Histone deacetylase inhibitors MS-275 and SAHA induced growth arrest and suppressed lipopolysaccharide-stimulated NF-kappaB p65 nuclear accumulation in human rheumatoid arthritis synovial fibroblastic E11 cells.
OBJECTIVE
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 non-cytotoxic manner. The anti-proliferative activities were associated with G(0)/G(1) phase arrest and induction of cyclin-dependent kinase inhibitor p21. In addition, MS-275 and SAHA suppressed lipopolysaccharide (LPS)-induced NF-kappaB 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-kappaB p65 nuclear accumulation and IL-1beta, IL-6, IL-18 and TNF-alpha 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-kappaB nuclear accumulation.
Choo
Qiu-Yi
QY
Department of Pharmacy, National University of Singapore, 10 Kent Ridge Crescent, Singapore 119260.
Ho
Paul C
PC
Tanaka
Yoshiya
Y
Lin
Hai-Shu
HS
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000378:metabolism*; D001549:Benzamides / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D015536:Down-Regulation; D005347:Fibroblasts / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D045726:Metalloproteases / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism*; D017942:Nitric Acid / Q000378:metabolism; D011725:Pyridines / Q000378:metabolism; D013583:Synovial Membrane; D000077337:Vorinostat
D001549:Benzamides; D016207:Cytokines; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011725:Pyridines; C118739:entinostat; D017942:Nitric Acid; D000077337:Vorinostat; D045726:Metalloproteases