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
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↵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.
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↵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.