Pioglitazone Reduces Hepatocellular Neoplasia in a Rat Model of Cirrhosis
Shen Li, Sarani Ghoshal, Gunisha Arora, Derek J. Erstad, Mozhdeh Sojoodi, Michael Lanuti, Kenneth K. Tanabe, Bryan C. Fuchs
Massachusetts General Hospital, Boston, MA, USA
Introduction: Hepatocellular carcinoma (HCC) is a leading cause of mortality worldwide. There is a readily identifiable cohort of patients with cirrhosis at risk and they are ideal candidates for chemoprevention. Pioglitazone, a selective PPAR-y agonist, has been shown to reduce non-alcoholic steatohepatitis (NASH), but its role as an anti-fibrotic and chemo-preventive agent has yet to be elucidated. The hypothesis of this study is that Pioglitazone reduces cirrhosis and subsequent HCC development in rats with diethylnitrosamine (DEN)-induced cirrhosis.
Methods: Male Wistar received DEN 50mg/kg by intraperitoneal injection. DEN-injured rats were randomized to receive oral gavage of pioglitazone at 3mg/kg/day (n=9) or vehicle control (n=9). All animals were sacrificed at 18 weeks.
Results: Treatment with pioglitazone resulted in a 56% reduction of surface nodules relative to treatment with vehicle (7.4±4.9 vs. 17±7; p<0.005). Liver sections were stained by picrosirius red to assess fibrosis. Pioglitazone significantly reduced collagen deposition in DEN-injured rats (collagen proportional area = 3.2±1.8% vs. 9.2±2%; p<0.035). The histological finding was confirmed by gene expression analysis with reductions in COL1A1, α-SMA, TGF-β, and TIMP1. Pioglitazone activation resulted in an upregulation of AMPK signaling, a well-recognized target for anti-tumor drug discovery as well as a down regulation of the mitogenic MAPK pathway.
Conclusion: Overall our data supports the hypothesis that the anti-diabetic agent pioglitazone may be repurposed as a drug to reduce fibrosis and prevent HCC. This could be beneficiary in patient management given the low cost as well as minimal side effects.
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