Carcinogenesis Advance Access published online on October 27, 2009
Carcinogenesis, doi:10.1093/carcin/bgp260
Rosiglitazone Prevents the Progression of Pre-invasive Lung Cancer in a Murine Model
1 Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, NM
2 Department of Internal Medicine, University of New Mexico, Albuquerque, NM
To whom all correspondence should be addressed: Dr. Steven A. Belinsky, Lung Cancer Program, Lovelace Respiratory Research Institute, 2425 Ridgecrest Dr. SE, Albuquerque, NM 87108. Phone: 505-348-9465; Fax: 505-348-4971; E-mail: sbelinsk{at}LRRI.org
There is a critical need to identify efficacious chemopreventive agents for lung cancer that can be taken chronically with no side effects and whose mechanisms of action do not involve genotoxicity that could drive, rather than impede cancer progression. We evaluated the ability of a chemopreventive cocktail that included selenium (antioxidant), rosiglitazone (PPAR
agonist), sodium phenylbutyrate or valproic acid (histone deacetylase inhibitors) and hydralazine (cytosine demethylating agent) to prevent the progression of lung cancer in A/J mice treated with NNK. Agents were administered alone or in various combinations. Effects of the chemopreventive agents were quantified based on the proportion of hyperplasias and adenomas within the mouse lung. Significant effects on tumor progression were seen in all treatment groups that included rosiglitazone as reflected by a 47–57% increase in number of hyperplasias and a 10–30% decrease in adenomas. Cell proliferation was also reduced in these treatment groups by approximately 40%. Interestingly, while treatment with rosiglitazone alone did not significantly affect lesion size, striking effects were seen in the combination therapy group that included sodium phenylbutyrate, with the volume of hyperplasias and adenomas decreasing by 40% and 77%, respectively. These studies demonstrate for the first time that chronic in vivo administration of rosiglitazone, used in the management of diabetis mellitus, can significantly block the progression of premalignant lung cancer in the A/J mouse model.
Key Words: lung cancer • prevention • rosiglitazone • sodium phenylbutyrate
Received July 7, 2009; revised October 20, 2009; accepted October 20, 2009.