Abstract LB-264: Effects of dietary metformin/pioglitazone on lung adenoma formation in A/J mice

Abstract

Abstract Introduction: Metabolomics and cancer chemoprevention are important contemporary concepts in cancer prevention and gaining traction as potential clinical trial topics. Our group has worked with type II diabetes agents clinically in oral cancer prevention and clinically and preclinically in both lung and head and neck cancer. Both pioglitazone and metformin are type II diabetes agents, and both drugs have promising epidemiologic evidence for efficacy as solid tumor prevention agents. They are well tolerated clinically for many years in millions of patients worldwide with acceptable toxicity profiles. We hypothesize these agents would be suitable in the chemoprevention setting and tested this hypothesis in experimental lung carcinogenesis in a benzo[a]pyrene (B[a]P) mouse model. Materials and Methods: We utilized 224 seven week old female A/J mice. All groups received 3 weekly doses of B[a]P by oral intubation and were randomized into 8 groups of 27 mice per group based on weights. Experimental diets were started one week after the last dose of B[a]P. Metformin (12 mg/g and 10.2 mg/g) and/or pioglitazone (0.18mg/g) were administered in the diet for 18 weeks, whereas late stage inhibition diets were started at 8 weeks post carcinogen. Animals were continued on the feeding schedule, weighed weekly, and monitored for weight loss, behavior changes, rough hair coat, or other signs of ill health. Results: The average number of adenomas per animal was 17.44 +/- 1.39 (SEM) in the control group. At the early stage intervention the average number of adenomas was 5.00 +/- 0.69 (P<0.0001) in the highest dose of metformin, 6.15 +/- 0.57 (P<0.0001) for the low dose metformin, and 11.92 +/-1.00 (P = 0.0023) for pioglitazone treatment. Metformin (low dose) and pioglitazone in combination resulted in 5.26 +/- 0.78 (P<0.0001) adenomas per animal. At the late stage intervention the average number of adenomas was 10.89 +/- 1.161 (P = 0.0007) for the low dose metformin, and 14.42 +/-1.24 (P = 0.1126, not significant) for pioglitazone treatment. Metformin (low dose) and pioglitazone in combination resulted in 9.77 +/- 0.85 (P<0.0001) adenomas per animal. The agents were well tolerated for the duration of the experiment from all physical appearance and other standard toxicities. However, animals treated with metformin had a 15% weight loss at the beginning of the experiment and completed the experiment with body weights 15% lower compared to non-metformin treated animals. Conclusions: We conclude metformin and pioglitazone are promising agents for lung adenoma prevention in A/J mice. We also conclude dose adjustments of these drugs may require further optimization. Drugs of the thiazolidinedione class and sulfonylureas are powerful controllers of glucose metabolism. Although we did not have observable toxicity in the animals, it is likely glucose metabolism was altered and this contributed to the 15% differences in weight between the animal groups. Therefore, well designed metabolomic studies may be helpful in the future. Citation Format: Donna Seabloom, Art Galbraith, Beverly Wuertz, Anna Haynes, Mark S. Miller, Vernon Steele, Lee Wattenberg, Frank G. Ondrey. Effects of dietary metformin/pioglitazone on lung adenoma formation in A/J mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-264. doi:10.1158/1538-7445.AM2015-LB-264