Silibinin suppresses growth and induces apoptotic death of human colorectal carcinoma LoVo cells in culture and tumor xenograft

摘要

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.