Oxaliplatin-rapamycin combination was superior to mono-drug in treatment of hepatocellular carcinoma both in vitro and in vivo

Abstract

The presented study aimed to investigate the antitumor efficacy of combination of oxaliplatin with rapamycin, an mTOR inhibitor, in hepatocellular carcinoma (HCC). The activation status of mTOR pathway was first examined in HCC cell lines HepG2, BEL7402, and HuH7 using Western blotting. Effects of rapamycin, oxaliplatin, and their combination on the proliferation of HCC cells were determined in vitro using MTT assay and in vivo using a nude mice model bearing HepG2 xenografts. Drug-induced cell apoptosis was examined by flow cytometry. Expression of apoptosis-related protein was determined by Western blotting. We observed that mTOR pathway was activated in all three cell lines used in the current study. MTT assay demonstrated that oxaliplatin in combination with rapamycin synergistically inhibited the proliferation of HCC cells. The combination regimen reduced terminal tumor burden more efficiently than the corresponding monotherapy. The percentages of apoptotic cells and the expression levels of apoptosis-related proteins including cleaved caspase-9, -3, and PARP were significantly higher in combination-treatment groups than those in mono-drug-treatment groups. The ratios of Bax/Bcl-2 in cells exposed to both oxaliplatin and rapamycin were significantly increased compared to those in cells subjected to oxaliplatin or rapamycin alone treatment. Results obtained in the presented study suggested that combination of oxaliplatin and rapamycin was superior to mono-drug and may have a potential value in treatment of HCC.