PPARγ Agonist Shown to Suppress Oral Cancer

At the 2004 annual meeting of the American Association for Cancer Research (AACR) in Orlando, FL, IITRI scientists reported the identification of a potentially useful molecular target for oral cancer prevention.

Peroxisome-proliferator-activated receptor γ (PPARγ) is a ligand-activated transcription factor that regulates cell proliferation, differentiation, and apoptosis (programmed cell death). IITRI scientists reported that rosiglitazone, a member of the thiazolidinedione family of PPARγ agonists, inhibits neoplastic development in a rat model of oral cancer.

Study authors are David L. McCormick, Thomas L. Horn, William D. Johnson and Jonathan Phillips of IITRI, and Ronald Lubet and Vernon Steele of the National Cancer Institute (NCI). The study was supported by the Chemopreventive Agent Development Research Group, Division of Cancer Prevention, NCI.

Chemoprevention Methods and Results

Oral squamous cell carcinomas were induced in rats by 4-nitroquinoline-1-oxide (NQO). After cessation of NQO administration, rats received either control diet or control diet supplemented with rosiglitazone (800 mg/kg diet). An additional group was exposed to rosiglitazone beginning at the mid-point of the study (delayed administration protocol).

Administration of rosiglitazone beginning immediately after NQO significantly increased animal survival and significantly decreased the incidence of oral squamous cell carcinoma. The decrease in cancer incidence was linked to an increase in the incidence of squamous cell papillomas, a precancerous lesion; these results suggest that rosiglitazone delayed or inhibited the transition of lesions from premalignant to fully malignant. Delayed administration of rosiglitazone had no effect on oral carcinogenesis.

In addition to reducing cancer incidence, rosiglitazone reduced the invasiveness of malignant oral lesions. Rats fed rosiglitazone beginning immediately post-carcinogen demonstrated a significant increase in the percentage of lesions with the least invasive (+1) phenotype, and reduced the incidence of highly invasive (+2 and +3) oral cancers.

** p < 0.05 versus dietary control.

The results of this study demonstrate that PPARγ agonists are a potentially useful class of agents for oral cancer chemoprevention, and that the mechanisms of oral carcinogenesis may involve alterations in biochemical pathways that are either linked to, or downstream of, PPARγ.