title: Carbocysteine restores steroid sensitivity by targeting histone deacetylase 2 in a thiol/GSH-dependent manner.
abstract: Steroid insensitivity is commonly observed in patients with chronic obstructive pulmonary disease. Here, we report the effects and mechanisms of carbocysteine (S-CMC), a mucolytic agent, in cellular and animal models of oxidative stress-mediated steroid insensitivity. The following results were obtained: oxidative stress induced higher levels of interleukin-8 (IL-8) and tumor necrosis factor alpha (TNF-α), which are insensitive to dexamethasone (DEX). The failure of DEX was improved by the addition of S-CMC by increasing histone deacetylase 2 (HDAC2) expression/activity. S-CMC also counteracted the oxidative stress-induced increase in reactive oxygen species (ROS) levels and decreases in glutathione (GSH) levels and superoxide dismutase (SOD) activity. Moreover, oxidative stress-induced events were decreased by the thiol-reducing agent dithiothreitol (DTT), enhanced by the thiol-oxidizing agent diamide, and the ability of DEX was strengthened by DTT. In addition, the oxidative stress-induced decrease in HDAC2 activity was counteracted by S-CMC by increasing thiol/GSH levels, which exhibited a direct interaction with HDAC2. S-CMC treatment increased HDAC2 recruitment and suppressed H4 acetylation of the IL-8 promoter, and this effect was further ablated by addition of buthionine sulfoximine, a specific inhibitor of GSH synthesis. Our results indicate that S-CMC restored steroid sensitivity by increasing HDAC2 expression/activity in a thiol/GSH-dependent manner and suggest that S-CMC may be useful in a combination therapy with glucocorticoids for treatment of steroid-insensitive pulmonary diseases.
authors.affiliation: Department of Pharmacology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Song
authors.affiliation: Department of Pharmacology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Hao-Zhong
authors.initials: HZ
authors.lastname: Lu
authors.affiliation: Department of Pharmacology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Jian-Rong
authors.initials: JR
authors.lastname: Xu
authors.affiliation: Department of Pharmacology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Xiao-Lin
authors.initials: XL
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Department of Pharmacology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Li-Na
authors.initials: LN
authors.lastname: Hou
authors.affiliation: Department of Pharmacology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Department of Pharmacology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Zhi-Hua
authors.initials: ZH
authors.lastname: Yu
authors.affiliation: Department of Pharmacology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address: hongzhuan_chen@hotmail.com.
authors.forename: Hong-Zhuan
authors.initials: HZ
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address: yongyaocui@hotmail.com.
authors.forename: Yong-Yao
authors.initials: YY
authors.lastname: Cui
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002233:Carbocysteine / Q000494:pharmacology*; D045744:Cell Line, Tumor; D045424:Complex Mixtures / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D004351:Drug Resistance / Q000187:drug effects* / Q000502:physiology; D055785:Gene Knockdown Techniques; D005938:Glucocorticoids / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism*; D056464:Histone Deacetylase 2 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D016209:Interleukin-8 / Q000276:immunology; D018384:Oxidative Stress; D034741:RNA, Small Interfering / Q000235:genetics; D017207:Rats, Sprague-Dawley; D012906:Smoke; D013438:Sulfhydryl Compounds / Q000378:metabolism*; D014026:Nicotiana; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D045424:Complex Mixtures; D005938:Glucocorticoids; D016209:Interleukin-8; D034741:RNA, Small Interfering; D012906:Smoke; D013438:Sulfhydryl Compounds; D014409:Tumor Necrosis Factor-alpha; D002233:Carbocysteine; D003907:Dexamethasone; D006861:Hydrogen Peroxide; D056464:Histone Deacetylase 2; D005978:Glutathione
keywords: Combination therapy; HDAC2; S-CMC; Steroid sensitivity; Thiol/GSH