Abstract
Abstract ABT-737, a novel small-molecule inhibitor of select Bcl-2 family survival proteins, holds excellent promise to complement current cytotoxic therapies for cancer, especially B-cell malignancies. However many types of solid cancer cells are resistant to ABT-737. One practical approach to improving its therapeutic efficacy is to combine with agents that can overcome such resistance to restore the sensitivity. In the present study, we sought to test the hypothesis that the cancer chemopreventive selenium compound methylseleninic acid (MSeA), known to suppress the expression of some Bcl-2 family members and AKT survival signaling, could synergistically sensitize cancer cells to ABT-737-induced apoptosis. Our results show that serum achievable levels of MSeA increased apoptosis induction by ABT-737 in several aggressive malignant cell lines: MDA-MB-231 human breast cancer cells, HT-29 human colon cancer cells and DU145 human prostate cancer cells, as evidenced by greater than additive enhancement of annexin V/FITC positive (apoptotic) cells and activation of multiple caspases and PARP cleavage. Mechanistic investigation demonstrated that MSeA significantly decreased the basal expression of Mcl-1 and ABT-737-induced Mcl-1 expression. Knocking down of Mcl-1 with RNAi increased ABT-737-induced apoptosis. More importantly, we identified activation of AKT phosphorylation and AKT-mediated inactivation of Bad by ser-136 and ser-112 phosphorylation as a novel mechanism involved in ABT-737 resistance which could be overcome by MSeA. In addition, we found that expression of Bax was required for the efficient execution of synergistic sensitization. These mitochondria-related apoptosis findings, to our knowledge for the first time, provide a strong mechanistic rationale for developing MSeA as a novel sensitizing agent of ABT-737 for cancer chemotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4898. doi:1538-7445.AM2012-4898
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