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- W2327483930 abstract "Radioresistance markedly impair the efficacy of cancer therapy and involve anti-apoptotic signal transduction pathways that prevent the treatment-induced cell death. Anti-apoptotic Bcl-2 family proteins such as Bcl-xL, Bcl-2 and Mcl-1 are overexpressed in prostate cancer and contribute to prostate tumor initiation, progression and resistance to radiotherapy. (−)-Gossypol, a natural product from cottonseed, has recently been identified as a potent small molecule inhibitor of Bcl-2/Bcl-xL/Mcl-1 and is now in advanced clinical trials. Since Bcl-2 also inhibits autophagy and radiation induces autophagy, we hypothesize that (−)-gossypol may improve prostate cancer9s response to radiotherapy by inducing autophagy in apoptosis-resistant prostate cancer cells with high Bcl-2. (−)-Gossypol inhibits tumor cell growth and preferentially induces autophagy in androgen-independent (AI) prostate cancer cells that have high levels of Bcl-2 and resistant to apoptosis, both in vitro and in vivo, but not in cells with low Bcl-2. (−)-Gossypol radiosensitized AI-prostate cancer PC-3 and CL-1 cells in clonogenic assay. (−)-Gossypol increased autophagy induced by X-ray radiation in these cells. Orally administered (−)-gossypol achieved a much greater efficacy with long-term tumor regression when used in combination with ionizing radiation. Immunoprecipitation /pull-down assay showed that (−)-gossypol induced autophagy via blocking Bcl-2-Beclin1 interaction, together with downregulating Bcl-2, upregulating Beclin1 and activating autophagic pathway signaling. Knockdown of the Beclin1 or atg5 expression blocked the autophagy induced by (−)-gossypol or radiation. Taken together, our data demonstrate that (−)-Gossypol exerts its radiosensitizing activity through promoting radiation-induced autophagy, via modulating Bcl-2-Beclin1 interaction and atg5. (−)-Gossypol significantly enhances the anti-tumor activity of radiotherapy in vitro and in vivo, and represents a promising new regime for treatment of hormone-refractory human prostate cancer with overexpression of Bcl-2. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4851." @default.
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- W2327483930 date "2010-04-15" @default.
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- W2327483930 title "Abstract 4851: BH-3 mimetics radiosensitizes human prostate cancer via modulating autophagy" @default.
- W2327483930 doi "https://doi.org/10.1158/1538-7445.am10-4851" @default.
- W2327483930 hasPublicationYear "2010" @default.
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