11-脱氧轮枝菌素A引起前列腺癌PC3M细胞Caspase依赖的凋亡

11'-Deoxyverticillin A induces caspase-dependent cell apoptosis in PC3M cells

摘要:

近几年，我国前列腺癌的发病率和致死率均明显升高。虽然早期肿瘤对去雄激素疗法敏感，但最终几乎所有病人均可转变为雄激素非依赖型。目前，对于此类病人还没有好的治疗手段和药物。11-脱氧轮枝菌素A (11'-deoxyverticillin A，C42) 是一种从冬虫夏草共生菌中分离得到的多硫代二氧基哌嗪 (Epipolythiodioxopiperazines，ETPs) 族结构化合物，通过利用研究前列腺癌雄激素非依赖性癌细胞生长的常用细胞系PC3M细胞，就其对雄激素非依赖性前列腺癌细胞的凋亡及凋亡机制进行了研究。结果发现，C42能够显著抑制细胞生长，并增加caspase-3/7的活性及PARP的剪切。C42引起的这种caspase依赖的细胞凋亡与处理时间和该化合物的浓度相关。上述结果表明，C42能够诱导caspase依赖的细胞凋亡。进一步深入研究此类化合物将有助于理解其诱导程序性细胞死亡的机理，为开发此类化合物进行可能的临床治疗雄激素非依赖性前列腺癌打下了一定的理论基础。

Abstract:

Recent years, the incidence and mortality of prostate cancer have increased dramatically in China. At earlier stages, most diagnosed prostate cancers are responsive to androgen depletion treatment, yet, nearly all patients will eventually progress to metastatic androgen-independent prostate cancer (AIPC), which still has no effective therapeutic method or drug to deal with. 11'-Deoxyverticillin A (C42) belongs to the family of epipolythiodioxopiperazines (ETPs), an interesting class of fungal toxins that inhibit farnesyl transferase. Compounds holding such a property have been explored as putative anticancer agents. In this study, using PC3M cells, an AIPC cell line, we investigated the effect of the compound on apoptosis and explored the underlying mechanism. It revealed that C42 markedly enhanced the activity of caspase-3/7 and increased the accumulation of the cleaved PARP, all of which are the markers of apoptosis. It also revealed that C42 either decreased cell viability or inhibited the growth of PC3M cells. Moreover, we observed that the loss of cell viability and cell growth inhibition induced by C42 were both time- and dosage dependent. Taken together, we indicated that C42 can induce caspase-dependent apoptosis in AIPC cells, and the results presented here will broaden our knowledge about the molecular mechanisms by which C42 exerts its anticancer activity, and future work in this direction may provide valuable information in the development of these compounds into effective cancer therapeutic strategies against androgen-independent prostate cancer.