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WL-276, an antagonist against Bcl-2 proteins, overcomes drug resistance and suppresses prostate tumor growth.

Abstract
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.
AuthorsLiangyou Wang, Daniel T Sloper, Sadiya N Addo, Defeng Tian, Joel W Slaton, Chengguo Xing
JournalCancer research (Cancer Res) Vol. 68 Issue 11 Pg. 4377-83 (Jun 01 2008) ISSN: 1538-7445 [Electronic] United States
PMID18519699 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Antineoplastic Agents
  • Proto-Oncogene Proteins c-bcl-2
  • Sulfonamides
  • Thiazoles
  • WL 276
Topics
  • Animals
  • Antineoplastic Agents (pharmacology)
  • Apoptosis
  • Cell Division (drug effects)
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm
  • Humans
  • Male
  • Mice
  • Mice, Nude
  • Prostatic Neoplasms (pathology)
  • Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors)
  • Sulfonamides (pharmacology)
  • Thiazoles (pharmacology)

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