title: Single chemical modifications of the C-1027 enediyne core, a radiomimetic antitumor drug, affect both drug potency and the role of ataxia-telangiectasia mutated in cellular responses to DNA double-strand breaks.
abstract: The radiomimetic enediyne C-1027 induces almost exclusively DNA double-strand breaks (DSB) and is extremely cytotoxic. Unique among radiomimetics, ataxia-telangiectasia mutated (ATM) is dispensable for cellular responses to C-1027-induced DNA damage. This study explores the biological activity of three recently bioengineered C-1027 analogues: 7''-desmethyl-C-1027 (desmethyl), 20'-deschloro-C-1027 (deschloro), and 22'-deshydroxy-C-1027 (deshydroxy). Each compound maintains the characteristic ability of radiomimetics to cleave DNA in cell-free systems, varying in activity from 2-fold (deschloro) to 55-fold (desmethyl) less than C-1027. The induction of cellular DNA breaks based on pulsed field gel electrophoresis, comet analysis, and gammaH2AX activation was in the same rank order as cell-free DNA break induction, although the amount of breaks induced by desmethyl is greatly reduced compared with the other analogues. Despite the disparity in inducing DNA DSBs, all of the analogues produced G2-M cell cycle arrest and activated DNA DSB damage response proteins, such as p53-Ser15 and Chk2-Thr68, at concentrations in concordance with their ability to inhibit cell growth. Interestingly, of the three analogues, only the desmethyl-induced DNA damage response was similar to C-1027, as it did not cause hypersensitive cell growth inhibition in the absence of ATM nor require the kinase to phosphorylate p53 or Chk2. These findings show that simple modifications of the chromophore of C-1027 can result in varied induction of, and cellular response to, DNA DSBs.
authors.affiliation: Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14623, and Division of Pharmaceutical Sciences, University of Wisconsin National Cooperative Drug Discovery Group, Madison, Wisconsin, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Kennedy
authors.forename: Loretta S
authors.initials: LS
authors.lastname: Gawron
authors.forename: Jianhua
authors.initials: J
authors.lastname: Ju
authors.forename: Wen
authors.initials: W
authors.lastname: Liu
authors.forename: Ben
authors.initials: B
authors.lastname: Shen
authors.forename: Terry A
authors.initials: TA
authors.lastname: Beerman
mesh_terms: D000617:Aminoglycosides / Q000737:chemistry / Q000494:pharmacology*; D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000494:pharmacology*; D064007:Ataxia Telangiectasia Mutated Proteins; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000235:genetics*; D048708:Cell Growth Processes / Q000187:drug effects; D002460:Cell Line; D002474:Cell-Free System; D004247:DNA / Q000187:drug effects* / Q000378:metabolism; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics*; D053281:Enediynes / Q000737:chemistry / Q000494:pharmacology*; D005347:Fibroblasts; D006801:Humans; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D013329:Structure-Activity Relationship; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D000617:Aminoglycosides; D000903:Antibiotics, Antineoplastic; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D053281:Enediynes; D025521:Tumor Suppressor Proteins; C058024:C 1027; D004247:DNA; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases