title: DNA damage induced by the anthracycline cosmomycin D in DNA repair-deficient cells.
abstract: OBJECTIVE
  Anthracyclines have been widely used as antitumor agents, playing a crucial role in the successful treatment of many types of cancer, despite some side effects related to cardiotoxicity. New anthracyclines have been designed and tested, but the first ones discovered, doxorubicin and daunorubicin, continue to be the drugs of choice. Despite their extensive use in chemotherapy, little is known about the DNA repair mechanisms involved in the removal of lesions caused by anthracyclines. The anthracycline cosmomycin D is the main product isolated from Streptomyces olindensis, characterized by a peculiar pattern of glycosylation with two trisaccharide rings attached to the A ring of the tetrahydrotetracene.
  
  
  METHODS
  We assessed the induction of apoptosis (Sub-G1) by cosmomycin D in nucleotide excision repair-deficient fibroblasts (XP-A and XP-C) as well as the levels of DNA damage (alkaline comet assay).
  
  
  RESULTS
  Treatment of XP-A and XP-C cells with cosmomycin D resulted in apoptosis in a time-dependent manner, with highest apoptosis levels observed 96 h after treatment. The effects of cosmomycin D were equivalent to those obtained with doxorubicin. The broad caspase inhibitor Z-VAD-FMK strongly inhibited apoptosis in these cells, and DNA damage induced by cosmomycin D was confirmed by alkaline comet assay.
  
  
  CONCLUSIONS
  Cosmomycin D induced time-dependent apoptosis in nucleotide excision repair-deficient fibroblasts. Despite similar apoptosis levels, cosmomycin D caused considerably lower levels of DNA damage compared to doxorubicin. This may be related to differences in structure between cosmomycin D and doxorubicin.
authors.affiliation: Department of Biological Sciences, Federal University of São Paulo, Diadema Campus, Diadema, SP, Brazil.
authors.forename: Helotonio
authors.initials: H
authors.lastname: Carvalho
authors.forename: Leandro M
authors.initials: LM
authors.lastname: Garrido
authors.forename: Renata L A
authors.initials: RL
authors.lastname: Furlan
authors.forename: Gabriel
authors.initials: G
authors.lastname: Padilla
authors.forename: Mateus
authors.initials: M
authors.lastname: Agnoletto
authors.forename: Temenouga
authors.initials: T
authors.lastname: Guecheva
authors.forename: João A P
authors.initials: JA
authors.lastname: Henriques
authors.forename: Jenifer
authors.initials: J
authors.lastname: Saffi
authors.forename: Carlos Frederico Martins
authors.initials: CF
authors.lastname: Menck
mesh_terms: D018943:Anthracyclines / Q000737:chemistry / Q000633:toxicity*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D020552:Comet Assay; D004249:DNA Damage; D004260:DNA Repair; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans
chemical_list: D018943:Anthracyclines; D000970:Antineoplastic Agents; C052002:cosmomycin D