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¹ Department of Internal Medicine, Division of Hematology and Oncology and ² Department of Radiation Oncology, University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan

Requests for reprints: Marc E. Lippman or Liang Xu, Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, 5301B Medical Science Research Building III, 1500 West Medical Center Drive, Ann Arbor, MI, 48109-0640. E-mail: lippmanm{at}umich.edu or liangxu{at}umich.edu

Radioresistance markedly impairs the efficacy of tumor radiotherapy and involves antiapoptotic signal transduction pathways that prevent radiation-induced cell death. The majority of human prostate cancers overexpress the important antiapoptotic proteins Bcl-2 and/or Bcl-xL, which render tumors resistant to radiation therapy. (–)-Gossypol, a natural polyphenol product from cottonseed, has recently been identified as a potent small molecule inhibitor of both Bcl-2 and Bcl-xL. In the current study, we investigated the antitumor activity of (–)-gossypol in prostate cancer and tested our hypothesis that (–)-gossypol may improve prostate cancer's response to radiation by potentiating radiation-induced apoptosis and thus making cancer cells more sensitive to ionizing radiation. Our data show that (–)-gossypol potently enhanced radiation-induced apoptosis and growth inhibition of human prostate cancer PC-3 cells, which have a high level of Bcl-2/Bcl-xL proteins. Our in vivo studies using PC-3 xenograft models in nude mice show that orally given (–)-gossypol significantly enhanced the antitumor activity of X-ray irradiation, leading to tumor regression in the combination therapy. In situ terminal deoxynucleotidyl transferase–mediated nick end labeling staining showed that significantly more apoptotic cells were induced in the tumors treated with (–)-gossypol plus radiation than either treatment alone. Anti-CD31 immunohistochemical staining indicates that (–)-gossypol plus radiation significantly inhibited tumor angiogenesis. Our results show that the natural polyphenol inhibitor of Bcl-2/Bcl-xL, (–)-gossypol, can radiosensitize prostate cancer in vitro and in vivo without augmenting toxicity. (–)-Gossypol may improve the outcome of current prostate cancer radiotherapy and represents a promising novel anticancer regime for molecular targeted therapy of hormone-refractory prostate cancer with Bcl-2/Bcl-xL overexpression.

Key Words: radiation • (–)-Gossypol • Bcl-xl • apoptosis • prostate cancer

Grant support: Department of Defense Prostate Cancer Research Program grant W81XWH-04-1-0215 (L. Xu), NIH Prostate Specialized Programs of Research Excellence, University of Michigan development projects grant 2P50 CA069568-06A1 (L. Xu and S. Wang), Department of Defense grant BC000914 (S. Wang), Breast Cancer Research Foundation (M.E. Lippman), and NIH National Cancer Institute Comprehensive Cancer Center Core grant 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.

³ S. Wang, in preparation.

⁴ L. Xu, in press.

Received 8/18/04; revised 12/ 2/04; accepted 12/ 8/04.