title: The protein kinase C inhibitor Gö6976 is a potent inhibitor of DNA damage-induced S and G2 cell cycle checkpoints.
abstract: In response to DNA damage, cells arrest progression through the cell cycle at either G(1), S, or G(2). We have reported that UCN-01 (7-hydroxystaurosporine) abrogates DNA damage-induced S and G(2) arrest and enhances cytotoxicity selectively in p53 mutant cells, thus providing a potential, tumor-targeted therapy. Unfortunately, UCN-01 binds avidly to human plasma proteins, limiting bioavailability. Because UCN-01 also inhibits protein kinase C (PKC), we screened other PKC inhibitors, expecting them to be unable to abrogate arrest. However, Gö6976 potently abrogated S and G(2) arrest and enhanced the cytotoxicity of the topoisomerase I inhibitor SN38 only in p53-defective cells. Importantly, Gö6976 was nearly as potent at abrogating S and G(2) arrest in human serum, a property not possessed by UCN-01. Cell viability studies demonstrated that Gö6976 was impressively nontoxic as a single agent. Analysis of proteins that regulate cell cycle arrest suggested that both drugs inhibit the checkpoint kinases Chk1 and/or Chk2. Additionally, Gö6976 abrogated S and G(2) arrest at a concentration substantially lower than that required to inhibit PKC; UCN-01 did not demonstrate this selectivity for checkpoint inhibition. These properties make Gö6976 a promising candidate for preclinical and clinical studies.
authors.affiliation: Department of Pharmacology, Dartmouth Medical School, Hanover, New Hampshire 03755, USA.
authors.forename: Ethan A
authors.initials: EA
authors.lastname: Kohn
authors.forename: Carolyn J
authors.initials: CJ
authors.lastname: Yoo
authors.forename: Alan
authors.initials: A
authors.lastname: Eastman
mesh_terms: D001943:Breast Neoplasms; D002227:Carbazoles / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D016195:G2 Phase; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D016196:S Phase / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: D002227:Carbazoles; D004791:Enzyme Inhibitors; D007211:Indoles; C081021:Go 6976; D011493:Protein Kinase C