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A novel macrolide/fluoroketolide, solithromycin ( CEM ‐101), reverses corticosteroid insensitivity via phosphoinositide 3‐kinase pathway inhibition
Author(s) -
Kobayashi Y,
Wada H,
Rossios C,
Takagi D,
Charron C,
Barnes P J,
Ito K
Publication year - 2013
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12187
Subject(s) - pharmacology , medicine , ex vivo , oxidative stress , endocrinology , chemistry , biochemistry , in vitro
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 IC 50 /EC 50 of dexamethasone ( D ex) on TNF ‐α‐induced CXCL 8 production in U937 monocytic cell line and peripheral blood mononuclear cells ( PBMC ) from COPD patients. Activities of HDAC and protein phosphatase 2 A ( PP2A ) were measured by fluorescence‐based assay in cells exposed to hydrogen peroxide ( H 2 O 2 ). We also investigated steroid insensitive airway neutrophilia in cigarette smoke exposed mice in vivo . Key Results SOL (10 μM) restored D ex sensitivity in PBMC from COPD patients, H 2 O 2 ‐treated U 937 cells and phorbol 12‐myristate 13‐acetate‐differentiated U 937 cells. In addition, SOL restored HDAC activity with concomitant inhibition of A kt phosphorylation as surrogate marker of PI3K activation. The inhibition of A kt 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 D ex (10 mg kg −1 , p.o.) showed no such effect. However, a combination of SOL and D ex inhibited neutrophilia by over 50%. Conclusions and Implications SOL has potential as novel therapy for corticosteroid‐insensitive diseases such as COPD .