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.
Highlights
HSP90 is a 90kDa protein that functions as an ATP-dependent molecular chaperone guiding late-stage tertiary folding and maintaining the conformational integrity of multiple clients especially networks of oncogenic proteins, including kinases and their transduction intermediates, steroid receptors and transcription factors [1]
The effect of GIB was first assessed on the inflammatory response 24 h after LPS exposure since we have previously shown that at this time-point, the peak of inflammation, there is a strong, statistically significant, steroid-resistant inflammatory response comprising predominantly neutrophils, with some lymphocyte and myelo-monocytic lineage cell infiltration into the lung when assessed in BALF [17]
To further characterise the effects of GIB on discrete cell populations we performed FACS analysis confirming the effect on neutrophils and showing that GIB suppresses several macrophage subsets and dendritic cells (DCs) (Fig. 1B, Table 1)
Summary
HSP90 is a 90kDa protein that functions as an ATP-dependent molecular chaperone guiding late-stage tertiary folding and maintaining the conformational integrity of multiple clients especially networks of oncogenic proteins, including kinases and their transduction intermediates, steroid receptors and transcription factors [1]. HSP90 is widely expressed in eukaryotic cells but PLOS ONE | DOI:10.1371/journal.pone.0114975. HSP90 is widely expressed in eukaryotic cells but PLOS ONE | DOI:10.1371/journal.pone.0114975 January 23, 2015
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