靈芝三萜T-612透過誘導細胞自噬以促進Sorafenib於肝癌細胞株之效能

Abstract

Hepatocellular carcinoma (HCC) is the third cause of cancer-related death in the world. There is no efficient treatment for unresectable HCC. Sorafenib, a multiple kinase inhibitor, is the only targeted therapy drug for the treatment of unresectable HCC. It can improve the overall survival and progression time of the HCC patients. In clinical, lowering dosage is the solution to reduce sorafenib-induced side effects, like rash and hand-foot skin reaction. However, it leads to lower effectiveness of treatment. Low-dose sorafenib combined with other drugs (or adjuvant) to improve sorafenib efficacy may resolve the dilemma. In this study, Ganoderma triterpenoid T-612 from Lingzhi, a traditional Chinese medicine, was developed as an adjuvant of sorafenib for HCC. In HCC cell lines, compared to sorafenib alone, the combination with T-612 displayed synergistic cytotoxicity and growth inhibitory effects (IC50 of sorafenib was reduced 12 % to 51 %). Sorafenib treatment decreased colony formation efficiency, arrested cell growth in G0/G1 phase resulted by insufficiency of cyclin D, E and CDK2, increased reactive oxygen species, induced mitochondrial membrane damage and inhibited ERK phosphorylation. Apoptosis phenotypes, such as DNA fragmentation, caspase activation and AIF activation, were not detected whereas slight autophagy occurred by sorafenib treatment. However, autophagy is not the reason of cell death. Combined treatment with T-612 reinforced the effects of sorafenib, except ERK phosphorylation. The combination treatment induced serious autophagy, indicated by the increases of LC3-II and acidic vacule organells. Autophagy could be partially restored by autophagy inhibitor 3-MA. In conclusion, T-612 is a potential anti-cancer adjuvant that enhances the therapeutic efficacy of sorafenib in HCC cells.