Silibinin suppresses growth and induces apoptotic death of human colorectal carcinoma LoVo cells in culture and tumor xenograft.
Silibinin suppresses growth and induces apoptotic death of human colorectal carcinoma LoVo cells in culture and tumor xenograft.
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DOI：
10.1158/1535-7163.mct-09-0304
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发表时间：
2009-08
影响因子：
5.7
通讯作者：
Agarwal R
中科院分区：
文献类型：
--
作者：
Kaur M;Velmurugan B;Tyagi A;Deep G;Katiyar S;Agarwal C;Agarwal R
结直肠癌（CRC）是癌症相关发病率和死亡率的主要原因之一。使用无毒植物化学物质预防和干预结直肠癌已被建议作为化疗的替代方案。在这里，我们在体外和体内评估了水飞蓟宾对晚期CRC LoVo细胞的抗癌功效。结果表明，水飞蓟宾能明显抑制LoVo细胞的生长（P< 0.05-0.001），诱导细胞凋亡（P< 0.01-0.001），这与caspases（3和9）和PARP的裂解水平升高有关。此外，水飞蓟宾在G1期引起强烈的细胞周期阻滞，在最高浓度时引起轻微但显著的G2/M期阻滞（P< 0.01-0.001）。细胞周期调节因子的分子分析表明，水飞蓟宾可降低细胞周期蛋白（D1、D3、A和B1）和CDKs的水平，提高CDKIs （p21和p27）的水平。与这些结果一致的是，水飞蓟宾处理也降低了Rb蛋白在Ser780、Ser795和Ser807/811位点的磷酸化，但没有显著影响其总水平。在动物实验中，口服水飞蓟宾6周（100和200 mg/kg/天，每周5天）可显著抑制胸腺裸小鼠LoVo异种移植物的生长（P<0.001），且无明显毒性。异种移植组织的分析表明，水飞蓟宾处理抑制增殖和增加凋亡，同时p27水平显著增加，但Rb磷酸化降低。总之，这些结果表明水飞蓟宾对晚期人类结直肠癌的潜在应用。
Colorectal cancer (CRC) is one of the leading causes of cancer-related morbidity and mortality. The use of non-toxic phytochemicals in the prevention and intervention of CRC has been suggested as an alternative to chemotherapy. Here we assessed the anticancer efficacy of silibinin against advance CRC 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 PARP. Additionally, silibinin caused a strong cell cycle arrest at G1 phase, and a slight but significant G2/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 CDKs and increases the level of CDKIs (p21 and p27). Consistent with these results, silibinin treatment also decreased the phosphorylation of Rb protein at Ser780, Ser795 and Ser807/811 sites without significantly affecting its total level. In animal studies, oral administration of silibinin for 6 weeks (at 100 and 200 mg/kg/day, 5 days per week) 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 Rb phosphorylation. Together these results suggest the potential use of silibinin against advanced human CRC.