Author/Authors :
Bonnet، نويسنده , , Sébastien and Archer، نويسنده , , Stephen L. and Allalunis-Turner، نويسنده , , Joan and Haromy، نويسنده , , Alois and Beaulieu، نويسنده , , Christian and Thompson، نويسنده , , Richard and Lee، نويسنده , , Christopher T. and Lopaschuk، نويسنده , , Gary D. and Puttagunta، نويسنده , , Lakshmi and Bonnet، نويسنده , , Sandra and Harry، نويسنده , , Gwyneth and Hashimoto، نويسنده , , Kyoko and Porter، نويسنده , , Christopher J. and Andrade، نويسنده , , Miguel A. and Thebaud، نويسنده , , Bernard and Michelakis، نويسنده , , Evangelos D.، نويسنده ,
Abstract :
Summary
ique metabolic profile of cancer (aerobic glycolysis) might confer apoptosis resistance and be therapeutically targeted. Compared to normal cells, several human cancers have high mitochondrial membrane potential (ΔΨm) and low expression of the K+ channel Kv1.5, both contributing to apoptosis resistance. Dichloroacetate (DCA) inhibits mitochondrial pyruvate dehydrogenase kinase (PDK), shifts metabolism from glycolysis to glucose oxidation, decreases ΔΨm, increases mitochondrial H2O2, and activates Kv channels in all cancer, but not normal, cells; DCA upregulates Kv1.5 by an NFAT1-dependent mechanism. DCA induces apoptosis, decreases proliferation, and inhibits tumor growth, without apparent toxicity. Molecular inhibition of PDK2 by siRNA mimics DCA. The mitochondria-NFAT-Kv axis and PDK are important therapeutic targets in cancer; the orally available DCA is a promising selective anticancer agent.
