Inhibition of mTOR enhances chemosensitivity in hepatocellular carcinoma

• Published in: Cancer letters Vol. 273; no. 2; pp. 201 - 209
• Main Authors: Tam, Ka Ho, Yang, Zhen Fan, Lau, Chi Keung, Lam, Chi Tat, Pang, Roberta W.C, Poon, Ronnie T.P
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 18-01-2009; Elsevier Limited
• Subjects: Animals; Antineoplastic Agents - pharmacology; Apoptosis; Biomedical research; Cancer therapies; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - metabolism; Cell culture; Cell cycle; Cell growth; Cell Line, Tumor; Chemoresistance; Chemosensitivity; Chemotherapy; Cisplatin - pharmacology; Cyclin D1 - biosynthesis; Cytotoxicity; Drug Resistance, Neoplasm; Genes, p53; HCC; Hematology, Oncology and Palliative Medicine; Humans; Inhibitor of Apoptosis Proteins; Kinases; Liver cancer; Liver Neoplasms - drug therapy; Liver Neoplasms - metabolism; Male; Mice; Mice, Nude; Microtubule-Associated Proteins - biosynthesis; mTOR; Neoplasm Proteins - biosynthesis; Neoplasm Transplantation; p53; Protein Kinases - metabolism; Proteins; Proto-Oncogene Proteins c-bcl-2 - metabolism; RAD001; Studies; TOR Serine-Threonine Kinases; Tumors; DMSO; 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; radioimmunoprecipitation assay; Chemoresistance; MTT; RIPA; p53; P; DMEM; SD; dimethyl sulfoxide; TUNEL; ANOVA; FBS; intra-peritoneal; eukaryotic initiation factor eIF4E binding protein; mTOR; transarterial chemoembolization; wt; hepatocellular carcinoma; PBS; hematoxylin and eosin; CO 2; carbon dioxide; H&E; TACE; HCC; i.p; phosphorylated; S6K1; analysis of variance between groups; fetal bovine serum; terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling; phosphate buffered saline; ribosomal p70S6 kinase; Chemosensitivity; Dulbecco’s modified Eagle medium; 4E-BP1; wild-type; RAD001; standard deviation
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2008.08.018

Abstract The present study investigated the effect of mammalian target of rapamycin (mTOR) inhibition on HCC cells in vitro and in vivo , either alone or in combination with cytotoxic agents. In vitro , HCC cell lines were exposed to RAD001, an mTOR inhibitor, either alone or in combination with cisplatin. Alone, RAD001 suppressed cell proliferation in all cell lines tested, but did not induce apoptosis. RAD001 in combination with cisplatin induced a significant increase in the number of apoptotic cells, downregulated the expression of pro-survival molecules, Bcl-2, survivin and cyclinD1, and increased the cleavage of PARP, compared to RAD001 or cisplatin alone. Transfection of p53 into the Hep3B cell line increased the sensitivity of tumor cells to cisplatin. The suppression of HCC tumor growth in vivo was enhanced by RAD001 combined with cisplatin, accompanied by a significant increase in the number of apoptotic cells in tumor tissues. This study demonstrates that inhibition of mTOR suppresses tumor growth and sensitizes tumor cells to chemocytotoxic agents.