Joshi B, Li L, Taffe B G, Zhu Z, Wahl S, Tian H, Ben-Josef E, Taylor J D, Porter A T, Tang D G
Biomide Laboratories, Detroit, Michigan 48202, USA.
Cancer Res. 1999 Sep 1;59(17):4343-55.
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.
我们最近研发了一类新型抗前列腺癌化合物，即环状异羟肟酸酯，它们能在体外培养的许多肿瘤细胞中引发强烈的凋亡反应（D.G. 唐等人，《生物化学与生物物理研究通讯》，242: 380 - 384，1998）。先导化合物BMD188在体外和体内均可诱导多种前列腺癌细胞发生程序性细胞死亡（L. 李等人，《抗癌研究》，19: 51 - 70，1999）。BMD188可杀死雄激素非依赖性前列腺癌细胞以及具有多药耐药表型的前列腺癌细胞。BMD188在前列腺癌细胞中的凋亡作用不依赖于细胞周期、p53状态或其所谓的靶标花生四烯酸12 - 脂氧合酶，但确实需要半胱天冬酶激活，且似乎涉及线粒体。为了合成更具特异性和有效性的抗前列腺癌异羟肟酸化合物，了解它们的作用机制很重要。在本研究中，我们研究了线粒体呼吸链（MRC）在BMD188诱导雄激素非依赖性前列腺癌PC3细胞凋亡中的作用，并将其与广泛使用的凋亡诱导剂星形孢菌素（STS）的作用效果进行比较。多项证据表明，BMD188诱导的细胞死亡依赖于MRC：（a）几种复合物特异性呼吸抑制剂可显著抑制细胞死亡；（b）呼吸缺陷型rho0细胞比野生型亲代细胞对BMD188诱导的凋亡更具抗性；（c）BMD188诱导线粒体中活性氧迅速增加、细胞色素c氧化酶亚基上调、线粒体膜电位（Δψm）出现双相改变（即早期超极化，随后是后期去极化）、半胱天冬酶激活之前线粒体形态和分布发生显著变化以及超微结构水平上线粒体异常增殖。相比之下，STS诱导的PC3细胞凋亡似乎不依赖于MRC。综上所述，数据表明MRC是抗前列腺癌异羟肟酸酯的一个功能靶点。
