Lu Lulu, Liu Delong, Ma Xudong, Beklemishev Anastasia, Seiter Karen, Ahmed Tauseef, Chiao J W
Department of Medicine, New York Medical College, Valhalla, NY 10595, USA.
Oncol Rep. 2006 Dec;16(6):1363-7.
Isothiocyanates are potent chemopreventive agents for carcinogen-induced cancers in rodents. The major mode of action for chemoprevention is cytoprotection i.e. inducing detoxifying enzymes to remove the carcinogens, thus blocking the initiation of carcinogenesis. Analysis has indicated that isothiocyanates also act at the post-initiation levels of carcinogenesis. We have also reported that the phenylhexyl isothiocyanate (PHI) induced growth arrest and apoptosis in human leukemia HL-60 cells in culture. Since then we have investigated the in vivo efficacy of PHI. The effects of PHI were evaluated in immunodeficient mice, with xenografts of human leukemia HL-60 cells. The maximum tolerated dose (MTD) was determined. The experimental mice received 80% of the MTD. Oral feedings of PHI significantly reduced tumor incidence (p<0.05) without overt toxicity. PHI inhibited cell cycle progression through the down-regulation of cyclin expression, Rb phosphorylation and the up-regulation of the cdk-inhibitors. Apoptosis was significantly increased in the treated tumors but not in the normal mouse tissues. In conclusion, PHI induced apoptosis and inhibited the growth of xenografts by targeting the cell cycle regulators. PHI induced selective apoptosis effects in the rapidly growing tumor cells but not in the normal tissues.
异硫氰酸盐是啮齿动物中致癌物诱发癌症的有效化学预防剂。化学预防的主要作用方式是细胞保护，即诱导解毒酶以清除致癌物，从而阻断致癌作用的起始。分析表明，异硫氰酸盐也作用于致癌作用的起始后阶段。我们还报道了苯己基异硫氰酸盐（PHI）在培养的人白血病HL-60细胞中诱导生长停滞和凋亡。从那时起，我们研究了PHI的体内疗效。在免疫缺陷小鼠中评估了PHI的作用，这些小鼠移植了人白血病HL-60细胞。确定了最大耐受剂量（MTD）。实验小鼠接受了80%的MTD。口服PHI显著降低了肿瘤发生率（p<0.05），且无明显毒性。PHI通过下调细胞周期蛋白表达、Rb磷酸化和上调细胞周期蛋白依赖性激酶抑制剂来抑制细胞周期进程。在治疗的肿瘤中凋亡显著增加，但在正常小鼠组织中未增加。总之，PHI通过靶向细胞周期调节因子诱导凋亡并抑制异种移植物的生长。PHI在快速生长的肿瘤细胞中诱导选择性凋亡作用，但在正常组织中不诱导。
