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The Warburg effect is considered a metabolic adaptation in response to cellular alterations caused by oncogenes, tumour suppressor genes, mitochondria and microenvironment, and has increasingly been recognised as a hallmark of cancer ( Hanahan and Weinberg, 2011 Ward and Thompson, 2012). This reprogrammed cancer metabolism, characterised by enhanced glycolysis and suppressed OXPHOS, is known as the Warburg effect ( Hsu and Sabatini, 2008 Kroemer and Pouyssegur 2008 Vander Heiden et al, 2009 Cairns et al, 2011 Koppenol et al, 2011). No effective therapies are available after sorafenib failure.Ĭancer cells usually rely more on glycolysis than glucose oxidative phosphorylation (OXPHOS) in energy production. However, sorafenib is beneficial in only around 30% of patients, and acquired resistance often develops within 6 months ( Llovet et al, 2008 Cheng et al, 2009). Sorafenib, a multikinase inhibitor targeting tumour angiogenesis and Raf/MEK/ERK pathway, is the only drug approved for patients with advanced HCC ( Bruix and Sherman 2011). 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.Īdvanced hepatocellular carcinoma (HCC) is characterised by inherent resistance to all systemic treatments.
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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). DCA markedly sensitised sorafenib-resistant HCC cells to sorafenib-induced apoptosis (sub-G1 (combination vs sorafenib): Hep3B, 65.4☘.4% vs 13☒.9% Huh-7 R, 25.3± 5.7% vs 4.3☑.5% each P<0.0001), whereas siRNA of HK2 did not. DCA reduced lactate production and increased ROS and ATP, indicating activation of oxidative phosphorylation (OXPHOS). 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). A subcutaneous xenograft mouse model was used for in vivo efficacy. Reactive oxygen species (ROS), adenosine triphosphate (ATP) and glucose uptake were also measured.
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Cell viability, mitochondrial membrane potential, and sub-G1 fraction were measured for in vitro efficacy. Dichloroacetate (DCA), a pyruvate dehydrogenase kinase (PDK) inhibitor, and siRNA of hexokinase 2 (HK2) were used to target relevant pathways of cancer metabolism. The bioenergetic propensity was calculated by measurement of lactate in the presence or absence of oligomycin. Six sorafenib-naive HCC cell lines and one sorafenib-resistant HCC cell line (Huh-7R derived from sorafenib-sensitive Huh-7) were used.
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The bioenergetic propensity of cancer cells has been correlated to anticancer drug resistance, but such correlation is unclear in sorafenib resistance of HCC. Sorafenib is the only drug approved for the treatment of hepatocellular carcinoma (HCC).