A novel macrolide/fluoroketolide, solithromycin (CEM-101), reverses corticosteroid insensitivity via phosphoinositide 3-kinase pathway inhibition

Br J Pharmacol. 2013 Jul;169(5):1024-34. doi: 10.1111/bph.12187.

Abstract

Background and purpose: 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.

Experimental approach: 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.

Key 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 and implications: SOL has potential as novel therapy for corticosteroid-insensitive diseases such as COPD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenal Cortex Hormones / pharmacology*
  • Animals
  • Anti-Bacterial Agents / pharmacology*
  • Cells, Cultured
  • Dexamethasone / pharmacology*
  • Drug Resistance / drug effects*
  • Histone Deacetylase 2 / metabolism
  • Humans
  • Hydrogen Peroxide / pharmacology
  • Interleukin-8 / metabolism
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / metabolism
  • Macrolides / pharmacology*
  • Male
  • Mice, Inbred C57BL
  • Neutrophils
  • Oxidative Stress / drug effects
  • Phosphoinositide-3 Kinase Inhibitors*
  • Protein Phosphatase 2 / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pulmonary Disease, Chronic Obstructive / metabolism
  • Smoke / adverse effects
  • Tobacco
  • Triazoles / pharmacology*
  • Tumor Necrosis Factor-alpha / pharmacology
  • U937 Cells

Substances

  • Adrenal Cortex Hormones
  • Anti-Bacterial Agents
  • CXCL8 protein, human
  • Interleukin-8
  • Macrolides
  • Phosphoinositide-3 Kinase Inhibitors
  • Smoke
  • Triazoles
  • Tumor Necrosis Factor-alpha
  • Dexamethasone
  • solithromycin
  • Hydrogen Peroxide
  • Proto-Oncogene Proteins c-akt
  • Protein Phosphatase 2
  • HDAC2 protein, human
  • Histone Deacetylase 2