Combination of sorafenib and Valproic acid synergistically induces cell apoptosis and inhibits hepatocellular carcinoma growth via down-regulating Notch3 and pAkt.

Sorafenib is currently the only approved first-line targeted drug against advanced hepatocellular carcinoma (HCC). However, unsatisfactory efficacy and resistance of sorafenib raises the urgent need to develop more effective therapeutic strategies for HCC. Here, we evaluated the effects of combination of histone deacetylase inhibitor Valproic acid (VPA) and sorafenib in HCC both in vitro and in vivo. Co-treatment of sorafenib and VPA synergistically inhibited HCC cell viability, induced cell apoptosis, along with the up-regulation of p21, Bax, cleaved caspase9, cleaved caspase3, cleaved PARP and down-regulation of Bcl-xL, suggesting this combination activated intrinsic apoptotic pathway. Our further experiment results showed that sorafenib plus VPA decreased tumor burden more effectively than sorafenib or VPA mono-therapy in nude mice subcutaneous xenograft model. Histological and serological analysis demonstrated well tolerance of this combination in vivo. On a molecular level, our results presented a possible crosstalk between Notch3 and Akt signaling. Sorafenib increased the expression of Notch3 in a dosage dependent manner, along with the phosphorylation of Akt in HCC cells. In comparison, this induction of Notch3 and pAkt could be decreased by VPA, implying that Notch3 and pAkt are of significance in the treatment of HCC, which may account for the synergism of sorafenib and VPA. In conclusion, the combination of sorafenib and VPA offers a potential targeting therapeutic regimen for HCC in the future.