s health. It is, therefore, highly desirable to develop more effective therapies that can specifically target carcinoma cells without damaging normal and healthy cells. Tremendous efforts have been made in the past to develop targeted drug delivery systems for solid cancer treatment. In this study, a new aptamer, A10-3-J1, which recognizes the extracellular domain of the prostate specific membrane antigen (PSMA), was designed. A super paramagnetic iron oxide nanoparticle-aptamer-doxorubicin (SPIO-Apt-Dox) was fabricated and employed as a targeted drug delivery platform for cancer therapy. This DNA RNA hybridized aptamer antitumor agent was able to enhance the cytotoxicity of targeted cells while minimizing collateral damage to non-targeted cells. This SPIO-Apt-Dox nanoparticle has specificity to PSMA+ prostate cancer cells. Aptamer inhibited nonspecific uptake of membrane-permeable doxorubic to the non-target cells, leading to reduced untargeted cytotoxicity and endocytic uptake while enhancing targeted cytotoxicity and endocytic uptake. The experimental results indicate that the drug delivery platform can yield statistically significant effectiveness being more cytotoxic to the targeted cells as opposed to the non-targeted cells. PMID:26985893

  10. THE FIRST RESULTS OF TARGETED THERAPY FOR KIDNEY CANCER IN MOSCOW

    Directory of Open Access Journals (Sweden)

    V. I. Shirokorad

    2014-07-01

    Full Text Available The paper provides the first interim analysis of a database including information on 427 metastatic kidney cancer patients receiving targeted therapy in the cancer facilities of the Moscow Healthcare Department. It shows a comparative analysis of the periods of first-line targeted therapy with different drugs until progression is established.

  11. THE FIRST RESULTS OF TARGETED THERAPY FOR KIDNEY CANCER IN MOSCOW

    Directory of Open Access Journals (Sweden)

    V. I. Shirokorad

    2013-01-01

    Full Text Available The paper provides the first interim analysis of a database including information on 427 metastatic kidney cancer patients receiving targeted therapy in the cancer facilities of the Moscow Healthcare Department. It shows a comparative analysis of the periods of first-line targeted therapy with different drugs until progression is established.

  12. Synthetic Genetic Targeting of Genome Instability in Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Sajesh, Babu V.; Guppy, Brent J.; McManus, Kirk J., E-mail: mcmanusk@cc.umanitoba.ca [Manitoba Institute of Cell Biology, Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba R3E 0V9 (Canada)

    2013-06-24

    Cancer is a leading cause of death throughout the World. A limitation of many current chemotherapeutic approaches is that their cytotoxic effects are not restricted to cancer cells, and adverse side effects can occur within normal tissues. Consequently, novel strategies are urgently needed to better target cancer cells. As we approach the era of personalized medicine, targeting the specific molecular defect(s) within a given patient’s tumor will become a more effective treatment strategy than traditional approaches that often target a given cancer type or sub-type. Synthetic genetic interactions are now being examined for their therapeutic potential and are designed to target the specific genetic and epigenetic phenomena associated with tumor formation, and thus are predicted to be highly selective. In general, two complementary approaches have been employed, including synthetic lethality and synthetic dosage lethality, to target aberrant expression and/or function associated with tumor suppressor genes and oncogenes, respectively. Here we discuss the concepts of synthetic lethality and synthetic dosage lethality, and explain three general experimental approaches designed to identify novel genetic interactors. We present examples and discuss the merits and caveats of each approach. Finally, we provide insight into the subsequent pre-clinical work required to validate novel candidate drug targets.

  13. Synthetic Genetic Targeting of Genome Instability in Cancer

    International Nuclear Information System (INIS)

    Cancer is a leading cause of death throughout the World. A limitation of many current chemotherapeutic approaches is that their cytotoxic effects are not restricted to cancer cells, and adverse side effects can occur within normal tissues. Consequently, novel strategies are urgently needed to better target cancer cells. As we approach the era of personalized medicine, targeting the specific molecular defect(s) within a given patient’s tumor will become a more effective treatment strategy than traditional approaches that often target a given cancer type or sub-type. Synthetic genetic interactions are now being examined for their therapeutic potential and are designed to target the specific genetic and epigenetic phenomena associated with tumor formation, and thus are predicted to be highly selective. In general, two complementary approaches have been employed, including synthetic lethality and synthetic dosage lethality, to target aberrant expression and/or function associated with tumor suppressor genes and oncogenes, respectively. Here we discuss the concepts of synthetic lethality and synthetic dosage lethality, and explain three general experimental approaches designed to identify novel genetic interactors. We present examples and discuss the merits and caveats of each approach. Finally, we provide insight into the subsequent pre-clinical work required to validate novel candidate drug targets

  14. Comparison of the cancer gene targeting and biochemical selectivities of all targeted kinase inhibitors approved for clinical use.

    Directory of Open Access Journals (Sweden)

    Joost C M Uitdehaag

    Full Text Available The anti-proliferative activities of all twenty-five targeted kinase inhibitor drugs that are in clinical use were measured in two large assay panels: (1 a panel of proliferation assays of forty-four human cancer cell lines from diverse tumour tissue origins; and (2 a panel of more than 300 kinase enzyme activity assays. This study provides a head-on comparison of all kinase inhibitor drugs in use (status Nov. 2013, and for six of these drugs, the first kinome profiling data in the public domain. Correlation of drug activities with cancer gene mutations revealed novel drug sensitivity markers, suggesting that cancers dependent on mutant CTNNB1 will respond to trametinib and other MEK inhibitors, and cancers dependent on SMAD4 to small molecule EGFR inhibitor drugs. Comparison of cellular targeting efficacies reveals the most targeted inhibitors for EGFR, ABL1 and BRAF(V600E-driven cell growth, and demonstrates that the best targeted agents combine high biochemical potency with good selectivity. For ABL1 inhibitors, we computationally deduce optimized kinase profiles for use in a next generation of drugs. Our study shows the power of combining biochemical and cellular profiling data in the evaluation of kinase inhibitor drug action.

  15. Identifying mechanism-of-action targets for drugs and probes.

    Science.gov (United States)

    Gregori-Puigjané, Elisabet; Setola, Vincent; Hert, Jérôme; Crews, Brenda A; Irwin, John J; Lounkine, Eugen; Marnett, Lawrence; Roth, Bryan L; Shoichet, Brian K

    2012-07-10

    Notwithstanding their key roles in therapy and as biological probes, 7% of approved drugs are purported to have no known primary target, and up to 18% lack a well-defined mechanism of action. Using a chemoinformatics approach, we sought to "de-orphanize" drugs that lack primary targets. Surprisingly, targets could be easily predicted for many: Whereas these targets were not known to us nor to the common databases, most could be confirmed by literature search, leaving only 13 Food and Drug Administration-approved drugs with unknown targets; the number of drugs without molecular targets likely is far fewer than reported. The number of worldwide drugs without reasonable molecular targets similarly dropped, from 352 (25%) to 44 (4%). Nevertheless, there remained at least seven drugs for which reasonable mechanism-of-action targets were unknown but could be predicted, including the antitussives clemastine, cloperastine, and nepinalone; the antiemetic benzquinamide; the muscle relaxant cyclobenzaprine; the analgesic nefopam; and the immunomodulator lobenzarit. For each, predicted targets were confirmed experimentally, with affinities within their physiological concentration ranges. Turning this question on its head, we next asked which drugs were specific enough to act as chemical probes. Over 100 drugs met the standard criteria for probes, and 40 did so by more stringent criteria. A chemical information approach to drug-target association can guide therapeutic development and reveal applications to probe biology, a focus of much current interest. PMID:22711801

  16. Multitask learning improves prediction of cancer drug sensitivity

    Science.gov (United States)

    Yuan, Han; Paskov, Ivan; Paskov, Hristo; González, Alvaro J.; Leslie, Christina S.

    2016-01-01

    Precision oncology seeks to predict the best therapeutic option for individual patients based on the molecular characteristics of their tumors. To assess the preclinical feasibility of drug sensitivity prediction, several studies have measured drug responses for cytotoxic and targeted therapies across large collections of genomically and transcriptomically characterized cancer cell lines and trained predictive models using standard methods like elastic net regression. Here we use existing drug response data sets to demonstrate that multitask learning across drugs strongly improves the accuracy and interpretability of drug prediction models. Our method uses trace norm regularization with a highly efficient ADMM (alternating direction method of multipliers) optimization algorithm that readily scales to large data sets. We anticipate that our approach will enhance efforts to exploit growing drug response compendia in order to advance personalized therapy. PMID:27550087

  17. Drugs Approved for Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

    Science.gov (United States)

    This page lists cancer drugs approved by the Food and Drug Administration (FDA) for ovarian cancer. The list includes generic names, brand names, and common drug combinations, which are shown in capital letters. The drug names link to NCI's Cancer Drug Information summaries.

  18. Drug-induced QT interval prolongation in cancer patients

    Directory of Open Access Journals (Sweden)

    Torben K. Becker

    2011-12-01

    Full Text Available Cancer patients are at an increased risk for QT interval prolongation and subsequent potentially fatal Torsade de pointes tachycardia due to the multiple drugs used for treatment of malignancies and the associated symptoms and complications. Based on a systematic review of the literature, this article analyzes the risk for prolongation of the QT interval with antineoplastic agents and commonly used concomitant drugs. This includes anthracyclines, fluorouracil, alkylating agents, and new molecularly targeted therapeutics, such as vascular disruption agents. Medications used in the supportive care can also prolong QT intervals, such as methadone, 5-HT3-antagonists and antihistamines, some antibiotics, antifungals, and antivirals. We describe the presumed mechanism of QT interval prolongation, drug-specific considerations, as well as important clinical interactions. Multiple risk factors and drug–drug interactions increase this risk for dangerous arrhythmias. We propose a systematic approach to evaluate cancer patients for the risk of QT interval prolongation and how to prevent adverse effects.

  19. Drug target identification using side-effect similarity

    DEFF Research Database (Denmark)

    Campillos, Monica; Kuhn, Michael; Gavin, Anne-Claude;

    2008-01-01

    Targets for drugs have so far been predicted on the basis of molecular or cellular features, for example, by exploiting similarity in chemical structure or in activity across cell lines. We used phenotypic side-effect similarities to infer whether two drugs share a target. Applied to 746 marketed...... drugs, a network of 1018 side effect-driven drug-drug relations became apparent, 261 of which are formed by chemically dissimilar drugs from different therapeutic indications. We experimentally tested 20 of these unexpected drug-drug relations and validated 13 implied drug-target relations by in vitro...... binding assays, of which 11 reveal inhibition constants equal to less than 10 micromolar. Nine of these were tested and confirmed in cell assays, documenting the feasibility of using phenotypic information to infer molecular interactions and hinting at new uses of marketed drugs....

  20. Prediction of Drug-Target Interactions for Drug Repositioning Only Based on Genomic Expression Similarity

    OpenAIRE

    Kejian Wang; Jiazhi Sun; Shufeng Zhou; Chunling Wan; Shengying Qin; Can Li; Lin He; Lun Yang

    2013-01-01

    Small drug molecules usually bind to multiple protein targets or even unintended off-targets. Such drug promiscuity has often led to unwanted or unexplained drug reactions, resulting in side effects or drug repositioning opportunities. So it is always an important issue in pharmacology to identify potential drug-target interactions (DTI). However, DTI discovery by experiment remains a challenging task, due to high expense of time and resources. Many computational methods are therefore develop...

  1. Cancer drugs inhibit morphogenesis in the human fungal pathogen, Candida albicans

    Directory of Open Access Journals (Sweden)

    Madhushree M Routh

    2013-09-01

    Full Text Available Candida infections are very common in cancer patients and it is a common practice to prescribe antifungal antibiotics along with anticancer drugs. Yeast to hyphal form switching is considered to be important in invasive candidiasis. Targeting morphogenetic switching may be useful against invasive candidiasis. In this study, we report the antimorphogenetic properties of thirty cancer drugs.

  2. Apoptosis : Target of cancer therapy

    NARCIS (Netherlands)

    Ferreira, CG; Epping, M; Kruyt, FAE; Giaccone, G

    2002-01-01

    Recent knowledge on apoptosis has made it possible to devise novel approaches, which exploit this process to treat cancer. In this review, we discuss in detail approaches to induce tumor cell apoptosis, their mechanism of action, stage of development, and possible drawbacks. Finally, the obstacles y

  3. Micro RNA, A Review: Pharmacogenomic drug targets for complex diseases

    Directory of Open Access Journals (Sweden)

    Ritesh Bajaj

    2010-01-01

    Full Text Available Micro RNAs (miRNAs are non-coding RNAs that can regulate gene expression to target several mRNAs in a gene regulatory network. MiRNA related Single Nucleotide Polymorphisms (S.N.P.s represent a newly identified type of genetic variability that can be of influence to the risk of certain human diseases and also affect how drugs can be activated and metabolized by patients. This will help in personalized medicines which are used for adminis-trating the correct dosage of drug and drug efficacy. miRNA deregulated expression has been extensively de-scribed in a variety of diseases such as Cancer, Obesity , Diabetes, Schizophrenia and control and self renewal of stem cells. MiRNA can function as oncogenes and/or tumor suppressors. MiRNAs may act as key regulators of processes as diverse as early development, cell proliferation and cell death, apoptosis and fat metabolism and cell differentiation .miRNA expression have shown their role in brain development chronic lymphocytic leukemia, colonic adeno carcinoma, Burkiff′s lymphoma and viral infection. These show their links with viral disease, neu-rodevelopment and cancer. It has been shown that they play a key role in melanoma metastasis. These may be differentially expressed in malignant cells compared to normal cells altering the regulation of expression of many important genes. MiRNA expression has been used for prognosis and early diagnosis of these complex diseases. The present paper focuses on the role of miRNAs in various complex diseases, which will help in improving the drug discovery process and personalized medicines.

  4. Identifying drug-target proteins based on network features

    Institute of Scientific and Technical Information of China (English)

    ZHU MingZhu; GAO Lei; LI Xia; LIU ZhiCheng

    2009-01-01

    Proteins rarely function in isolation Inside and outside cells, but operate as part of a highly Intercon-nected cellular network called the interaction network. Therefore, the analysis of the properties of drug-target proteins in the biological network is especially helpful for understanding the mechanism of drug action In terms of informatice. At present, no detailed characterization and description of the topological features of drug-target proteins have been available in the human protein-protein interac-tion network. In this work, by mapping the drug-targets in DrugBank onto the interaction network of human proteins, five topological indices of drug-targets were analyzed and compared with those of the whole protein interactome set and the non-drug-target set. The experimental results showed that drug-target proteins have higher connectivity and quicker communication with each other in the PPI network. Based on these features, all proteins In the interaction network were ranked. The results showed that, of the top 100 proteins, 48 are covered by DrugBank; of the remaining 52 proteins, 9 are drug-target proteins covered by the TTD, Matador and other databases, while others have been dem-onstrated to be drug-target proteins in the literature.

  5. Identifying drug-target proteins based on network features

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    Proteins rarely function in isolation inside and outside cells, but operate as part of a highly intercon- nected cellular network called the interaction network. Therefore, the analysis of the properties of drug-target proteins in the biological network is especially helpful for understanding the mechanism of drug action in terms of informatics. At present, no detailed characterization and description of the topological features of drug-target proteins have been available in the human protein-protein interac- tion network. In this work, by mapping the drug-targets in DrugBank onto the interaction network of human proteins, five topological indices of drug-targets were analyzed and compared with those of the whole protein interactome set and the non-drug-target set. The experimental results showed that drug-target proteins have higher connectivity and quicker communication with each other in the PPI network. Based on these features, all proteins in the interaction network were ranked. The results showed that, of the top 100 proteins, 48 are covered by DrugBank; of the remaining 52 proteins, 9 are drug-target proteins covered by the TTD, Matador and other databases, while others have been dem- onstrated to be drug-target proteins in the literature.

  6. Targeting prostate cancer stem cells for cancer therapy

    OpenAIRE

    Wang, Guocan; Wang, Zhiwei; Sarkar, Fazlul H; Wei, Wenyi

    2012-01-01

    Prostate cancer (PCa) is the most common malignant neoplasm in men and the second most frequent cause of cancer death for males in the United States. Recently, emerging evidence suggests that prostate cancer stem cells (CSCs) may play a critical role in the development and progression of PCa. Therefore, targeting prostate CSCs for the prevention of tumor progression and treatment of PCa could become a novel strategy for better treatment of patients diagnosed with PCa. In this review article, ...

  7. Cancer therapy leading to state of cancer metabolism depression for efficient operation of small dosage cytotoxic drugs

    Directory of Open Access Journals (Sweden)

    Ponizovskiy MR

    2015-04-01

    Full Text Available “Prolonged medical starvation” as the method of cancer therapy was borrowed from folk healers Omelchenko A and Breuss R. Author was convinced in efficiency of this method of cancer treatment via examination of cured patients and on own experience. The mechanism of this method of cancer therapy operates via Warburg effect targeting that promotes efficient cancer treatment with small cytotoxic drugs. Just it was described the mechanism of Warburg effect as well as mechanism transmutation of mitochondrial function in cancer metabolism which are exhibited in connection with operation of described method cancer therapy. There were described the biochemical and biophysical mechanisms of formations resistance to some cytotoxic drugs and recurrence cancer disease after disease remission which occur sometimes as result of treatment with great dosage of cytotoxic drugs. Also it was described the benefits of use the method “Prolonged medical starvation” with decreased dosage of cytotoxic drugs for cancer treatment. The significance of this work that it was substantiated the mechanism operation of combination “Prolonged medical starvation” with small dosages cytotoxic drugs of cancer treatment, which mechanism leads to prevention recurrence cancer disease and resistance to anticancer drugs in comparison with intensive anticancer chemotherapy with great dosages of cytotoxic drugs in cancer therapy. Also the offered concepts of cancer therapy mechanism gave possibility to explain mechanisms of some results of experiments eliminating the doubts of the authors these experiments.

