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Induction of DNA Topoisomerase II-mediated DNA Cleavage by ß-Lapachone and Related Naphthoquinones¹

Medical School [B. F.], Department of Pathology and Laboratory Medicine, McArdle Laboratory for Cancer Research, Department of Oncology [L. J. M.], and Division of Medicinal Chemistry, School of Pharmacy [B. F., J. S. S., K. N., D. T. W.], University of Wisconsin-Madison, Madison, Wisconsin 53706, and Department of Pharmacology, University of Medicine and Dentistry-New Jersey-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854 [A. A. L., H. W., Y. M., H. W., M. M. S., L. F. L.]

Recent studies have suggested that 3,4-dihydro-2,2-dimethyl-2H-naphtho[1,2-b]pyran-5,6-dione (ß-lapachone) inhibits DNA topoisomerase I by a mechanism distinct from that of camptothecin. To study the mechanism of action of ß-lapachone, a series of ß-lapachone and related naphthoquinones were synthesized, and their activity against drug-sensitive and -resistant cell lines and purified human DNA topoisomerases as evaluated. Consistent with the previous report, ß-lapachone does not induce topoisomerase I-mediated DNA breaks. However, ß-lapachone and related naphthoquinones, like menadione, induce protein-linked DNA breaks in the presence of purified human DNA topoisomerase II. Poisoning of topoisomerase II by ß-lapachone and related naphthoquinones is independent of ATP and involves the formation of reversible cleavable complexes. The structural similarity between menadione, a para-quinone, and ß-lapachone, an ortho-quinone, together with their similar activity in poisoning topoisomerase II, suggests a common mechanism of action involving chemical reactivity of these quinones. Indeed, both quinones form adducts with mercaptoethanol, and ß-lapachone is 10-fold more reactive. There is an apparent correlation between the rates of the adduct formation with thiols and of the topoisomerase II-poisoning activity of the aforementioned quinones. In preliminary studies, ß-lapachone and related naphthoquinones are found to be cytotoxic against a panel of drug-sensitive and drug-resistant tumor cell lines, including MDR1-overexpressing cell lines, camptothecin-resistant cell lines, and the atypical multidrug-resistant CEM/V-1 cell line.

¹ This work was supported by NIH Grant CA39662 (to L. F. L.) and a University-Industry Relations grant from the University of Wisconsin-Madison (to B. F. and D. T. W.).

² To whom requests for reprints should be addressed, at S'LIL Pharmaceuticals, LLC, 535 Science Drive, Suite C, Madison, WI 53711-1066. Phone: (608) 231-3854; Fax: (608) 263-3397; E-mail: bif@mail.slil.wisc.edu.

Received 4/15/96. Accepted 12/20/96.

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