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Research Articles: Therapeutics, Targets, and Development

Natural BH3 mimetic (-)-gossypol chemosensitizes human prostate cancer via Bcl-xL inhibition accompanied by increase of Puma and Noxa

Departments of ¹ Radiation Oncology and ² Urology, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan and ³ School of Chemistry and Chemical Engineering, Southeast University, Nanjing, Jiangsu, People's Republic of China

Requests for reprints: Liang Xu, Department of Radiation Oncology, Division of Cancer Biology, University of Michigan Comprehensive Cancer Center, 4424E Med Sci I/SPC5637, 1301 Catherine Street, Ann Arbor, MI 48109-5637. Phone: 734-615-7017; Fax: 734-615-3422. E-mail: liangxu{at}umich.edu

Abstract

Antiapoptotic members of the Bcl-2 family proteins are overexpressed in prostate cancer and are promising molecular targets for modulating chemoresistance of prostate cancer. (-)-Gossypol, a natural BH3 mimetic, is a small-molecule inhibitor of Bcl-2/Bcl-xL/Mcl-1 currently in phase II clinical trials as an adjuvant therapy for human prostate cancer. Our objective is to examine the chemosensitization potential of (-)-gossypol in prostate cancer and its molecular mechanisms of action. (-)-Gossypol inhibited cell growth and induced apoptosis through mitochondria pathway in human prostate cancer PC-3 cells and synergistically enhanced the antitumor activity of docetaxel both in vitro and in vivo in PC-3 xenograft model in nude mouse. (-)-Gossypol blocked the interactions of Bcl-xL with Bax or Bad in cancer cells by fluorescence resonance energy transfer assay and overcame the Bcl-xL protection of FL5.12 model cells on interleukin-3 withdrawal. Western blot and real-time PCR studies showed that a dose-dependent increase of the proapoptotic BH3-only proteins Noxa and Puma contributed to the cell death induced by (-)-gossypol and to the synergistic effects of (-)-gossypol and docetaxel. The small interfering RNA knockdown studies showed that Noxa and Puma are required in the (-)-gossypol-induced cell death. Taken together, these data suggest that (-)-gossypol exerts its antitumor activity through inhibition of the antiapoptotic protein Bcl-xL accompanied by an increase of proapoptotic Noxa and Puma. (-)-Gossypol significantly enhances the antitumor activity of chemotherapy in vitro and in vivo, representing a promising new regime for the treatment of human hormone-refractory prostate cancer with Bcl-2/Bcl-xL/Mcl-1 overexpression. [Mol Cancer Ther 2008;7(7):2192–202]

Grant support: Department of Defense Prostate Cancer Research Program W81XWH-04-1-0215 and W81XWH-06-1-0010 (L. Xu), NIH/National Cancer Institute Prostate Cancer SPORE in University of Michigan Developmental Project 2P50 CA069568-06A1 (L. Xu), NIH grants R01 CA121830-01 and R21 CA128220-01 (L. Xu), and NIH through the University of Michigan Cancer Center Support Grant 5 P30 CA46592.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁴ http://ClinicalTrials.gov

⁵ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 4/ 7/08; revised 5/ 8/08; accepted 5/18/08.