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Apoptosis Induction by a Novel Anti-Prostate Cancer Compound, BMD188 (a Fatty Acid-containing Hydroxamic Acid), Requires the Mitochondrial Respiratory Chain¹

Biomide Laboratories [B. J., L. L., Z. Z., A. T. P., D. G. T] and Departments of Radiation Oncology [E. B-J., A. T. P., D. G. T.], Occupational and Environmental Health Sciences [B. G. T.], Chemistry [Z. Z.], and Biological Sciences [J. D. T.], Wayne State University, Detroit, Michigan 48202; Barbara Ann Karmanos Cancer Institute, Detroit, Michigan 48201 [E. B-J., J. D. T., A. T. P., D. G. T.]; Gershensen Radiation Oncology Center, Harper Hospital, Detroit, Michigan 48201 [E. B-J., J. D. T., A. T. P., D. G. T.]; and National Institute of Dental Research, NIH, Bethesda, Maryland 20892 [S. W., H. T.]

We recently developed a class of novel anti-prostate cancer compounds, cyclic hydroxamates that elicit a potent apoptotic response in many tumor cells cultured in vitro (D.G. Tang et al., Biochem. Biophys. Res. Commun., 242: 380–384, 1998). The lead compound, termed BMD188, induces programmed cell death in a variety of prostate cancer cells in vitro as well as in vivo (L. Li et al., Anticancer Res., 19: 51–70, 1999). BMD188 kills androgen-independent prostate cancer cells as well as prostate cancer cells with a multidrug-resistance phenotype. The apoptotic effect of BMD188 in prostate cancer cells does not depend on cell cycle, p53 status, or its purported target, arachidonate 12-lipoxygenase, but does require caspase activation and seems to involve mitochondria. To synthesize more specific and effective anti-prostate cancer hydroxamic acid compounds, it is important to understand their mechanism(s) of action.

In the present study, we studied the role of mitochondrial respiratory chain (MRC) in BMD188-induced apoptosis in androgen-independent prostate cancer PC3 cells and compared its effect with that of staurosporine (STS), a widely used apoptosis inducer. Several lines of evidence indicate that BMD188-induced cell death depends on MRC: (a) the death could be significantly inhibited by several complex-specific respiration inhibitors; (b) respiration-deficient ⁰ cells were more resistant than wild-type parent cells to apoptosis induction by BMD188; and (c) BMD188 induced a rapid increase in reactive oxygen species in mitochondria, an up-regulation of cytochrome c oxidase subunits, a biphasic alteration (i.e., an early hyperpolarization, followed by later hypopolarization) in the mitochondrial membrane potential (_m), dramatic changes in mitochondrial morphology and distribution prior to caspase activation, and an abnormal proliferation of mitochondria at the ultrastructural level. By contrast, STS-induced PC3 apoptosis seemed not to depend on MRC. Taken together, the data suggest that the MRC represents a functional target for anti-prostate cancer hydroxamates.

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