Histone deacetylase inhibitors MS-275 and SAHA induced growth arrest and suppressed lipopolysaccharide-stimulated NF-ΚB p65 nuclear accumulation in human rheumatoid arthritis synovial fibroblastic E11 cells

Abstract

Objectives: MS-275 and suberoylanilide hydroxamic acid (SAHA) are histone deacetylase (HDAC) inhibitors currently tested in oncology trials. They have also been found to display potent anti-rheumatic activities in rodent models for RA. However, the anti-rheumatic mechanisms of action remain unknown. The study was carried out with the intent of determining the anti-inflammatory and anti-rheumatic mechanisms of the HDAC inhibitors. Methods: In this study, the anti-rheumatic mechanisms of MS-275 and SAHA were investigated in several cell culture models. Results: MS-275 and SAHA inhibited human RA synovial fibroblastic E11 cell proliferation in a noncytotoxic manner. The anti-proliferative activities were associated with G0/G1 phase arrest and induction of cyclin-dependent kinase inhibitor p21. In addition, MS-275 and SAHA suppressed lipopolysaccharide (LPS)-induced NF-ΚB p65 nuclear accumulation, IL-6, IL-18 and nitric oxide (NO) secretion as well as down-regulated pro-angiogenic VEGF and MMP-2 and MMP-9 production in E11 cells at sub-micromolar levels. At similar concentrations, MS-275 and SAHA suppressed LPS-induced NF-ΚB p65 nuclear accumulation and IL-1β, IL-6, IL-18 and TNF-β secretion in THP-1 monocytic cells. Moreover, NO secretion in RAW264.7 macrophage cells was also inhibited. Conclusions: In summary, MS-275 and SAHA exhibited their anti-rheumatic activities by growth arrest in RA synovial fibroblasts, inhibition of pro-inflammatory cytokines and NO, as well as down-regulation in angiogenesis and MMPs. Their anti-rheumatic activities may be mediated through induction of p21 and suppression of NF-ΚB nuclear accumulation. © The Author 2010.