Altered metabolism is an important hallmark of cancer cells and confers them a selective advantage for survival and proliferation. Metabolism in cancer cells is shifted towards glycolysis and decreased dependence on mitochondrial glucose oxidation, a phenomenon known as ‘Warburg effect’ (aerobic glycolysis). Lactate, the end product of glycolysis, is produced in large excess by cancer cells that used it as metabolic fuel, and has been directly involved in cancer progression. Growth of cancer cells often occurs in a hypoxic microenvironment and thus, these cells rely on anaerobic glycolysis as a primary energy source. Nevertheless, conversion of glucose to lactate persists in cancer cells despite the presence of oxygen (aerobic glycolysis). This adaptation is initiated, in part, by activation of hypoxia-inducible factor 1α (HIF-1) that regulates expression of several glycolytic enzymes, glucose transporters, and mitochondrial enzymes, including pyruvate dehydrogenase kinases (PDKs) which inactivate the pyruvate dehydrogenase complex (PDHC) [1]. The PDHC is an important enzyme in metabolism linking glycolysis to the tricarboxylic acid (TCA) cycle and lipogenic pathway. PDHC catalyzes in mitochondria the irreversible conversion of pyruvate into acetyl-CoA that initiates the TCA cycle. PDHC is formed by three different enzymes: thiamine diphosphate-dependent heterotetrameric (α 2 β 2 ) E1, dihydrolipoamide acetyltransferase (E2), and FAD containing dihydrolipoamide dehydrogenase (E3), that is integrated into the complex by an E3-binding protein (E3BP). Phosphorylation of specific E1α serine residues by PDKs (PDK1, PDK2, PDK3, and PDK4) results in inactivation of PDHC, whereas dephosphorylation by pyruvate dehydrogenase phosphatases (PDP1 and PDP2) restores PDHC activity (Fig. 1). Inhibition of PDHC activity results in conversion of pyruvate into lactate by lactate dehydrogenase (LDH) in the cytoplasm. Deficiency of PDHC is one of the most common inborn errors of energy metabolism and affected patients present with progressive neurological degeneration and lactic acidosis [2]. Dichloroacetate (DCA) increases PDHC activity by inhibition of PDK and is effective in reducing blood and tissue lactate [3]. However, DCA has been associated with hepatocellular and peripheral nerve toxicity. We have recently found that phenylbutyrate, a drug used in patients with urea cycle defects and cancer, results in reduction of phosphorylated E1α and increased