Inhibition of cisplatin-induced ATR activity and enhanced sensitivity to cisplatin.
Ataxia teleangiectasia mutated (ATM) kinase, ATM-Rad3-related (ATR) kinase and DNA-protein kinase (DNA-PK) belong to a subgroup of protein kinases which play a role in the DNA damage response. In this study, cisplatin was shown to increase ATR activity and decrease ATM and DNA-PK activity. Caffeine, a nonspecific inhibitor of ATR, enhanced the cytotoxic effect of cisplatin, modestly decreased the p53 and p21WAF-1 response to cisplatin, and affected the cdc2-p34/cyclin B1 complex by decreasing both cyclin B1 protein accumulation and cdc2-p34 tyrosine 15 phosphorylation. The observed alteration of several potential ATR downstream targets suggests that inhibition of ATR activity may be one of the mechanism by which caffeine regulates sensitivity to cisplatin.
Yazlovitskaya
Eugenia M
EM
Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USA.
Persons
Diane L
DL
D000230:Adenocarcinoma / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D064007:Ataxia Telangiectasia Mutated Proteins; D016203:CDC2 Protein Kinase / Q000378:metabolism; D002110:Caffeine / Q000494:pharmacology*; D018797:Cell Cycle Proteins; D002945:Cisplatin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D019926:Cyclin B / Q000378:metabolism; D056744:Cyclin B1; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins; D004357:Drug Synergism; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D006801:Humans; D009687:Nuclear Proteins; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins
D000970:Antineoplastic Agents; C534699:CCNB1 protein, human; D018797:Cell Cycle Proteins; D019926:Cyclin B; D056744:Cyclin B1; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D002110:Caffeine; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D017346:Protein Serine-Threonine Kinases; D016203:CDC2 Protein Kinase; D002945:Cisplatin