Rapid activation of apoptosis in human promyelocytic leukemic cells by (+/-)-anti-benzo[a]pyrene diol epoxide induced DNA damage.
Genotoxic damage in responsive mammalian cells is implicated as a critical event in the induction of apoptosis. We have evaluated the time course of activation of apoptosis in HL-60 cells following treatment with (+/-)-anti-BPDE metabolite, a well established DNA damaging carcinogen. Programmed cell death, determined by typical cellular and molecular markers of apoptosis, was apparent with 1.5 h following treatment with varying concentrations of (+/-)-anti-BPDE. The fraction of apoptotic cell population and corresponding DNA fragmentation indicated a minimum threshold damage (approximately 1-2 x 10(-5) adduct/base or about 1 putative lesion/human gene) necessary to elicit apoptosis. Suppression of apoptosis (60-90% inhibition of DNA fragmentation) by 3-aminobenzamide and lack of an effect by aphidicolin indicated the role of poly(ADP-ribosylation) but not of blocked DNA replication. Our data suggest that DNA damage triggers an acute response that sets the responsive cells on path of an "immediate apoptotic" mode of cell death.
Venkatachalam
S
S
Biochemistry Program, Ohio State University, Columbus 43210.
Denissenko
M F
MF
Alvi
N
N
Wani
A A
AA
D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000378:metabolism / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007536:Isomerism; D007700:Kinetics; D015473:Leukemia, Promyelocytic, Acute / Q000473:pathology*; D013997:Time Factors; D014407:Tumor Cells, Cultured
D004273:DNA, Neoplasm; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide