HSP90 inhibition suppresses lipopolysaccharide-induced lung inflammation in vivo

Lilja, A; Weeden, CE; McArthur, K; Nguyen, T; Donald, A; Wong, ZX; Dousha, L; Bozinovski, S; Vlahos, R; Burns, CJ; Asselin-Labat, ML; Anderson, GP

Author(s): Lilja, A; Weeden, CE; McArthur, K; Nguyen, T; Donald, A; Wong, ZX; Dousha, L; Bozinovski, S; Vlahos, R; Burns, CJ; Asselin-Labat, ML; Anderson, GP;
Details: Publication Year 2015,Volume 10,Issue #1,Page e0114975
Journal Title: PLoS One
Publication Type: Journal Article
Abstract: Inflammation is an important component of cancer diathesis and treatment-refractory inflammation is a feature of many chronic degenerative lung diseases. HSP90 is a 90kDa protein which functions as an ATP-dependent molecular chaperone that regulates the signalling conformation and expression of multiple protein client proteins especially oncogenic mediators. HSP90 inhibitors are in clinical development as cancer therapies but the myeleosuppressive and neutropenic effect of first generation geldanamycin-class inhibitors has confounded studies on the effects on HSP90 inhibitors on inflammation. To address this we assessed the ability of Ganetespib, a non-geldanamycin HSP90 blocker, to suppress lipopolysaccharide (LPS)-induced cellular infiltrates, proteases and inflammatory mediator and transcriptional profiles. Ganetespib (10-100mg/kg, i.v.) did not directly cause myelosuppression, as assessed by video micrography and basal blood cell count, but it strongly and dose-dependently suppressed LPS-induced neutrophil mobilization into blood and neutrophil- and mononuclear cell-rich steroid-refractory lung inflammation. Ganetespib also suppressed B cell and NK cell accumulation, inflammatory cytokine and chemokine induction and MMP9 levels. These data identify non-myelosuppresssive HSP90 inhibitors as potential therapies for inflammatory diseases refractory to conventional therapy, in particular those of the lung.
Publisher: PLOS
Research Division(s): Stem Cells And Cancer; Chemical Biology
Publisher's Version: https://doi.org/10.1371/journal.pone.0114975
Open Access at Publisher's Site: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0114975
Terms of Use/Rights Notice: Copyright: © 2015 Lilja et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Documents: journal.pone.0114975.pdf - (0.75MB, application/pdf)

Creation Date: 2015-01-27 10:32:56

Last Modified: 2015-05-12 09:39:29