Safety & preclinical efficacy of aerosol pioglitazone on lung adenoma Prevention in A/J Mice

Donna E. Seabloom, Arthur R. Galbraith, Anna M. Haynes, Jennifer D. Antonides, Beverly RWuertz, Wendy A. Miller, Kimberly A. Miller, Vernon E. Steele, Chen S. Suen, M. Gerard O'sullivan, Frank G. Ondrey

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Abstract

Pioglitazone is a PPARg agonist commonly prescribed for the clinical treatment of diabetes. We sought to expand its use to lung cancer prevention in a benzo[a]pyrene (B[a]P) mouse model with direct lung delivery via inhalation. Initially, we conducted inhalational toxicity experiments with 0, 15, 50, 150, and 450 mg/kg body weight/day pioglitazone in 40 A/J mice. We examined the animals for any physical toxicity and bronchoalveolar lavage fluids for inflammatory and cytotoxicitymarkers. Doses up to and including 450 mg/kg bw/d failed to demonstrate toxicity with aerosol pioglitazone. For chemoprevention experiments, A/J mice were randomized to treatment groups of inhaled doses of 0, 50, 150, or 450 mg/kg bw/d pioglitazone 1 or 8 weeks after the last dose of B[a]P. For the early treatment group, we found up to 32% decrease in lung adenoma formation with 450 mg/kg bw/d pioglitazone. We repeated the treatments in a second late-stage experiment and found up to 44% decreases in lung adenoma formation in doses of pioglitazone of 150 and 450 mg/kg bw/day. Both the early-And the late-stage experiments demonstrated biologically relevant and statistically significant decreases in adenoma formation. We conclude that aerosol pioglitazone is well-Tolerated in the A/J mouse model and a promising chemoprevention agent for the lower respiratory tract.

Original languageEnglish (US)
Pages (from-to)124-132
Number of pages9
JournalCancer Prevention Research
Volume10
Issue number2
DOIs
StatePublished - Feb 2017

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    Seabloom, D. E., Galbraith, A. R., Haynes, A. M., Antonides, J. D., RWuertz, B., Miller, W. A., Miller, K. A., Steele, V. E., Suen, C. S., O'sullivan, M. G., & Ondrey, F. G. (2017). Safety & preclinical efficacy of aerosol pioglitazone on lung adenoma Prevention in A/J Mice. Cancer Prevention Research, 10(2), 124-132. https://doi.org/10.1158/1940-6207.CAPR-16-0174