Yu R, Mandlekar S, Harvey K J, Ucker D S, Kong A N
Department of Pharmaceutics and Pharmacodynamics, Center for Pharmaceutical Biotechnology, College of Pharmacy, University of Illinois at Chicago, 60607-7173, USA.
Cancer Res. 1998 Feb 1;58(3):402-8.
Isothiocyanates exert strong anticarcinogenic effects in a number of animal models of cancer, presumably by modulation of xenobiotic-metabolizing enzymes, such as by inhibition of cytochrome P-450 and/or by induction of phase II detoxifying enzymes. Here, we report that phenethyl isothiocyanate and other structurally related isothiocyanates, phenylmethyl isothiocyanate, phenylbutyl isothiocyanate, and phenylhexyl isothiocyanate, but not phenyl isothiocyanate induced apoptosis in HeLa cells in a time- and dose-dependent manner. Treatment with apoptosis-inducing concentrations of isothiocyanates also caused rapid and transient induction of caspase-3/CPP32-like activity. Furthermore, these isothiocyanates, except phenyl isothiocyanate, stimulated proteolytic cleavage of poly(ADP-ribose) polymerase, which followed the appearance of caspase activity and preceded DNA fragmentation. Pretreatment with a potent caspase-3 inhibitor acetyl-Asp-Glu-Val-Asp-aldehyde inhibited isothiocyanate-induced caspase-3-like activity and apoptosis. These results suggest that isothiocyanates may induce apoptosis through a caspase-3-dependent mechanism. The induction of apoptosis by isothiocyanates may provide a distinct mechanism for their chemopreventive functions.
异硫氰酸酯在多种癌症动物模型中发挥强大的抗癌作用，可能是通过调节外源性代谢酶，例如抑制细胞色素P - 450和/或诱导Ⅱ相解毒酶。在此，我们报告苯乙基异硫氰酸酯及其他结构相关的异硫氰酸酯，即苯甲基异硫氰酸酯、苯丁基异硫氰酸酯和苯己基异硫氰酸酯，但不是苯异硫氰酸酯，能以时间和剂量依赖的方式诱导HeLa细胞凋亡。用诱导凋亡浓度的异硫氰酸酯处理也会导致caspase - 3/CPP32样活性的快速和短暂诱导。此外，除苯异硫氰酸酯外，这些异硫氰酸酯还刺激了聚（ADP - 核糖）聚合酶的蛋白水解切割，这发生在caspase活性出现之后且DNA片段化之前。用强效caspase - 3抑制剂乙酰 - 天冬氨酸 - 谷氨酸 - 缬氨酸 - 天冬氨酸 - 醛预处理可抑制异硫氰酸酯诱导的caspase - 3样活性和凋亡。这些结果表明异硫氰酸酯可能通过caspase - 3依赖性机制诱导凋亡。异硫氰酸酯诱导凋亡可能为其化学预防功能提供一种独特的机制。
