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

Biochemical Pharmacology
María A Rodríguez-HernándezJordi Muntané

Abstract

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) generatio...Continue Reading

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Citations

Jul 23, 2020·Frontiers in Oncology·Yuehui LiangFang Xiao
May 4, 2020·Biochemical Pharmacology·Khosrow Kashfi
Jun 3, 2020·European Journal of Pharmacology·Milad AshrafizadehMasoud Najafi

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