RAD001 (everolimus) inhibits tumour growth in xenograft models of human hepatocellular carcinoma
Open Access
- 30 July 2009
- journal article
- Published by Wiley in Journal of Cellular and Molecular Medicine
- Vol. 13 (7), 1371-1380
- https://doi.org/10.1111/j.1582-4934.2008.00364.x
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 p27Kip1 and down-regulation of p21Cip1/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.Keywords
This publication has 55 references indexed in Scilit:
- Regulation of Hepatitis B Virus Replication by the Phosphatidylinositol 3-Kinase-Akt Signal Transduction PathwayJournal of Virology, 2007
- Phase III Randomized Controlled Trial Comparing the Survival of Patients With Unresectable Hepatocellular Carcinoma Treated With Nolatrexed or DoxorubicinJournal of Clinical Oncology, 2007
- Phase II Study of Sorafenib in Patients With Advanced Hepatocellular CarcinomaJournal of Clinical Oncology, 2006
- mTOR and cancer: insights into a complex relationshipNature Reviews Cancer, 2006
- Systemic Therapy of Advanced Hepatocellular Carcinoma: How Hopeful Should We Be?The Oncologist, 2006
- A Randomized Phase III Study of Doxorubicin Versus Cisplatin/Interferon α-2b/Doxorubicin/Fluorouracil (PIAF) Combination Chemotherapy for Unresectable Hepatocellular CarcinomaJNCI Journal of the National Cancer Institute, 2005
- The mTOR Inhibitor RAD001 Sensitizes Tumor Cells to DNA-Damaged Induced Apoptosis through Inhibition of p21 TranslationCell, 2005
- Rapamycin is an effective inhibitor of human renal cancer metastasis11See Editorial by Sukhatme and Strom, p. 1160.Kidney International, 2003
- Hepatocyte growth factor stimulates the growth and activates mitogen-activated protein kinase in human hepatoma cellsJournal of Biomedical Science, 1998
- Recurrence of hepatocellular carcinoma after surgeryBritish Journal of Surgery, 1996