Abstract 2260: Novel molecular therapy targeting Mcl-1 and modulating autophagy in castration-resistant prostate cancer

Abstract

Abstract Chemo/radioresistance markedly impair the efficacy of cancer therapy. Anti-apoptotic Bcl-2 family proteins such as Bcl-xL, Bcl-2 and Mcl-1 are overexpressed in castration-resistant prostate cancer (CRPC) and contribute to prostate tumor initiation, progression and resistance to radiotherapy. A natural BH3-mimetic small molecule inhibitor of Bcl-2, (-)-gossypol, shows promise in ongoing Phase II clinical trials for human prostate cancer. We have recently shown that (-)-gossypol preferentially induces autophagy in CRPC cells that have high levels of Bcl-2 and are resistant to apoptosis, both in vitro and in vivo, but not in androgen-dependent cells with low Bcl-2 and sensitive to apoptosis. We have explored a series of gossypol derivatives and identified two novel BH3-mimetic lead compounds that are more potent than the parental compound in inducing autophagic cell death in CRPC. A novel pan-Bcl-2 inhibitor, apogossypolone (ApoG2), a derivative of (-)-gossypol, has a better binding affinity to Mcl-1 and an improved antitumor activity, and shows promising efficacy on a variety of cancers in vitro and in vivo. Treatment with the ApoG2 prior to radiotherapy enhances cell death via autophagic pathway in cancer cells which have high Mcl-1 and resistant to apoptosis. In addition to abrogating Bcl-2/Mcl-1–Beclin1 interactions, ApoG2 activates the autophagic pathway Atg5-dependently which synergizes with the effect of radiation. We further investigated the precise mechanism governing the influence of ApoG2 on IR-induced cell death. Our data suggest that, ApoG2 pretreatment suppresses IR induced Akt activation and mTOR phosphorylation. In this way, it serves as a potent radiosensitizer to affect autophagic cell death in cancer cells. Administration of ApoG2 prior to IR further delayed tumor growth of castration resistant prostate cancer xenograft model and increased autophagic cell death in vivo. Together, our data demonstrate a novel mode of action of ApoG2 as an enhancer of radiation induced autophagic cell death and provide mechanistic details of its tumor cell killing activities. These new insights into different modes of cell death induced by Mcl-1 inhibitors may facilitate the rational design of clinical trials by selecting patients most likely to benefit from the Mcl-1-targeted molecular therapy. 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 2260. doi:1538-7445.AM2012-2260