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      Adenoviral neutral endopeptidase gene delivery in combination with paclitaxel for the treatment of prostate cancer

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          Abstract

          Neutral endopeptidase (NEP) is a cell-surface peptidase that inhibits prostate cancer cell growth partly via inhibition of Akt kinase. We investigated the antitumor effects of an adenovirus gene delivery system (AdNEP) to restore NEP expression in DU145 prostate cancer cells in combination with paclitaxel chemotherapy. DU145 cells were infected with adenovirus expressing NEP or LacZ, treated with paclitaxel, and assessed for cell viability, Akt activation and induction of apoptosis. Athymic mice with established DU145 xenografts were injected intratumorally with AdNEP or AdLacZ and intraperitoneally with paclitaxel and monitored for tumor growth over 28 days. Compared to AdLacZ plus paclitaxel, AdNEP plus paclitaxel significantly inhibited DU145 cell growth and increased apoptosis as determined by increased caspase-3 and PARP-1 proteolytic fragments. In a xenograft model, tumor volume was reduced in mice treated with AdNEP plus paclitaxel (122.85±89.5 mm 3; P<0.01) compared with mice treated with AdNEP plus saline (653.9±230.3 mm 3), AdLacZ plus paclitaxel (575.9±176.6 mm 3) or AdLacZ plus saline (920.2±238.2 mm 3). In conclusion, these data suggest that NEP can augment taxane-induced apoptosis through inhibition of Akt/Bad signaling, and that the combination of NEP plus paclitaxel may be an effective strategy to inhibit castration-resistant prostate cancer growth.

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          Taxanes, microtubules and chemoresistant breast cancer.

          The taxanes, paclitaxel and docetaxel are microtubule-stabilizing agents that function primarily by interfering with spindle microtubule dynamics causing cell cycle arrest and apoptosis. However, the mechanisms underlying their action have yet to be fully elucidated. These agents have become widely recognized as active chemotherapeutic agents in the treatment of metastatic breast cancer and early-stage breast cancer with benefits gained in terms of overall survival (OS) and disease-free survival (DFS). However, even with response to taxane treatment the time to progression (TTP) is relatively short, prolonging life for a matter of months, with studies showing that patients treated with taxanes eventually relapse. This review focuses on chemoresistance to taxane treatment particularly in relation to the spindle assembly checkpoint (SAC) and dysfunctional regulation of apoptotic signaling. Since spindle microtubules are the primary drug targets for taxanes, important SAC proteins such as MAD2, BUBR1, Synuclein-gamma and Aurora A have emerged as potentially important predictive markers of taxane resistance, as have specific checkpoint proteins such as BRCA1. Moreover, overexpression of the drug efflux pump MDR-1/P-gp, altered expression of microtubule-associated proteins (MAPs) including tau, stathmin and MAP4 may help to identify those patients who are most at risk of recurrence and those patients most likely to benefit from taxane treatment.
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            Concise review: neutral endopeptidase (CD10): a multifaceted environment actor in stem cells, physiological mechanisms, and cancer.

            CD10 is a remarkable member of the major class of widely expressed cell surface proteins, endopeptidases. First identified in leukemia as a tumor-specific antigen (common acute lymphoblastic leukemia antigen), CD10 has become largely used in cancer diagnosis. However, its function in oncogenesis remains unclear. We previously identified CD10 as a tool to access sphere-forming cells and showed its involvement in mammary stem cell (SC) regulation. We further illustrated that its enzymatic activity is involved, through signaling peptides, in SC maintenance. Therefore, CD10 is not only a cell surface marker in normal and malignant contexts but also affects the extracellular environment and plays a key role in regulation of a number of biological functions and likely in SC. In tumors, the "niche" favors the survival of sheltered cancer SC whose eradication has become the new challenge in oncology. This highlights the importance of understanding the role of CD10 in cancer SC. We will review the characteristics, main functions, and mechanism of action of CD10. Finally, we will review its clinical use and involvement in cancer. Copyright © 2011 AlphaMed Press.
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              The Akt pathway: molecular targets for anti-cancer drug development.

              The serine/threonine kinase Akt functions intracellularly as a cardinal nodal point for a constellation of converging upstream signaling pathways, which involve stimulation of receptor tyrosine kinases such as IGF-1R, HER2/Neu, VEGF-R, PDGF-R), and an assembly of membrane-localized complexes of receptor-PI-3K and activation of Akt through the second messenger PIP(3). The integration of these intracellular signals at the level of Akt and its kinase activity, regulates the phosphorylation of its several downstream effectors, such as NF-kappa B, mTOR, Forkhead, Bad, GSK-3 and MDM-2. These phosphorylation events in turn mediate the effects of Akt on cell growth, proliferation, protection from pro-apoptotic stimuli, and stimulation of neo-angiogenesis. Because Akt and its upstream regulators are deregulated in a wide range of solid tumors and hematologic malignancies, and in view of the aforementioned biologic sequelae of this pathway, the Akt pathway is considered a key determinant of biologic aggressiveness of these tumors, and a major potential target for novel anti-cancer therapies. This review focuses on ongoing translational efforts to therapeutically target Akt and its biologic sequelae, either at the level of Akt itself or at the levels of its upstream regulators and downstream effectors. Because Akt is also important for proliferative and anti-apoptotic signaling pathways critical for normal cells, particular emphasis is placed on the fine-tuning the targeting of individual components of this pathway to maximize the therapeutic index of anti-cancer strategies based on the PI-3K/Akt pathway.
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                Author and article information

                Journal
                Int J Oncol
                Int. J. Oncol
                IJO
                International Journal of Oncology
                D.A. Spandidos
                1019-6439
                1791-2423
                October 2012
                08 August 2012
                08 August 2012
                : 41
                : 4
                : 1192-1198
                Affiliations
                [1 ]Genitourinary Oncology Research Laboratory, Department of Medicine, Weill Cornell Medical College and Weill Cornell Cancer Center;
                [2 ]Division of Hematology and Medical Oncology, Department of Medicine
                [3 ]Department of Urology, Weill Cornell Medical College, New York, NY, USA
                Author notes
                Correspondence to: Dr David M. Nanus, Weill Cornell Medical College, 1305 York Avenue, New York, NY 10021, USA, E-mail: dnanus@ 123456med.cornell.edu
                Article
                ijo-41-04-1192
                10.3892/ijo.2012.1586
                3583657
                22895534
                1a2af241-40df-47bb-ba57-b6895c9cb3ee
                Copyright © 2012, Spandidos Publications

                This is an open-access article licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. The article may be redistributed, reproduced, and reused for non-commercial purposes, provided the original source is properly cited.

                History
                : 11 May 2012
                : 02 July 2012
                Categories
                Articles

                adenovirus,gene therapy,neutral endopeptidase,prostate cancer

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