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Phorbol Ester Effects on Topoisomerase II Activity and Gene Expression in HL-60 Human Leukemia Cells with Different Proclivities toward Monocytoid Differentiation

Leonard A. Zwelling, Michael Hinds, Diana Chan, Elizabeth Altschuler, Janice Mayes and Theodore F. Zipf
Leonard A. Zwelling
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Michael Hinds
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Diana Chan
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Elizabeth Altschuler
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Janice Mayes
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Theodore F. Zipf
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DOI:  Published November 1990
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Abstract

We examined the effects of phorbol ester treatment on topoisomerase II-mediated events in two human leukemia cell lines with different proclivities toward phorbol ester-induced monocytoid differentiation. HL-60 is the parent line that will terminally differentiate; 1E3 is a derived line that will not terminally differentiate. Within 24 h of phorbol ester treatment, etoposide-induced, topoisomerase II-mediated DNA cleavage declined 10-fold, whereas 4′-(9-acridinylamino)-methanesulfon-m-anisidide-induced DNA cleavage declined 3-fold in HL-60. In phorbol-treated 1E3, etoposide-induced DNA cleavage declined only 2-fold, whereas 4′-(9-acridinylamino)methanesulfon-m-anisidide-induced cleavage was barely affected. There was a 2- to 3-fold decline in topoisomerase II activity within the nuclear extracts from phorbol-treated HL-60 cells but not from phorbol-treated 1E3 cells. Immunoblotting experiments with anti-topoisomerase II antibodies indicated that phorbol treatment produced a structural change in the immunoreactive topoisomerase II in HL-60 nuclear extracts but produced no change in 1E3 topoisomerase II. Phorbol ester treatment also produced a decline in the level of topoisomerase II gene expression in HL-60 but not in 1E3 cells. By contrast, the cytotoxicity of etoposide in both lines was decreased following phorbol treatment. Thus, phorbols may uncouple the mechanisms linking drug-induced, topoisomerase II-DNA cleavable complex stabilization with drug-induced cytotoxicity, particularly in 1E3.

Footnotes

  • ↵1 This study was supported by USPHS Research Grants CA40090 (L. A. Z.) and CA39809 (to Dr. Emil J Freireich), Grant CH-324C from the American Cancer Society (L. A. Z.), a grant from the Dunn Foundation (to Dr. Emil J Freireich), and a gift to the M. D. Anderson Annual Fund for the Chemotherapy Research Program from Henry C. Beck, Jr., of Dallas, TX.

  • ↵2 To whom requests for reprints should be addressed, at Box 52, 1515 Holcombe Boulevard, Houston, TX 77030.

  • Received April 27, 1990.
  • Accepted August 14, 1990.
  • ©1990 American Association for Cancer Research.
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November 1990
Volume 50, Issue 22
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Phorbol Ester Effects on Topoisomerase II Activity and Gene Expression in HL-60 Human Leukemia Cells with Different Proclivities toward Monocytoid Differentiation
Leonard A. Zwelling, Michael Hinds, Diana Chan, Elizabeth Altschuler, Janice Mayes and Theodore F. Zipf
Cancer Res November 15 1990 (50) (22) 7116-7122;

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Phorbol Ester Effects on Topoisomerase II Activity and Gene Expression in HL-60 Human Leukemia Cells with Different Proclivities toward Monocytoid Differentiation
Leonard A. Zwelling, Michael Hinds, Diana Chan, Elizabeth Altschuler, Janice Mayes and Theodore F. Zipf
Cancer Res November 15 1990 (50) (22) 7116-7122;
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Cancer Research Online ISSN: 1538-7445
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