S. Li1, S. Ghosal1, G. Arora1, D. J. Erstad1, M. Lanuti2, K. K. Tanabe1, B. Fuchs1 1Massachusetts General Hospital,Surgical Oncology,Boston, MA, USA 2Massachusetts General Hospital,Thoracic Surgery,Boston, MA, USA
Introduction: Advanced hepatocellular carcinoma (HCC) is a leading cause of mortality worldwide with limited treatment options. There is a readily identifiable cohort of cirrhosis patients at risk and they are ideal candidates for chemoprevention. Anti-hyperglycemic agents have garnered interest for their chemo-preventive effects. 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 injury reliably recapitulates human HCC development with induction of hepatic fibrosis at 8 weeks, cirrhosis at 12 weeks, and HCC by 18 weeks. DEN-injured rats were randomized to receive oral gavage of pioglitazone at 3mg/kg/day (n=9) or vehicle control (n=9). Initiation of pioglitazone coincided with the development of liver fibrosis at 8 weeks. All animals were sacrificed at 18 weeks.
Results: As expected, repeated injections of DEN in rats resulted in progressive fibrosis, cirrhosis, followed by HCC formation. 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). Pioglitazone treatment resulted primarily in a reduction of nodules<8mm compared to vehicle (6.3±1.5 vs. 15.14±2.5; p<0.001). 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). This histology was confirmed by gene expression analysis with reductions in COL1A1, α-SMA, TGF-β, and TIMP1. Pioglitazone treatment resulted in an upregulation of Adiponectin, which has been shown to antagonize carcinogenesis. Pioglitazone treatment also increased AMPK signaling, a well-recognized target for anti-tumor drug discovery as well as a down regulation of the mitogenic MAPK pathway. Daily pioglitazone dosing signifcantly reduced the gene expression of progenitor cell activation including CD44, RAGE, and DLK1.
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.
