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WL-276, an Antagonist against Bcl-2 Proteins, Overcomes Drug Resistance and Suppresses Prostate Tumor Growth

Departments of ¹ Medicinal Chemistry and ² Urology, University of Minnesota, Minneapolis, Minnesota

Requests for reprints: Chengguo Xing, Department of Medicinal Chemistry, University of Minnesota, 8-101 WDH, 308 Harvard Street Southeast, Minneapolis, MN 55455. Phone: 612-626-5675; Fax: 612-624-0139; E-mail: xingx009{at}umn.edu.

Key Words: WL-276 • Bcl-2 • apoptosis • antagonist • drug resistance • HRPC

Patients with hormone-refractory prostate cancer (HRPC) have an estimated median survival of only 10 months because of acquired drug resistance, urging the need to develop therapies against the drug-resistant HRPC phenotype. Accumulating evidence suggests that overexpressing antiapoptotic Bcl-2 family proteins is at least partially responsible for the development of drug resistance among HRPC patients. Antagonizing the antiapoptotic Bcl-2 family proteins, therefore, is one potential approach to circumventing drug resistance in HRPC. WL-276 was developed as a small-molecule antagonist against antiapoptotic Bcl-2 family proteins, with binding potency comparable to (–)-gossypol. Overexpressing Bcl-2 or Bcl-X_L failed to confer resistance to WL-276. WL-276 also effectively induced apoptosis in PC-3 cells. In addition, three PC-3 cell lines with acquired drug resistance against standard cancer chemotherapies were more sensitive to WL-276 than the parent PC-3 cell line. The increased cytotoxicity toward drug-resistant PC-3 cells shows the clinical potential of WL-276 against HRPC that is resistant to conventional therapies. The anticancer activity of WL-276 was manifested in its suppression of PC-3–induced prostate tumor growth in vivo. The selective toxicity of WL-276 against drug-resistant PC-3 cells and its in vivo suppression of PC-3 prostate tumor growth suggest that WL-276 is a promising lead candidate for the development of Bcl-2 antagonists against drug-resistant HRPC. [Cancer Res 2008;68(11):4377–83]

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