2-Methoxy antimycin reveals a unique mechanism for Bcl-xL inhibition
| Autor: | Christine B. Emerson, Pamela S. Schwartz, Michael K. Manion, Ian R. Sweet, David M. Hockenbery, John S. Fry, Craig M. Schulz |
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| Rok vydání: | 2007 |
| Předmět: |
Cancer Research
Cell Survival bcl-X Protein Antimycin A Gene Expression Bcl-xL Oxidative phosphorylation Biology Cell Line Mice chemistry.chemical_compound medicine Animals Staurosporine Lactic Acid Cytotoxicity Cell Death Drug Synergism Mitochondria Rats Cell biology Glucose Phenotype Oncology chemistry Cell culture Apoptosis biology.protein NAD+ kinase Energy Metabolism NADP medicine.drug |
| Zdroj: | Molecular Cancer Therapeutics. 6:2073-2080 |
| ISSN: | 1538-8514 1535-7163 |
| DOI: | 10.1158/1535-7163.mct-06-0767 |
| Popis: | Overexpression of Bcl-xL in multiple cancers correlates with resistance to chemotherapy and radiation therapy, and provides a rationale for development of small-molecule Bcl-xL inhibitors. Based on knockout studies, nonneoplastic cells also require Bcl-xL survival functions, particularly when challenged with cytotoxic agents. We analyze the selective cytotoxicity of one Bcl-xL inhibitor, 2-methoxy antimycin A, toward cells with excess exogenous Bcl-xL in isogenic cell line pairs. This selectivity, characteristic of a gain-of-function mechanism, is not shared by other known Bcl-xL inhibitors, including BH3I-2, HA14-1, ABT-737, gossypol, or the stapled BH3 helical peptide SAHB-BID. We show that Bcl-xL overexpression induces a shift in energy metabolism from oxidative phosphorylation to glycolysis. Treatment with 2-methoxy antimycin A acutely reverses the metabolic effects of Bcl-xL, causing mitochondrial hyperpolarization and a progressive increase in mitochondrial NAD(P)H. We identify an additional small-molecule Bcl-xL inhibitor, NSC 310343, establishing a class of Bcl-xL inhibitors with gain-of-function activity. In contrast to other Bcl-xL inhibitors, combining gain-of-function Bcl-xL inhibitors with a standard inducer of apoptosis, staurosporine, enhances selective cytotoxicity toward Bcl-xL–overexpressing cells. These results provide an example of the intersection of bioenergetic metabolism and Bcl-xL functions and suggest a metabolic basis for the gain-of-function mechanism of Bcl-xL inhibitors. [Mol Cancer Ther 2007;6(7):2073–80] |
| Databáze: | OpenAIRE |
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