title: 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.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors: Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, 110016 Shenyang, PR China.
authors: Fangyang
authors: F
authors: Wang
authors: Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, 110016 Shenyang, PR China.
authors: Lihui
authors: L
authors: Wang
authors: Department of Medicinal Chemistry, Shenyang Pharmaceutical University, 103 Wenhua Road, 110016 Shenyang, PR China.
authors: Yanfang
authors: Y
authors: Zhao
authors: Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, 110016 Shenyang, PR China.
authors: Yi
authors: Y
authors: Li
authors: Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, 110016 Shenyang, PR China.
authors: Guanfang
authors: G
authors: Ping
authors: Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, 110016 Shenyang, PR China.
authors: Shu
authors: S
authors: Xiao
authors: Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, 110016 Shenyang, PR China.
authors: Kang
authors: K
authors: Chen
authors: Department of Medicinal Chemistry, Shenyang Pharmaceutical University, 103 Wenhua Road, 110016 Shenyang, PR China.
authors: Wufu
authors: W
authors: Zhu
authors: Department of Medicinal Chemistry, Shenyang Pharmaceutical University, 103 Wenhua Road, 110016 Shenyang, PR China. Electronic address: gongpinggp@126.com.
authors: Ping
authors: P
authors: Gong
authors: Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, 110016 Shenyang, PR China. Electronic address: yangjingyu2006@gmail.com.
authors: Jingyu
authors: J
authors: Yang
authors: Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, 110016 Shenyang, PR China. Electronic address: wucf@syphu.edu.cn.
authors: Chunfu
authors: C
authors: Wu
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D053148:Caspase 3 / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D005706:Gallbladder Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D018922:HL-60 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D053148:Caspase 3
keywords: Apoptosis; Procaspase-3; Small molecular activator; Tumor