Activating oxidative phosphorylation by a pyruvate dehydrogenase kinase inhibitor overcomes sorafenib resistance of hepatocellular carcinoma

• Published in: British journal of cancer Vol. 108; no. 1; pp. 72 - 81
• Main Authors: Shen, Y-C, Ou, D-L, Hsu, C, Lin, K-L, Chang, C-Y, Lin, C-Y, Liu, S-H, Cheng, A-L
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15.01.2013; Nature Publishing Group
• Subjects: 631/67/1059/2326; 692/53/2423; 692/699/67/1504/1610; Adenosine triphosphate; Animals; Apoptosis; Bioenergetics; Biological and medical sciences; Biomarkers; Biomedical and Life Sciences; Biomedicine; Cancer Research; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - metabolism; Cell Line, Tumor; Dehydrogenases; Drug Resistance; Drug Resistance, Neoplasm; Epidemiology; Gastroenterology. Liver. Pancreas. Abdomen; Glucose; Glycolysis; Hospitals; Humans; Kinases; Liver cancer; Liver Neoplasms - drug therapy; Liver Neoplasms - metabolism; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Medical research; Medical sciences; Medicine; Metabolism; Mice; Mitochondrial DNA; Molecular Medicine; Niacinamide - analogs & derivatives; Oncology; Oxidative Phosphorylation; Phenylurea Compounds; Phosphorylation; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Translational Therapeutics; Tumors; Xenograft Model Antitumor Assays; United States > US; Taiwan; dichloroacetate; sorafenib; oxidative phosphorylation; hepatocellular carcinoma; glycolysis; Antineoplastic agent; Pyruvate kinase; Enzyme; Tyrosine kinase inhibitor; Transferases; Pyruvate dehydrogenase (lipoamide); Enzyme inhibitor; Hepatic disease; Hepatocellular carcinoma; Malignant tumor; Resistance; Liver cancer; Cancerology; Oxidative phosphorylation; Sorafenib; Glycolysis; Digestive diseases; Multikinase inhibitor; Oxidoreductases; Antiangiogenic agent; Cancer
• ISSN: 0007-0920; 1532-1827; 1532-1827
• DOI: 10.1038/bjc.2012.559

Background: Sorafenib is the only drug approved for the treatment of hepatocellular carcinoma (HCC). The bioenergetic propensity of cancer cells has been correlated to anticancer drug resistance, but such correlation is unclear in sorafenib resistance of HCC. Methods: Six sorafenib-naive HCC cell lines and one sorafenib-resistant HCC cell line (Huh-7R; derived from sorafenib-sensitive Huh-7) were used. The bioenergetic propensity was calculated by measurement of lactate in the presence or absence of oligomycin. Dichloroacetate (DCA), a pyruvate dehydrogenase kinase (PDK) inhibitor, and siRNA of hexokinase 2 (HK2) were used to target relevant pathways of cancer metabolism. Cell viability, mitochondrial membrane potential, and sub-G1 fraction were measured for in vitro efficacy. Reactive oxygen species (ROS), adenosine triphosphate (ATP) and glucose uptake were also measured. A subcutaneous xenograft mouse model was used for in vivo efficacy. Results: The bioenergetic propensity for using glycolysis correlated with decreased sorafenib sensitivity ( R 2 =0.9067, among sorafenib-naive cell lines; P =0.003, compared between Huh-7 and Huh-7 R). DCA reduced lactate production and increased ROS and ATP, indicating activation of oxidative phosphorylation (OXPHOS). DCA markedly sensitised sorafenib-resistant HCC cells to sorafenib-induced apoptosis (sub-G1 (combination vs sorafenib): Hep3B, 65.4±8.4% vs 13±2.9%; Huh-7 R, 25.3± 5.7% vs 4.3±1.5%; each P <0.0001), whereas siRNA of HK2 did not. Sorafenib (10 mg kg −1 per day) plus DCA (100 mg kg −1 per day) also resulted in superior tumour regression than sorafenib alone in mice (tumour size: −87% vs −36%, P <0.001). Conclusion: The bioenergetic propensity is a potentially useful predictive biomarker of sorafenib sensitivity, and activation of OXPHOS by PDK inhibitors may overcome sorafenib resistance of HCC.