Sodium dichloroacetate selectively targets cells with defects in the mitochondrial ETC
| Autor: | Chad N. Hancock, Luke H. Stockwin, Dianne L. Newton, Suzanne Borgel, Lawrence R. Phillips, Melinda G. Hollingshead, Sherry X. Yu, Tracy L. Wolfe |
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| Rok vydání: | 2010 |
| Předmět: |
Proteomics
Cancer Research Lung Neoplasms Pyruvate dehydrogenase kinase Cell Survival Apoptosis HL-60 Cells Oxidative phosphorylation Mitochondrion Biology Electron Transport Cell Line Tumor Animals Humans Glycolysis Membrane Potential Mitochondrial Dichloroacetic Acid Dose-Response Relationship Drug Sodium Dichloroacetate HCT116 Cells Xenograft Model Antitumor Assays Warburg effect Mitochondria Oncology Biochemistry Anaerobic glycolysis Rabbits Pyruvate kinase |
| Zdroj: | International Journal of Cancer. 127:2510-2519 |
| ISSN: | 0020-7136 |
| DOI: | 10.1002/ijc.25499 |
| Popis: | The "Warburg effect," also termed aerobic glycolysis, describes the increased reliance of cancer cells on glycolysis for ATP production, even in the presence of oxygen. Consequently, there is continued interest in inhibitors of glycolysis as cancer therapeutics. One example is dichloroacetate (DCA), a pyruvate mimetic that stimulates oxidative phosphorylation through inhibition of pyruvate dehydrogenase kinase. In this study, the mechanistic basis for DCA anti-cancer activity was re-evaluated in vitro using biochemical, cellular and proteomic approaches. Results demonstrated that DCA is relatively inactive (IC(50) ≥ 17 mM, 48 hr), induces apoptosis only at high concentrations (≥ 25 mM, 48 hr) and is not cancer cell selective. Subsequent 2D-PAGE proteomic analysis confirmed DCA-induced growth suppression without apoptosis induction. Furthermore, DCA depolarizes mitochondria and promotes reactive oxygen species (ROS) generation in all cell types. However, DCA was found to have selective activity against rho(0) cells [mitochondrial DNA (mtDNA) deficient] and to synergize with 2-deoxyglucose in complex IV deficient HCT116 p53(-/-) cells. DCA also synergized in vitro with cisplatin and topotecan, two antineoplastic agents known to damage mitochondrial DNA. These data suggest that in cells "hardwired" to selectively utilize glycolysis for ATP generation (e.g., through mtDNA mutations), the ability of DCA to force oxidative phosphorylation confers selective toxicity. In conclusion, although we provide a mechanism distinct from that reported previously, the ability of DCA to target cell lines with defects in the electron transport chain and to synergize with existing chemotherapeutics supports further preclinical development. |
| Databáze: | OpenAIRE |
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