Abstract
Vorinostat and other inhibitors of different histone deacetylase (HDAC) enzymes are currently being sought to modulate a variety of human conditions, including chronic inflammatory diseases. Some HDAC inhibitors are anti-inflammatory in rodent models of arthritis and colitis, usually at cytotoxic doses that may cause side effects. Here, we investigate the dose-dependent pro- and anti-inflammatory efficacy of two known inhibitors of multiple HDACs, vorinostat and BML281, in human macrophages and in a rat model of collagen-induced arthritis by monitoring effects on disease progression, histopathology, and immunohistochemistry. Both HDAC inhibitors differentially modulated lipopolysaccharide (LPS)-induced cytokine release from human macrophages, suppressing release of some inflammatory mediators (IL12p40, IL6) at low concentrations (<3 µM) but amplifying production of others (TNF, IL1β) at higher concentration (>3 μΜ). This trend translated in vivo to rat arthritis, with anti-inflammatory activity inversely correlating with dose. Both compounds were efficacious only at a low dose (1 mg⋅kg−1⋅day−1 s.c.), whereas a higher dose (5 mg⋅kg−1⋅day−1 s.c.) showed no positive effects on reducing pathology, even showing signs of exacerbating disease. These striking effects suggest a smaller therapeutic window than previously reported for HDAC inhibition in experimental arthritis. The findings support new investigations into repurposing HDAC inhibitors for anti-inflammatory therapeutic applications. However, HDAC inhibitors should be reinvestigated at lower, rather than higher, doses for enhanced efficacy in chronic diseases that require long-term treatment, with careful management of efficacy and long-term safety.
Footnotes
- Received September 14, 2015.
- Accepted December 7, 2015.
R.J.L. and A.I. contributed equally to this work.
Funding for this work was provided by the National Health and Medical Research Council of Australia for a Senior Principal Research Fellowship to D.F. [1027369], a Senior Research Fellowship to M.J.S. [APP1003470], and grant funding [Grants APP1047921, APP1030169, APP1074016]; the Australian Research Council for funding of a Centre of Excellence in Advanced Molecular Imaging [Grant CE140100011]; and the University of Queensland for a UQ Postdoctoral Fellowship to A.I. and a UQ Early Career Grant to R.J.L. and A.I.
- Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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