  8. 靶向血管内皮生长因子及其受体的抗肿瘤药物研究进展%Anti-cancer drugs targeting vascular endothelial growth factors and receptors: research advances

    Institute of Scientific and Technical Information of China (English)

    张娜; 姚文兵; 徐晨

    2012-01-01

    Angiogenesis plays a critical rede in the process of tumor growth and metastasis, and vascular endothelial growth factor and its' receptor (VEGF/VEGFR) signaling pathway is an important mechanism of neovascularization, At present, drug inhibition of angiogenesis has become a significant research topic and a variety of anti-angiogenesis agents aimed at blocking VECF or its receptor-signaling system have been marketed or issued to the clinical trials. The main purpose of this review is to summarize the available information regarding the importance of VEGF/VEGFR in cancer therapy, with a focus on the latest development, clinical use and challenges of the anti-cancer drugs targeting VEGF/VEGFR.%血管生成对肿瘤的生长和转移起着关键作用,血管内皮生长因子(VEGF)及其受体信号通路是调节肿瘤新生血管生成的重要途径,因此,近年来以VEGF及其受体为作用靶标的抗肿瘤血管生成治疗已经成为研究热点,目前已有多种药物上市或处于临床试验阶段.本文主要综述了VEGF及其受体在肿瘤血管生成调节机制中的作用,同时着重介绍靶向VEGF及其受体的抗肿瘤药物的新近研究进展、临床应用及存在的问题.

  9. Strategic development on generic anti-cancer drugs Bevacizumab and Erlotinib Hydrochloride for Harbin Pharmaceutical Group

    Institute of Scientific and Technical Information of China (English)

    Cheung Fat Ping

    2011-01-01

    @@ With improved economy, changing life styles, aging population and health care reform, China had a very potential anti-cancer drug market.The patents of popular anti-cancer drugs Avastin and Tarceva would expire in few years.Generic versions of Avastin and Tarceva were Bevacizumab and Erlotinib Hydrochloride respectively.Harbin Pharmaceutical Group was proposed to develop strategically both generic medicines to enter the high-end anti-cancer drug market for targeted cancer therapies.The vital to success of developing the generic drugs were discussed.

  10. New molecular targets against cervical cancer

    Directory of Open Access Journals (Sweden)

    Duenas-Gonzalez A

    2014-12-01

    Full Text Available Alfonso Duenas-Gonzalez,1,2 Alberto Serrano-Olvera,3 Lucely Cetina,4 Jaime Coronel4 1Unit of Biomedical Research in Cancer, Instituto de Investigaciones Biomedicas UNAM/Instituto Nacional de Cancerologia, Mexico City, 2ISSEMyM Cancer Center, Toluca, 3Medical Oncology Service, ABC Medical Center, Mexico City, 4Division of Clinical Research, Instituto Nacional de Cancerologia, Mexico City, Mexico On behalf of the Tumor Study Group Abstract: Cervical cancer is the third most commonly diagnosed cancer worldwide and the fourth leading cause of cancer death in women. Major advances but still insufficient achievements in the treatment of locally advanced and high-risk early stage patients have occurred in the last decade with the incorporation of concurrent cisplatin with radiation and, lately, gemcitabine added to cisplatin chemoradiation. Despite a number of clinical studies incorporating molecular-targeted therapy as radiosensitizers being in progress, so far, only antiangiogenic therapy with bevacizumab added to cisplatin chemoradiation has demonstrated safety and shown encouraging results in a Phase II study. In advanced disease, cisplatin doublets do not have a great impact on the natural history of the disease with median survival rates not exceeding 13 months. The first Phase III study of bevacizumab, added to cisplatin or a non-cisplatin-containing doublet, showed significant increase in both overall survival and progression-free survival. Further studies are needed before bevacizumab plus chemotherapy can be considered the standard of care for advanced disease. Characterization of the mutational landscape of cervical cancer has already been initiated, indicating that, for now, few of these targetable alterations match with available agents. Progress in both the mutational landscape knowledge and developments of novel targeted therapies may result in more effective and individualized treatments for cervical cancer. The potential efficacy of

  11. Versatile surface engineering of porous nanomaterials with bioinspired polyphenol coatings for targeted and controlled drug delivery

    Science.gov (United States)

    Li, Juan; Wu, Shuxian; Wu, Cuichen; Qiu, Liping; Zhu, Guizhi; Cui, Cheng; Liu, Yuan; Hou, Weijia; Wang, Yanyue; Zhang, Liqin; Teng, I.-Ting; Yang, Huang-Hao; Tan, Weihong

    2016-04-01

    The development of biocompatible drug delivery systems with targeted recognition and controlled release has experienced a number of design challenges, including, for example, complicated preparation steps and premature drug release. Herein, we address these problems through an in situ self-polymerization method that synthesizes biodegradable polyphenol-coated porous nanomaterials for targeted and controlled drug delivery. As a proof of concept, we synthesized polyphenol-coated mesoporous silica nanoparticles, termed MSN@polyphenol. The polyphenol coatings not only improved colloidal stability and prevented premature drug leakage, but also provided a scaffold for immobilization of targeting moieties, such as aptamers. Both immobilization of targeting aptamers and synthesis of polyphenol coating are easily accomplished without the aid of any other organic reagents. Importantly, the polyphenol coating (EGCg) used in this study could be biodegraded by acidic pH and intracellular glutathione, resulting in the release of trapped anticancer drugs. Based on confocal fluorescence microscopy and cytotoxicity experiments, drug-loaded and polyphenol-coated MSNs were shown to possess highly efficient internalization and an apparent cytotoxic effect on target cancer, but not control, cells. Our results suggest that these highly biocompatible and biodegradable polyphenol-coated MSNs are promising vectors for controlled-release biomedical applications and cancer therapy.The development of biocompatible drug delivery systems with targeted recognition and controlled release has experienced a number of design challenges, including, for example, complicated preparation steps and premature drug release. Herein, we address these problems through an in situ self-polymerization method that synthesizes biodegradable polyphenol-coated porous nanomaterials for targeted and controlled drug delivery. As a proof of concept, we synthesized polyphenol-coated mesoporous silica nanoparticles

  12. New insight into p-glycoprotein as a drug target.

    Science.gov (United States)

    Breier, Albert; Gibalova, Lenka; Seres, Mario; Barancik, Miroslav; Sulova, Zdenka

    2013-01-01

    changes in cell sensitivity to substances that are not P-gp substrates or modulators. We recently reported that P-gppositive L1210 cells exhibit reduced sensitivity to cisplatin, concanavalin A, thapsigargin and tunicamycin. Thus, P-gp-mediated MDR represents a more complex process than was expected, and the unintended effects of P-gp overexpression should be considered when describing this phenotype. The present review aims to provide the most current informations about P-gp-mediated MDR while paying particular attention to the possible dual function of this protein as a drug efflux pump and a regulatory protein that influences diverse cell processes. From a clinical standpoint, overexpression of P-gp in cancer cells represents a real obstacle to effective chemotherapy for malignant diseases. Therefore, this protein should be considered as a viable target for pharmaceutical design. PMID:22931413

  13. A multifunctional poly(curcumin) nanomedicine for dual-modal targeted delivery, intracellular responsive release, dual-drug treatment and imaging of multidrug resistant cancer cells† †Electronic supplementary information (ESI) available: The synthesis procedure of Biotin–PEG–PCDA and the experimental results of MTT. See DOI: 10.1039/c5tb02450a Click here for additional data file.

    Science.gov (United States)

    Wang, Jining; Wang, Feihu; Li, Fangzhou; Zhang, Wenjun

    2016-01-01

    A multifunctional anti-cancer nanomedicine based on a biotin–poly(ethylene glycol)–poly(curcumin-dithio dipropionic acid) (Biotin–PEG–PCDA) polymeric nanocarrier loaded with paclitaxel (PTX), magnetic nanoparticles (MNPs) and quantum dots (QDs) is developed. It combines advantageous properties of efficient targeted delivery and uptake (via biotin and MNP), intracellular responsive release (via cleavable PCDA polymer), fluorescence imaging (via QD) and combined PTX-curcumin dual-drug treatment, allowing for overcoming drug resistance mechanisms of model multidrug resistant breast cancer cells (MCF-7/ADR). The PTX/MNPs/QDs@Biotin–PEG–PCDA nanoparticles are highly stable under physiological conditions, but are quickly disassembled to release their drug load in the presence of 10 mM glutathione (GSH). The nanoparticles show high uptake by tumour cells from a combined effect of magnet targeting and biotin receptor-mediated internalization. Moreover, curcumin, an intracellularly cleaved product of PCDA, can effectively down regulate the expression of drug efflux transporters such as P-glycoprotein (P-gp) to increase PTX accumulation within target cancer cells, thereby enhancing PTX induced cytotoxicity and therapeutic efficacy against MCF-7/ADR cells. Taken together, this novel tumour-targeting and traceable multifunctional nanomedicine is highly effective against model MDR cancer at the cellular level. PMID:27152196

  14. Predictive Assay For Cancer Targets

    Energy Technology Data Exchange (ETDEWEB)

    Suess, A; Nguyen, C; Sorensen, K; Montgomery, J; Souza, B; Kulp, K; Dugan, L; Christian, A

    2005-09-19

    Early detection of cancer is a key element in successful treatment of the disease. Understanding the particular type of cancer involved, its origins and probable course, is also important. PhIP (2-amino-1-methyl-6 phenylimidazo [4,5-b]pyridine), a heterocyclic amine produced during the cooking of meat at elevated temperatures, has been shown to induce mammary cancer in female, Sprague-Dawley rats. Tumors induced by PhIP have been shown to contain discreet cytogenetic signature patterns of gains and losses using comparative genomic hybridization (CGH). To determine if a protein signature exists for these tumors, we are analyzing expression levels of the protein products of the above-mentioned tumors in combination with a new bulk protein subtractive assay. This assay produces a panel of antibodies against proteins that are either on or off in the tumor. Hybridization of the antibody panel onto a 2-D gel of tumor or control protein will allow for identification of a distinct protein signature in the tumor. Analysis of several gene databases has identified a number of rat homologs of human cancer genes located in these regions of gain and loss. These genes include the oncogenes c-MYK, ERBB2/NEU, THRA and tumor suppressor genes EGR1 and HDAC3. The listed genes have been shown to be estrogen-responsive, suggesting a possible link between delivery of bio-activated PhIP to the cell nucleus via estrogen receptors and gene-specific PhIP-induced DNA damage, leading to cell transformation. All three tumors showed similar silver staining patterns compared to each other, while they all were different than the control tissue. Subsequent screening of these genes against those from tumors know to be caused by other agents may produce a protein signature unique to PhIP, which can be used as a diagnostic to augment optical and radiation-based detection schemes.

  15. Inhibition of GSK-3β activity can result in drug and hormonal resistance and alter sensitivity to targeted therapy in MCF-7 breast cancer cells

    OpenAIRE

    Sokolosky, Melissa; Chappell, William H.; Stadelman, Kristin; Abrams, Stephen L.; Davis, Nicole M.; Steelman, Linda S.; McCubrey, James A.

    2014-01-01

    The PI3K/Akt/mTORC1 pathway plays prominent roles in malignant transformation, prevention of apoptosis, drug resistance, and metastasis. One molecule regulated by this pathway is GSK-3β. GSK-3β is phosphorylated by Akt on S9, which leads to its inactivation; however, GSK-3β also can regulate the activity of the PI3K/Akt/mTORC1 pathway by phosphorylating molecules such as PTEN, TSC2, p70S6K, and 4E-BP1. To further elucidate the roles of GSK-3β in chemotherapeutic drug and hormonal resistance o...

  16. Bcl-2 Inhibitors: Targeting Mitochondrial Apoptotic Pathways in Cancer Therapy

    OpenAIRE

    Kang, Min H.; Reynolds, C. Patrick

    2009-01-01

    Defects in apoptotic pathways can promote cancer cell survival and also confer resistance to antineoplastic drugs. One pathway being targeted for antineoplastic therapy is the anti-apoptotic B-cell lymphoma-2 (Bcl-2) family of proteins (Bcl-2, Bcl-XL, Bcl-w, Mcl-1, Bfl1/A-1, and Bcl-B) that bind to and inactivate BH3-domain pro-apoptotic proteins. Signals transmitted by cellular damage (including antineoplastic drugs) or cytokine deprivation can initiate apoptosis via the intrinsic apoptotic ...

  17. Epigenetic modulators as therapeutic targets in prostate cancer.

    Science.gov (United States)

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

    2016-01-01

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

  18. Prediction of Candidate Drugs for Treating Pancreatic Cancer by Using a Combined Approach.

    Directory of Open Access Journals (Sweden)

    Yanfen Ma

    Full Text Available Pancreatic cancer is the leading cause of death from solid malignancies worldwide. Currently, gemcitabine is the only drug approved for treating pancreatic cancer. Developing new therapeutic drugs for this disease is, therefore, an urgent need. The C-Map project has provided a wealth of gene expression data that can be mined for repositioning drugs, a promising approach to new drug discovery. Typically, a drug is considered potentially useful for treating a disease if the drug-induced differential gene expression profile is negatively correlated with the differentially expressed genes in the target disease. However, many of the potentially useful drugs (PUDs identified by gene expression profile correlation are likely false positives because, in C-Map, the cultured cell lines to which the drug is applied are not derived from diseased tissues. To solve this problem, we developed a combined approach for predicting candidate drugs for treating pancreatic cancer. We first identified PUDs for pancreatic cancer by using C-Map-based gene expression correlation analyses. We then applied an algorithm (Met-express to predict key pancreatic cancer (KPC enzymes involved in pancreatic cancer metabolism. Finally, we selected candidates from the PUDs by requiring that their targets be KPC enzymes or the substrates/products of KPC enzymes. Using this combined approach, we predicted seven candidate drugs for treating pancreatic cancer, three of which are supported by literature evidence, and three were experimentally validated to be inhibitory to pancreatic cancer celllines.

  19. Targeting Notch Signaling in Colorectal Cancer.

    Science.gov (United States)

    Suman, Suman; Das, Trinath P; Ankem, Murali K; Damodaran, Chendil

    2014-12-01

    The activation of Notch signaling is implicated in tumorigenesis in the colon due to the induction of pro-survival signaling in colonic epithelial cells. Chemoresistance is a major obstacle for treatment and for the complete eradication of colorectal cancer (CRC), hence, the inhibition of Notch is an attractive target for CRC and several groups are working to identify small molecules or monoclonal antibodies that inhibit Notch or its downstream events; however, toxicity profiles in normal cells and organs often impede the clinical translation of these molecules. Dietary agents have gained momentum for targeting several pro-survival signaling cascades, and recent studies demonstrated that agents that inhibit Notch signaling result in growth inhibition in preclinical models of CRC. In this review, we focus on the importance of Notch as a preventive and therapeutic target for colon cancer and on the effect of WA on this signaling pathway in the context of colon cancer. PMID:25395896

  20. Anti-malarial Drug Design by Targeting Apicoplasts: New Perspectives

    Directory of Open Access Journals (Sweden)

    Avinaba Mukherjee

    2016-03-01

    Full Text Available Objectives: Malaria has been a major global health problem in recent times with increasing mortality. Current treatment methods include parasiticidal drugs and vaccinations. However, resistance among malarial parasites to the existing drugs has emerged as a significant area of concern in anti-malarial drug design. Researchers are now desperately looking for new targets to develop anti-malarials drug which is more target specific. Malarial parasites harbor a plastid-like organelle known as the ‘apicoplast’, which is thought to provide an exciting new outlook for the development of drugs to be used against the parasite. This review elaborates on the current state of development of novel compounds targeted againstemerging malaria parasites. Methods: The apicoplast, originates by an endosymbiotic process, contains a range of metabolic pathways and housekeeping processes that differ from the host body and thereby presents ideal strategies for anti-malarial drug therapy. Drugs are designed by targeting the unique mechanism of the apicoplasts genetic machinery. Several anabolic and catabolic processes, like fatty acid, isopenetyl diphosphate and heme synthess in this organelle, have also been targeted by drugs. Results: Apicoplasts offer exciting opportunities for the development of malarial treatment specific drugs have been found to act by disrupting this organelle’s function, which wouldimpede the survival of the parasite. Conclusion: Recent advanced drugs, their modes of action, and their advantages in the treatment of malaria by using apicoplasts as a target are discussed in this review which thought to be very useful in desigining anti-malarial drugs. Targetting the genetic machinery of apicoplast shows a great advantange regarding anti-malarial drug design. Critical knowledge of these new drugs would give a healthier understanding for deciphering the mechanism of action of anti-malarial drugs when targeting apicoplasts to overcome drug

  1. Transcriptional Targeting in Cancer Gene Therapy

    OpenAIRE

    Tracy Robson; David G. Hirst

    2003-01-01

    Cancer gene therapy has been one of the most exciting areas of therapeutic research in the past decade. In this review, we discuss strategies to restrict transcription of transgenes to tumour cells. A range of promoters which are tissue-specific, tumour-specific, or inducible by exogenous agents are presented. Transcriptional targeting should prevent normal tissue toxicities associated with other cancer treatments, such as radiation and chemotherapy. In addition, the specificity of these stra...

