title: A novel macrolide/fluoroketolide, solithromycin (CEM-101), reverses corticosteroid insensitivity via phosphoinositide 3-kinase pathway inhibition.
abstract: OBJECTIVE
  Corticosteroid insensitivity is a major therapeutic problem for some inflammatory diseases including chronic obstructive pulmonary disease (COPD), and it is known to be induced by reduced histone deacetylase (HDAC)-2 activities via activation of the phosphoinositide 3-kinase (PI3K) pathway. The aim of this study is to evaluate effects of a novel macrolide/fluoroketolide, solithromycin (SOL, CEM-101), on corticosteroid sensitivity induced by oxidative stress.
  
  
  METHODS
  Corticosteroid sensitivity was determined by IC50/EC50 of dexamethasone (Dex) on TNF-α-induced CXCL8 production in U937 monocytic cell line and peripheral blood mononuclear cells (PBMC) from COPD patients. Activities of HDAC and protein phosphatase 2A (PP2A) were measured by fluorescence-based assay in cells exposed to hydrogen peroxide (H2O2). We also investigated steroid insensitive airway neutrophilia in cigarette smoke exposed mice in vivo.
  
  
  RESULTS
  SOL (10 μM) restored Dex sensitivity in PBMC from COPD patients, H2O2-treated U937 cells and phorbol 12-myristate 13-acetate-differentiated U937 cells. In addition, SOL restored HDAC activity with concomitant inhibition of Akt phosphorylation as surrogate marker of PI3K activation. The inhibition of Akt phosphorylation by SOL was due to increased PP2A phosphatase activity, which was reduced in COPD and oxidative stress model. Other known macrolides, such as eryhthromycin, clarithromycin and azithromycin, were significantly less effective in these responses. In cigarette smoke-exposed mice, SOL (100 mg kg(-1), po) showed significant but weak inhibition of neutrophilia, whereas Dex (10 mg kg(-1), p.o.) showed no such effect. However, a combination of SOL and Dex inhibited neutrophilia by over 50%.
  
  
  CONCLUSIONS
  SOL has potential as novel therapy for corticosteroid-insensitive diseases such as COPD.
authors.affiliation: Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, UK.
authors.forename: Y
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: H
authors.initials: H
authors.lastname: Wada
authors.forename: C
authors.initials: C
authors.lastname: Rossios
authors.forename: D
authors.initials: D
authors.lastname: Takagi
authors.forename: C
authors.initials: C
authors.lastname: Charron
authors.forename: P J
authors.initials: PJ
authors.lastname: Barnes
authors.forename: K
authors.initials: K
authors.lastname: Ito
mesh_terms: D000305:Adrenal Cortex Hormones / Q000494:pharmacology*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology*; D004351:Drug Resistance / Q000187:drug effects*; D056464:Histone Deacetylase 2 / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D016209:Interleukin-8 / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D018942:Macrolides / Q000494:pharmacology*; D008297:Male; D008810:Mice, Inbred C57BL; D009504:Neutrophils; D018384:Oxidative Stress / Q000187:drug effects; D000081082:Phosphoinositide-3 Kinase Inhibitors; D054648:Protein Phosphatase 2 / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism; D012906:Smoke / Q000009:adverse effects; D014026:Nicotiana; D014230:Triazoles / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D020298:U937 Cells
chemical_list: D000305:Adrenal Cortex Hormones; D000900:Anti-Bacterial Agents; C508606:CXCL8 protein, human; D016209:Interleukin-8; D018942:Macrolides; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012906:Smoke; D014230:Triazoles; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone; C547755:solithromycin; D006861:Hydrogen Peroxide; D051057:Proto-Oncogene Proteins c-akt; D054648:Protein Phosphatase 2; C533423:HDAC2 protein, human; D056464:Histone Deacetylase 2