BEZ235 enhances antitumor efficacy of HPG-PCL-PTX in HCC by suppressed the PI3K/Akt/mTOR and MAPK pathway

Abstract Hepatocellular carcinoma (HCC) is the sixth most common cancer in the global. It could be a potential resistant mechanism that paclitaxel activated the PI3K/mTOR and MAPK pathway in HCC cells. So inhibiting the abnormal activation of two pathway, which may a promising targeted therapy strategy. MTT and clone formation assays were used to measure cells proliferation activity; cell cycle distribution and apoptosis were measured by flow cytometry; western blot assessed phosphorylation level of proteins associated with cell cycle, apoptosis, PI3K/mTOR and MAPK pathway; Student t test or one-way ANOVA to measure significant differences between the means.BEZ235 combined with HPG-PCL-PTX blocked the activation of PI3K/mTOR and MAPK pathway in HCC cells, effectively inhibited cells proliferation and arrested the cell cycle at the G2/M phase. The most important is that the combination of two drugs caused mitochondrial membrane potential change, induced cytochrome C release and bind to APAF-1 to initiate the caspase-9 apoptosis program, promoted HCC cell apoptosis. HPG-PCL-PTX/BEZ235 enhanced antitumor effectiveness in HepG2R cell xenograft mouse models. In vivo study suggested that BEZ235 combined with HPG-PCL-PTX enhanced effects of HPG-PCL-PTX through inhibited the PI3K/Akt/mTOR and MAPK pathway in HCC cells, supressed cells proliferation, arrested the cell cycle in a G2/M phase and promoted apoptosis. Antitumor effects of BEZ235 and HPG-PCL-PTX were also confirmed in mice bearing HepG2R tumors. Taken together, the results of this study describe a promising strategy using PTX and BEZ235 in a nanoparticle formulation for treatment of PTX-resistant HCC.