  2. Researchers Identify Genomic Alterations Associated with Drug-Targetable Kinase Activation in Ph-like Acute Lymphoblastic Leukemia | Office of Cancer Genomics

    Science.gov (United States)

    Acute lymphoblastic leukemia (ALL) is the most prevalent cancer among children and young adults, and standard treatments within this population generally result in favorable outcomes. By contrast, one particular subtype of this disease, Philadelphia chromosome-like ALL (Ph-like ALL), is associated with inferior outcomes. Ph-like ALL exhibits a gene expression profile similar to chromosome 9:22 translocation positive ALL, yet it lacks the characteristic BCR-ABL fusion protein.

  3. Nanoparticle Based Drug Delivery System: Milestone for Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Gousia Chashoo

    2012-09-01

    Full Text Available The challenge of modern drug therapy is the optimization of the pharmacological action of the drugs coupled with the reduction of their toxic effects in vivo. The prime objectives in the design of drug delivery systems (DDS are the controlled delivery of the drug to its site of action at a therapeutically optimal rate and dosage to avoid toxicity and improve the drug effectiveness and therapeutic index. DDS has improved many of the pharmacological properties of conventional ("free" drugs including particulate carriers which are primarily composed of lipids and/or polymers and their associated therapeutics. It alters the pharmacokinetics (PK and biodistribution (BD of the associated drugs or functions as drug reservoir or both. Nanoparticles provide a range of new opportunities to increase the targeting of currently approved diagnostic and therapeutic agents to cancers. Nanoparticles carrying a chemotherapeutic can reduce the undesirable distribution of such agents. The problems related to cancer chemotherapy can partially be overcome by direct intratumoral delivery of controlled release biodegradable nanoparticles (NPs.

  4. Targeting cancer stem cells: emerging role of Nanog transcription factor

    Directory of Open Access Journals (Sweden)

    Wang ML

    2013-09-01

    Full Text Available Mong-Lien Wang,1 Shih-Hwa Chiou,2,3 Cheng-Wen Wu1,4–61Institute of Biochemistry and Molecular Biology, 2Institute of Pharmacology, National Yang Ming University, Taipei, Taiwan; 3Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan; 4Institute of Microbiology and Immunology, 5Institute of Clinical Medicine, National Yang Ming University, Taipei, Taiwan; 6Institute of Biomedical Science, Academia Sinica, Taipei, TaiwanAbstract: The involvement of stemness factors in cancer initiation and progression has drawn much attention recently, especially after the finding that introducing four stemness factors in somatic cells is able to reprogram the cells back to an embryonic stem cell-like state. Following accumulating data revealing abnormal elevated expression levels of key stemness factors, like Nanog, Oct4, and Sox2, in several types of cancer stem cells; the importance and therapeutic potential of targeting these stemness regulators in cancers has turned to research focus. Nanog determines cell fate in both embryonic and cancer stem cells; activating Nanog at an inappropriate time would result in cancer stem cells rather than normal pluripotent stem cells or differentiated somatic cells. Upregulated Nanog is correlated with poor survival outcome of patients with various types of cancer. The discoveries of downstream regulatory pathways directly or indirectly mediated by Nanog indicate that Nanog regulates several aspects of cancer development such as tumor cell proliferation, self-renewal, motility, epithelial-mesenchymal transition, immune evasion, and drug-resistance, which are all defined features for cancer stem cells. The current review paper illustrates the central role of Nanog in the regulatory networks of cancer malignant development and stemness acquirement, as well as in the communication between cancer cells and the surrounding stroma. Though a more defined model is needed to test the

  5. Drug cocktail optimization in chemotherapy of cancer.

    Directory of Open Access Journals (Sweden)

    Saskia Preissner

    Full Text Available BACKGROUND: In general, drug metabolism has to be considered to avoid adverse effects and ineffective therapy. In particular, chemotherapeutic drug cocktails strain drug metabolizing enzymes especially the cytochrome P450 family (CYP. Furthermore, a number of important chemotherapeutic drugs such as cyclophosphamide, ifosfamide, tamoxifen or procarbazine are administered as prodrugs and have to be activated by CYP. Therefore, the genetic variability of these enzymes should be taken into account to design appropriate therapeutic regimens to avoid inadequate drug administration, toxicity and inefficiency. OBJECTIVE: The aim of this work was to find drug interactions and to avoid side effects or ineffective therapy in chemotherapy. DATA SOURCES AND METHODS: Information on drug administration in the therapy of leukemia and their drug metabolism was collected from scientific literature and various web resources. We carried out an automated textmining approach. Abstracts of PubMed were filtered for relevant articles using specific keywords. Abstracts were automatically screened for antineoplastic drugs and their synonyms in combination with a set of human CYPs in title or abstract. RESULTS: We present a comprehensive analysis of over 100 common cancer treatment regimens regarding drug-drug interactions and present alternatives avoiding CYP overload. Typical concomitant medication, e.g. antiemetics or antibiotics is a preferred subject to improvement. A webtool, which allows drug cocktail optimization was developed and is publicly available on http://bioinformatics.charite.de/chemotherapy.

  6. Assessing drug target association using semantic linked data.

    Directory of Open Access Journals (Sweden)

    Bin Chen

    Full Text Available The rapidly increasing amount of public data in chemistry and biology provides new opportunities for large-scale data mining for drug discovery. Systematic integration of these heterogeneous sets and provision of algorithms to data mine the integrated sets would permit investigation of complex mechanisms of action of drugs. In this work we integrated and annotated data from public datasets relating to drugs, chemical compounds, protein targets, diseases, side effects and pathways, building a semantic linked network consisting of over 290,000 nodes and 720,000 edges. We developed a statistical model to assess the association of drug target pairs based on their relation with other linked objects. Validation experiments demonstrate the model can correctly identify known direct drug target pairs with high precision. Indirect drug target pairs (for example drugs which change gene expression level are also identified but not as strongly as direct pairs. We further calculated the association scores for 157 drugs from 10 disease areas against 1683 human targets, and measured their similarity using a [Formula: see text] score matrix. The similarity network indicates that drugs from the same disease area tend to cluster together in ways that are not captured by structural similarity, with several potential new drug pairings being identified. This work thus provides a novel, validated alternative to existing drug target prediction algorithms. The web service is freely available at: http://chem2bio2rdf.org/slap.

  7. Assessing drug target association using semantic linked data.

    Science.gov (United States)

    Chen, Bin; Ding, Ying; Wild, David J

    2012-01-01

    The rapidly increasing amount of public data in chemistry and biology provides new opportunities for large-scale data mining for drug discovery. Systematic integration of these heterogeneous sets and provision of algorithms to data mine the integrated sets would permit investigation of complex mechanisms of action of drugs. In this work we integrated and annotated data from public datasets relating to drugs, chemical compounds, protein targets, diseases, side effects and pathways, building a semantic linked network consisting of over 290,000 nodes and 720,000 edges. We developed a statistical model to assess the association of drug target pairs based on their relation with other linked objects. Validation experiments demonstrate the model can correctly identify known direct drug target pairs with high precision. Indirect drug target pairs (for example drugs which change gene expression level) are also identified but not as strongly as direct pairs. We further calculated the association scores for 157 drugs from 10 disease areas against 1683 human targets, and measured their similarity using a [Formula: see text] score matrix. The similarity network indicates that drugs from the same disease area tend to cluster together in ways that are not captured by structural similarity, with several potential new drug pairings being identified. This work thus provides a novel, validated alternative to existing drug target prediction algorithms. The web service is freely available at: http://chem2bio2rdf.org/slap.

  8. Novel epigenetic target therapy for prostate cancer: a preclinical study.

    Directory of Open Access Journals (Sweden)

    Ilaria Naldi

    Full Text Available Epigenetic events are critical contributors to the pathogenesis of cancer, and targeting epigenetic mechanisms represents a novel strategy in anticancer therapy. Classic demethylating agents, such as 5-Aza-2'-deoxycytidine (Decitabine, hold the potential for reprograming somatic cancer cells demonstrating high therapeutic efficacy in haematological malignancies. On the other hand, epigenetic treatment of solid tumours often gives rise to undesired cytotoxic side effects. Appropriate delivery systems able to enrich Decitabine at the site of action and improve its bioavailability would reduce the incidence of toxicity on healthy tissues. In this work we provide preclinical evidences of a safe, versatile and efficient targeted epigenetic therapy to treat hormone sensitive (LNCap and hormone refractory (DU145 prostate cancers. A novel Decitabine formulation, based on the use of engineered erythrocyte (Erythro-Magneto-Hemagglutinin Virosomes, EMHVs drug delivery system (DDS carrying this drug, has been refined. Inside the EMHVs, the drug was shielded from the environment and phosphorylated in its active form. The novel magnetic EMHV DDS, endowed with fusogenic protein, improved the stability of the carried drug and exhibited a high efficiency in confining its delivery at the site of action in vivo by applying an external static magnetic field. Here we show that Decitabine loaded into EMHVs induces a significant tumour mass reduction in prostate cancer xenograft models at a concentration, which is seven hundred times lower than the therapeutic dose, suggesting an improved pharmacokinetics/pharmacodynamics of drug. These results are relevant for and discussed in light of developing personalised autologous therapies and innovative clinical approach for the treatment of solid tumours.

  9. Novel targeted agents for gastric cancer

    Directory of Open Access Journals (Sweden)

    Liu Lian

    2012-06-01

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

  10. Polo-like kinase 1 as target for cancer therapy

    Directory of Open Access Journals (Sweden)

    Weiß Lily

    2012-12-01

    Full Text Available Abstract Polo-like kinase 1 (Plk1 is an interesting molecule both as a biomarker and as a target for highly specific cancer therapy for several reasons. Firstly, it is over-expressed in many cancers and can serve as a biomarker to monitor treatment efficacy of Plk1 inhibitors. Furthermore, the Plk1 enzyme is expressed only in dividing cells and is a major regulator of the cell cycle. It controls entry into mitosis and regulates the spindle checkpoint. The expression of Plk1 in normal cells is not nearly as strong as that in cancer cells, which makes Plk1 a discriminating tartget for the development of cancer-specific small molecule drugs. RNA interference experiments in vitro and in vivo have indicated that downregulation of Plk1 expression represents an attractive concept for cancer therapy. Over the years, a number of Plk1 inhibitors have been discovered. Many of these inhibitors are substances that compete with ATP for the substrate binding site. The ATP-competitive inhibitor BI 6727 is currently being clinically tested in cancer patients. Another drug in development, poloxin, is the first Polo-box domain inhibitor of Plk1. This compound is a derivative of the natural product, thymoquinone, derived from Nigella sativa. A novel and promising strategy is to synthesize bifunctional inhibitors that combine the high binding affinity of ATP inhibitors with the specificity of competitive inhibitors.

  11. Repurposing Drugs to Target the Diabetes Epidemic.

    Science.gov (United States)

    Turner, Nigel; Zeng, Xiao-Yi; Osborne, Brenna; Rogers, Suzanne; Ye, Ji-Ming

    2016-05-01

    Despite major investment by pharmaceutical companies in conventional drug discovery pipelines, development of new drugs has failed to keep up with the increasing incidence of many diseases, including type 2 diabetes (T2D). Drug repurposing, where existing drugs are applied to a new indication, is gaining momentum as a successful approach to overcome the bottlenecks commonly encountered with conventional approaches. Repurposing takes advantage of available information on the molecular pharmacology of clinical agents to drastically shorten drug development timelines. This review discusses recent advances in the discovery of new antidiabetic agents using repurposing strategies. PMID:26900045

  12. Direct targeting of cancer cells: a multiparameter approach.

    Science.gov (United States)

    Heinrich, Eileen L; Welty, Lily Anne Y; Banner, Lisa R; Oppenheimer, Steven B

    2005-01-01

    Lectins have been widely used in cell surface studies and in the development of potential anticancer drugs. Many past studies that have examined lectin toxicity have only evaluated the effects on cancer cells, not their non-cancer counterparts. In addition, few past studies have evaluated the relationship between lectin-cell binding and lectin toxicity on both cell types. Here we examine these parameters in one study: lectin-cell binding and lectin toxicity with both cancer cells and their normal counterparts. We found that the human colon cancer cell line CCL-220/Colo320DM bound to agarose beads derivatized with Phaseolus vulgaris agglutinin (PHA-L) and wheat germ agglutinin (WGA), while the non-cancer human colon cell line CRL-1459/CCD-18Co did not. When these lectins were tested for their effects on cell viability in culture, both cell lines were affected by the lectins but at 6, 48 and 72 h incubation times, PHA-L was most toxic to the cancer cell line in a concentration dependent manner. At 48 h incubation, WGA was more toxic to the cancer cell line. The results suggest that it may be possible to develop lectin protocols that selectively target cancer cells for death. In any case, examination of both malignant cells and their non-malignant counterparts, analysis of their binding characteristics to immobilized lectins, and examination of the toxicity of free lectins in culture, provides a multiparameter model for obtaining more comprehensive information than from more limited approaches. PMID:16181664

  13. Targeting of two aspects of metabolism in breast cancer treatment.

    Science.gov (United States)

    Gang, Bevan P; Dilda, Pierre J; Hogg, Phillip J; Blackburn, Anneke C

    2014-01-01

    Deregulated metabolism is gaining recognition as a hallmark of cancer cells, and is being explored for therapeutic potential. The Warburg effect is a metabolic phenotype that occurs in 90% of tumors, where glycolysis is favored despite the presence of oxygen. Dichloroacetate (DCA) is a pyruvate dehydrogenase kinase (PDK) inhibitor that can reverse the Warburg effect. PENAO (4-(N-(S-penicillaminylacetyl)amino) phenylarsonous acid) is a novel anti-mitochondrial agent that targets the adenine nucleotide transporter in mitochondria and is currently in clinical trials for solid tumors. We have investigated the targeting of two aspects of metabolism, using DCA to promote mitochondrial activity combined with PENAO to inhibit mitochondrial activity, in breast and other carcinoma cell lines. PENAO was effective at low uM concentrations in luminal (T-47D) and triple negative (MDA-MB-231) breast cancer cells, in normoxia and hypoxia. The cytotoxicity of PENAO was enhanced by DCA by a mechanism involving increased reactive oxygen species in both T-47D and MDA-MB-231 cells, however further investigations found it did not always involve PDK2 inhibition or reduction of the mitochondrial membrane potential, which are the accepted mechanisms for DCA induction of apoptosis. Nevertheless, DCA sensitized all cancer cell lines tested toward apoptosis of PENAO. DCA and PENAO are both currently in clinical trials and targeting cancer metabolism with these drugs may offer options for difficult to treat cancers. PMID:25482950

  14. The potential therapeutic targets for cervical cancer

    OpenAIRE

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

    2013-01-01

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

  15. Leptin signaling molecular actions and drug target in hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Jiang N

    2014-11-01

    leptin and Ob-R in cancer cells compared to normal cells, makes leptin an ideal drug target for the prevention and treatment of HCC, especially in obese patients. Keywords: hepatocellular carcinoma, leptin, leptin antagonist, leptin signaling, tumor angiogenesis, drug target

  16. Cancer therapy leading to state of cancer metabolism depression for efficient operation of small dosage cytotoxic drugs

    OpenAIRE

    Ponizovskiy MR

    2015-01-01

    “Prolonged medical starvation” as the method of cancer therapy was borrowed from folk healers Omelchenko A and Breuss R. Author was convinced in efficiency of this method of cancer treatment via examination of cured patients and on own experience. The mechanism of this method of cancer therapy operates via Warburg effect targeting that promotes efficient cancer treatment with small cytotoxic drugs. Just it was described the mechanism of Warburg effect as well as mechanism transmutation of mit...

