Authors
Sébastien Bonnet, Stephen L Archer, Joan Allalunis-Turner, Alois Haromy, Christian Beaulieu, Richard Thompson, Christopher T Lee, Gary D Lopaschuk, Lakshmi Puttagunta, Sandra Bonnet, Gwyneth Harry, Kyoko Hashimoto, Christopher J Porter, Miguel A Andrade, Bernard Thebaud, Evangelos D Michelakis
Publication date
2007/1/1
Journal
Cancer cell
Volume
11
Issue
1
Pages
37-51
Publisher
Elsevier
Description
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 (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 …
Total citations
Scholar articles
S Bonnet, SL Archer, J Allalunis-Turner, A Haromy… - Cancer cell, 2007