Chemopreventive Effects of Pioglitazone on Chemically Induced Lung Carcinogenesis in Mice

Abstract

Pioglitazone [(RS)-5-(4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl)thiazolidine-2,4-dione] is a ligand of nuclear receptor peroxisome proliferator-activated receptor γ that is approved for the treatment of type II diabetes mellitus. Activation of peroxisome proliferator-activated receptor γ has been associated with anticancer activities in a variety of cancer cell lines through inhibition of proliferation and promotion of apoptosis. We examined the effect of pioglitazone on lung cancer development in carcinogen-induced lung adenocarcinoma and squamous cell carcinoma (SCC). When pioglitazone was administered beginning 8 weeks after the first carcinogen treatment when microscopic adenomas already existed, pioglitazone significantly inhibited tumor load (sum of tumor volume per lung in average) by 64% (P < 0.05) in p53 wt/wt mice and 50% (P < 0.05) in p53 wt/Ala135Val mice in the lung adenocarcinoma model. Delayed administration of pioglitazone caused a limited (35%, P < 0.05) decrease in lung SCC. Induction of apoptosis occurred in both model systems. These data show that pioglitazone significantly inhibited progression of both adenocarcinoma and SCC in the two mouse model systems. Mol Cancer Ther; 9(11); 3074-82. ©2010 AACR.

Pioglitazone-mediated reversal of elevated glucose metabolism in the airway epithelium of mouse lung adenocarcinomas

“…Pioglitazone treatment significantly repressed lung ADC phenotypes, such as tumor size and multiplicity, in mice, as shown previously by our laboratory (8,9) and others (10). However, the underlying mechanism remained obscure.…”

“…Previous work from our (8,9) and other laboratories (10) has shown that pioglitazone treatment significantly prevented the formation of or inhibited the progression of lung ADCs. However, the underlying mechanisms remained unclear.…”

Inflammation and Lung Cancer: Prevention

“…Additionally, RZD in the presence of histone deacetylase (HDAC) inhibitors (valproic acid and phenylbutyrate) in the same NNK model also significantly reduced tumor size [252]. Two others studies used PZD to study the therapeutic effects in mice [39,253]. Vinyl carbamate, a metabolite of urethane (ethyl carbamate), was used to induce ADC followed by treatment with PZD (oral gavage daily, up to 20 weeks) started 8 weeks after carcinogen to assure small adenomas were already present (~ 8 per mouse) [253] (see Table 4.2).…”

“…Two others studies used PZD to study the therapeutic effects in mice [39,253]. Vinyl carbamate, a metabolite of urethane (ethyl carbamate), was used to induce ADC followed by treatment with PZD (oral gavage daily, up to 20 weeks) started 8 weeks after carcinogen to assure small adenomas were already present (~ 8 per mouse) [253] (see Table 4.2). Little change in tumor multiplicity was observed, however a ~ 50 % significant reduction in tumor load (size) was seen in this ADC model.…”

Lung Cancer Chemoprevention

“…Thiazolidinediones have also been shown to induce 15-hydroxyprostaglandin dehydrogenase (15-PGDH), the enzyme that inactivates the antiapoptotic and immunosuppressive PGE 2 by conversion to 15-keto prostaglandins (43). PPARg overexpression chemoprevents murine lung cancer (37), and the PPARg agonist pioglitazone has been shown to chemoprevent lung cancer in the N-nitroso-tris, chloroethylurea model (44). There is a current chemoprevention trial at the Denver Veterans Affairs Medical Center evaluating pioglitazone in high-risk current and former smokers.…”