Antidiabetic thiazolidinediones inhibit hepatic tumor formation in HBV transgenic mouse model.

Background Antidiabetic Thiazolidinediones (TZD) such as Rosiglitazone (RGZ) and Pioglitazone (PGZ) were found to be ligand for the nuclear receptor PPARg. These drugs attenuate the insulin resistance associated with obesity. The antiproliferative and prodifferentiation effect of PPARg activators suggest that these compounds might be useful in slowing the proliferation of the dedifferentiated tumor cells. Although TZD were demonstrated to inhibit proliferation of hepatic cancer cell line in vitro, there is no evidence of an in vivo effect of these drugs. Aim of this study was to test whether TZD inhibit HCC development in HBV trangenic model of hepatic carcinogenesis. Materials and methods: 8 months-old HBV transgenic mice (C57BLIB-TGN-AlblHBV-44Bri male mice) underwent treatment with RGZ (n=lO) or PGZ (n=10) (3 mg/Kg) , vehicle (n=10) for 5 months. At 13 months of age, all surviving animals were weighed, sacrificed, number of neoplastic foci counted and livers weighed. The ability of nuclear extract to bind PPAR response element (PPRE) was monitored by EMSA. Oxidative damage was evaluated by 8-OHdG incorporation and mtDNA delation analysis. Proliferating cell nuclear antigen (PCNA) and vWFVIII immunoistichemistry was performed to test proliferation and angiogenesis in treated and untreated mice, respectively. Results: 5 untreated animals had died between 9 and 13 months of age. One PGZ-treated animal had died at 12 month. RGZ-treated animals were all alive at time of sacrifice. Body weight of TZDtreated mice was 4022 vs 2622 in controls. Number of neoplastic foci was 523 in TZD-treated animals, and 12t3 in controls. Nuclear extract from treated animals showed a significant increased of the PPRE binding. At microscopic levels, TZD treatment showed improved liver histology, and exhibited only mild dysplasia with no advanced nuclear atypia commonly seen in livers of control littermates. Furthermore the PCNA-labeling indices were significantly reduced in TZD-treated mice. Similarly strong reduction of FVIII staining was demonstrated in TZD-treated mice compare to controls. Finally treatment with TZD inhibits oxidative tissue damage as demonstrated by the reduction of 8-OHdG incorporation and mtDNA delation. Conclusions: Both PGZ and RGZ was able to inhibit tumor development in HBV transgenic mice suggesting a therapeutic use of these drugs in hepatic carcinogenesis. (Supported by grant Cofin 1999/2000