A novel small-molecule activator of procaspase-3 induces apoptosis in cancer cells and reduces tumor growth in human breast, liver and gallbladder cancer xenografts

Mol Oncol. 2014 Dec;8(8):1640-52. doi: 10.1016/j.molonc.2014.06.015. Epub 2014 Jul 3.


Purpose: Procaspase-3, a proenzyme of apoptotic executioner caspase-3, is overexpressed in numerous tumors. We aimed to characterize a novel procaspase-3 activator, WF-210, which may have potential as an anticancer drug.

Experimental design: The procaspase-3 activating ability, antitumor efficacy, mechanisms of action, and toxicity profiles of WF-210 were investigated in vitro and in vivo, using normal cells, cancer cells, and mouse xenograft models. The role of procaspase-3 in WF-210-induced apoptosis was explored by manipulating procaspase-3 expression in cultured cells.

Results: WF-210 activated procaspase-3 with an EC50 of 0.95 μM, less than half that of its mother compound PAC-1 (2.08 μM). The mechanism involved the chelation of inhibitory zinc ions, subsequently resulting in an auto-activation of procaspase-3. WF-210 was more cytotoxic than PAC-1 to human cancer cells, but less cytotoxic to normal cells. Cancer cells with high procaspase-3 expression, like HL-60 and U-937, were particularly sensitive. WF-210-induced the apoptosis of HL-60 and U-937 cells by activating procaspases and promoting proteasome-dependent degradation of XIAP and Survivin. The level of WF-210-induced apoptosis in cultured cells was related to the level of procaspase-3 expression. Finally, WF-210 was superior to PAC-1 in retarding the in vivo growth of breast, liver and gallbladder xenograft tumors which overexpress procaspase-3, and induced no substantial weight loss or neurotoxicity. WF-210 and PAC-1 had no effect on the growth of MCF-7 xenograft tumors, which do not express procaspase-3.

Conclusion: We identified WF-210 as a potent small-molecule activator of procaspase-3. The favorable antitumor activity and acceptable toxicity profile of WF-210 provide a strong rationale for its clinical evaluation in the treatment of tumors with high procaspase-3 expression.

Keywords: Apoptosis; Procaspase-3; Small molecular activator; Tumor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / therapeutic use*
  • Apoptosis
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / enzymology
  • Caspase 3 / metabolism*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Female
  • Gallbladder Neoplasms / drug therapy*
  • Gallbladder Neoplasms / enzymology
  • HL-60 Cells
  • Humans
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / enzymology
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • Caspase 3