Non-redox-active lipoate derivates disrupt cancer cell mitochondrial metabolism and are potent anticancer agents in vivo
| Autor: | Claudia Maturo, Zuzana Zachar, James F. Marecek, Robert Shorr, Joanna Lem, Sameer Karnik, Paul M. Bingham, Sunita Gupta, Shawn D. Stuart, Robert J. Rodriguez, Alexandra Schauble, Katy Howell, Arin Piramzadian, King Lee |
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| Rok vydání: | 2011 |
| Předmět: |
Enzyme complex
Programmed cell death Transplantation Heterologous Cell Antineoplastic Agents Pyruvate Dehydrogenase Complex Sulfides Biology Mitochondrion Antioxidants Oxidative Phosphorylation Mice Cell Line Tumor Neoplasms Drug Discovery medicine Animals Humans Genetics (clinical) Thioctic Acid Kinase Mitochondria Cell biology medicine.anatomical_structure Biochemistry Cell culture Gene Knockdown Techniques Cancer cell Molecular Medicine Phosphorylation Caprylates Drug Screening Assays Antitumor Oxidation-Reduction Neoplasm Transplantation |
| Zdroj: | Journal of Molecular Medicine. 89:1137-1148 |
| ISSN: | 1432-1440 0946-2716 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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