http://www.thedcasite.com/DCA%20(Cancer%20Cell).pdf
http://www.depmed.ualberta.ca/dca/vid1.htm
Cancer Cell 11, 37–51, January 2007
A Mitochondria-K+ Channel Axis Is Suppressed in Cancer and Its Normalization Promotes Apoptosis and Inhibits Cancer Growth
Se´bastien Bonnet,1 Stephen L. Archer,1,2 Joan Allalunis-Turner,3 Alois Haromy,1 Christian Beaulieu,4 Richard Thompson,4 Christopher T. Lee,5 Gary D. Lopaschuk,5,6 Lakshmi Puttagunta,7 Sandra Bonnet,1 Gwyneth Harry,1 Kyoko Hashimoto,1 Christopher J. Porter,8 Miguel A. Andrade,8 Bernard Thebaud,1,6 and Evangelos D. Michelakis1,*
1Pulmonary Hypertension Program and Vascular Biology Group,2Department of Physiology,3Department of Oncology,4Department of Biomedical Engineering,5Department of Pharmacology,6Department of Pediatrics,7Department of Laboratory Medicine and Pathology
University of Alberta, Edmonton, AB T6G 2B7, Canada,8 Ontario Genomics Innovation Centre, Ottawa Health Research Institute, and Department of Cellular and Molecular Medicine,University of Ottawa, Ottawa, ON K1N 6N5, Canada,
*Correspondence: emichela@cha.ab.ca
DOI 10.1016/j.ccr.2006.10.020
(full pdf)
SUMMARY
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 (DJm) 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 DJm, 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.
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