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Antimicrobial Agents and Chemotherapy, May 2006, p. 1738-1744, Vol. 50, No. 5
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.5.1738-1744.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Clarithromycin Delays Progression of Bronchial Epithelial Cells from G1 Phase to S Phase and Delays Cell Growth via Extracellular Signal-Regulated Protein Kinase Suppression

Masaharu Shinkai,1 Jun Tamaoki,4 Hideo Kobayashi,3 Soichiro Kanoh,3 Kazuo Motoyoshi,3 Tim Kute,2 and Bruce K. Rubin1*

Department of Pediatrics,1 Department of Pathology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina 27157-1081,2 Third Department of Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan,3 First Department of Medicine, Tokyo Women's Medical University, Tokyo, Japan4

Received 29 August 2005/ Returned for modification 20 November 2005/ Accepted 28 February 2006

The nonsteroidal anti-inflammatory drugs have been shown to support cytoprotection of cells by shifting cells toward a quiescent state (G0/G1). Extracellular signal-regulated kinase (ERK) is required for cells to pass from G1 phase into S phase, and macrolide antibiotics can inhibit ERK1/2 phosphorylation. However, previous reports suggest that macrolide antibiotics do not affect cell growth in bronchial epithelial cells. Therefore, we studied normal human bronchial epithelial (NHBE) cells to determine whether clarithromycin (CAM) suppresses ERK, delays bronchial epithelial cells from progressing to S phase, and delays cell growth. Exposure to CAM at 10 µg/ml daily over 4 days irreversibly decreased the cell proliferation with and without growth supplements (P < 0.0001). CAM also inhibited ERK1/2 phosphorylation over the first 90 min of exposure (P < 0.05 for 30 min, P < 0.0001 for 60 min, and P < 0.01 for 90 min) and decreased the ratio of phosphorylated ERK1/2 (pERK1/2) to total ERK1/2 (tERK1/2) (P < 0.0001). Incubation with CAM for 48 h increased the proportion of cells in G1 phase (means ± standard deviations) from 63.5% ± 0.9% to 79.1% ± 1.4% (P < 0.0001), decreased that in S phase from 19.8% ± 1.2% to 10.0% ± 2.1% (P < 0.01), and decreased that in G2/M phase from 16.7% ± 0.4% to 11.0% ± 0.8% (P < 0.001). In contrast, the ratio of pMEK1/2 to tMEK1/2 was not altered after exposure to CAM. These results suggest that macrolide antibiotics can delay the progression of NHBE cells from G1 phase to S phase and can slow cell growth, probably through the suppression of ERK1/2.

* Corresponding author. Mailing address: Department of Pediatrics, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1081. Phone: (336) 716-0262. Fax: (336) 716-9229. E-mail: brubin{at}wfubmc.edu.

Antimicrobial Agents and Chemotherapy, May 2006, p. 1738-1744, Vol. 50, No. 5
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.5.1738-1744.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.





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