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 rho0 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 (delta psi(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.