Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado-Denver, Aurora, Colorado 80045, USA.
Mol Cancer Ther. 2009 Aug;8(8):2366-74. doi: 10.1158/1535-7163.MCT-09-0304. Epub 2009 Jul 28.
Colorectal cancer is one of the leading causes of cancer-related morbidity and mortality. The use of nontoxic phytochemicals in the prevention and intervention of colorectal cancer has been suggested as an alternative to chemotherapy. Here we assessed the anticancer efficacy of silibinin against advanced colorectal cancer LoVo cells both in vitro and in vivo. Our results showed that silibinin treatment strongly inhibits the growth of LoVo cells (P < 0.05-0.001) and induces apoptotic death (P < 0.01-0.001), which was associated with increased levels of cleaved caspases (3 and 9) and cleaved poly(ADP-ribose) polymerase. Additionally, silibinin caused a strong cell cycle arrest at G(1) phase and a slight but significant G(2)-M-phase arrest at highest concentration (P < 0.01-0.001). Molecular analyses for cell cycle regulators showed that silibinin decreases the level of cyclins (D1, D3, A and B1) and cyclin-dependent kinases (1, 2, 4, and 6) and increases the level of cyclin-dependent kinase inhibitors (p21 and p27). Consistent with these results, silibinin treatment also decreased the phosphorylation of retinoblastoma protein at Ser(780), Ser(795), and Ser(807)/Ser(811) sites without significantly affecting its total level. In animal studies, oral administration of silibinin for 6 weeks (at 100 and 200 mg/kg/d for 5 days/wk) significantly inhibited the growth of LoVo xenograft (P < 0.001) in athymic nude mice without any apparent toxicity. Analyses of xenograft tissue showed that silibinin treatment inhibits proliferation and increases apoptosis along with a strong increase in p27 levels but a decrease in retinoblastoma phosphorylation. Together, these results suggest the potential use of silibinin against advanced human colorectal cancer.
结直肠癌是癌症相关发病率和死亡率的主要原因之一。在预防和干预结直肠癌方面，使用无毒的植物化学物质已被认为是化疗的替代方法。在这里，我们评估了水飞蓟素对体外和体内晚期结直肠癌细胞 LoVo 的抗癌疗效。我们的结果表明，水飞蓟素处理强烈抑制 LoVo 细胞的生长（P<0.05-0.001）并诱导细胞凋亡死亡（P<0.01-0.001），这与切割的半胱天冬酶（3 和 9）和切割的多聚（ADP-核糖）聚合酶水平的增加有关。此外，水飞蓟素在最高浓度时引起强烈的 G1 期细胞周期停滞和轻微但显著的 G2-M 期停滞（P<0.01-0.001）。细胞周期调节剂的分子分析表明，水飞蓟素降低了细胞周期蛋白（D1、D3、A 和 B1）和细胞周期蛋白依赖性激酶（1、2、4 和 6）的水平，并增加了细胞周期蛋白依赖性激酶抑制剂（p21 和 p27）的水平。与这些结果一致，水飞蓟素处理还降低了视网膜母细胞瘤蛋白在 Ser（780）、Ser（795）和 Ser（807）/Ser（811）位点的磷酸化，而对其总水平没有明显影响。在动物研究中，水飞蓟素口服给药 6 周（100 和 200mg/kg/d，每周 5 天）显著抑制了裸鼠皮下移植瘤的生长（P<0.001），而没有明显的毒性。移植瘤组织分析表明，水飞蓟素处理抑制增殖并增加凋亡，同时强烈增加 p27 水平但降低视网膜母细胞瘤磷酸化。总之，这些结果表明水飞蓟素可能对晚期人结直肠癌有潜在的应用价值。