  17. Targeted Therapies for Brain Metastases from Breast Cancer

    Science.gov (United States)

    Venur, Vyshak Alva; Leone, José Pablo

    2016-01-01

    The discovery of various driver pathways and targeted small molecule agents/antibodies have revolutionized the management of metastatic breast cancer. Currently, the major targets of clinical utility in breast cancer include the human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF) receptor, mechanistic target of rapamycin (mTOR) pathway, and the cyclin-dependent kinase 4/6 (CDK-4/6) pathway. Brain metastasis, however, remains a thorn in the flesh, leading to morbidity, neuro-cognitive decline, and interruptions in the management of systemic disease. Approximately 20%–30% of patients with metastatic breast cancer develop brain metastases. Surgery, whole brain radiation therapy, and stereotactic radiosurgery are the traditional treatment options for patients with brain metastases. The therapeutic paradigm is changing due to better understanding of the blood brain barrier and the advent of tyrosine kinase inhibitors and monoclonal antibodies. Several of these agents are in clinical practice and several others are in early stage clinical trials. In this article, we will review the common targetable pathways in the management of breast cancer patients with brain metastases, and the current state of the clinical development of drugs against these pathways. PMID:27649142

  18. Targeted Therapies for Brain Metastases from Breast Cancer

    Directory of Open Access Journals (Sweden)

    Vyshak Alva Venur

    2016-09-01

    Full Text Available The discovery of various driver pathways and targeted small molecule agents/antibodies have revolutionized the management of metastatic breast cancer. Currently, the major targets of clinical utility in breast cancer include the human epidermal growth factor receptor 2 (HER2 and epidermal growth factor receptor (EGFR, vascular endothelial growth factor (VEGF receptor, mechanistic target of rapamycin (mTOR pathway, and the cyclin-dependent kinase 4/6 (CDK-4/6 pathway. Brain metastasis, however, remains a thorn in the flesh, leading to morbidity, neuro-cognitive decline, and interruptions in the management of systemic disease. Approximately 20%–30% of patients with metastatic breast cancer develop brain metastases. Surgery, whole brain radiation therapy, and stereotactic radiosurgery are the traditional treatment options for patients with brain metastases. The therapeutic paradigm is changing due to better understanding of the blood brain barrier and the advent of tyrosine kinase inhibitors and monoclonal antibodies. Several of these agents are in clinical practice and several others are in early stage clinical trials. In this article, we will review the common targetable pathways in the management of breast cancer patients with brain metastases, and the current state of the clinical development of drugs against these pathways.

  19. Radionuclide-Based Cancer Imaging Targeting the Carcinoembryonic Antigen

    Directory of Open Access Journals (Sweden)

    Hao Hong

    2008-01-01

    Full Text Available Carcinoembryonic antigen (CEA, highly expressed in many cancer types, is an important target for cancer diagnosis and therapy. Radionuclide-based imaging techniques (gamma camera, single photon emission computed tomography [SPECT] and positron emission tomography [PET] have been extensively explored for CEA-targeted cancer imaging both preclinically and clinically. Briefly, these studies can be divided into three major categories: antibody-based, antibody fragment-based and pretargeted imaging. Radiolabeled anti-CEA antibodies, reported the earliest among the three categories, typically gave suboptimal tumor contrast due to the prolonged circulation life time of intact antibodies. Subsequently, a number of engineered anti-CEA antibody fragments (e.g. Fab’, scFv, minibody, diabody and scFv-Fc have been labeled with a variety of radioisotopes for CEA imaging, many of which have entered clinical investigation. CEA-Scan (a 99mTc-labeled anti-CEA Fab’ fragment has already been approved by the United States Food and Drug Administration for cancer imaging. Meanwhile, pretargeting strategies have also been developed for CEA imaging which can give much better tumor contrast than the other two methods, if the system is designed properly. In this review article, we will summarize the current state-of-the-art of radionuclide-based cancer imaging targeting CEA. Generally, isotopes with short half-lives (e.g. 18F and 99mTc are more suitable for labeling small engineered antibody fragments while the isotopes with longer half-lives (e.g. 123I and 111In are needed for antibody labeling to match its relatively long circulation half-life. With further improvement in tumor targeting efficacy and radiolabeling strategies, novel CEA-targeted agents may play an important role in cancer patient management, paving the way to “personalized medicine”.

  20. Triple-negative breast cancer: new perspectives for targeted therapies

    Directory of Open Access Journals (Sweden)

    Tomao F

    2015-01-01

    Full Text Available Federica Tomao,1 Anselmo Papa,2 Eleonora Zaccarelli,2 Luigi Rossi,2 Davide Caruso,2 Marina Minozzi,2 Patrizia Vici,3 Luigi Frati,4 Silverio Tomao21Department of Gynecology and Obstetrics, “Sapienza” University of Rome, Policlinico “Umberto I”, Rome, 2Department of Medico-Surgical Sciences and Biotechnologies, “Sapienza” University of Rome, Oncology Unit, Istituto Chirurgico Ortopedico Traumatologico, Latina, 3Division of Medical Oncology B, Regina Elena National Cancer Institute, Rome, Italy; 4Department of Molecular Medicine, “Sapienza” University of Rome, Policlinico “Umberto I”, Rome, ItalyAbstract: Breast cancer is a heterogeneous disease, encompassing a large number of entities showing different morphological features and having clinical behaviors. It has became apparent that this diversity may be justified by distinct patterns of genetic, epigenetic, and transcriptomic aberrations. The identification of gene-expression microarray-based characteristics has led to the identification of at least five breast cancer subgroups: luminal A, luminal B, normal breast-like, human epidermal growth factor receptor 2, and basal-like. Triple-negative breast cancer is a complex disease diagnosed by immunohistochemistry, and it is characterized by malignant cells not expressing estrogen receptors or progesterone receptors at all, and human epidermal growth factor receptor 2. Along with this knowledge, recent data show that triple-negative breast cancer has specific molecular features that could be possible targets for new biological targeted drugs. The aim of this article is to explore the use of new drugs in this particular setting, which is still associated with poor prognosis and high risk of distant recurrence and death.Keywords: basal-like breast cancer, estrogen–progesterone receptors, gene-expression microarray, human epidermal growth factor receptor 2, chemotherapy, target therapy

  1. Importins and exportins as therapeutic targets in cancer.

    Science.gov (United States)

    Mahipal, Amit; Malafa, Mokenge

    2016-08-01

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

  2. Identification of Multiple Cryptococcal Fungicidal Drug Targets by Combined Gene Dosing and Drug Affinity Responsive Target Stability Screening

    Directory of Open Access Journals (Sweden)

    Yoon-Dong Park

    2016-08-01

    Full Text Available Cryptococcus neoformans is a pathogenic fungus that is responsible for up to half a million cases of meningitis globally, especially in immunocompromised individuals. Common fungistatic drugs, such as fluconazole, are less toxic for patients but have low efficacy for initial therapy of the disease. Effective therapy against the disease is provided by the fungicidal drug amphotericin B; however, due to its high toxicity and the difficulty in administering its intravenous formulation, it is imperative to find new therapies targeting the fungus. The antiparasitic drug bithionol has been recently identified as having potent fungicidal activity. In this study, we used a combined gene dosing and drug affinity responsive target stability (GD-DARTS screen as well as protein modeling to identify a common drug binding site of bithionol within multiple NAD-dependent dehydrogenase drug targets. This combination genetic and proteomic method thus provides a powerful method for identifying novel fungicidal drug targets for further development.

  3. Identification of Multiple Cryptococcal Fungicidal Drug Targets by Combined Gene Dosing and Drug Affinity Responsive Target Stability Screening

    Science.gov (United States)

    Park, Yoon-Dong; Sun, Wei; Salas, Antonio; Antia, Avan; Carvajal, Cindy; Wang, Amy; Xu, Xin; Meng, Zhaojin; Zhou, Ming; Tawa, Gregory J.; Dehdashti, Jean; Zheng, Wei; Henderson, Christina M.; Zelazny, Adrian M.

    2016-01-01

    ABSTRACT Cryptococcus neoformans is a pathogenic fungus that is responsible for up to half a million cases of meningitis globally, especially in immunocompromised individuals. Common fungistatic drugs, such as fluconazole, are less toxic for patients but have low efficacy for initial therapy of the disease. Effective therapy against the disease is provided by the fungicidal drug amphotericin B; however, due to its high toxicity and the difficulty in administering its intravenous formulation, it is imperative to find new therapies targeting the fungus. The antiparasitic drug bithionol has been recently identified as having potent fungicidal activity. In this study, we used a combined gene dosing and drug affinity responsive target stability (GD-DARTS) screen as well as protein modeling to identify a common drug binding site of bithionol within multiple NAD-dependent dehydrogenase drug targets. This combination genetic and proteomic method thus provides a powerful method for identifying novel fungicidal drug targets for further development. PMID:27486194

  4. Antimetastatic therapy targeting aberrant sialylation profiles in cancer cells

    Directory of Open Access Journals (Sweden)

    Da Yong Lu

    2011-09-01

    Full Text Available Neoplasm metastases involve a fixed cascade of pathological processes, and are responsible for more than 60% cancer deaths worldwide and can only be controlled or inhibited by drugs now. Antimetastatic drugs targeting aberrantly sialylated in tumors have involved about a quarter of a century and might be a future therapeutic option apart from currently utilized antimetastatic drugs, such as antivascular and matrix metalloproteinase (MMP inhibitors. Since neoplasm tissues often manifest high levels of sialic acids and sialyl antigens or glycoligands, and some types of sialic acid analogue, such as N-glycolylneuraminic acid (Nau5Gc occurred in most tumor tissues, is absent in common humans, more attentions are needed to work with new therapeutic approaches to target these changes. Previously preliminary data have shown some compounds that inhibit some pathways of sialic acids can inhibit the tumor metastasis in vitro and tumor metastasis in experimental animal models. This type of pharmacological work can be helped by glycome investigations in order to deep understanding their mechanisms. As the central dogma of glycobiology is still unknown, some fundamental questions related to carbohydrate itself are even more welcoming and decisive to our understanding to nature of cancer. These types of work also need mathematical analysis of data. In this review, we will document and discuss the latest experimental therapeutic data and their clinical significance between cancer pathological profiles and therapeutics benefits.

  5. Hydrodynamic modeling of ferrofluid flow in magnetic targeting drug delivery

    Institute of Scientific and Technical Information of China (English)

    LIU Han-dan; XU Wei; WANG Shi-gang; KE Zun-ji

    2008-01-01

    Among the proposed techniques for delivering drugs to specific locations within human body, magnetic drug targeting prevails due to its non-invasive character and its high targeting efficiency. Magnetic targeting drug delivery is a method of carrying drug-loaded magnetic nanoparticles to a target tissue target under the applied magnetic field. This method increases the drug concentration in the target while reducing the adverse side-effects. Although there have been some theoretical analyses for magnetic drug targeting, very few researchers have addressed the hydrodynamic models of magnetic fluids in the blood vessel. A mathematical model is presented to describe the hydrodynamics of ferrofluids as drug carriers flowing in a blood vessel under the applied magnetic field. In this model, magnetic force and asymmetrical force are added, and an angular momentum equation of magnetic nanoparticles in the applied magnetic field is modeled. Engineering approximations are achieved by retaining the physically most significant items in the model due to the mathematical complexity of the motion equations. Numerical simulations are performed to obtain better insight into the theoretical model with computational fluid dynamics. Simulation results demonstrate the important parameters leading to adequate drug delivery to the target site depending on the magnetic field intensity, which coincident with those of animal experiments. Results of the analysis provide important information and suggest strategies for improving delivery in clinical application.

  6. Large-scale prediction of drug-target relationships

    DEFF Research Database (Denmark)

    Kuhn, Michael; Campillos, Mónica; González, Paula;

    2008-01-01

    also provides a more global view on drug-target relations. Here we review recent attempts to apply large-scale computational analyses to predict novel interactions of drugs and targets from molecular and cellular features. In this context, we quantify the family-dependent probability of two proteins to...

  7. Breast cancer stem cells, EMT and therapeutic targets

    Energy Technology Data Exchange (ETDEWEB)

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

    2014-10-10

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

  8. New advances in targeted gastric cancer treatment

    Science.gov (United States)

    Lazăr, Daniela Cornelia; Tăban, Sorina; Cornianu, Marioara; Faur, Alexandra; Goldiş, Adrian

    2016-01-01

    Despite a decrease in incidence over past decades, gastric cancer remains a major global health problem. In the more recent period, survival has shown only minor improvement, despite significant advances in diagnostic techniques, surgical and chemotherapeutic approaches, the development of novel therapeutic agents and treatment by multidisciplinary teams. Because multiple genetic mutations, epigenetic alterations, and aberrant molecular signalling pathways are involved in the development of gastric cancers, recent research has attempted to determine the molecular heterogeneity responsible for the processes of carcinogenesis, spread and metastasis. Currently, some novel agents targeting a part of these dysfunctional molecular signalling pathways have already been integrated into the standard treatment of gastric cancer, whereas others remain in phases of investigation within clinical trials. It is essential to identify the unique molecular patterns of tumours and specific biomarkers to develop treatments targeted to the individual tumour behaviour. This review analyses the global impact of gastric cancer, as well as the role of Helicobacter pylori infection and the efficacy of bacterial eradication in preventing gastric cancer development. Furthermore, the paper discusses the currently available targeted treatments and future directions of research using promising novel classes of molecular agents for advanced tumours.

  9. Liposomal drug delivery in multimodal cancer therapy

    OpenAIRE

    2011-01-01

    Encapsulating cytostatics into lipid vesicles, i.e. liposomes, improves tumour drug accumulation and reduce adverse effects. Liposomal doxorubicin (DXR) has been used in the treatment of a variety of cancers and may also be suitable for combining with other treatment modalities. By modulating liposomal membranes, liposomes can be made ultrasound (US) sensitive releasing encapsulated drug in tumour tissue upon external US stimulation and may thereby improve therapeutic outcome. Moreover, as DX...

  10. Selectively targeting estrogen receptors for cancer treatment

    NARCIS (Netherlands)

    Shanle, Erin K.; Xu, Wei

    2010-01-01

    Estrogens regulate growth and development through the action of two distinct estrogen receptors (ERs), ER alpha and ER beta, which mediate proliferation and differentiation of cells. For decades, ER alpha mediated estrogen signaling has been therapeutically targeted to treat breast cancer, most nota

  11. Bioinformatics for cancer immunotherapy target discovery

    DEFF Research Database (Denmark)

    Olsen, Lars Rønn; Campos, Benito; Barnkob, Mike Stein;

    2014-01-01

    cancer immunotherapies has yet to be fulfilled. The insufficient efficacy of existing treatments can be attributed to a number of biological and technical issues. In this review, we detail the current limitations of immunotherapy target selection and design, and review computational methods to streamline...

  12. Tumor Microenvironment: A New Treatment Target for Cancer

    OpenAIRE

    Ming-Ju Tsai; Wei-An Chang; Ming-Shyan Huang; Po-Lin Kuo

    2014-01-01

    Recent advances in cancer therapy encounter a bottleneck. Relapsing/recurrent disease almost always developed eventually with resistance to the initially effective drugs. Tumor microenvironment has been gradually recognized as a key contributor for cancer progression, epithelial-mesenchymal transition of the cancer cells, angiogenesis, cancer metastasis, and development of drug resistance, while dysregulated immune responses and interactions between various components in the microenvironment ...

  13. Targeting Axl and Mer kinases in cancer.

    Science.gov (United States)

    Verma, Anupam; Warner, Steven L; Vankayalapati, Hariprasad; Bearss, David J; Sharma, Sunil

    2011-10-01

    Receptor tyrosine kinases (RTK) are cell-surface transmembrane receptors that contain regulated kinase activity within their cytoplasmic domain and play an important role in signal transduction in both normal and malignant cells. The mammalian TAM RTK family includes 3 closely related members: Tyro-3, Axl, and Mer. Overexpression or ectopic expression of the TAM receptors has been detected in a wide array of human cancers. Growth arrest-specific gene 6 has been identified as the major ligand for these TAM RTKs, and its binding to the receptors has been shown to promote proliferation and survival of cancer cells in vitro. Abnormal expression and activation of Axl or Mer can provide a survival advantage for certain cancer cells. Inhibition of Axl and Mer may enhance the sensitivity of cancer cells to cytotoxic agents and would potentially be a therapeutic strategy to target cancer cells. This review elucidates the role of Axl and Mer in normal cellular function and their role in oncogenesis. In addition, we review the potential to inhibit these RTKs for the development of therapeutic targets in treatment of cancer. PMID:21933973

  14. Identifying mechanism-of-action targets for drugs and probes

    OpenAIRE

    Gregori-Puigjané, Elisabet; Setola, Vincent; Hert, Jérôme; Crews, Brenda A.; Irwin, John J.; Lounkine, Eugen; Marnett, Lawrence; Roth, Bryan L.; Brian K Shoichet

    2012-01-01

    Notwithstanding their key roles in therapy and as biological probes, 7% of approved drugs are purported to have no known primary target, and up to 18% lack a well-defined mechanism of action. Using a chemoinformatics approach, we sought to “de-orphanize” drugs that lack primary targets. Surprisingly, targets could be easily predicted for many: Whereas these targets were not known to us nor to the common databases, most could be confirmed by literature search, leaving only 13 Food and Drug Adm...

