Abstract
Hepatocellular carcinoma (HCC), the third major cause of cancer mortality, can result from non-alcoholic steatohepatitis (NASH). Due to limited efficacy of drugs approved for HCC and no drug available yet for NASH, identification of new effective treatments is crucial. Here, we investigated whether NV556, a cyclophilin inhibitor derived from sanglifehrins, would decrease the development of NASH and HCC in a preclinical mouse model. For our experiment, male mice were administered streptozotocin to disrupt pancreatic cells and nourished with high-fat diet since 3 weeks of age. Afterward, NV556 or vehicle was orally administered daily for 6 weeks before the 14-week-old time point for the development of NASH, or 10 weeks before the 30-week-old time point for the establishment of HCC. Body weight, blood glucose level, and liver weight were recorded. Moreover, for NASH, livers were histologically examined for inflammation and steatosis. Collagen was measured by Sirius Red staining of hepatic tissues. Systemic cytokine levels in serum were detected by multiplex assays. For HCC, nodules of livers were measured and scored according to a developed system with number and size of nodules as criteria. NV556 significantly decreased collagen deposition (p = 0.0281), but did not alter inflammation, steatosis, body and liver weight, and systemic cytokine production compared to control mice with NASH symptoms. For HCC, NV556 statistically reduced the number (p = 0.0091) and diameter of tumorous nodules (p = 0.0264), along with liver weight (p = 0.0026) of mice.Our study suggests NV556 as a promising candidate for treatment of NASH-derived fibrosis and HCC.
Highlights
Hepatocellular carcinoma (HCC) is the third major cause of cancer mortality, globally accounting for 800,000 deaths per year (Flores and Marrero, 2014)
We aimed to examine whether administration of cyclophilin inhibitor (CypI) NV556 would decrease the development of non-alcoholic steatohepatitis (NASH) and HCC in a preclinical murine model, with symptoms established in months compared to years and decades in human patients
C57BL/6J murine strain was used since other strains are shown with more resistance to STZ-induced diabetes, adiposity, liver inflammation, and fibrosis from high-fat diet (HFD) compared to C57BL/6J mice (Gurley et al, 2006; Jovicic et al, 2015)
Summary
Hepatocellular carcinoma (HCC) is the third major cause of cancer mortality, globally accounting for 800,000 deaths per year (Flores and Marrero, 2014). HCC is one of the fastest-growing causes of cancer mortality in the United States (Flores and Marrero, 2014). Current treatment for HCC includes liver transplantation, segmentectomy, chemotherapy, and systemic drug therapy. Tumor recurrence may occur after transplantation and segmentectomy, and HCC is Hepatocellular Carcinoma, Fibrosis, and Cyclophilin Inhibition minimally responsive to chemotherapy. Chemotherapy presents numerous toxic side effects (Llovet and Bruix, 2008; Bruix and Sherman, 2011). Unexpectedly high rates of HCC recurrence occur after hepatic resection (Pravisani et al, 2017) and chemotherapy (Conti et al, 2016; Reig et al, 2016). The identification of new effective treatments for HCC is of a crucial research interest
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