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.