Abstract
MS-275 (entinostat) and SAHA (vorinostat), two histone deacetylase (HDAC) inhibitors currently in oncological trials, have displayed potent anti-rheumatic activities in rodent models of rheumatoid arthritis (RA). To further elucidate their anti-inflammatory mechanisms, the impact of MS-275 and SAHA on the p38 mitogen-activated protein kinase (MAPK) signaling pathway and chemotaxis was assessed in human rheumatoid arthritic synovial fibroblastic E11 cells. MS-275 and SAHA significantly suppressed the expression of p38α MAPK, but induced the expression of MAPK phosphatase-1 (MKP-1), an endogenous suppressor of p38α in E11 cells. At the same time, the association between p38α and MKP-1 was up-regulated and consequently, the activation (phosphorylation) of p38α was inhibited. Moreover, MS-275 and SAHA suppressed granulocyte chemotactic protein-2 (GCP-2), monocyte chemotactic protein-2 (MCP-2) and macrophage migration inhibitory factor (MIF) in E11 cells in a concentration-dependent manner. Subsequently, E11-driven migration of THP-1 and U937 monocytes was inhibited. In summary, suppression of the p38 MAPK signaling pathway and chemotaxis appear to be important anti-rheumatic mechanisms of action of these HDAC inhibitors.
Highlights
Histone deacetylase (HDAC) inhibitors are a new class of anti-cancer agents that have attracted significant interest in drug discovery during the past 10-15 years [1]
We identified suppression of NF-κB signaling as one of the major anti-rheumatic mechanisms of MS-275 and SAHA [11], but other signaling pathways may contribute to the anti-rheumatic activities of histone deacetylase (HDAC) inhibitors
The activity of p38 mitogen-activated protein kinase (MAPK) is tightly regulated by MAPK phosphatase-1 (MKP-1), an endogenous inhibitor for p38α [14]
Summary
Histone deacetylase (HDAC) inhibitors are a new class of anti-cancer agents that have attracted significant interest in drug discovery during the past 10-15 years [1]. MS-275 and SAHA are two structurally distinct orally active histone deacetylase (HDAC) inhibitors currently being studied in various oncological trials [1,2]. Their in vivo anti-inflammatory activities have been observed in pre-clinical models of rheumatoid arthritis (RA) [6]. Tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1) and interleukin-6 (IL-6) are crucial pro-inflammatory cytokines that drive joint inflammation in RA [7,8]. Blockade of such cytokines offers clinical therapeutic strategies for treating RA [7,8]. Our study provides useful information to further elucidate the anti-rheumatic mechanisms of HDAC inhibitors
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