title: Enhancement of cisplatin cytotoxicity by disulfiram involves activating transcription factor 3.
abstract: BACKGROUND
  Activating transcription factor 3 (ATF3), a stress-inducible gene, is a regulator of cisplatin-induced cytotoxicity, and enhancement of the ATF3 expression potentiates this cytotoxicity.
  
  
  METHODS
  ATF3 expression and its binding to the transcription target CHOP were evaluated by western blot and chromatin immunoprecipitation (ChIP), respectively, in a panel of five cell lines (WI38, MCF7, PC3, A549). MTT assays were employed to assess the effects of many drugs, including disulfiram, on cell viability.
  
  
  RESULTS
  ATF3 protein expression was up-regulated after cytotoxic doses of cisplatin treatment and it directly bound to the CHOP gene promoter, increasing this pro-apoptotic protein's expression. In a library screen of 1200 compounds, disulfiram, a dithiocarbamate drug, was identified as an enhancer of the cytotoxic effects of cisplatin. This increased cytotoxic action was synergistic and likely due to their ability to induce ATF3 independently.
  
  
  CONCLUSIONS
  Understanding the role of ATF3 in cisplatin-induced cytotoxicity will lead to novel therapeutic approaches that could improve this drug's efficacy.
authors: Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, 501 Smyth Road, Box 926, Ottawa, ON, K1H 8L6, Canada.
authors: Anna
authors: A
authors: O'Brien
authors: Janet E B
authors: JE
authors: Barber
authors: Stephanie
authors: S
authors: Reid
authors: Nima
authors: N
authors: Niknejad
authors: Jim
authors: J
authors: Dimitroulakos
mesh_terms: D051700:Activating Transcription Factor 3 / Q000096:biosynthesis* / Q000235:genetics; D000230:Adenocarcinoma / Q000188:drug therapy; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D002460:Cell Line; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology*; D004221:Disulfiram / Q000008:administration & dosage / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D008297:Male; D010051:Ovarian Neoplasms / Q000188:drug therapy; D011471:Prostatic Neoplasms / Q000188:drug therapy; D051742:Transcription Factor CHOP / Q000096:biosynthesis / Q000235:genetics; D014158:Transcription, Genetic; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3; C497249:DDIT3 protein, human; D051742:Transcription Factor CHOP; D002945:Cisplatin; D004221:Disulfiram