The unique 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 (DeltaPsim) 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 DeltaPsim, 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.