Abstract LB-118: 17AAG, through hydrophobic binding, targets mitochondrial VDAC and inhibits cell invasion

Abstract

Abstract 17-allylamino-17-demethoxygeldanamycin (17AAG) is a member of the geldanamycin (GA) benzoquinone ansamycin family of anticancer drugs that is in clinical trials against several types of cancer. GA compounds bind to the ATP pocket of HSP90, and block its chaperone function resulting in the degradation of a wide variety of substrate oncoproteins, thereby providing a powerful “multi-target therapy”. GA compounds, however, are highly hydrophobic, requiring complicated drug vehicle formulation. In attempting to understand the influence of the hydrophobicity of GA drugs in vitro, we discovered that the hydrophobic molecules, GA or 17AAG, can bind directly to the highly hydrophobic voltage-dependent anion channel (VDAC) or to purified mitochondria where VDAC resides. Moreover, 17AAG binds to purified mitochondria prepared from all tissues and cells tested and compete with HSP90. Consistent with benzoquinone-ubiquinones functioning as classical Ca2+ mitochondrial regulators we associated the benzoquinone ring which all members of the GA family of drugs have as the responsible GA binding moiety with mitochondria. We show that both the ubiquinone, UbO, and GA drugs increase intracellular Ca2+, most likely through intracellular mitochondrial stores and both drugs diminish the plasma cationic current. By contrast, radicicol, with only an ansamycin ring, binds tightly to HSP90, but lacking the benzoquinone ring, has no measurable effect on cationic current or intercellular Ca2+ concentration. Thus, we propose that benzoquinone mitochondria binding through hydrophobic VDAC represents an alternative mode of action of GA drugs that can either alter HSP90 activity or be responsible for toxicity. Both activities must be considered when novel GA derivatives are developed as therapeutics. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-118.