| Literature DB >> 17222789 |
Sébastien Bonnet1, 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.
Abstract
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.Entities:
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Year: 2007 PMID： 17222789 DOI： 10.1016/j.ccr.2006.10.020
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743