title: Non-redox-active lipoate derivates disrupt cancer cell mitochondrial metabolism and are potent anticancer agents in vivo.
abstract: We report the analysis of CPI-613, the first member of a large set of analogs of lipoic acid (lipoate) we have investigated as potential anticancer agents. CPI-613 strongly disrupts mitochondrial metabolism, with selectivity for tumor cells in culture. This mitochondrial disruption includes activation of the well-characterized, lipoate-responsive regulatory phosphorylation of the E1α pyruvate dehydrogenase (PDH) subunit. This phosphorylation inactivates flux of glycolysis-derived carbon through this enzyme complex and implicates the PDH regulatory kinases (PDKs) as a possible drug target. Supporting this hypothesis, RNAi knockdown of the PDK protein levels substantially attenuates CPI-613 cancer cell killing. In both cell culture and in vivo tumor environments, the observed strong mitochondrial metabolic disruption is expected to significantly compromise cell survival. Consistent with this prediction, CPI-613 disruption of tumor mitochondrial metabolism is followed by efficient commitment to cell death by multiple, apparently redundant pathways, including apoptosis, in all tested cancer cell lines. Further, CPI-613 shows strong antitumor activity in vivo against human non-small cell lung and pancreatic cancers in xenograft models with low side-effect toxicity.
authors.affiliation: Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY, USA.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Zachar
authors.forename: James
authors.initials: J
authors.lastname: Marecek
authors.forename: Claudia
authors.initials: C
authors.lastname: Maturo
authors.forename: Sunita
authors.initials: S
authors.lastname: Gupta
authors.forename: Shawn D
authors.initials: SD
authors.lastname: Stuart
authors.forename: Katy
authors.initials: K
authors.lastname: Howell
authors.forename: Alexandra
authors.initials: A
authors.lastname: Schauble
authors.forename: Joanna
authors.initials: J
authors.lastname: Lem
authors.forename: Arin
authors.initials: A
authors.lastname: Piramzadian
authors.forename: Sameer
authors.initials: S
authors.lastname: Karnik
authors.forename: King
authors.initials: K
authors.lastname: Lee
authors.forename: Robert
authors.initials: R
authors.lastname: Rodriguez
authors.forename: Robert
authors.initials: R
authors.lastname: Shorr
authors.forename: Paul M
authors.initials: PM
authors.lastname: Bingham
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D002210:Caprylates / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000201:enzymology*; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D010084:Oxidation-Reduction / Q000187:drug effects; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D011768:Pyruvate Dehydrogenase Complex / Q000235:genetics / Q000378:metabolism*; D013440:Sulfides / Q000737:chemistry / Q000494:pharmacology*; D008063:Thioctic Acid / Q000737:chemistry / Q000494:pharmacology*; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D002210:Caprylates; D011768:Pyruvate Dehydrogenase Complex; D013440:Sulfides; D008063:Thioctic Acid; C568850:devimistat