title: Chemopreventive effect of phosphodieasterase-4 inhibition in benzo(a)pyrene-induced murine lung cancer model.
abstract: OBJECTIVE
  Cigarette smoking increases chronic airway inflammation, oxidative stress, and epithelial mesenchymal transition (EMT), which may result in chronic obstructive pulmonary disease (COPD) and tumor growth in the lung. Phosphodiesterase 4 (PDE4) inhibitors are known to reduce inflammation, and they have recently been introduced for the treatment of COPD. We assessed the impact of rolipram, a selective PDE4 inhibitor, on chemoprevention in benzo(a)pyrene-induced lung cancer in mice.
  
  
  METHODS
  Female A/J mice were given a single dose of benzo(a)pyrene. Intraperitoneal administration of rolipram began 2 weeks post-carcinogen treatment and continued tri-weekly for 28 weeks. Tumor load was determined by averaging the total tumor volume in each group.
  
  
  RESULTS
  Benzo(a)pyrene induced an average tumor size of 10.4 ± 1.7 tumors per mouse, with an average tumor load of 25.9 ± 3.8 mm(3). Rolipram significantly decreased tumor number, by 45.1%, and tumor load, by 52.9%, compared with the benzo(a)pyrene group. Ki67 staining was reduced in rolipram-treated mice compared with benzo(a)pyrene-treated mice. The increased expression of EMT markers caused by benzo(a)pyrene was inhibited by rolipram. Rolipram significantly attenuated NF-κB and Nrf2 expression in benzo(a)pyrene-induced lung cancer tissues.
  
  
  CONCLUSIONS
  In vivo experiments in the benzo(a)pyrene-induced model of lung cancer show that PDE4 inhibition significant inhibits lung carcinogenesis. Our results provide evidence that PDE4 inhibitors may be suitable for the prevention of the lung cancer in high-risk groups, for example, heavy smokers and patients with COPD.
authors.affiliation: Division of Pulmonology, Department of Internal Medicine, School of Medicine, The Catholic University of Korea , Seoul , Korea.
authors.forename: Chang Dong
authors.initials: CD
authors.lastname: Yeo
authors.forename: Jin Woo
authors.initials: JW
authors.lastname: Kim
authors.forename: Jick Hwan
authors.initials: JH
authors.lastname: Ha
authors.forename: Seung Joon
authors.initials: SJ
authors.lastname: Kim
authors.forename: Sang Haak
authors.initials: SH
authors.lastname: Lee
authors.forename: In Kyoung
authors.initials: IK
authors.lastname: Kim
authors.forename: Young Kyoon
authors.initials: YK
authors.lastname: Kim
mesh_terms: D000818:Animals; D001564:Benzo(a)pyrene / Q000009:adverse effects*; D015820:Cadherins / Q000378:metabolism; D063646:Carcinogenesis / Q000187:drug effects; D018890:Chemoprevention / Q000379:methods*; D004195:Disease Models, Animal; D005260:Female; D007274:Injections, Intraperitoneal; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control*; D051379:Mice; D008815:Mice, Inbred Strains; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D058988:Phosphodiesterase 4 Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D020889:Rolipram / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D014746:Vimentin / Q000378:metabolism
chemical_list: D015820:Cadherins; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495636:Nfe2l2 protein, mouse; D058988:Phosphodiesterase 4 Inhibitors; D014746:Vimentin; D001564:Benzo(a)pyrene; D020889:Rolipram
keywords: chemoprevention; lung cancer; phsophodiesterase-4 inhibition