  15. Aptamer-loaded Gold Nanoconstructs for Targeted Cancer Therapy

    Science.gov (United States)

    Dam, Duncan Hieu Minh

    Traditional cancer treatments, including chemotherapy, often cause severe side effects in patients. Targeted therapy where tumor cells are targeted via biomarkers overexpressed on the cell surface has been shown to reduce such adverse effects. Monoclonal antibodies (mAbs) are currently the most common chemotherapeutic agents that bind with high affinity to these cancer markers. However, poor intratumoral uptake of mAb and release of drugs from mAb carriers have been the biggest challenge for this delivery method. As a result, recent work has focused on other strategies to improve the efficacy of drug delivery in targeted therapy. Among potential carriers for drug delivery, gold nanoparticles (AuNPs) have emerged as one of the most promising vehicles. This thesis describes the development of a drug delivery nanoconstruct that can both target cancer cells and induce therapeutic effects. The nanoconstructs are composed of gold nanostars (AuNS) as delivery vehicles loaded with the DNA aptamer AS1411 that can target the ubiquitous shuttle protein nucleolin (NCL) in various cancer cell types. The gold nanocarrier stabilizes the oligonucleotides for intracellular delivery and promotes high loading densities of the oligonucleotide drugs. We have investigated the interactions of the nanoconstruct with different subcellular compartments of the cancer cells. This physical phenomenon has shown to correlate with the biological activities such as apoptosis and cell death that happen in the cancer cells after incubation with the nanoconstructs. A thorough screening of the nanoconstructs in 13 different cancer cell lines is conducted to narrow down the potential targets for in vivo study. Before testing the in vivo efficacy, we evaluate the toxicity of the nanoconstructs in non-tumor animals, which confirms its safety for further in vivo applications. The accumulation of the nanoconstructs in two different cancerous tumors, however, suggests that further optimization of the design

  16. Targeted electrohydrodynamic printing for micro-reservoir drug delivery systems

    International Nuclear Information System (INIS)

    Microfluidic drug delivery systems consisting of a drug reservoir and microfluidic channels have shown the possibility of simple and robust modulation of drug release rate. However, the difficulty of loading a small quantity of drug into drug reservoirs at a micro-scale limited further development of such systems. Electrohydrodynamic (EHD) printing was employed to fill micro-reservoirs with controlled amount of drugs in the range of a few hundreds of picograms to tens of micrograms with spatial resolution of as small as 20 µm. Unlike most EHD systems, this system was configured in combination with an inverted microscope that allows in situ targeting of drug loading at micrometer scale accuracy. Methylene blue and rhodamine B were used as model drugs in distilled water, isopropanol and a polymer solution of a biodegradable polymer and dimethyl sulfoxide (DMSO). Also tetracycline-HCl/DI water was used as actual drug ink. The optimal parameters of EHD printing to load an extremely small quantity of drug into microscale drug reservoirs were investigated by changing pumping rates, the strength of an electric field and drug concentration. This targeted EHD technique was used to load drugs into the microreservoirs of PDMS microfluidic drug delivery devices and their drug release performance was demonstrated in vitro. (paper)

  17. Targeting WEE1 Kinase in Cancer.

    Science.gov (United States)

    Matheson, Christopher J; Backos, Donald S; Reigan, Philip

    2016-10-01

    WEE1 kinase plays a crucial role in the G2-M cell-cycle checkpoint arrest for DNA repair before mitotic entry. Normal cells repair damaged DNA during G1 arrest; however, cancer cells often have a deficient G1-S checkpoint and depend on a functional G2-M checkpoint for DNA repair. WEE1 is expressed at high levels in various cancer types including breast cancers, leukemia, melanoma, and adult and pediatric brain tumors. Many of these cancers are treated with DNA-damaging agents; therefore, targeting WEE1 for inhibition and compromising the G2-M checkpoint presents an opportunity to potentiate therapy. In this review we summarize the current WEE1 inhibitors, the potential for further inhibitor development, and the challenges in the clinic for the WEE1 inhibitor strategy. PMID:27427153

  18. Advances of Driver Gene and Targeted Therapy of Non-small Cell Lung Cancer

    OpenAIRE

    Zhang, Dan; Huang, Yan; Wang, Hongyang

    2014-01-01

    Lung cancer is the leading cause of cancer-related mortality in the worldwide. The discovery of drive gene makes tumor treatment is no longer "one-size-fits-all". Targeted therapy to change the present situation of cancer drugs become "bullet" with eyes, the effect is visible and bring a revolution in the treatment of lung cancer. The diver gene and targeted therapy have became the new cedule of non-small cell lung cancer (NSCLC). Society of Clinical Oncology (ASCO) has showed 11 kinds of div...

  19. Drugs acting on central nervous system (CNS) targets as leads for non-CNS targets

    OpenAIRE

    Kharkar, Prashant S.

    2014-01-01

    Innovative drug discovery approaches are currently needed to rejuvenate the shrinking product pipelines of the pharmaceutical companies across the globe. Here a theme is presented – the use of central nervous system (CNS) drugs as leads for non-CNS targets. The approach is related to the use of existing drugs for new indications. Suitable chemical modifications of the CNS drugs abolish their CNS penetration. These novel analogs may then be screened for activity against non-CNS targets. Carefu...

  20. Targeted liposomal drug delivery to monocytes and macrophages.

    OpenAIRE

    Ciara Kelly; Caroline Jefferies; Sally-Ann Cryan

    2011-01-01

    As the role of monocytes and macrophages in a range of diseases is better understood, strategies to target these cell types are of growing importance both scientifically and therapeutically. As particulate carriers, liposomes naturally target cells of the mononuclear phagocytic system (MPS), particularly macrophages. Loading drugs into liposomes can therefore offer an efficient means of drug targeting to MPS cells. Physicochemical properties including size, charge and lipid composition can ha...

  1. Intracellular Trafficking Considerations in the Development of Natural Ligand-Drug Molecular Conjugates for Cancer

    OpenAIRE

    Yoon, Dennis J.; Liu, Christina T.; Quinlan, Devin S.; Nafisi, Parsa M.; Kamei, Daniel T.

    2011-01-01

    Overexpressed receptors, characteristic of many cancers, have been targeted by various researchers to achieve a more specific treatment for cancer. A common approach is to use the natural ligand for the overexpressed receptor as a cancer-targeting agent which can deliver a chemically or genetically conjugated toxic molecule. However, it has been found that the therapeutic efficacy of such ligand-drug molecular conjugates can be limited, since they naturally follow the intracellular traffickin...

  2. Targeting cancer using KAT inhibitors to mimic lethal knockouts

    Science.gov (United States)

    Brown, James A.L.; Bourke, Emer; Eriksson, Leif A.; Kerin, Michael J.

    2016-01-01

    Two opposing enzyme classes regulate fundamental elements of genome maintenance, gene regulation and metabolism, either through addition of an acetyl moiety by histone acetyltransferases (HATs) or its removal by histone de-acetyltransferases (HDAC), and are exciting targets for drug development. Importantly, dysfunctional acetylation has been implicated in numerous diseases, including cancer. Within the HAT superfamily the MYST family holds particular interest, as its members are directly involved in the DNA damage response and repair pathways and crucially, several members have been shown to be down-regulated in common cancers (such as breast and prostate). In the present study we focus on the development of lysine (K) acetyltransferase inhibitors (KATi) targeting the MYST family member Tip60 (Kat5), an essential protein, designed or discovered through screening libraries. Importantly, Tip60 has been demonstrated to be significantly down-regulated in many cancers which urgently require new treatment options. We highlight current and future efforts employing these KATi as cancer treatments and their ability to synergize and enhance current cancer treatments. We investigate the different methods of KATi production or discovery, their mechanisms and their validation models. Importantly, the utility of KATi is based on a key concept: using KATi to abrogate the activity of an already down-regulated essential protein (effectively creating a lethal knockout) provides another innovative mechanism for targeting cancer cells, while significantly minimizing any off-target effects to normal cells. This approach, combined with the rapidly developing interest in KATi, suggests that KATi have a bright future for providing truly personalized therapies. PMID:27528742

  3. Computational optimisation of targeted DNA sequencing for cancer detection

    Science.gov (United States)

    Martinez, Pierre; McGranahan, Nicholas; Birkbak, Nicolai Juul; Gerlinger, Marco; Swanton, Charles

    2013-12-01

    Despite recent progress thanks to next-generation sequencing technologies, personalised cancer medicine is still hampered by intra-tumour heterogeneity and drug resistance. As most patients with advanced metastatic disease face poor survival, there is need to improve early diagnosis. Analysing circulating tumour DNA (ctDNA) might represent a non-invasive method to detect mutations in patients, facilitating early detection. In this article, we define reduced gene panels from publicly available datasets as a first step to assess and optimise the potential of targeted ctDNA scans for early tumour detection. Dividing 4,467 samples into one discovery and two independent validation cohorts, we show that up to 76% of 10 cancer types harbour at least one mutation in a panel of only 25 genes, with high sensitivity across most tumour types. Our analyses demonstrate that targeting ``hotspot'' regions would introduce biases towards in-frame mutations and would compromise the reproducibility of tumour detection.

  4. Polymeric micelles for solubilization and targeting of hydrophobic drugs

    OpenAIRE

    Miller, Tobias

    2013-01-01

    This thesis focussed on the encapsulation of hydrophobic drugs into polymeric micelles and was intended to show the strengths and limitations of these self-assembling systems in terms of solubilization and drug targeting. Characterization of hydrophobic drug solubilization prior to intravenous injection was one of the key goals of this thesis. For this purpose a novel drug loading procedure was developed based on mechanistic considerations during the loading processes (Chapter 2). The cosolve...

  5. Magnetic polymer nanospheres for anticancer drug targeting

    Energy Technology Data Exchange (ETDEWEB)

    JurIkova, A; Csach, K; Koneracka, M; Zavisova, V; Tomasovicova, N; Lancz, G; Kopcansky, P; Timko, M; Miskuf, J [Institute of Experimental Physics, Slovak Academy of Sciences, 040 01 Kosice (Slovakia); Muckova, M, E-mail: akasard@saske.s [Hameln rds a.s., 900 01 Modra (Slovakia)

    2010-01-01

    Poly(D,L-lactide-co-glycolide) polymer (PLGA) nanospheres loaded with biocom-patible magnetic fluid as a magnetic carrier and anticancer drug Taxol were prepared by the modified nanoprecipitation method with size of 200-250 nm in diameter. The PLGA polymer was utilized as a capsulation material due to its biodegradability and biocompatibility. Taxol as an important anticancer drug was chosen for its significant role against a wide range of tumours. Thermal properties of the drug-polymer system were characterized using thermal analysis methods. It was determined the solubility of Taxol in PLGA nanospheres. Magnetic properties investigated using SQUID magnetometry showed superparamagnetism of the prepared magnetic polymer nanospheres.

  6. Drug Repurposing: Far Beyond New Targets for Old Drugs

    DEFF Research Database (Denmark)

    Oprea, Tudor; Mestres, J.

    2012-01-01

    Repurposing drugs requires finding novel therapeutic indications compared to the ones for which they were already approved. This is an increasingly utilized strategy for finding novel medicines, one that capitalizes on previous investments while derisking clinical activities. This approach...

  7. Study Progress on Non-small Cell Lung Cancer Treated by EGFR-targeted Drug%EGFR靶向治疗非小细胞肺癌研究进展

    Institute of Scientific and Technical Information of China (English)

    陈勇

    2013-01-01

    非小细胞肺癌(NSCLC)是造成死亡最多的恶性肿瘤之一,发现晚、进展快、预后差,而且对于常规放疗化疗敏感性极低,数十年来其五年生存率一直徘徊在20%以下.EGFR靶向药物的发现为NSCLC的治疗带来了新的希望,以gefitinib(吉非替尼)和erlotinib(厄洛替尼)为代表的EGFR酪氨酸激酶抑制剂(EGFR tyrosine kinase inhibitor,EGFRTKI)对于携带某些EGFR突变的非小细胞肺癌(NSCLC)具有良好的疗效.虽然在EGFR靶向治疗非小细胞肺癌(NSCLC)上已经取得了一定成果,但是目前依然有很多相关问题亟待解决.%Of all malignant tumors, non - small cell lung cancer (NSCLC) is one of the biggest killers all over the world, normally with a late discovery, a rapid progression and a poor prognosis. NSCLC has a very low sensibility to conventional radiotherapy as well as chemotherapy, which make its five - year survival rate low than 20 % . However, recently the discovery of EGFR- targeted drug brings new hope to NSCLC patients. Represented by gefitinib and erlotinib, EGFR tyrosine kinase inhibitor (EGFR- TKI) has a good therapeutic effect on a part of NSCLC patients, who have some special EGFR mutations. Even if we get a big step on EGFR- targeted therapy on NSCLC, we still have many problems to solve.

  8. Targeted Immune Therapy of Ovarian Cancer

    Science.gov (United States)

    Knutson, Keith L.; Karyampudi, Lavakumar; Lamichhane, Purushottam; Preston, Claudia

    2014-01-01

    Clinical outcomes, such as recurrence free survival and overall survival, in ovarian cancer are quite variable, independent of common characteristics such as stage, response to therapy and grade. This disparity in outcomes warrants further exploration and therapeutic targeting into the interaction between the tumor and host. One compelling host characteristic that contributes both to the initiation and progression of ovarian cancer is the immune system. Hundreds of studies have confirmed a prominent role for the immune system in modifying the clinical course of the disease. Recent studies also show that anti-tumor immunity is often negated by immune regulatory cells present in the tumor microenvironment. Regulatory immune cells also directly enhance the pathogenesis through the release of various cytokines and chemokines, which together form an integrated pathologic network. Thus, in the future, research into immunotherapy targeting ovarian cancer will probably become increasingly focused on combination approaches that simultaneously augment immunity while preventing local immune suppression. In this article, we summarize important immunological targets that influence ovarian cancer outcome as well as include an update on newer immunotherapeutic strategies. PMID:25544369

  9. Targeting DNA Replication Stress for Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Jun Zhang

    2016-08-01

    Full Text Available The human cellular genome is under constant stress from extrinsic and intrinsic factors, which can lead to DNA damage and defective replication. In normal cells, DNA damage response (DDR mediated by various checkpoints will either activate the DNA repair system or induce cellular apoptosis/senescence, therefore maintaining overall genomic integrity. Cancer cells, however, due to constitutive growth signaling and defective DDR, may exhibit “replication stress” —a phenomenon unique to cancer cells that is described as the perturbation of error-free DNA replication and slow-down of DNA synthesis. Although replication stress has been proven to induce genomic instability and tumorigenesis, recent studies have counterintuitively shown that enhancing replicative stress through further loosening of the remaining checkpoints in cancer cells to induce their catastrophic failure of proliferation may provide an alternative therapeutic approach. In this review, we discuss the rationale to enhance replicative stress in cancer cells, past approaches using traditional radiation and chemotherapy, and emerging approaches targeting the signaling cascades induced by DNA damage. We also summarize current clinical trials exploring these strategies and propose future research directions including the use of combination therapies, and the identification of potential new targets and biomarkers to track and predict treatment responses to targeting DNA replication stress.

  10. Targeting DNA Replication Stress for Cancer Therapy

    Science.gov (United States)

    Zhang, Jun; Dai, Qun; Park, Dongkyoo; Deng, Xingming

    2016-01-01

    The human cellular genome is under constant stress from extrinsic and intrinsic factors, which can lead to DNA damage and defective replication. In normal cells, DNA damage response (DDR) mediated by various checkpoints will either activate the DNA repair system or induce cellular apoptosis/senescence, therefore maintaining overall genomic integrity. Cancer cells, however, due to constitutive growth signaling and defective DDR, may exhibit “replication stress” —a phenomenon unique to cancer cells that is described as the perturbation of error-free DNA replication and slow-down of DNA synthesis. Although replication stress has been proven to induce genomic instability and tumorigenesis, recent studies have counterintuitively shown that enhancing replicative stress through further loosening of the remaining checkpoints in cancer cells to induce their catastrophic failure of proliferation may provide an alternative therapeutic approach. In this review, we discuss the rationale to enhance replicative stress in cancer cells, past approaches using traditional radiation and chemotherapy, and emerging approaches targeting the signaling cascades induced by DNA damage. We also summarize current clinical trials exploring these strategies and propose future research directions including the use of combination therapies, and the identification of potential new targets and biomarkers to track and predict treatment responses to targeting DNA replication stress. PMID:27548226

  11. Novel perspectives in cancer therapy: Targeting ion channels.

    Science.gov (United States)

    Arcangeli, Annarosa; Becchetti, Andrea

    2015-01-01

    By controlling ion fluxes at multiple time scales, ion channels shape rapid cell signals, such as action potential and synaptic transmission, as well as much slower processes, such as mitosis and cell migration. As is currently increasingly recognized, a variety of channel types are involved in cancer hallmarks, and regulate specific stages of neoplastic progression. Long-term in vitro work has established that inhibition of these ion channels impairs the growth of cancer cells. Recently, these studies have been followed up in vivo, hence revealing that ion channels constitute promising pharmacological targets in oncology. The channel proteins can be often accessed from the extracellular milieu, which allows use of lower drug doses and decrease untoward toxicity. However, because of the central physiological roles exerted by ion channels in excitable cells, other types of side effects may arise, the gravest of which is cardiac arrhythmia. A paradigmatic case is offered by Kv11.1 (hERG1) channels. HERG1 blockers attenuate the progression of both hematologic malignancies and solid tumors, but may also lead to the lengthening of the electrocardiographic QT interval, thus predisposing the patient to ventricular arrhythmias. These side effects can be avoided by specifically inhibiting the channel isoforms which are highly expressed in certain tumors, such as Kv11.1B and the neonatal forms of voltage-gated Na(+) channels. Preclinical studies are also being explored in breast and prostate cancer (targeting voltage-gated Na(+) channels), and gliomas (targeting CLC-3). Overall, the possible approaches to improve the efficacy and safety of ion channel targeting in oncology include: (1) the development of specific inhibitors for the channel subtypes expressed in specific tumors; (2) drug delivery into the tumor by using antibodies or nanotechnology-based approaches; (3) combination regimen therapy and (4) blocking specific conformational states of the ion channel. We believe

