Targeting Mitochondrial Function with the BCL-2 Inhibitor ABT-263 Increases Therapy Efficacy and Evades Sorafenib Resistance

Trabajo presentado en el International Liver Congress, celebrado en Barcelona, España, del 13 al 17 de abril de 2016[Background and Aims] Multikinase inhibitor sorafenib has limited efficacy in the treatment of advanced hepatocellular carcinoma (HCC). The lack of positive results from other drugs, underscore the importance of identifying weaknesses in HCC biology that current approaches have not recognized. While mitochondrial damage caused by sorafenib has been previously reported, mitochondrial participation in sorafenib toxicity and HCC therapy has drawn little attention. Novel therapies are demanded to increase drug efficacy in HCC treatment.[Methods] Hepatoma cell lines sensitive and with sorafenib resistance (HepG2 S/R and Hep3B S/R) were treated with sorafenib and Bcl2- inhibitors, and transfected with Bcl-2, Bcl-xL and Mcl-1 siRNAs. Western blots in total, cytosolic and mitochondrial extracts and qPCRs were performed. Mitochondrial functionality, caspase activation and apoptosis induction were analyzed in sorafenibtreated hepatoma cells. Tumor growth was determined in mice xenografts after subcutaneous injection of HepG2 S/R cells.[Results] Sorafenib induction of mitochondrial dysfunction is mediated by blocking respiratory complex I activity and membrane potential that is followed by Mcl-1 depletion. Co-treatment of sorafenib-exposed hepatoma cells with ABT-263, (Navitoclax) a potent inhibitor of Bcl-xL and Bcl-2 in clinical trials for leukemia and solid tumors, strongly increased sorafenib-induced cell death. In a similar extent, Mcl-1 silencing sensitized hepatoma cells to ABT- 263 supporting an important role for Mcl-1 in sorafenib efficacy. Moreover, ABT-263 potentiated sorafenib-mediated cell death via an apoptotic mechanism inducing cytochrome c release, PARP-1 cleavage and nuclear condensation. In addition, ABT-263 was equally effective to sensitize hepatoma resistant cell lines (Hep3B R and HepG2 R) to sorafenib exposure. Finally, in vivo administration of ABT-263 combined with sorafenib greatly potentiated sorafenib effects, decreasing subcutaneous tumor growth of HepG2 sensitive and resistant cells in nude mice.[Conclusions] ABT-263, via inhibition of Bcl-2 and Bcl-xL, combined with sorafenib-induced reduction of Mcl-1 in hepatoma cells potentiates the mitochondrial vulnerability induced by sorafenib leading to apoptotic death, even in sorafenib-resistant cells. ABT-263 (Navitoclax), in combination with sorafenib administration is a therapeutic strategy to take into account in HCC management.Peer Reviewe