17-AAG: mechanisms of antitumour activity

Abstract

Heat-shock protein 90 (Hsp90) is a molecular chaperone involved in three-dimensional folding, intracellular translocation and degradation of multiple key regulatory proteins. Accumulated evidence has indicated an important role of Hsp90 in several signal transduction pathways that are deregulated in carcinogenesis. 17-allylamino-17-demethoxygeldanamycin (17-AAG), a selective inhibitor of Hsp90, is currently under clinical investigation in advanced malignancies in which Hsp90 client proteins are implicated. This article discusses the mechanistic evidence underlying 17-AAG's cytostatic, proapoptotic, antiangiogenic and anti-invasive properties that provide the basis for its antitumour activity and underscores its unique therapeutic potential as a multi-targeted agent, as opposed to most of the current-generation molecular therapeutics.