Chemopreventive effects of pioglitazone on chemically induced lung carcinogenesis in mice.
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.
Department of Surgery and The Alvin J. Siteman Cancer Center, Washington University School of Medicine, Campus Box 8109, 660 South Euclid Avenue, St. Louis, MO 63110, USA. wangyi@wustl.edu
Yian
Y
Wang
Michael
M
James
Weidong
W
Wen
Yan
Y
Lu
Eva
E
Szabo
Ronald A
RA
Lubet
Ming
M
You
D000230:Adenocarcinoma / Q000139:chemically induced / Q000517:prevention & control*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002273:Carcinogens; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000517:prevention & control*; D018890:Chemoprevention; D019610:Cytoprotection / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000139:chemically induced / Q000517:prevention & control*; D051379:Mice; D008822:Mice, Transgenic; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured; D014520:Urethane / Q000031:analogs & derivatives
D000970:Antineoplastic Agents; D002273:Carcinogens; D045162:Thiazolidinediones; D014520:Urethane; C017963:vinyl carbamate; D000077205:Pioglitazone