Introduction: The purpose of this study was to examine whether nizatidine could reduce liver fibrosis and subsequent tumor burden in two rodent models of hepatocellular carcinoma (HCC).
Methods: An in silico screen identified nizatidine as a compound that can reverse a previously identified gene signature associated with disease progression and HCC development in human cirrhosis patients. We tested the ability of nizatidine to inhibit HCC development in two rodent models. In the first study, male Wistar rats received weekly intraperitoneal injections of 50 mg/kg diethylnitrosamine (DEN). This model has previously been shown to reliably recapitulate the histologic and molecular features of human HCC development including fibrosis after 8 weeks, cirrhosis after 12 weeks, and HCC by 18 weeks. DEN-injured rats were randomized to receive oral gavage of nizatidine (n=7) or vehicle control (n=9) after 8 weeks. In the second study, male C57BL/6J mice received a single intraperitoneal injection of 25 mg/kg DEN at day 15 followed by initiation of a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) at 6 weeks of age. DEN+CDAHFD-injured mice were randomized to receive oral gavage of nizatidine (n=7) or vehicle control (n=9) at 12 weeks of age and were sacrificed at 30 weeks of age after development of HCC in the setting of nonalcoholic steatohepatitis (NASH).
Results: As expected, repeated injections of DEN in rats resulted in progressive fibrosis followed by HCC formation. Treatment with nizatidine resulted in a 35% reduction of tumor nodules relative to vehicle controls (p<0.18). Liver sections were stained by picrosirius red to assess fibrosis and nizatidine reduced collagen deposition in DEN-injured rats (collagen proportional area = 5±0.03 vs. 9.2±0.04; p<0.05). This histologic observation was further confirmed by gene expression analysis with reduction in several profibrotic markers, such as alpha-smooth muscle actin and collagen type I, after treatment with nizatidine. All mice receiving DEN+CDAHFD developed HCC. Treatment with nizatidine resulted in a 60% reduction in tumor nodules relative to vehicle controls (p<0.0001). Nizatidine treatment also resulted in a significant reduction in liver to body weight (p<0.01). Nizatidine treatment reduced collagen proportional area (11±0.05 vs. 15±.01; p<0.05) and expression of profibrotic markers. Nizatidine treatment also reduced the expression of several proinflammatory markers including CD68, interferon gamma, and interleukin-6.
Conclusion: Our data suggest that the H2 receptor antagonist nizatidine reduces fibrosis and subsequent HCC development. This could be beneficial in patient management given the low cost and ready availability of this agent.
Citation Format: Shen Li, Sarani Ghoshal, Gunisha Arora, Derek J. Erstad, Mozhdeh Sojoodi, Michael Lanuti, Yujin Hoshida, Thomas Baumert, Kenneth K. Tanabe, Bryan C. Fuchs. The H2 receptor antagonist nizatidine inhibits carcinogenesis in two rodent models of hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4004.