WL-276, an antagonist against Bcl-2 proteins, overcomes drug resistance and suppresses prostate tumor growth.
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.
Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Liangyou
L
Wang
Daniel T
DT
Sloper
Sadiya N
SN
Addo
Defeng
D
Tian
Joel W
JW
Slaton
Chengguo
C
Xing
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000473:pathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*
D000970:Antineoplastic Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D013844:Thiazoles; C530697:WL 276