Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and the fourth most frequent cause of cancer-related death worldwide. Sorafenib is the first line recommended therapy for patients with locally advanced/metastatic HCC. The low response rate is attributed to intrinsic resistance of HCC cells to Sorafenib. The potential resistance to Sorafenib-induced cell death is multifactorial and involves all hallmarks of cancer. However, the presence of sub-therapeutic dose can negatively influence the antitumoral properties of the drug. In this sense, the present study showed that the sub-optimal Sorafenib concentration (10 nM) was associated with activation of caspase-9, AMP-activated protein kinase (AMPK), sustained autophagy, peroxisome proliferator-activated receptor-coactivator 1α (PGC-1α) and mitochondrial function in HepG2 cells. The increased mitochondrial respiration by Sorafenib (10 nM) was also observed in permeabilized HepG2 cells, but not in isolated rat mitochondria, which suggests the involvement of an upstream component in this regulatory mechanism. The basal glycolysis was dose dependently increased at early time point studied (6 h). Interestingly, Sorafenib increased nitric oxide (NO) generation that played an inhibitory role in mitochondrial respiration in sub-therapeutic dose of Sorafenib. The administration of sustained therapeutic dose of Sorafenib (10 µM, 24 h) induced mitochondrial dysfunction and dropped basal glycolysis derived acidification, as well as increased oxidative stress and apoptosis in HepG2. In conclusion, the accurate control of the administered dose of Sorafenib is relevant for the potential prosurvival or proapoptotic properties induced by the drug in liver cancer cells.

Department of Physiology Faculty of Medicine in Hradec Kralove Charles University Hradec Kralove Czech Republic

Department of Physiology Faculty of Medicine in Hradec Kralove Charles University Hradec Kralove Czech Republic; COST European Cooperation in Science and Technology Mitoeagle Action number CA15203 Brussels Belgium

Institute of Biomedicine of Seville IBiS Hospital University Virgen del Rocío CSIC University of Seville Seville Spain

Institute of Biomedicine of Seville Spain

Institute of Biomedicine of Seville Spain; COST European Cooperation in Science and Technology Mitoeagle Action number CA15203 Brussels Belgium; Department of General Surgery Virgen del Rocío University Hospital IBiS CSIC University of Seville Seville Spain

Biochem Pharmacol. 2022 Dec;206:115351. doi: 10.1016/j.bcp.2022.115351. PubMed

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