RAD001 (everolimus) inhibits tumour growth in xenograft models of human hepatocellular carcinoma.
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.
Huynh
Hung
H
Laboratory of Molecular Endocrinology, Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore. cmrhth@nccs.com.sg
Chow
K H Pierce
KH
Soo
Khee Chee
KC
Toh
Han Chong
HC
Choo
Su Pin
SP
Foo
Kian Fong
KF
Poon
Donald
D
Ngo
Van Chanh
VC
Tran
Evelyn
E
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
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