  12. Targeting Cancer Metabolism - Revisiting the Warburg Effects.

    Science.gov (United States)

    Tran, Quangdon; Lee, Hyunji; Park, Jisoo; Kim, Seon-Hwan; Park, Jongsun

    2016-07-01

    After more than half of century since the Warburg effect was described, this atypical metabolism has been standing true for almost every type of cancer, exhibiting higher glycolysis and lactate metabolism and defective mitochondrial ATP production. This phenomenon had attracted many scientists to the problem of elucidating the mechanism of, and reason for, this effect. Several models based on oncogenic studies have been proposed, such as the accumulation of mitochondrial gene mutations, the switch from oxidative phosphorylation respiration to glycolysis, the enhancement of lactate metabolism, and the alteration of glycolytic genes. Whether the Warburg phenomenon is the consequence of genetic dysregulation in cancer or the cause of cancer remains unknown. Moreover, the exact reasons and physiological values of this peculiar metabolism in cancer remain unclear. Although there are some pharmacological compounds, such as 2-deoxy-D-glucose, dichloroacetic acid, and 3-bromopyruvate, therapeutic strategies, including diet, have been developed based on targeting the Warburg effect. In this review, we will revisit the Warburg effect to determine how much scientists currently understand about this phenomenon and how we can treat the cancer based on targeting metabolism. PMID:27437085

  13. Targeting Cancer Metabolism - Revisiting the Warburg Effects

    Science.gov (United States)

    Tran, Quangdon; Lee, Hyunji; Park, Jisoo; Kim, Seon-Hwan; Park, Jongsun

    2016-01-01

    After more than half of century since the Warburg effect was described, this atypical metabolism has been standing true for almost every type of cancer, exhibiting higher glycolysis and lactate metabolism and defective mitochondrial ATP production. This phenomenon had attracted many scientists to the problem of elucidating the mechanism of, and reason for, this effect. Several models based on oncogenic studies have been proposed, such as the accumulation of mitochondrial gene mutations, the switch from oxidative phosphorylation respiration to glycolysis, the enhancement of lactate metabolism, and the alteration of glycolytic genes. Whether the Warburg phenomenon is the consequence of genetic dysregulation in cancer or the cause of cancer remains unknown. Moreover, the exact reasons and physiological values of this peculiar metabolism in cancer remain unclear. Although there are some pharmacological compounds, such as 2-deoxy-D-glucose, dichloroacetic acid, and 3-bromopyruvate, therapeutic strategies, including diet, have been developed based on targeting the Warburg effect. In this review, we will revisit the Warburg effect to determine how much scientists currently understand about this phenomenon and how we can treat the cancer based on targeting metabolism. PMID:27437085

  14. Targeting cancer stem cells in hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    He AR

    2014-12-01

    Full Text Available Aiwu Ruth He,1 Daniel C Smith,1 Lopa Mishra2 1Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, 2Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Abstract: The poor outcome of patients with hepatocellular carcinoma (HCC is attributed to recurrence of the disease after curative treatment and the resistance of HCC cells to conventional chemotherapy, which may be explained partly by the function of liver cancer stem cells (CSCs. Liver CSCs have emerged as an important therapeutic target against HCC. Numerous surface markers for liver CSCs have been identified, and include CD133, CD90, CD44, CD13, and epithelial cell adhesion molecules. These surface markers serve not only as tools for identifying and isolating liver CSCs but also as therapeutic targets for eradicating these cells. In studies of animal models and large-scale genomic analyses of human HCC samples, many signaling pathways observed in normal stem cells have been found to be altered in liver CSCs, which accounts for the stemness and aggressive behavior of these cells. Antibodies and small molecule inhibitors targeting the signaling pathways have been evaluated at different levels of preclinical and clinical development. Another strategy is to promote the differentiation of liver CSCs to less aggressive HCC that is sensitive to conventional chemotherapy. Disruption of the tumor niche essential for liver CSC homeostasis has become a novel strategy in cancer treatment. To overcome the challenges in developing treatment for liver CSCs, more research into the genetic makeup of patient tumors that respond to treatment may lead to more effective therapy. Standardization of HCC CSC tumor markers would be helpful for measuring the CSC response to these agents. Herein, we review the current strategies for developing treatment to eradicate liver CSCs and to improve the outcome for patients with

  15. A meta-analysis for CXCR4 as a prognostic marker and potential drug target in non-small cell lung cancer

    Directory of Open Access Journals (Sweden)

    Zhang C

    2015-06-01

    Full Text Available Changyuan Zhang,1,* Jie Li,2,* Yi Han,3 Jian Jiang4 1Department of Cardiothoracic Surgery, Inner Mongolia Autonomous Region People’s Hospital, Inner Mongolia; 2Department of Oncology, 3Department of Thoracic Surgery, Beijing Chest Hospital, 4Department of Thoracic Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, People’s Republic of China *These authors contributed equally to this work Background: Recent reports have shown that C-X-C chemokine receptor type 4 (CXCR4 is a candidate oncogene in several types of human tumors, including non-small cell lung cancer (NSCLC. However, the correlation between CXCR4 expression and clinicopathological characteristics of NSCLC remains controversial and has not been emphasized. The aim of this study is to quantitatively evaluate the association of CXCR4 expression with the incidence of NSCLC and clinicopathological characteristics by performing a meta-analysis.Methods: A detailed literature search was carried out for related research publications. Only articles in which CXCR4 expression was detected by immunohistochemical staining were included. Odds ratio (OR and hazard ratio (HR with 95% confidence intervals (CIs were calculated and summarized.Results: Final analysis of 1,872 NSCLC patients from 19 eligible studies was performed. We observed that CXCR4 expression was significantly higher in NSCLC than in normal lung tissue, based on the pooled OR from ten studies, including 678 NSCLCs and 189 normal lung tissues (OR =16.66, 95% CI =6.94–40.02, P<0.00001. CXCR4 expression was also significantly associated with clinical stages, metastatic status, and overall survival (OS in NSCLC patients. In addition, CXCR4 mRNA high expression was found to correlate with worse OS of all NSCLC patients followed for 20 years, HR =1.24, P=0.0047.Conclusion: The present meta-analysis indicated that CXCR4 protein expression is associated with an increased risk and worse survival in NSCLC patients

  16. Carbon materials for drug delivery & cancer therapy

    Directory of Open Access Journals (Sweden)

    Zhuang Liu

    2011-07-01

    Full Text Available Carbon nanotubes and graphene are both low-dimensional sp2 carbon nanomaterials exhibiting many unique physical and chemical properties that are interesting in a wide range of areas including nanomedicine. Since 2004, carbon nanotubes have been extensively explored as drug delivery carriers for the intracellular transport of chemotherapy drugs, proteins, and genes. In vivo cancer treatment with carbon nanotubes has been demonstrated in animal experiments by several different groups. Recently, graphene, another allotrope of carbon, has also shown promise in various biomedical applications. In this article, we will highlight recent research on these two categories of closely related carbon nanomaterials for applications in drug delivery and cancer therapy, and discuss the opportunities and challenges in this rapidly growing field.

  17. Metformin: An Emerging New Therapeutic Option for Targeting Cancer Stem Cells and Metastasis

    Directory of Open Access Journals (Sweden)

    Ramandeep Rattan

    2012-01-01

    Full Text Available Metastasis is an intricate process by which a small number of cancer cells from the primary tumor site undergo numerous alterations, which enables them to form secondary tumors at another and often multiple sites in the host. Transition of a cancer cell from epithelial to mesenchymal phenotype is thought to be the first step in the progression of metastasis. Recently, the recognition of cancer stem cells has added to the perplexity in understanding metastasis, as studies suggest cancer stem cells to be the originators of metastasis. All current and investigative drugs have been unable to prevent or reverse metastasis, as a result of which most metastatic cancers are incurable. A potential drug that can be considered is metformin, an oral hypoglycemic drug. In this review we discuss the potential of metformin in targeting both epithelial to mesenchymal transition and cancer stem cells in combating cancer metastases.

  18. Targeting oncogenes to improve breast cancer chemotherapy.

    Science.gov (United States)

    Christensen, Laura A; Finch, Rick A; Booker, Adam J; Vasquez, Karen M

    2006-04-15

    Despite recent advances in treatment, breast cancer remains a serious health threat for women. Traditional chemotherapies are limited by a lack of specificity for tumor cells and the cell cycle dependence of many chemotherapeutic agents. Here we report a novel strategy to help overcome these limitations. Using triplex-forming oligonucleotides (TFOs) to direct DNA damage site-specifically to oncogenes overexpressed in human breast cancer cells, we show that the effectiveness of the anticancer nucleoside analogue gemcitabine can be improved significantly. TFOs targeted to the promoter region of c-myc directly inhibited gene expression by approximately 40%. When used in combination, specific TFOs increased the incorporation of gemcitabine at the targeted site approximately 4-fold, presumably due to induction of replication-independent DNA synthesis. Cells treated with TFOs and gemcitabine in combination showed a reduction in both cell survival and capacity for anchorage-independent growth (approximately 19% of untreated cells). This combination affected the tumorigenic potential of these cancer cells to a significantly greater extent than either treatment alone. This novel strategy may be used to increase the range of effectiveness of antitumor nucleosides in any tumor which overexpresses a targetable oncogene. Multifaceted chemotherapeutic approaches such as this, coupled with triplex-directed gene targeting, may lead to more than incremental improvements in nonsurgical treatment of breast tumors. PMID:16618728

  19. Breast Cancer Survivorship Care: Targeting a Colorectal Cancer Education Intervention

    Directory of Open Access Journals (Sweden)

    Sherri G. Homan

    2015-08-01

    Full Text Available Breast cancer survivors are at risk of developing a second primary cancer. Colorectal cancer (CRC is one of the leading second primary cancers, and it is often preventable. We developed a multi-component educational tool to inform and encourage women breast cancer survivors to engage in CRC screening. To assess the strengths and weakness of the tool and to improve the relevancy to the target audience, we convened four focus groups of women breast cancer survivors in Missouri. We also assessed the potential impact of the tool on the knowledge, attitudes, and beliefs regarding CRC and collected information on the barriers to CRC screening through pre- and post-focus groups’ questionnaires. A total of 43 women breast cancer survivors participated and provided very valuable suggestions on design and content to update the tool. Through the process and comparing pre- and post-focus group assessments, a significantly higher proportion of breast cancer survivors strongly agreed or agreed that CRC is preventable (78.6% vs. 96.9%, p = 0.02 and became aware that they were at a slightly increased risk for CRC (18.6% vs. 51.7%, p = 0.003. The most cited barrier was the complexity of preparation for colonoscopy.

  20. Efficient intracellular delivery of 5-fluorodeoxyuridine into colon cancer cells by targeted immunoliposomes

    NARCIS (Netherlands)

    Koning, GA; Kamps, JAAM; Scherphof, GL

    2002-01-01

    Immunoliposomes, liposomes with monoclonal antibodies attached, are being developed for targeting the anti-cancer drug 5-fluoro-2'-deoxyuridine (FUdR) to colon cancer cells. A monoclonal antibody against the rat colon carcinoma CC531 was covalently coupled to liposomes containing a dipalmitoylated d

  1. Novel therapeutic Strategies for Targeting Liver Cancer Stem Cells

    Directory of Open Access Journals (Sweden)

    Naoki Oishi, Xin Wei Wang

    2011-01-01

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

  2. 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.

  3. 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

  4. Limited Efficiency of Drug Delivery to Specific Intracellular Organelles Using Subcellularly "Targeted" Drug Delivery Systems.

    Science.gov (United States)

    Maity, Amit Ranjan; Stepensky, David

    2016-01-01

    Many drugs have been designed to act on intracellular targets and to affect intracellular processes inside target cells. For the desired effects to be exerted, these drugs should permeate target cells and reach specific intracellular organelles. This subcellular drug targeting approach has been proposed for enhancement of accumulation of these drugs in target organelles and improved efficiency. This approach is based on drug encapsulation in drug delivery systems (DDSs) and/or their decoration with specific targeting moieties that are intended to enhance the drug/DDS accumulation in the intracellular organelle of interest. During recent years, there has been a constant increase in interest in DDSs targeted to specific intracellular organelles, and many different approaches have been proposed for attaining efficient drug delivery to specific organelles of interest. However, it appears that in many studies insufficient efforts have been devoted to quantitative analysis of the major formulation parameters of the DDSs disposition (efficiency of DDS endocytosis and endosomal escape, intracellular trafficking, and efficiency of DDS delivery to the target organelle) and of the resulting pharmacological effects. Thus, in many cases, claims regarding efficient delivery of drug/DDS to a specific organelle and efficient subcellular targeting appear to be exaggerated. On the basis of the available experimental data, it appears that drugs/DDS decoration with specific targeting residues can affect their intracellular fate and result in preferential drug accumulation within an organelle of interest. However, it is not clear whether these approaches will be efficient in in vivo settings and be translated into preclinical and clinical applications. Studies that quantitatively assess the mechanisms, barriers, and efficiencies of subcellular drug delivery and of the associated toxic effects are required to determine the therapeutic potential of subcellular DDS targeting.

  5. Nanoparticle-based targeted gene therapy for lung cancer

    OpenAIRE

    Lee, Hung-Yen; Mohammed, Kamal A; Nasreen, Najmunnisa

    2016-01-01

    Despite striking insights on lung cancer progression, and cutting-edge therapeutic approaches the survival of patients with lung cancer, remains poor. In recent years, targeted gene therapy with nanoparticles is one of the most rapidly evolving and extensive areas of research for lung cancer. The major goal of targeted gene therapy is to bring forward a safe and efficient treatment to cancer patients via specifically targeting and deterring cancer cells in the body. To achieve high therapeuti...

  6. Transcription factors as targets of anticancer drugs.

    Science.gov (United States)

    Gniazdowski, M; Czyz, M

    1999-01-01

    Several general and gene- and cell-selective transcription factors are required for specific transcription to occur. Many of them exert their functions through specific contacts either in the promoter region or at distant sequences regulating the initiation. These contacts may be altered by anticancer drugs which form non-covalent complexes with DNA. Covalent modifications of DNA by alkylating agents may prevent transcription factors from recognizing their specific sequences or may constitute multiple "unnatural" binding sites in DNA which attract the factors thus decreasing their availability in the cell. The anticancer drug-transcription factor interplay which is based on specific interactions with DNA may contribute to pharmacological properties of the former and provide a basis for the search for new drugs. PMID:10547027

  7. New targeted therapies in pancreatic cancer.

    Science.gov (United States)

    Seicean, Andrada; Petrusel, Livia; Seicean, Radu

    2015-05-28

    Patients with pancreatic cancer have a poor prognosis with a median survival of 4-6 mo and a 5-year survival of less than 5%. Despite therapy with gemcitabine, patient survival does not exceed 6 mo, likely due to natural resistance to gemcitabine. Therefore, it is hoped that more favorable results can be obtained by using guided immunotherapy against molecular targets. This review summarizes the new leading targeted therapies in pancreatic cancers, focusing on passive and specific immunotherapies. Passive immunotherapy may have a role for treatment in combination with radiochemotherapy, which otherwise destroys the immune system along with tumor cells. It includes mainly therapies targeting against kinases, including epidermal growth factor receptor, Ras/Raf/mitogen-activated protein kinase cascade, human epidermal growth factor receptor 2, insulin growth factor-1 receptor, phosphoinositide 3-kinase/Akt/mTOR and hepatocyte growth factor receptor. Therapies against DNA repair genes, histone deacetylases, microRNA, and pancreatic tumor tissue stromal elements (stromal extracellular matric and stromal pathways) are also discussed. Specific immunotherapies, such as vaccines (whole cell recombinant, peptide, and dendritic cell vaccines), adoptive cell therapy and immunotherapy targeting tumor stem cells, have the role of activating antitumor immune responses. In the future, treatments will likely include personalized medicine, tailored for numerous molecular therapeutic targets of multiple pathogenetic pathways. PMID:26034349

  8. Lipoproteins tethered dendrimeric nanoconstructs for effective targeting to cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Jain, Anupriya; Jain, Keerti, E-mail: keertijain02@gmail.com; Mehra, Neelesh Kumar, E-mail: neelesh81mph@gmail.com; Jain, N. K., E-mail: dr.jnarendr@gmail.com [Dr. H. S. Gour University, Pharmaceutics Research Laboratory, Department of Pharmaceutical Sciences (India)

    2013-10-15

    In the present investigation, poly (propylene imine) dendrimers up to fifth generation (PPI G5.0) were synthesized using ethylene diamine and acrylonitrile. Lipoproteins (high-density lipoprotein; HDL and low-density lipoprotein; LDL) were isolated from human plasma by discontinuous density gradient ultracentrifugation, characterized and tethered to G5.0 PPI dendrimers to construct LDL- and HDL-conjugated dendrimeric nanoconstructs for tumor-specific delivery of docetaxel. Developed formulations showed sustained release characteristics in in vitro drug release and in vivo pharmacokinetic studies. The cancer targeting potential of lipoprotein coupled dendrimers was investigated by ex vivo cytotoxicity and cell uptake studies using human hepatocellular carcinoma cell lines (HepG2 cells) and biodistribution studies in albino rats of Sprague-Dawley strain. Lipoprotein anchored dendrimeric nanoconstructs showed significant uptake by cancer cells as well as higher biodistribution of docetaxel to liver and spleen. It is concluded that these precisely synthesized engineered dendrimeric nanoconstructs could serve as promising drug carrier for fighting with the fatal disease, i.e., cancer, attributed to their defined targeting and therapeutic potential.

  9. Evolving molecularly targeted therapies for advanced-stage thyroid cancers.

    Science.gov (United States)

    Bible, Keith C; Ryder, Mabel

    2016-07-01

    Increased understanding of disease-specific molecular targets of therapy has led to the regulatory approval of two drugs (vandetanib and cabozantinib) for the treatment of medullary thyroid cancer (MTC), and two agents (sorafenib and lenvatinib) for the treatment of radioactive- iodine refractory differentiated thyroid cancer (DTC) in both the USA and in the EU. The effects of these and other therapies on overall survival and quality of life among patients with thyroid cancer, however, remain to be more-clearly defined. When applied early in the disease course, intensive multimodality therapy seems to improve the survival outcomes of patients with anaplastic thyroid cancer (ATC), but salvage therapies for ATC are of uncertain benefit. Additional innovative, rationally designed therapeutic strategies are under active development both for patients with DTC and for patients with ATC, with multiple phase II and phase III randomized clinical trials currently ongoing. Continued effort is being made to identify further signalling pathways with potential therapeutic relevance in thyroid cancers, as well as to elaborate on the complex interactions between signalling pathways, with the intention of translating these discoveries into effective and personalized therapies. Herein, we summarize the progress made in molecular medicine for advanced-stage thyroid cancers of different histotypes, analyse how these developments have altered - and might further refine - patient care, and identify open questions for future research. PMID:26925962

  10. 抗癌药研发的新策略:纳米靶向的高分子偶联抗癌症干细胞药物%New Strategy for the Research & DeveloPment of Anti - cancer Drugs:Nano - Targeting Polymer -(Anti - CSC Drug)Conjugates

    Institute of Scientific and Technical Information of China (English)

    谢爱云; 李小华; 李高全

    2015-01-01

    In the past 20 years,a total of 5 polymer - drug conjugates(including 3 antibody - drug conjugates)have been approved by FDA for market sale. Besides these,many polymer - drug conjugates have been moved to clinical trials. As a very small subpopulation in tumor(only 0. 1% ~ 5% ),the cancer stem cell(cSc)is the root to cause drug resistance, relapse and metastasis of cancer. In the past few years,great progress has been made on the investigation of the anti - cSc drugs. About 30 anti - cSc investigational new drugs have been advanced to clinical trials. Synthesis of polymer -(anti -cSc drug)conjugates can help to solve the problems of anti - cSc drugs such as poor aqueous solubility,poor metabolic stability,side - effect,drug resistance,targetability,etc. Overall,combining polymer therapeutics nanomedicine with the anti - cSc drugs and synthesizing polymer -(anti - cSc drug)conjugates has brought new hope for curing the cancer and possesses bright prospect.%过去二十多年来,已有5个高分子偶联抗癌药(包括3个抗体偶联药物)被 FDA 批准进入市场,此外还有很多高分子偶联抗癌药被推向临床试验。作为肿瘤中存在的很小的细胞亚群(只占0.1%~5%),癌症干细胞是导致肿瘤耐药、复发和转移的根源。过去几年来,抗癌症干细胞药物的研究获得了飞速的进展,已有近30个抗癌症干细胞药物被推向临床试验。合成高分子偶联抗癌症干细胞药物有助于解决抗癌症干细胞药物水溶性差、代谢稳定性差、毒副作用、抗药性、靶向性等问题。将高分子治疗纳米医学与抗癌症干细胞药物结合,合成高分子偶联抗癌症干细胞药物,在与传统抗癌药联用的情况下,既能清除癌症干细胞,又能杀灭癌细胞,为治愈癌症带来了新的希望,具有极其广阔的前景。

  11. Nanotechnology-based intelligent drug design for cancer metastasis treatment.

    Science.gov (United States)

    Gao, Yu; Xie, Jingjing; Chen, Haijun; Gu, Songen; Zhao, Rongli; Shao, Jingwei; Jia, Lee

    2014-01-01

    Traditional chemotherapy used today at clinics is mainly inherited from the thinking and designs made four decades ago when the Cancer War was declared. The potency of those chemotherapy drugs on in-vitro cancer cells is clearly demonstrated at even nanomolar levels. However, due to their non-specific effects in the body on normal tissues, these drugs cause toxicity, deteriorate patient's life quality, weaken the host immunosurveillance system, and result in an irreversible damage to human's own recovery power. Owing to their unique physical and biological properties, nanotechnology-based chemotherapies seem to have an ability to specifically and safely reach tumor foci with enhanced efficacy and low toxicity. Herein, we comprehensively examine the current nanotechnology-based pharmaceutical platforms and strategies for intelligent design of new nanomedicines based on targeted drug delivery system (TDDS) for cancer metastasis treatment, analyze the pros and cons of nanomedicines versus traditional chemotherapy, and evaluate the importance that nanomaterials can bring in to significantly improve cancer metastasis treatment.

  12. Cell-specific biomarkers and targeted biopharmaceuticals for breast cancer treatment.

    Science.gov (United States)

    Liu, Mei; Li, Zhiyang; Yang, Jingjing; Jiang, Yanyun; Chen, Zhongsi; Ali, Zeeshan; He, Nongyue; Wang, Zhifei

    2016-08-01

    Breast cancer is the second leading cause of cancer death among women, and its related treatment has been attracting significant attention over the past decades. Among the various treatments, targeted therapy has shown great promise as a precision treatment, by binding to cancer cell-specific biomarkers. So far, great achievements have been made in targeted therapy of breast cancer. In this review, we first discuss cell-specific biomarkers, which are not only useful for classification of breast cancer subtyping but also can be utilized as goals for targeted therapy. Then, the innovative and generic-targeted biopharmaceuticals for breast cancer, including monoclonal antibodies, non-antibody proteins and small molecule drugs, are reviewed. Finally, we provide our outlook on future developments of biopharmaceuticals, and provide solutions to problems in this field. PMID:27312135

  13. Cell-specific biomarkers and targeted biopharmaceuticals for breast cancer treatment.

    Science.gov (United States)

    Liu, Mei; Li, Zhiyang; Yang, Jingjing; Jiang, Yanyun; Chen, Zhongsi; Ali, Zeeshan; He, Nongyue; Wang, Zhifei

    2016-08-01

    Breast cancer is the second leading cause of cancer death among women, and its related treatment has been attracting significant attention over the past decades. Among the various treatments, targeted therapy has shown great promise as a precision treatment, by binding to cancer cell-specific biomarkers. So far, great achievements have been made in targeted therapy of breast cancer. In this review, we first discuss cell-specific biomarkers, which are not only useful for classification of breast cancer subtyping but also can be utilized as goals for targeted therapy. Then, the innovative and generic-targeted biopharmaceuticals for breast cancer, including monoclonal antibodies, non-antibody proteins and small molecule drugs, are reviewed. Finally, we provide our outlook on future developments of biopharmaceuticals, and provide solutions to problems in this field.

  14. A review on target drug delivery:magnetic microspheres

    Institute of Scientific and Technical Information of China (English)

    Amit Chandna; Deepa Batra; Satinder Kakar; Ramandeep Singh

    2013-01-01

    Novel drug delivery system aims to deliver the drug at a rate directed by the needs of the body during the period of treatment, and target the active entity to the site of action.A number of novel drug delivery systems have emerged encompassing various routes of administration, to achieve controlled and targeted drug delivery, magnetic micro carriers being one of them. Magnetic microsphere is newer approach in pharmaceutical field.Magnetic microspheres as an alternative to traditional radiation methods which use highly penetrating radiation that is absorbed throughout the body.Its use is limited by toxicity and side effects.The aim of the specific targeting is to enhance the efficiency of drug delivery & at the same time to reduce the toxicity & side effects.This kind of delivery system is very much important which localises the drug to the disease site.In this larger amount of freely circulating drug can be replaced by smaller amount of magnetically targeted drug.Magnetic carriers receive magnetic responses to a magnetic field from incorporated materials that are used for magnetic microspheres are chitosan, dextran etc. magnetic microspheres can be prepared from a variety of carrier material. One of the most utilized is serum albumin from human or other appropriate species.Drug release from albumin microspheres can be sustained or controlled by various stabilization procedures generally involving heat or chemical cross-linking of the protein carrier matrix.

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

    Science.gov (United States)

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

    2014-02-01

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

  16. Bioreductive prodrugs as cancer therapeutics:targeting tumor hypoxia

    Institute of Scientific and Technical Information of China (English)

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

    2014-01-01

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

  17. Targeting inflammation in pancreatic cancer: Clinical translation.

    Science.gov (United States)

    Steele, Colin William; Kaur Gill, Nina Angharad; Jamieson, Nigel Balfour; Carter, Christopher Ross

    2016-04-15

    Preclinical modelling studies are beginning to aid development of therapies targeted against key regulators of pancreatic cancer progression. Pancreatic cancer is an aggressive, stromally-rich tumor, from which few people survive. Within the tumor microenvironment cellular and extracellular components exist, shielding tumor cells from immune cell clearance, and chemotherapy, enhancing progression of the disease. The cellular component of this microenvironment consists mainly of stellate cells and inflammatory cells. New findings suggest that manipulation of the cellular component of the tumor microenvironment is possible to promote immune cell killing of tumor cells. Here we explore possible immunogenic therapeutic strategies. Additionally extracellular stromal elements play a key role in protecting tumor cells from chemotherapies targeted at the pancreas. We describe the experimental findings and the pitfalls associated with translation of stromally targeted therapies to clinical trial. Finally, we discuss the key inflammatory signal transducers activated subsequent to driver mutations in oncogenic Kras in pancreatic cancer. We present the preclinical findings that have led to successful early trials of STAT3 inhibitors in pancreatic adenocarcinoma. PMID:27096033

  18. TargetNet: a web service for predicting potential drug-target interaction profiling via multi-target SAR models.

    Science.gov (United States)

    Yao, Zhi-Jiang; Dong, Jie; Che, Yu-Jing; Zhu, Min-Feng; Wen, Ming; Wang, Ning-Ning; Wang, Shan; Lu, Ai-Ping; Cao, Dong-Sheng

    2016-05-01

    Drug-target interactions (DTIs) are central to current drug discovery processes and public health fields. Analyzing the DTI profiling of the drugs helps to infer drug indications, adverse drug reactions, drug-drug interactions, and drug mode of actions. Therefore, it is of high importance to reliably and fast predict DTI profiling of the drugs on a genome-scale level. Here, we develop the TargetNet server, which can make real-time DTI predictions based only on molecular structures, following the spirit of multi-target SAR methodology. Naïve Bayes models together with various molecular fingerprints were employed to construct prediction models. Ensemble learning from these fingerprints was also provided to improve the prediction ability. When the user submits a molecule, the server will predict the activity of the user's molecule across 623 human proteins by the established high quality SAR model, thus generating a DTI profiling that can be used as a feature vector of chemicals for wide applications. The 623 SAR models related to 623 human proteins were strictly evaluated and validated by several model validation strategies, resulting in the AUC scores of 75-100 %. We applied the generated DTI profiling to successfully predict potential targets, toxicity classification, drug-drug interactions, and drug mode of action, which sufficiently demonstrated the wide application value of the potential DTI profiling. The TargetNet webserver is designed based on the Django framework in Python, and is freely accessible at http://targetnet.scbdd.com . PMID:27167132

  19. A RNA-DNA Hybrid Aptamer for Nanoparticle-Based Prostate Tumor Targeted Drug Delivery

    OpenAIRE

    Leach, John C.; Andrew Wang; Kaiming Ye; Sha Jin

    2016-01-01

    The side effects of radio- and chemo-therapy pose long-term challenges on a cancer patient’s health. It is, therefore, highly desirable to develop more effective therapies that can specifically target carcinoma cells without damaging normal and healthy cells. Tremendous efforts have been made in the past to develop targeted drug delivery systems for solid cancer treatment. In this study, a new aptamer, A10-3-J1, which recognizes the extracellular domain of the prostate specific membrane antig...

  20. Leveraging Big Data to Transform Target Selection and Drug Discovery

    Science.gov (United States)

    Chen, B; Butte, AJ

    2016-01-01

    The advances of genomics, sequencing, and high throughput technologies have led to the creation of large volumes of diverse datasets for drug discovery. Analyzing these datasets to better understand disease and discover new drugs is becoming more common. Recent open data initiatives in basic and clinical research have dramatically increased the types of data available to the public. The past few years have witnessed successful use of big data in many sectors across the whole drug discovery pipeline. In this review, we will highlight the state of the art in leveraging big data to identify new targets, drug indications, and drug response biomarkers in this era of precision medicine. PMID:26659699

  1. Leveraging big data to transform target selection and drug discovery

    Science.gov (United States)

    Butte, AJ

    2016-01-01

    The advances of genomics, sequencing, and high throughput technologies have led to the creation of large volumes of diverse datasets for drug discovery. Analyzing these datasets to better understand disease and discover new drugs is becoming more common. Recent open data initiatives in basic and clinical research have dramatically increased the types of data available to the public. The past few years have witnessed successful use of big data in many sectors across the whole drug discovery pipeline. In this review, we will highlight the state of the art in leveraging big data to identify new targets, drug indications, and drug response biomarkers in this era of precision medicine. PMID:26659699

  2. Peptide based platforms for cancer drug delivery

    OpenAIRE

    Perillo, Emiliana

    2015-01-01

    Cancer remains one of main causes of death in humans, accounting for 8.2 milion deaths worldwide in 2012. Chemotherapy, the most widely used cancer therapy, is the most effective and potent strategy to treat malignant tumors, but has the disadvantage of not delivering the therapeutic agents only to tumor sites. Nanomedicine may allow the controlled release of drugs by biodegradation and self-regulation of nanomaterials in vitro and in vivo. The goal of this PhD project was to create a del...

  3. Targeting copper in cancer therapy: 'Copper That Cancer'.

    Science.gov (United States)

    Denoyer, Delphine; Masaldan, Shashank; La Fontaine, Sharon; Cater, Michael A

    2015-11-01

    Copper is an essential micronutrient involved in fundamental life processes that are conserved throughout all forms of life. The ability of copper to catalyze oxidation-reduction (redox) reactions, which can inadvertently lead to the production of reactive oxygen species (ROS), necessitates the tight homeostatic regulation of copper within the body. Many cancer types exhibit increased intratumoral copper and/or altered systemic copper distribution. The realization that copper serves as a limiting factor for multiple aspects of tumor progression, including growth, angiogenesis and metastasis, has prompted the development of copper-specific chelators as therapies to inhibit these processes. Another therapeutic approach utilizes specific ionophores that deliver copper to cells to increase intracellular copper levels. The therapeutic window between normal and cancerous cells when intracellular copper is forcibly increased, is the premise for the development of copper-ionophores endowed with anticancer properties. Also under investigation is the use of copper to replace platinum in coordination complexes currently used as mainstream chemotherapies. In comparison to platinum-based drugs, these promising copper coordination complexes may be more potent anticancer agents, with reduced toxicity toward normal cells and they may potentially circumvent the chemoresistance associated with recurrent platinum treatment. In addition, cancerous cells can adapt their copper homeostatic mechanisms to acquire resistance to conventional platinum-based drugs and certain copper coordination complexes can re-sensitize cancer cells to these drugs. This review will outline the biological importance of copper and copper homeostasis in mammalian cells, followed by a discussion of our current understanding of copper dysregulation in cancer, and the recent therapeutic advances using copper coordination complexes as anticancer agents.

  4. Liver Label Retaining Cancer Cells Are Relatively Resistant to the Reported Anti-Cancer Stem Cell Drug Metformin

    OpenAIRE

    Xin, Hong-Wu; Ambe, Chenwi M.; Miller, Tyler C.; Chen, Jin-Qiu; Wiegand, Gordon W.; Anderson, Andrew J.; Ray, Satyajit; Mullinax, John E.; Hari, Danielle M; Koizumi, Tomotake; Godbout, Jessica D.; Goldsmith, Paul K.; Stojadinovic, Alexander; Rudloff, Udo; Thorgeirsson, Snorri S.

    2016-01-01

    Background & Aims: Recently, we reported that liver Label Retaining Cancer Cells (LRCC) can initiate tumors with only 10 cells and are relatively resistant to the targeted drug Sorafenib, a standard of practice in advanced hepatocellular carcinoma (HCC). LRCC are the only cancer stem cells (CSC) isolated alive according to a stem cell fundamental function, asymmetric cell division. Metformin has been reported to preferentially target many other types of CSC of different organs, including live...

