RT Journal Article SR Electronic T1 2-Methoxy antimycin reveals a unique mechanism for Bcl-xL inhibition JF Molecular Cancer Therapeutics JO Mol Cancer Ther FD American Association for Cancer Research SP 2073 OP 2080 DO 10.1158/1535-7163.MCT-06-0767 VO 6 IS 7 A1 Schwartz, Pamela S. A1 Manion, Michael K. A1 Emerson, Christine B. A1 Fry, John S. A1 Schulz, Craig M. A1 Sweet, Ian R. A1 Hockenbery, David M. YR 2007 UL http://mct.aacrjournals.org/content/6/7/2073.abstract AB 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]