The multikinase inhibitor Sorafenib targets mitochondria and synergizes with glycolysis blockade for cancer cell killing.

Objective: identify novel and relevant aspects of Sorafenib action on liver cancer cells. We found that in rat hepatocholangiocarcinoma (LCSC-2) cells, exposure to the MEK/multikinase inhibitor sorafenib did not inhibit ERK phosphorylation nor induced appreciable cell death in the low micromolar range; instead, the drug elicited a raise of intracellular reactive oxygen species (ROS) accompanied by a severe decrease of oxygen consumption and intracellular ATP levels, all changes consistent with mitochondrial damage. Moreover, Sorafenib induced depolarization of isolated rat liver mitochondria, indicating a possible direct effect on the organelle. Microarray analysis of gene expression in sorafenib-trated cells revealed a metabolic reprogramming toward aerobic glycolysis, that likely accounts for resitance to drug toxicity in this cell line. Importantly, cytotoxicity was strongly potentiated by glucose withdrawal from the culture medium or by the glycolytic inhibitor 2-deoxy-glucose, a finding also confirmed in the highly malignant melanoma cell line B16F10. Mechanistic studies revealed that ROS are pivotal to cell killing by the Sorafenib + 2DG combination, and that a low content of intracellular oxidants is associated with resistance to the drug; instead, Thr172phosphorylation/activation of the AMP-activated protein kinase (AMPK), induced by Sorafenib, may exert protective effects, since cytotoxicity was enhanced by an AMPK specific inhibitor and prevented by the AMPK activator Metformin. Overall, this study identifies novel and relevant aspects of Sorafenib action on liver cancer cells, including mitochondrial damage, induction of ROS and a metabolic cell reprogramming towards glucose addiction, potentially exploitable in therapy.

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Tesori V, Piscaglia AC, Samengo D, Barba M, Bernardini C, Scatena R, Pontoglio A, Castellini L, Spelbrink JN, Maulucci G, Puglisi MA, Pani G, Gasbarrini A