Tesori 2015 Sci Rep

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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 (2015) The multikinase inhibitor Sorafenib enhances glycolysis and synergizes with glycolysis blockade for cancer cell killing. Sci Rep 5:9149.

» PMID: 25779766 Open Access

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 (2015) Sci Rep

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 mitochondrial damage and ROS drive cell killing by SFB, while glycolytic cell reprogramming may represent a resistance strategy potentially targetable by combination therapies.

Keywords: rat hepatocholangiocarcinoma cell line LCSC-2

O2k-Network Lab: IT Rome Scatena R


Labels: MiParea: Respiration, Pharmacology;toxicology  Pathology: Cancer 

Organism: Rat  Tissue;cell: Liver, Other cell lines, Stem cells  Preparation: Intact cells 


Coupling state: LEAK, ROUTINE, ET 

HRR: Oxygraph-2k 

2016-02