Muzio G, Martinasso G, Trombetta A, Di Simone D, Canuto R A, Maggiora M
Department of Experimental Oncology and Medicine, Turin University, Corso Raffaello 30, 10125, Turin, Italy.
Apoptosis. 2006 Feb;11(2):265-75. doi: 10.1007/s10495-006-3559-y.
Contrasting data have been reported on the effects of clofibrate, a PPARalpha agonist and hypolipidemic drug. The carcinogenic and anti-apoptotic effects have been demonstrated especially in rodents in both "in vivo" and "in vitro" experiments. In contrast, in rat and human hepatoma cell lines, several reports have shown its concentration-dependent pro-apoptotic effect. No epidemiological data exist about its carcinogenetic effect in man. This study shows that clofibrate also induced apoptosis in a human non-tumour cell line, NCTC 2544, which shares the characteristic of proliferation with tumour cells. Both HMG-CoA reductase and PPARalpha were found to be involved in the signal transduction pathway inducing apoptosis, the former being the principal target: HMG-CoA reductase decreased and PPARalpha increased. Changes in HMG-CoA reductase expression caused activation of parameters leading to apoptosis via the mitochondria pathway. Clofibrate must be considered a pro-apoptotic molecule at concentrations of 0.25 mM and above: the effect is exercised not only on tumour cells but also on normal human proliferating cells. Clofibrate should thus be regarded as a potential drug to reduce the number of proliferating cells in pathological conditions.
关于氯贝丁酯（一种过氧化物酶体增殖物激活受体α激动剂和降血脂药物）的作用，已有相互矛盾的数据报道。其致癌和抗凋亡作用已在“体内”和“体外”实验中得到证实，尤其是在啮齿动物中。相比之下，在大鼠和人类肝癌细胞系中，有几份报告显示了其浓度依赖性的促凋亡作用。目前尚无关于其对人类致癌作用的流行病学数据。本研究表明，氯贝丁酯也能诱导人类非肿瘤细胞系NCTC 2544发生凋亡，该细胞系与肿瘤细胞具有增殖特性。研究发现，3-羟基-3-甲基戊二酰辅酶A还原酶（HMG-CoA还原酶）和过氧化物酶体增殖物激活受体α均参与了诱导凋亡的信号转导途径，前者是主要靶点：HMG-CoA还原酶减少而过氧化物酶体增殖物激活受体α增加。HMG-CoA还原酶表达的变化通过线粒体途径导致了诱导凋亡的参数激活。在浓度为0.25 mM及以上时，氯贝丁酯必须被视为一种促凋亡分子：其作用不仅体现在肿瘤细胞上，也体现在正常人类增殖细胞上。因此，氯贝丁酯应被视为一种在病理条件下减少增殖细胞数量的潜在药物。
