The effect of staurosporine on drug-induced, topoisomerase II-mediated DNA cleavage in human leukemia cells.

Abstract

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.

• Authors: L A Zwelling, E Altschuler, J Mayes, M Hinds, D Chan
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 29 Issue 1 Pg. 48-52 ( 1991) ISSN: 0344-5704 [Print] Germany
• PMID: 1660353 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Alkaloids
• DNA, Neoplasm
• Amsacrine
• Etoposide
• Protein Kinase C
• DNA Topoisomerases, Type II
• Staurosporine
• Tetradecanoylphorbol Acetate

Topics

• Alkaloids (pharmacology)
• Amsacrine (pharmacology)
• Cell Line
• DNA Damage (drug effects)
• DNA Topoisomerases, Type II (pharmacology)
• DNA, Neoplasm (drug effects, metabolism)
• Dose-Response Relationship, Drug
• Drug Interactions
• Etoposide (pharmacology)
• Humans
• Leukemia (pathology)
• Protein Kinase C (antagonists & inhibitors)
• Staurosporine
• Tetradecanoylphorbol Acetate (pharmacology)
• Time Factors
• Tumor Cells, Cultured (drug effects)