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Background: Human multiple myeloma (MM) re- mains an incurable hematological malignancy. We have reported that  -lapachone, a pure compound derived from a plant, can induce cell death in a vari- ety of human carcinoma cells, including ovary, colon, lung, prostate, pancreas, and breast, suggest- ing a wide spectrum of anticancer activity. Materials and Methods: We first studied anti- survival effects of  -lapachone in human MM cells by colony formation assay. To determine whether the differential inhibition of colony formation occurs through antiproliferative activity, we performed MTT assays. The cytotoxicity of  -lapachone on hu- man peripheral blood mononuclear cells was also measured by MTT assay. To determine whether the cell death induced by  -lapachone occurs through necrosis or apoptosis, we used the propidium iodide staining procedure to determine the sub-G1 fraction, Annexin-V staining for externalization of phosphati- dylserine, and fragmentation of cellular genomic DNA subjected to gel electrophoresis. To investigate the mechanism of anti-MM activity, we examined Bcl-2 expression, cytochrome C release, and poly (ADP ribose) polymerase cleavage by Western blot assay. Results: We found that  -lapachone (less than 4  M) inhibits cell survival and proliferation by triggering cell death with characteristics of apopto- sis in ARH-77, HS Sultan, and MM.1S cell lines, in freshly derived patient MM cells (MM.As), MM cell lines resistant to dexamethasone (MM.1R), doxoru- bicin (DOX.40), mitoxantrone (MR.20), and mepha- lan (LR5). Importantly, after treatment with  -lapa- chone, we observed no apoptosis in peripheral blood mononuclear cells in either quiescent or pro- liferative states, freshly isolated from healthy donors. In  -lapachone treated ARH-77, cytochrome C was released from mitochondria to cytosol, and poly (ADP ribose) polymerase was cleaved, signature events of apoptosis. Finally, the apoptosis induced by  -lapachone in MM cells was not blocked by ei- ther interleukin-6 or Bcl-2, which confer multidrug resistance in MM. Conclusions: Our results suggest potential therapeu- tic application of  -lapachone against MM, particu- larly to overcome drug resistance in relapsed patients.

Potent Induction of Apoptosis by β-Lapachone in Human Multiple Myeloma Cell Lines and Patient Cells