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. 2005 Aug 19;94(4):365–371. doi: 10.1111/j.1349-7006.2003.tb01448.x

Inhibitory effects of troglitazone, a peroxisome proliferator‐activated receptor γ ligand, in rat tongue carcinogenesis initiated with 4‐nitroquinoline 1‐oxide

Koujiro Yoshida 1,3,✉, Yoshinobu Hirose 1, Takuji Tanaka 2, Yasuhiro Yamada 1, Toshiya Kuno 1, Hiroyuki Kohno 2, Masaki Katayama 1, Zheng Qiao 1, Keiko Sakata 1, Shigeyuki Sugie 1, Toshiyuki Shibata 3, Hideki Mori 1
PMCID: PMC11160187  PMID: 12824906

Abstract

Ligands for peroxisome proliferator‐activated receptor (PPAR) γ have been implicated in growth inhibition and cell differentiation in certain malignancies. In this study, the effects of troglitazone, a PPARy ligand, given during the postinitiation phase of oral carcinogenesis initiated with 4‐nitroquinoline 1‐oxide (4‐NQO) were investigated in male F344 rats. Rats aged 6 weeks were given 4‐NQO at 20 ppm for 8 weeks to induce tongue neoplasms. Starting 1 week after the cessation of 4‐NQO exposure, animals were fed diets containing 0, 30 or 100 ppm troglitazone for 22 weeks. At the end of the study (week 32), the incidences of 4‐NQO‐induced tongue neoplasms and preneoplasms were determined histo‐pathologically and cell proliferation activity was estimated by counting bromodeoxyuridine (BrdU)‐labeling indices and cyclin D1‐positive cell ratios. In addition, immunohistochemical expression of cyclooxygenase (COX)‐2 and PPARγ was assessed in the tongue lesions. Feeding with 100 ppm troglitazone significantly decreased the incidence of squamous cell carcinoma when compared to the group without troglitazone treatment (5.0% vs. 45.8%, P<0.005). Interestingly, the BrdU‐labeling index and cyclin D1‐positive cell ratio assessed in the non‐lesional tongue squamous epithelium were reduced by dietary administration of troglitazone (P<0.0001–0.005). Additionally, the immunoreactivity of COX‐2 in the tongue lesions was also decreased by the treatment (P<0.01–0.05). These results clearly showed that dietary troglitazone inhibits 4‐NQO‐induced tongue carcinogenesis and such inhibition is related to suppression of increased cell proliferation and/or COX‐2 expression. This study warrants further investigation on the use of PPARy ligands as a novel preventive approach for oral malignancy. (Cancer Sci 2003; 94: 365–371)

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