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

Summary

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 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 ofm-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.

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Abbreviations

m-AMSA:

4′-(9-Acridinylamino)methanesulfon-m-anisidide; etoposide

VP-16:

4′-demethylepipodiphyllotoxin 4-(4,6-O-ethylidene-β-d-glucopyranoside)

STSN:

staurosporine

PMA:

phorbol-12-myristate 13-acetate

DMSO:

dimethylsulfoxide

AD:

adherent cells

SN:

supernatant cells

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Correspondence to Leonard A. Zwelling.

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Zwelling, L.A., Altschuler, E., Mayes, J. et al. The effect of staurosporine on drug-induced, topoisomerase II-mediated DNA cleavage in human leukemia cells. Cancer Chemother. Pharmacol. 29, 48–52 (1991). https://doi.org/10.1007/BF00686335

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Keywords

  • Cell Proliferation
  • Leukemia
  • Protein Kinase
  • Human Cell
  • Leukemia Cell