Methylseleninic acid enhances therapeutic efficacy of taxol against androgen-independent prostate cancer by targeting anti-apoptotic proteins Bcl-XL and survivin

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Prostate cancer (PCa) is a serious threat to the health and quality of life of American men, being second only to lung cancer as the causes of cancer-deaths. Two landmark studies (SWOG 9916 and TAX 327) have demonstrated a small but significant survival benefit of taxane (docetaxel)-based treatments, which remain the only FDA-approved chemotherapy modality for patients with hormone refractory prostate cancer (HRPCa). Dose-limiting toxicity and development of drug resistance are the two major hurdles for taxane-based chemotherapy. Novel agents that can increase apoptosis and lower the toxic side effects of taxanes are being actively investigated to further improve the therapeutic benefit through synergistic combinations. Here, we report that serum achievable levels of methylseleninic acid (MSeA), a second-generation anti-cancer selenium compound, greatly sensitized DU145 and PC-3 human androgen independent prostate cancer cells to taxol-induced apoptosis which was assessed by multiple methods. An in vivo study with DU145 xenografts in nude mice showed a synergistic suppression of tumor growth by combing taxol (5 mg/kg body weight, weekly i.p. injection) with MSeA (2 mg Se/kg body weight, daily oral treatment). Further mechanistic studies demonstrated a down-regulation by MSeA in vitro and in vivo of Bcl-XL and survivin, two anti-apoptosis proteins that have been implicated as important novel drug resistance mediators for taxol-based chemotherapy. Over-expression of Bcl-XL in DU145 cells significantly attenuated caspase-mediated apoptosis induced by MSeA/taxol combination. The inhibitory effects on these survival proteins are distinct from traditional strategies for overcoming MDR mechanisms (such as drug pump) and could lower the threshold for apoptosis induction to contribute to the synergistic enhancement of taxol efficacy. Collectively, our data strongly suggest that taxol and MSeA combination could be a mechanism-based effective regimen for improving therapeutic efficacy of taxol against HRPCa. Grant supports: CA95642 from National Cancer Institute and DAMD17-02-1-0007 from Department of Defense Prostate Cancer Program.