The effect of staurosporine on drug-induced, topoisomerase II-mediated DNA cleavage in human leukemia cells.
Phorbol-12-myristate 13-acetate (PMA), a stimulator of protein kinase C, dramatically decreased topoisomerase II-reactive drug-induced DNA cleavage in HL-60 human leukemia cells. The effect of staurosporine, an inhibitor of protein kinase C, on drug-induced, topoisomerase II-mediated DNA cleavage was quantified in the same cells. Staurosporine decreased the magnitude of 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA)- and etoposide-induced DNA cleavage in a dose- and time-dependent fashion. Measurement of several parameters of cell proliferation revealed no clear and uniform correlation between staurosporine's inhibition of these parameters and its effects on drug-induced DNA cleavage. A direct comparison with PMA's effects on drug-induced DNA cleavage showed that whereas PMA's inhibition of etoposide-induced cleavage was much greater than its inhibition of m-AMSA-induced cleavage, the magnitude of staurosporine's effect on the cleavage produced by the two topoisomerase II-reactive drugs was similar. Thus, although PMA stimulates protein kinase C and staurosporine inhibits this enzyme, it is unlikely that the actions of either on topoisomerase II-reactive, drug-induced DNA cleavage are mediated directly via protein kinase C. Furthermore, it is likely that the mechanisms by which PMA and staurosporine inhibit topoisomerase II-reactive drug-induced cleavage are different.
Zwelling
L A
LA
Department of Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston 77030.
Altschuler
E
E
Mayes
J
J
Hinds
M
M
Chan
D
D
D000470:Alkaloids / Q000494:pharmacology*; D000677:Amsacrine / Q000494:pharmacology; D002460:Cell Line; D004249:DNA Damage / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000494:pharmacology*; D004273:DNA, Neoplasm / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D007938:Leukemia / Q000473:pathology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013997:Time Factors; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000470:Alkaloids; D004273:DNA, Neoplasm; D000677:Amsacrine; D005047:Etoposide; D011493:Protein Kinase C; D004250:DNA Topoisomerases, Type II; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate