Cancer chemoprevention by an adenosine derivative in a model of cirrhosis-hepatocellular carcinoma induced by diethylnitrosamine in rats

Abstract

Hepatocellular carcinoma is one of the most common cancers, and approximately 80% develop from cirrhotic livers. We have previously shown that the aspartate salt of adenosine prevents and reverses carbon tetrachloride-induced liver fibrosis in rats. Considering the hepatoprotective role of this adenosine derivative in fibrogenesis, we were interested in evaluating its effect in a hepatocarcinogenesis model induced by diethylnitrosamine in rats, where multinodular cancer is preceded by cirrhosis. Rats were injected with diethylnitrosamine for 12 weeks to induce cirrhosis and for 16 weeks to induce hepatocarcinogenesis. Groups of rats were treated with aspartate salt of adenosine from the beginning of carcinogen administration for 12 or 18 weeks total, and another group received the compound from weeks 12 to 18. Fibrogenesis was estimated and the proportion of preneoplastic nodules and tumors was measured. The apoptotic and proliferation rates in liver tissues were evaluated, as well as the expression of cell signaling and cell cycle proteins participating in hepatocarcinogenesis. The adenosine derivative treatment reduced diethylnitrosamine-induced collagen expression and decreased the proportion of nodules positive for the tumor marker γ-glutamyl transferase. This compound down-regulated the expression of thymidylate synthase and hepatocyte growth factor, and augmented the protein level of the cell cycle inhibitor p27; these effects could be part of its chemopreventive mechanism. These findings suggest a hepatoprotective role of aspartate salt of adenosine that could be used as a therapeutic compound in the prevention of liver tumorigenesis as described earlier for hepatic fibrosis.

Functional, Metabolic, and Dynamic Mitochondrial Changes in the Rat Cirrhosis-Hepatocellular Carcinoma Model and the Protective Effect of IFC-305

“…Our research group demonstrated the hepatoprotective effects of IFC-305, an adenosine-derived compound (Perez-Carreon et al, 2010;Velasco-Loyden et al, 2010;Chagoya de Sanchez et al, 2012;Velasco-Loyden, 2016); this compound has been evaluated in a diethylnitrosamine (DEN)-induced sequential rat model of cirrhosis-HCC, where it inhibited preneoplastic lesion development in comparison with DENtreated groups. The chemopreventive effect was associated with the reduction of the expression of collagen, thymidylate synthase, the tumor marker g-glutamyl transferase, the hepatocyte growth factor, and the induction of the cell cycle inhibitor p27 expression (Velasco-Loyden, 2016).…”

Interaction of Mitochondrial and Epigenetic Regulation in Hepatocellular Carcinoma

“…This effect was associated with a decreased expression of PCNA, thymidylate synthase, HGF and its receptor c-Met, and the induction of the cell cycle inhibitor p27. IFC-305 also induced a diminution of gankyrin expression contributing to restoring p53 protein expression to control levels [39]. in cell proliferation, survival, morphogenesis, cell motility, and metastasis.…”

“…We observed that, in the cirrhotic liver induced by CCl 4 , the hepatoprotector IFC-305 incremented HGF expression [38], which could have a protective role in the regenerative capacity of the liver. On the other hand, in DEN-induced HCC, the IFC305 treatment downregulated HGF and c-Met expression, which contribute to liver tumorigenesis reduction [39]. HGF and c-Met can be potentiated by ROS in hepatoma cells [41,42].…”

Molecular and Cellular Aspects of Cirrhosis and How an Adenosine Derivative Could Revert Fibrosis

“…Preclinical studies indicated that IFC-305 is not toxic, neither genotoxic, nor teratogenic and it is anti-carcinogenic [33]. Considering this last property, we assessed IFC-305 effects on a chronic model of liver intoxication with diethylnitrosamine and found that it could act as a HCC chemopreventive agent [109,110]. The above suggests that some anti-fibrotic effects of the compound could prevent cancer development, being an adjuvant in chronic liver disease treatment.…”