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Induction of the Differentiation of WEHI-3B D⁺ Monomyelocytic Leukemia Cells by Inhibitors of Topoisomerase II¹

Department of Pharmacology and Developmental Therapeutics Program, Comprehensive Cancer Center, Yale University School of Medicine, New Haven, Connecticut 06510 [G. R., A. C. S.], and Department of Experimental Therapeutics, Bristol-Myers Company, Wallingford, Connecticut [A. L.]

Topoisomerase II has been suggested to have a role in the early events of differentiation. This possibility was evaluated by measuring the effects of inhibitors of topoisomerase II on the induction of the differentiation of WEHI-3B D⁺ monomyelocytic leukemia cells. Differentiation of this cell line was induced along the granulocytic pathway by treatment with the topoisomerase II inhibitors novobiocin (150–300 µM), teniposide (20–50 nM), etoposide (0.1 µM), elsamicin (0.5 µM), and doxorubicin (40 nM). Maturation was assessed by the morphological appearance of mature forms of the granulocytic lineage, an increase in cell surface Fc receptors, the ability to reduce nitroblue tetrazolium, and the loss of proliferative capacity. In contrast, the non-topoisomerase II-reactive agent cisplatin and the topoisomerase I-reactive drug camptothecin did not cause the maturation of WEHI-3B D⁺ cells. Aclacinomycin A and retinoic acid, which are known efficacious inducers of the differentiation of this cell line, affected topoisomerase II extracted from WEHI-3B D⁺ cells in vitro, causing concentration-dependent inhibition of the strand-passing activity of the enzyme. Treatment of WEHI-3B D⁺ cells with novobiocin at 150 µM for 3 h or with teniposide at 50 nM for 24 h resulted in a 2- to 3-fold increase in etoposide-induced protein-DNA cross-links. Nuclear proteins in 0.35 M NaCl extracts from cells treated with novobiocin at 150 µM for 3 h or with teniposide at 50 nM for 24 h showed a slight increase in topoisomerase II activity compared to untreated cells. No changes in topoisomerase II levels, as measured by immunoblotting, were detected after treatment of WEHI-3B D⁺ cells with 150 µM novobiocin or 50 nM teniposide during the first 2 days of treatment. At day 3 of treatment, however, a decrease in topoisomerase II was observed in cells treated with either drug, possibly due to decreased cellular proliferation consequent to cell differentiation. The findings support the conclusion that topoisomerase II may have a role in the induction of granulocytic differentiation of WEHI-3B D⁺ leukemia cells.

¹ This investigation was supported in part by USPHS grant CA-02817 from the National Cancer Institute and by a fellowship from the Italian Association for Cancer Research (G. R.).

² On leave of absence from the Department of Experimental Oncology, C.R.O., Aviano, Italy.

³ To whom requests for reprints should be addressed, at the Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510.

Received 5/ 1/89. Accepted 6/27/90.

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