  5. Mitochondrial drug targets in neurodegenerative diseases.

    Science.gov (United States)

    Lee, Jiyoun

    2016-02-01

    Growing evidence suggests that mitochondrial dysfunction is the main culprit in neurodegenerative diseases. Given the fact that mitochondria participate in diverse cellular processes, including energetics, metabolism, and death, the consequences of mitochondrial dysfunction in neuronal cells are inevitable. In fact, new strategies targeting mitochondrial dysfunction are emerging as potential alternatives to current treatment options for neurodegenerative diseases. In this review, we focus on mitochondrial proteins that are directly associated with mitochondrial dysfunction. We also examine recently identified small molecule modulators of these mitochondrial targets and assess their potential in research and therapeutic applications.

  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. Insulin-like growth factor 2 silencing restores taxol sensitivity in drug resistant ovarian cancer.

    Science.gov (United States)

    Brouwer-Visser, Jurriaan; Lee, Jiyeon; McCullagh, KellyAnne; Cossio, Maria J; Wang, Yanhua; Huang, Gloria S

    2014-01-01

    Drug resistance is an obstacle to the effective treatment of ovarian cancer. We and others have shown that the insulin-like growth factor (IGF) signaling pathway is a novel potential target to overcome drug resistance. The purpose of this study was to validate IGF2 as a potential therapeutic target in drug resistant ovarian cancer and to determine the efficacy of targeting IGF2 in vivo. An analysis of The Cancer Genome Atlas (TCGA) data in the serous ovarian cancer cohort showed that high IGF2 mRNA expression is significantly associated with shortened interval to disease progression and death, clinical indicators of drug resistance. In a genetically diverse panel of ovarian cancer cell lines, the IGF2 mRNA levels measured in cell lines resistant to various microtubule-stabilizing agents including Taxol were found to be significantly elevated compared to the drug sensitive cell lines. The effect of IGF2 knockdown on Taxol resistance was investigated in vitro and in vivo. Transient IGF2 knockdown significantly sensitized drug resistant cells to Taxol treatment. A Taxol-resistant ovarian cancer xenograft model, developed from HEY-T30 cells, exhibited extreme drug resistance, wherein the maximal tolerated dose of Taxol did not delay tumor growth in mice. Blocking the IGF1R (a transmembrane receptor that transmits signals from IGF1 and IGF2) using a monoclonal antibody did not alter the response to Taxol. However, stable IGF2 knockdown using short-hairpin RNA in HEY-T30 effectively restored Taxol sensitivity. These findings validate IGF2 as a potential therapeutic target in drug resistant ovarian cancer and show that directly targeting IGF2 may be a preferable strategy compared with targeting IGF1R alone.

  8. Targeting Calcium Signaling Induces Epigenetic Reactivation of Tumor Suppressor Genes in Cancer.

    Science.gov (United States)

    Raynal, Noël J-M; Lee, Justin T; Wang, Youjun; Beaudry, Annie; Madireddi, Priyanka; Garriga, Judith; Malouf, Gabriel G; Dumont, Sarah; Dettman, Elisha J; Gharibyan, Vazganush; Ahmed, Saira; Chung, Woonbok; Childers, Wayne E; Abou-Gharbia, Magid; Henry, Ryan A; Andrews, Andrew J; Jelinek, Jaroslav; Cui, Ying; Baylin, Stephen B; Gill, Donald L; Issa, Jean-Pierre J

    2016-03-15

    Targeting epigenetic pathways is a promising approach for cancer therapy. Here, we report on the unexpected finding that targeting calcium signaling can reverse epigenetic silencing of tumor suppressor genes (TSG). In a screen for drugs that reactivate silenced gene expression in colon cancer cells, we found three classical epigenetic targeted drugs (DNA methylation and histone deacetylase inhibitors) and 11 other drugs that induced methylated and silenced CpG island promoters driving a reporter gene (GFP) as well as endogenous TSGs in multiple cancer cell lines. These newly identified drugs, most prominently cardiac glycosides, did not change DNA methylation locally or histone modifications globally. Instead, all 11 drugs altered calcium signaling and triggered calcium-calmodulin kinase (CamK) activity, leading to MeCP2 nuclear exclusion. Blocking CamK activity abolished gene reactivation and cancer cell killing by these drugs, showing that triggering calcium fluxes is an essential component of their epigenetic mechanism of action. Our data identify calcium signaling as a new pathway that can be targeted to reactivate TSGs in cancer.

  9. Tumor targeting using liposomal antineoplastic drugs

    OpenAIRE

    Jörg Huwyler; Jürgen Drewe; Stephan Krähenbühl

    2008-01-01

    Jörg Huwyler1, Jürgen Drewe2, Stephan Krähenbühl21University of Applied Sciences Northwestern Switzerland, Institute of Pharma Technology, Muttenz, Switzerland; 2Department of Research and Division of Clinical Pharmacology, University Hospital Basel, Basel, SwitzerlandAbstract: During the last years, liposomes (microparticulate phospholipid vesicles) have beenused with growing success as pharmaceutical carriers for antineoplastic drugs. Fields of applicatio...

  10. Sequencing targeting insurgents and drugs in Colombia

    OpenAIRE

    Farrell, Michelle L.

    2007-01-01

    Colombia President Pastrana President Uribe Drug Trade Coca Counter-narcotics FARC FARC-EP Revolutionary Armed Forces of Colombia Government of Colombia Insurgency Terrorism Plan Colombia Plan Patriota Demilitarized Zone Democratic Defense and Security Policy DSP Peru's success in first defeating the Shining Path guerrilla movement in the early 1990s and then reducing coca cultivation in the mid-1990s demonstrates the effectiveness of a s...

  11. Targeting Gene-Virotherapy for Cancer

    Institute of Scientific and Technical Information of China (English)

    Xin-Yuan LIU; Jing-Fa GU; Wen-Fang SHI

    2005-01-01

    Gene therapy and viral therapy for cancer have therapeutic effects, but there has been no significant breakthrough in these two forms of therapy. Therefore, a new strategy called "targeting genevirotherapy", which combines the advantages of gene therapy and viral therapy, has been formulated. This new therapy has stronger antitumor effects than either gene therapy or viral therapy. A tumor-specific replicative adenovirus vector ZD55 (E1B55KD deleted Adv.) was constructed and various single therapeutic genes were inserted into ZD55 to form ZD55-gene. These are the targeting gene-virotherapy genes. But experiments showed that a single gene was not effective in eliminating the tumor mass, and therefore two genes were separately inserted into ZD55. This strategy is called "targeting dual gene-virotherapy" (with PCT patent). Better results were obtained with this strategy, and all the xenograft tumor masses were completely eliminated in all mice when two suitable genes producing a synergetic or compensative effect were chosen. Twenty-six papers on these strategies have been published by researchers in our laboratory.Furthermore, an adenoviral vector with two targeting promoters harboring two antitumor genes has been constructed for cancer therapy. Promising results have been obtained with this adenoviral vectorand another patent has been applied for. This antitumor strategy can be used to kill tumor cells completely with minimum damage to normal cells.

  12. Alleviating Cancer Drug Toxicity by Inhibiting a Bacterial Enzyme

    Energy Technology Data Exchange (ETDEWEB)

    Wallace, Bret D.; Wang, Hongwei; Lane, Kimberly T.; Scott, John E.; Orans, Jillian; Koo, Ja Seol; Venkatesh, Madhukumar; Jobin, Christian; Yeh, Li-An; Mani, Sridhar; Redinbo, Matthew R. (Einstein); (UNC); (North Carolina Central University)

    2011-08-12

    The dose-limiting side effect of the common colon cancer chemotherapeutic CPT-11 is severe diarrhea caused by symbiotic bacterial {beta}-glucuronidases that reactivate the drug in the gut. We sought to target these enzymes without killing the commensal bacteria essential for human health. Potent bacterial {beta}-glucuronidase inhibitors were identified by high-throughput screening and shown to have no effect on the orthologous mammalian enzyme. Crystal structures established that selectivity was based on a loop unique to bacterial {beta}-glucuronidases. Inhibitors were highly effective against the enzyme target in living aerobic and anaerobic bacteria, but did not kill the bacteria or harm mammalian cells. Finally, oral administration of an inhibitor protected mice from CPT-11-induced toxicity. Thus, drugs may be designed to inhibit undesirable enzyme activities in essential microbial symbiotes to enhance chemotherapeutic efficacy.

  13. REVIEW ON ADVANCES IN COLON TARGETED DRUG DELIVERY SYSTEM

    Directory of Open Access Journals (Sweden)

    Sunena Sethi, SL Harikumar* and Nirmala

    2012-09-01

    Full Text Available The colon is the terminal part of the GIT which has gained in recent years as a potential site for delivery of various novel therapeutic drugs, i.e. peptides. However, colon is rich in microflora which can be used to target the drug release in the colon. Colon is a site where both local and systemic drug delivery can take place. Local delivery allows the topical treatment of inflammatory bowel disease. If drug can be targeted directly into the colon, treatment can become more effective and side effects can be minimized. These systemic side effects can be minimized by primary approaches for CDDS (Colon specific drug delivery namely prodrugs, pH and time dependent systems and microbially triggered system which gained limited success and have limitations as compared with recently new CDDS namely pressure controlled colon delivery capsules (PCDCS, CODESTM (Novel colon targeted delivery system osmotic controlled drug delivery system, Pulsincap system, time clock system, chronotropic system. This review is to understand the pharmaceutical approaches to colon targeted drug delivery systems for better therapeutic action without compromising on drug degradation (or its low bioavailability.

  14. Liposomes and nanotechnology in drug development: focus on ocular targets.

    Science.gov (United States)

    Honda, Miki; Asai, Tomohiro; Oku, Naoto; Araki, Yoshihiko; Tanaka, Minoru; Ebihara, Nobuyuki

    2013-01-01

    Poor drug delivery to lesions in patients' eyes is a major obstacle to the treatment of ocular diseases. The accessibility of these areas to drugs is highly restricted by the presence of barriers, including the corneal barrier, aqueous barrier, and the inner and outer blood-retinal barriers. In particular, the posterior segment is difficult to reach for drugs because of its structural peculiarities. This review discusses various barriers to drug delivery and provides comprehensive information for designing nanoparticle-mediated drug delivery systems for the treatment of ocular diseases. Nanoparticles can be designed to improve penetration, controlled release, and drug targeting. As highlighted in this review, the therapeutic efficacy of drugs in ocular diseases has been reported to be enhanced by the use of nanoparticles such as liposomes, micro/nanospheres, microemulsions, and dendrimers. Our recent data show that intravitreal injection of targeted liposomes encapsulating an angiogenesis inhibitor caused significantly greater suppression of choroidal neovascularization than did the injection of free drug. Recent progress in ocular drug delivery systems research has provided new insights into drug development, and the use of nanoparticles for drug delivery is thus a promising approach for advanced therapy of ocular diseases. PMID:23439842

  15. Overall Response Rate, Progression-Free Survival, and Overall Survival With Targeted and Standard Therapies in Advanced Non–Small-Cell Lung Cancer: US Food and Drug Administration Trial-Level and Patient-Level Analyses

    Science.gov (United States)

    Blumenthal, Gideon M.; Karuri, Stella W.; Zhang, Hui; Zhang, Lijun; Khozin, Sean; Kazandjian, Dickran; Tang, Shenghui; Sridhara, Rajeshwari; Keegan, Patricia; Pazdur, Richard

    2015-01-01

    Purpose To conduct analyses exploring trial-level and patient-level associations between overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) in advanced non–small-cell lung cancer (NSCLC) trials. Methods We identified 14 trials (N = 12,567) submitted to US Food and Drug Administration since 2003 of treatments for advanced NSCLC. Only randomized, active-controlled trials with more than 150 patients were included. Associations between trial-level PFS hazard ratio (HR), OS HR, and ORR odds ratio were analyzed using a weighted linear regression model. Patient-level responder analyses comparing PFS and OS between patients with and without an objective response were performed using pooled data from all studies. Results In the trial-level analysis, the association between PFS and ORR was strong (R2 = 0.89; 95% CI, 0.80 to 0.98). There was no association between OS and ORR (R2 = 0.09; 95% CI, 0 to 0.33) and OS and PFS (R2 = 0.08; 95% CI, 0 to 0.31). In the patient-level responder analyses, patients who achieved a response had better PFS and OS compared with nonresponders (PFS: HR, 0.40; 95% CI, 0.38 to 0.42; OS: HR, 0.40; 95% CI, 0.38 to 0.43). Conclusion On a trial level, there is a strong association between ORR and PFS. An association between ORR and OS and between PFS and OS was not established, possibly because of cross-over and longer survival after progression in the targeted therapy and first-line trials. The patient-level analysis showed that responders have a better PFS and OS compared with nonresponders. A therapy in advanced NSCLC with a large magnitude of effect on ORR may have a large PFS effect. PMID:25667291

  16. A multifunctional poly(curcumin) nanomedicine for dual-modal targeted delivery, intracellular responsive release, dual-drug treatment and imaging of multidrug resistant cancer cells† †Electronic supplementary information (ESI) available: The synthesis procedure of Biotin–PEG–PCDA and the experimental results of MTT. See DOI: 10.1039/c5tb02450a Click here for additional data file.

    OpenAIRE

    Wang, Jining; Wang, Feihu; Li, Fangzhou; Zhang, Wenjun; Shen, Yuanyuan; Zhou, Dejian; Guo, Shengrong

    2016-01-01

    A multifunctional anti-cancer nanomedicine based on a biotin–poly(ethylene glycol)–poly(curcumin-dithio dipropionic acid) (Biotin–PEG–PCDA) polymeric nanocarrier loaded with paclitaxel (PTX), magnetic nanoparticles (MNPs) and quantum dots (QDs) is developed. It combines advantageous properties of efficient targeted delivery and uptake (via biotin and MNP), intracellular responsive release (via cleavable PCDA polymer), fluorescence imaging (via QD) and combined PTX-curcumin dual-drug treatment...

  17. Potential Targets for Colorectal Cancer Prevention

    Directory of Open Access Journals (Sweden)

    Ali Shamseddine

    2013-08-01

    Full Text Available The step-wise development of colorectal neoplasia from adenoma to carcinoma suggests that specific interventions could delay or prevent the development of invasive cancer. Several key factors involved in colorectal cancer pathogenesis have already been identified including cyclooxygenase 2 (COX-2, nuclear factor kappa B (NF-κB, survivin and insulin-like growth factor-I (IGF-I. Clinical trials of COX-2 inhibitors have provided the “proof of principle” that inhibition of this enzyme can prevent the formation of colonic adenomas and potentially carcinomas, however concerns regarding the potential toxicity of these drugs have limited their use as a chemopreventative strategy. Curcumin, resveratrol and quercetin are chemopreventive agents that are able to suppress multiple signaling pathways involved in carcinogenesis and hence are attractive candidates for further research.

  18. Tubulin-Targeting Chemotherapy Impairs Androgen Receptor Activity in Prostate Cancer

    OpenAIRE

    Zhu, Meng-Lei; Horbinski, Craig; Garzotto, Mark; Qian, David Z.; Beer, Tomasz M.; Kyprianou, Natasha

    2010-01-01

    Recent insights into the regulation of the androgen receptor (AR) activity led to novel therapeutic targeting of AR function in prostate cancer patients. Docetaxel is an approved chemotherapy for treatment of castration-resistant-prostate cancer (CRPC), but the mechanism underlying the action of this tubulin-targeting drug is not fully understood. This study investigates the contribution of microtubules and the cytoskeleton to androgen-mediated signaling, and the consequences of their inhibit...

  19. Prediction of drug-target interactions for drug repositioning only based on genomic expression similarity.

    Directory of Open Access Journals (Sweden)

    Kejian Wang

    Full Text Available Small drug molecules usually bind to multiple protein targets or even unintended off-targets. Such drug promiscuity has often led to unwanted or unexplained drug reactions, resulting in side effects or drug repositioning opportunities. So it is always an important issue in pharmacology to identify potential drug-target interactions (DTI. However, DTI discovery by experiment remains a challenging task, due to high expense of time and resources. Many computational methods are therefore developed to predict DTI with high throughput biological and clinical data. Here, we initiatively demonstrate that the on-target and off-target effects could be characterized by drug-induced in vitro genomic expression changes, e.g. the data in Connectivity Map (CMap. Thus, unknown ligands of a certain target can be found from the compounds showing high gene-expression similarity to the known ligands. Then to clarify the detailed practice of CMap based DTI prediction, we objectively evaluate how well each target is characterized by CMap. The results suggest that (1 some targets are better characterized than others, so the prediction models specific to these well characterized targets would be more accurate and reliable; (2 in some cases, a family of ligands for the same target tend to interact with common off-targets, which may help increase the efficiency of DTI discovery and explain the mechanisms of complicated drug actions. In the present study, CMap expression similarity is proposed as a novel indicator of drug-target interactions. The detailed strategies of improving data quality by decreasing the batch effect and building prediction models are also effectively established. We believe the success in CMap can be further translated into other public and commercial data of genomic expression, thus increasing research productivity towards valid drug repositioning and minimal side effects.

  20. Cardiovascular Toxicity and Management of Targeted Cancer Therapy.

    Science.gov (United States)

    Bossaer, John B; Geraci, Stephen A; Chakraborty, Kanishka

    2016-05-01

    The advent of effective oral, molecular-targeted drugs in oncology has changed many incurable malignancies such as chronic myeloid leukemia into chronic diseases similar to coronary artery disease and diabetes mellitus. Oral agents including monoclonal antibodies, kinase i