Please use this identifier to cite or link to this item: https://doi.org/10.1093/rheumatology/keq108
Title: 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
Authors: Choo, Q.-Y.
Ho, P.C. 
Tanaka, Y.
Lin, H.-S. 
Keywords: Angiogenesis
Histone deacetylase inhibitor
Metalloproteinase
MS-275
NF-ΚB
Nitric oxide
P21
Pro-inflammatory cytokines
Rheumatoid arthritis
Suberoylanilide hydroxamic acid
Issue Date: 24-Apr-2010
Citation: Choo, Q.-Y., Ho, P.C., Tanaka, Y., Lin, H.-S. (2010-04-24). 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. Rheumatology 49 (8) : 1447-1460. ScholarBank@NUS Repository. https://doi.org/10.1093/rheumatology/keq108
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.
Source Title: Rheumatology
URI: http://scholarbank.nus.edu.sg/handle/10635/106000
ISSN: 14620324
DOI: 10.1093/rheumatology/keq108
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