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Research Articles

2-Methoxy antimycin reveals a unique mechanism for Bcl-x_L inhibition

¹ Divisions of Clinical Research and Human Biology, Fred Hutchinson Cancer Research Center and ² Department of Chemistry and ³ Islet Core Facility, University of Washington, Seattle, Washington

Requests for reprints: David M. Hockenbery, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue D2-190, Seattle, WA 98109. Phone: 206-667-4611; Fax: 206-667-6519. E-mail: dhockenb{at}fhcrc.org

Abstract

Overexpression of Bcl-x_L in multiple cancers correlates with resistance to chemotherapy and radiation therapy, and provides a rationale for development of small-molecule Bcl-x_L inhibitors. Based on knockout studies, nonneoplastic cells also require Bcl-x_L survival functions, particularly when challenged with cytotoxic agents. We analyze the selective cytotoxicity of one Bcl-x_L inhibitor, 2-methoxy antimycin A, toward cells with excess exogenous Bcl-x_L in isogenic cell line pairs. This selectivity, characteristic of a gain-of-function mechanism, is not shared by other known Bcl-x_L inhibitors, including BH3I-2, HA14-1, ABT-737, gossypol, or the stapled BH3 helical peptide SAHB-BID. We show that Bcl-x_L 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-x_L, causing mitochondrial hyperpolarization and a progressive increase in mitochondrial NAD(P)H. We identify an additional small-molecule Bcl-x_L inhibitor, NSC 310343, establishing a class of Bcl-x_L inhibitors with gain-of-function activity. In contrast to other Bcl-x_L inhibitors, combining gain-of-function Bcl-x_L inhibitors with a standard inducer of apoptosis, staurosporine, enhances selective cytotoxicity toward Bcl-x_L–overexpressing cells. These results provide an example of the intersection of bioenergetic metabolism and Bcl-x_L functions and suggest a metabolic basis for the gain-of-function mechanism of Bcl-x_L inhibitors. [Mol Cancer Ther 2007;6(7):2073–80]

Grant support: Interdisciplinary Cancer Training Grant CA80416-08, U01 CA91310 (D.H.), and R03AA15681 (M.M.).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁴ Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

⁵ http://www.dtp.nci.nih.gov/docs/cancer/cancer_data.html

Received 12/15/06; revised 3/14/07; accepted 5/17/07.

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