Abstract B41: Overcoming chemo/radioresistance of castration-resistant prostate cancer via modulating autophagy.

Abstract

Abstract Chemo/radioresistance markedly impair the efficacy of prostate 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/Bcl-xL/Mcl-1, (−)-gossypol, shows promise in multiple Phase I-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/Bcl-xL/Mcl-1 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 (Cell Death Diff 2011, 18(1):60–71). Our results demonstrate for the first time that (−)-gossypol can interrupt the interaction between Beclin1 and Bcl-2/Bcl-xL at the endoplasmic reticulum, thus releasing the BH3-only pro-autophagic protein Beclin1, which in turn triggers the autophagic cascade. (−)-Gossypol-induced autophagy is Beclin1- and Atg5-dependent, together with Bcl-2 downregulation and Beclin1 upregulation. (−)-Gossypol increased autophagic cell death induced by either X-ray radiation or chemotherapeutics in the CRPC cells. Orally administered (−)-gossypol achieved a much greater efficacy with long-term tumor regression when used in combination with ionizing radiation or first-line chemotherapy. We have also 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. Taken together, (−)-gossypol significantly enhances the anti-tumor activity of chemo/radiotherapy in vitro and in vivo, and represents a promising new regime for treatment of castration-resistant human prostate cancer with overexpression of Bcl-2. Our data provide new insights into the mode of cell death induced by Bcl-2 inhibitors, which would facilitate the rational design of clinical trials by selecting patients who are most likely to benefit from the Bcl-2-targeted molecular therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B41.