title: RAD001 (everolimus) inhibits tumour growth in xenograft models of human hepatocellular carcinoma.
abstract: 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.
authors.affiliation: Laboratory of Molecular Endocrinology, Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore. cmrhth@nccs.com.sg
authors.forename: Hung
authors.initials: H
authors.lastname: Huynh
authors.forename: K H Pierce
authors.initials: KH
authors.lastname: Chow
authors.forename: Khee Chee
authors.initials: KC
authors.lastname: Soo
authors.forename: Han Chong
authors.initials: HC
authors.lastname: Toh
authors.forename: Su Pin
authors.initials: SP
authors.lastname: Choo
authors.forename: Kian Fong
authors.initials: KF
authors.lastname: Foo
authors.forename: Donald
authors.initials: D
authors.lastname: Poon
authors.forename: Van Chanh
authors.initials: VC
authors.lastname: Ngo
authors.forename: Evelyn
authors.initials: E
authors.lastname: Tran
mesh_terms: D000818:Animals; D017209:Apoptosis; D001835:Body Weight; D006528:Carcinoma, Hepatocellular / Q000097:blood / Q000188:drug therapy*; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation; D000068338:Everolimus; D006801:Humans; D008113:Liver Neoplasms / Q000097:blood / Q000188:drug therapy*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D055806:Microvessels / Q000473:pathology; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases; D042461:Vascular Endothelial Growth Factor A / Q000097:blood; D023041:Xenograft Model Antitumor Assays
chemical_list: D018797:Cell Cycle Proteins; D042461:Vascular Endothelial Growth Factor A; D000068338:Everolimus; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus