title: Tubastatin, a selective histone deacetylase 6 inhibitor shows anti-inflammatory and anti-rheumatic effects.
abstract: Epigenetic modifications represent a promising new approach to modulate cell functions as observed in autoimmune diseases. Emerging evidence suggests the utility of HDAC inhibitors in the treatment of chronic immune and inflammatory disorders. However, class and isoform selective inhibition of HDAC is currently favored as it limits the toxicity that has been observed with pan-HDAC inhibitors. HDAC6, a member of the HDAC family, whose major substrate is α-tubulin, is being increasingly implicated in the pathogenesis of inflammatory disorders. The present study was carried out to study the potential anti-inflammatory and anti-rheumatic effects of HDAC6 selective inhibitor Tubastatin. Tubastatin, a potent human HDAC6 inhibitor with an IC50 of 11 nM showed significant inhibition of TNF-α and IL-6 in LPS stimulated human THP-1 macrophages with an IC50 of 272 nM and 712 nM respectively. Additionally, Tubastatin inhibited nitric oxide (NO) secretion in murine Raw 264.7 macrophages dose dependently with an IC50 of 4.2 μM and induced α-tubulin hyperacetylation corresponding to HDAC6 inhibition in THP-1 cells without affecting the cell viability. Tubastatin showed significant inhibition of paw volume at 30 mg/kg i.p. in a Freund's complete adjuvant (FCA) induced animal model of inflammation. The disease modifying activity of Tubastatin was also evident in collagen induced arthritis DBA1 mouse model at 30 mg/kg i.p. The significant attenuation of clinical scores (~70%) by Tubastatin was confirmed histopathologically and was found comparable to dexamethasone (~90% inhibition of clinical scores). Tubastatin showed significant inhibition of IL-6 in paw tissues of arthritic mice. The present work has demonstrated anti-inflammatory and antirheumatic effects of a selective HDAC6 inhibitor Tubastatin.
authors.affiliation: Department of Biology, Drug Discovery Research, Orchid Chemicals and Pharmaceuticals Ltd., Sozhanganallur, Chennai, India. santoshv@orchidpharma.com
authors.forename: Santosh
authors.initials: S
authors.lastname: Vishwakarma
authors.forename: Lakshmi R
authors.initials: LR
authors.lastname: Iyer
authors.forename: Milind
authors.initials: M
authors.lastname: Muley
authors.forename: Pankaj Kumar
authors.initials: PK
authors.lastname: Singh
authors.forename: Arun
authors.initials: A
authors.lastname: Shastry
authors.forename: Ambrish
authors.initials: A
authors.lastname: Saxena
authors.forename: Jayanarayan
authors.initials: J
authors.lastname: Kulathingal
authors.forename: G
authors.initials: G
authors.lastname: Vijaykanth
authors.forename: J
authors.initials: J
authors.lastname: Raghul
authors.forename: Navin
authors.initials: N
authors.lastname: Rajesh
authors.forename: Suresh
authors.initials: S
authors.lastname: Rathinasamy
authors.forename: Virendra
authors.initials: V
authors.lastname: Kachhadia
authors.forename: Narasimhan
authors.initials: N
authors.lastname: Kilambi
authors.forename: Sridharan
authors.initials: S
authors.lastname: Rajgopal
authors.forename: Gopalan
authors.initials: G
authors.lastname: Balasubramanian
authors.forename: Shridhar
authors.initials: S
authors.lastname: Narayanan
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D018501:Antirheumatic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D005260:Female; D005620:Freund's Adjuvant; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D008811:Mice, Inbred DBA; D009569:Nitric Oxide / Q000378:metabolism; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D018501:Antirheumatic Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; C553587:tubastatin A; D009569:Nitric Oxide; D005620:Freund's Adjuvant; C433811:HDAC6 protein, human; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases