Abstract
Sorafenib is a tyrosine kinase inhibitor for the treatment of advanced-stage HCC; however, clinical trials of sorafenib failed to demonstrate long-term survival benefits due to drug resistance. Low Pi stress has been shown to inhibit tumor growth and the expression of multidrug resistance-associated proteins. In this study, we investigated the sensitivity of HCC to sorafenib under conditions of low Pi stress. As a result, we found that low Pi stress facilitated sorafenib-mediated suppression of migration and invasion of HepG-2 and Hepa1-6 cells by decreasing the phosphorylation or expression of AKT, Erk and MMP-9. Angiogenesis was inhibited due to decreased expression of PDGFR under low Pi stress. Low Pi stress also decreased the viability of sorafenib-resistant cells by directly regulating the expression of AKT, HIF-1a and P62. In vivo drug sensitivity analysis in the four animal models showed a similar tendency that low Pi stress enhances sorafenib sensitivity in both the normal and drug-resistant models. Altogether, low Pi stress enhances the sensitivity of hepatocellular carcinoma to sorafenib and expands the indications for sevelamer.