Roflumilast treatment inhibits lung carcinogenesis in benzo(a)pyrene-induced murine lung cancer model.

Abstract

Roflumilast, a potent and selective inhibitor of phosphodiesterase-4 (PDE4), has been used in treatment of COPD. PDE4 inhibitor is associated with inhibition of chronic airway inflammation, oxidative stress, and mesenchymal markers in B(a)P-induced lung tumors. The aim of this study was to assess whether roflumilast alone or added to inhaled budesonide might have dose-dependent inhibition on lung carcinogenesis induced by carcinogen B(a)P in mice. Female A/J mice were given a single dose of benzo(a)pyrene. Administration of roflumilast (1mg/kg or 5mg/kg) via oral gavage and aerosolized budesonide (2.25mg/ml) began 2 weeks post-carcinogen treatment and continued for 26 weeks. Tumor load was determined by averaging the total tumor volume in each group. Benzo(a)pyrene induced an average tumor size of 9.38 ± 1.75 tumors per mouse, with an average tumor load of 19.53 ± 3.81mm3. Roflumilast 5mg/kg treatment decreased (P < 0.05) tumor load per mouse compared to the B(a)P group. Roflumilast 5mg/kg treatment significantly increased the levels of cAMP in tumors with adjacent lung tissues (P < 0.05). The expression level of PDE4D gene was decreased by roflumilast 5mg/kg treatment, significantly (P < 0.05). Compared to the B(a)P exposure group, expression levels of HIF-1α and VEGFA were attenuated by roflumilast 5mg/kg treatment (P < 0.05). High-dose roflumilast can attenuate lung carcinogenesis in B(a)P-induced murine lung cancer model. The chemopreventive effect of roflumilast might be associated with inhibition of increased cAMP-mediated inflammatory process and markers of angiogenesis in tumor tissues.

• Authors: Chang Dong Yeo, Young Ae Kim, Hwa Young Lee, Jin Woo Kim, Seung Joon Kim, Sang Haak Lee, Young Kyoon Kim
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 812 Pg. 189-195 (Oct 05 2017) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 28684234 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier B.V. All rights reserved.

Chemical References

• Aminopyridines
• Benzamides
• Biomarkers, Tumor
• Cyclopropanes
• Roflumilast
• Benzo(a)pyrene
• Cyclic AMP
• Cyclic Nucleotide Phosphodiesterases, Type 4

Topics

• Aminopyridines (pharmacology)
• Animals
• Benzamides (pharmacology)
• Benzo(a)pyrene (pharmacology)
• Biomarkers, Tumor (metabolism)
• Carcinogenesis (drug effects)
• Cell Line, Tumor
• Cyclic AMP (metabolism)
• Cyclic Nucleotide Phosphodiesterases, Type 4 (genetics)
• Cyclopropanes (pharmacology)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Lung Neoplasms (chemically induced, metabolism, pathology, physiopathology)
• Mice
• Neovascularization, Pathologic (metabolism)