DNA damage induced by the anthracycline cosmomycin D in DNA repair-deficient cells.
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.
Carvalho
Helotonio
H
Department of Biological Sciences, Federal University of São Paulo, Diadema Campus, Diadema, SP, Brazil.
Garrido
Leandro M
LM
Furlan
Renata L A
RL
Padilla
Gabriel
G
Agnoletto
Mateus
M
Guecheva
Temenouga
T
Henriques
João A P
JA
Saffi
Jenifer
J
Menck
Carlos Frederico Martins
CF
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
D018943:Anthracyclines; D000970:Antineoplastic Agents; C052002:cosmomycin D