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ß-Lapachone-mediated Apoptosis in Human Promyelocytic Leukemia (HL-60) and Human Prostate Cancer Cells: A p53-independent Response¹

Department of Human Oncology [S. M. P., S. W., D. A. B.] and Medicine and Middleton VA Hospital [D. R. C., G. W.], and Division of Medicinal Chemistry [B. F., D. T. W., P. H.], Schools of Medicine and Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin 53792

ß-Lapachone and certain of its derivatives directly bind and inhibit topoisomerase I (Topo I) DNA unwinding activity and form DNA-Topo I complexes, which are not resolvable by SDS-K⁺ assays. We show that ß-lapachone can induce apoptosis in certain cells, such as in human promyelocytic leukemia (HL-60) and human prostate cancer (DU-145, PC-3, and LNCaP) cells, as also described by Li et al. (Cancer Res., 55: 0000–0000, 1995). Characteristic 180–200-bp oligonucleosome DNA laddering and fragmented DNA-containing apoptotic cells via flow cytometry and morphological examinations were observed in 4 h in HL-60 cells after a 4-h, 0.5 µM ß-lapachone exposure. HL-60 cells treated with camptothecin or topotecan resulted in greater apoptotic DNA laddering and apoptotic cell populations than comparable equitoxic concentrations of ß-lapachone, although ß-lapachone was a more effective Topo I inhibitor. ß-Lapachone treatment (4 h, 1–5 µM) resulted in a block at G₀/G₁, with decreases in S and G₂/M phases and increases in apoptotic cell populations over time in HL-60 and three separate human prostate cancer (DU-145, PC-3, and LNCaP) cells. Similar treatments with topotecan or camptothecin (4 h, 1–5 µM) resulted in blockage of cells in S and apoptosis. Thus, ß-lapachone causes a block in G₀/G₁ of the cell cycle and induces apoptosis in cells before, or at early times during, DNA synthesis. These events are p53 independent, since PC-3 and HL-60 cells are null cells, LNCaP are wild-type, and DU-145 contain mutant p53, yet all undergo apoptosis after ß-lapachone treatment. Interestingly, ß-lapachone treatment of p53 wild type-containing prostate cancer cells (i.e., LNCaP) did not result in the induction of nuclear levels of p53 protein, as did camptothecin-treated cells. Like other Topo I inhibitors, ß-lapachone may induce apoptosis by locking Topo I onto DNA, blocking replication fork movement, and inducing apoptosis in a p53-independent fashion. ß-Lapachone and its derivatives, as well as other Topo I inhibitors, have potential clinical utility alone against human leukemia and prostate cancers.

¹ This work was funded by grants from the Wisconsin Alumni Research Foundation (to D. A. B., D. T. W., and B. F.), the University of Wisconsin Comprehensive Cancer Center (to D. A. B. and B. F.), and the CapCure Foundation (to G. W.).

² S. M. P. and S. W. are co-first authors.

³ To whom requests for reprints should be addressed, at Department of Human Oncology, K4/626 Clinical Sciences Center, 600 Highland Avenue, Madison, WI 53792.

Received 6/14/95. Accepted 7/21/95.

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