Silibinin inhibits colorectal cancer growth by inhibiting tumor cell proliferation and angiogenesis

被引:150
作者
Singh, Rana P. [1 ,3 ]
Gu, Mallikarjuna [1 ]
Agarwal, Rajesh [1 ,2 ]
机构
[1] Univ Colorado, Dept Pharmaceut Sci, Sch Pharm, Denver, CO 80262 USA
[2] Univ Colorado, Ctr Canc, Denver, CO 80262 USA
[3] Jawaharlal Nehru Univ, Sch Life Sci, Canc Biol Lab, New Delhi 110067, India
关键词
D O I
10.1158/0008-5472.CAN-07-6247
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Herein, for the first time, we investigated in vivo efficacy and associated molecular biomarkers and mechanisms of a chemopreventive agent, silibinin, against human colorectal carcinoma (CRC) HT29 xenograft growth. Nude mice were implanted with HT29 cells and fed with vehicle (carboxymethyl cellulose or phosphatidylcholine) or 200 mg/kg/d dose of silibinin or 100 and 200 mg/kg/d doses of silybin-phytosome (5 days per week) for 32 days. Silibinin inhibited tumor growth that accounted for 48% (P = 0.002) decrease in tumor volume and 42% (P = 0.012) decrease in tumor weight at the end of the experiment without any adverse health effect. A stronger antitumor efficacy was observed with silybin-phytosome preparation. Silibinin decreased proliferation index by 40% (P < 0.001), increased apoptotic index by similar to 2-fold (P = 0.001), and reduced microvessel density by 36% (P = 0.001) in tumors. Antiproliferative and proapoptotic effects of silibinin were associated with down-regulation of extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt phosphorylation as well as cyclin D1 expression. Antiangiogenic effect of silibinin was coupled with a strong decrease in inducible nitric oxide synthase (NOS) and NOS3, cyclooxygenase-1 (COX-1) and COX-2, and hypoxia-inducing factor-alpha (HIF-1 alpha) and vascular endothelial growth factor (VEGF). These findings suggest in vivo antitumor efficacy of silibinin against CRC involving its antiproliferative, proapoptotic, and antiangiogenic activities. The inhibition of ERK1/2 and Akt signaling may account for antiproliferative and proapoptotic effects, whereas down-regulation of NOS, COX, HIF-1 alpha, and VEGF expression could lead to antiangiogenic effect of silibinin against CRC. Overall, potential use of silibinin against human CRC could be suggested.
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收藏
页码:2043 / 2050
页数:8
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