The multikinase inhibitor Sorafenib enhances glycolysis and synergizes with glycolysis blockade for cancer cell killing

Scientific Reports
Valentina TesoriAntonio Gasbarrini

Abstract

Although the only effective drug against primary hepatocarcinoma, the multikinase inhibitor Sorafenib (SFB) usually fails to eradicate liver cancer. Since SFB targets mitochondria, cell metabolic reprogramming may underlie intrinsic tumor resistance. To characterize cancer cell metabolic response to SFB, we measured oxygen consumption, generation of reactive oxygen species (ROS) and ATP content in rat LCSC (Liver Cancer Stem Cells) -2 cells exposed to the drug. Genome wide analysis of gene expression was performed by Affymetrix technology. SFB cytotoxicity was evaluated by multiple assays in the presence or absence of metabolic inhibitors, or in cells genetically depleted of mitochondria. We found that low concentrations (2.5-5 μM) of SFB had a relatively modest effect on LCSC-2 or 293 T cell growth, but damaged mitochondria and increased intracellular ROS. Gene expression profiling of SFB-treated cells was consistent with a shift toward aerobic glycolysis and, accordingly, SFB cytotoxicity was dramatically increased by glucose withdrawal or the glycolytic inhibitor 2-DG. Under metabolic stress, activation of the AMP dependent Protein Kinase (AMPK), but not ROS blockade, protected cells from death. We conclude that mitochondria...Continue Reading

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Citations

Jan 12, 2016·British Journal of Pharmacology·Bhaskar BhattacharyaRichie Soong
Aug 11, 2015·The FEBS Journal·Yazhi XingJun Mi
Apr 19, 2016·International Journal of Molecular Sciences·Yushuang DingYing Cheng
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Datasets Mentioned

BETA
GSE43053

Methods Mentioned

BETA
flow cytometry
PCR
fluorescence-activated cell sorting
Assay

Software Mentioned

STATE

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