RAD001 (everolimus) inhibits tumour growth in xenograft models of human hepatocellular carcinoma

作者：Hung Huynh, Pierce K. H. Chow, Khee Chee Soo, Han Chong Toh, Su Pin Choo, Kian Fong Foo, Donald Y. H. Poon, Van Chanh Ngo, Evelyn Tran · 发表于：Journal of Cellular and Molecular Medicine · 年份：2008 · DOI：10.1111/j.1582-4934.2008.00364.x · 被引用次数：137 · 研究领域：PI3K/AKT/mTOR signaling in cancer、Cancer Mechanisms and Therapy、Hepatocellular Carcinoma Treatment and Prognosis

Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide and highly resistant to available chemotherapies. Mammalian target of rapamycin (mTOR) functions to regulate protein translation, angiogenesis and cell cycle progression in many cancers including HCC. In the present study, subcutaneous patient-derived HCC xenografts were used to study the effects of an mTOR inhibitor, RAD001 (everolimus), on tumour growth, apoptosis and angiogenesis. We report that oral administration of RAD001 to mice bearing patient-derived HCC xenografts resulted in a dose-dependent inhibition of tumour growth. RAD001-induced growth suppression was associated with inactivation of downstream targets of mTOR, reduction in VEGF expression and microvessel density, inhibition of cell proliferation, up-regulation of p27(Kip1) and down-regulation of p21(Cip1/Waf1), Cdk-6, Cdk-2, Cdk-4, cdc-25C, cyclin B1 and c-Myc. Our data indicate that the mTOR pathway plays an important role in angiogenesis, cell cycle progression and proliferation of liver cancer cells. Our study provides a strong rationale for clinical investigation of mTOR inhibitor RAD001 in patients with HCC.