Phenformin Synergistically Sensitizes Liver Cancer Cells To Sorafenib And Its Mechanism

Objective: We herein explored the ability of phenformin to enhance the anti-cancer activity of sorafenib against HCC and the mechanisms underlying such synergy.Methods: The Hep-G2 and SMMC-7721 HCC cell lines were treated with sorafenib and/or phenformin,after which the proliferation of these cells was evaluated via MTT and colony formation assays,while invasion and apoptotic cell death were evaluated via Transwell and flow cytometry assays,respectively.In addition,protein levels were assessed by Western blotting,drug synergy was assessed with the Compu Syn software,and xenograft models were established by implanting Hep-G2 cells into nude mice and then assessing drug antitumor efficacy.Results: Sorafenib and phenformin exhibited a synergistic ability to suppress HCC cell proliferation,migration,and survival.Phenformin further bolstered the ability of sorafenib to inhibit the CRAF/ERK and PI3K/AKT/m TOR pathways.Treatment with ERK inhibitor(AZD6244)and AKT inhibitor(MK2206)enhanced the response of HCC cells to sorafenib and phenformin.Strikingly,the combination of these two drugs achieved better in vivo efficacy in a murine model system,without causing significant weight loss or hepatorenal toxicity.Conclusion: Sorafenib and phenformin can synergistically suppress CRAF/ERK and PI3K/AKT/m TOR pathway activation in HCC cells,and may thus represent a promising approach to treating this deadly cancer.