Dose-dependent regulation of mitochondrial function and cell death pathway by sorafenib in liver cancer cells

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.We thank Dr. María Monsalve (Biomedical Research Institute "Alberto Sols", IIBM, Spain) for supplying the PGC-1α constructs. We also thank the Institute of Health Carlos III (ISCIII) (Spain) (PI13/00021 and PI16/00090), the Andalusian Government (Consejería de Igualdad, Salud y Políticas Sociales) (Spain) (PI-00025-2013 and PI-0198-2016), and Charles University research program PROGRES Q40/02 (Czech Republic) for their financial support. We thank the Biomedical Research Network Center for Liver and Digestive Diseases (CIBERehd) founded by the ISCIII (Spain) and co-financed by European Development Regional Fund ”A way to achieve Europe“ ERDF (Belgium) for their financial support