Antioxidants threaten multikinase inhibitor efficacy against liver cancer by blocking mitochondrial reactive oxygen species

Sorafenib and regorafenib, multikinase inhibitors (MKIs) used as standard chemotherapeutic agents for hepatocellular carcinoma (HCC), generate reactive oxygen species (ROS) during cancer treatment. Antioxidant supplements are becoming popular additions to our diet, particularly glutathione derivatives and mitochondrial-directed compounds. To address their possible interference during HCC chemotherapy, we analyzed the effect of common antioxidants using hepatoma cell lines and tumor spheroids. In liver cancer cell lines, sorafenib and regorafenib induced mitochondrial ROS production and potent cell death after glutathione depletion. In contrast, cabozantinib only exhibited oxidative cell death in specific HCC cell lines. After sorafenib and regorafenib administration, antioxidants such as glutathione methyl ester and the superoxide scavenger MnTBAP decreased cell death and ROS production, precluding the MKI activity against hepatoma cells. Interestingly, sorafenib-induced mitochondrial damage caused PINK/Parkin-dependent mitophagy stimulation, altered by increased ROS production. Finally, in sorafenib-treated tumor spheroids, while ROS induction reduced tumor growth, antioxidant treatments favored tumor development. In conclusion, the anti-tumor activity of specific MKIs, such as regorafenib and sorafenib, is altered by the cellular redox status, suggesting that uncontrolled antioxidant intake during HCC treatment should be avoided or only endorsed to diminish chemotherapy-induced side effects, always under medical scrutiny.Study funded by grants from Instituto de Salud Carlos III (PI19/01410 to M.M., and PI19/00358 to M.R.), CIBEREHD and CIBERNED; Ministerio de Ciencia, Innovación y Universidades (RTI2018-095672-B-I00 to A.M. and P.G.F., and RTI2018-095572-B-100 to A.C.) and co-funded by FEDER (Fondo Europeo de Desarrollo Regional, Unión Europea); AGAUR (2017_SGR_177 to A.M.) and CERCA Programme/Generalitat de Catalunya