Metabolic targeting as an anticancer strategy: dawn of a new era?
As a result of a spectrum of mitochondrial defects, tumor cells often preferentially use glycolysis to generate adenosine triphosphate (ATP), even in the presence of oxygen, a phenomenon known as aerobic glycolysis, or the "Warburg effect." Dichloroacetate (DCA) is an inhibitor of mitochondrial pyruvate dehydrogenase kinase (PDK), which inhibits pyruvate dehydrogenase (PDH), a gatekeeping enzyme for the entry of pyruvate into the mitochondrial tricarboxylic acid (TCA) cycle. In mice, DCA treatment appears to reactivate mitochondrial respiration in tumor cells, induces their selective killing, and suppresses cancer growth. These observations provide intriguing insights into the plasticity of tumor metabolism that may offer new opportunities for therapeutic intervention.
Pan
James G
JG
Campbell Family Institute for Breast Cancer Research, University Health Network TMDT East Tower, MaRs Centre, Toronto, ON, Canada. jpan@uhnres.utoronto.ca
Mak
Tak W
TW
D000255:Adenosine Triphosphate / Q000096:biosynthesis; D002952:Citric Acid Cycle / Q000187:drug effects; D003999:Dichloroacetic Acid / Q000627:therapeutic use*; D016503:Drug Delivery Systems; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006019:Glycolysis / Q000187:drug effects*; D006801:Humans; D008928:Mitochondria / Q000201:enzymology* / Q000473:pathology; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D010100:Oxygen / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects*
D004791:Enzyme Inhibitors; D000255:Adenosine Triphosphate; D003999:Dichloroacetic Acid; D010100:Oxygen