Possible role of selective, irreversible, proteasome inhibitor (carfilzomib) in the treatment of rat hepatocellular carcinoma

• Carfilzomib at lower dose ameliorated hepatic cancer induced by DENA.
• Carilzomib down-regulated hepatic growth factors mediated angiogenesis.
• It exhibited high ability to inhibit MMP-2 activity and TIMP-1 hepatic level.
• Hepatic endostatin mediated anti-angiogenesis and metallothionein have been elevated.
• It succeeded in induction of apoptosis in hepatic transformed cells.

We investigated the possible therapeutic effect of irreversible proteasome inhibitor, carfilzomib against hepatocellular carcinoma induced chemically by chronic administration of diethylnitrosoamines (DENA).Hepatocellular carcinoma induced by DENA in male Wistar rats was manifested biochemically by significant elevation of serum α-feto protein (AFP) and carcinoembryonic antigen (CEA). In addition, hepatic cancer was further confirmed by a significant increase in hepatic tissue growth factors; vascular endothelial growth factor (VEGF), transforming growth factor-β1 (TGF-β1) and basic fibroblast growth factor (FGF). Moreover a marked increase in matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinase-1 (TIMP-1) content were also observed, along with a profound decrease in hepatic endostatin and metallothionein level.Treatment of rats with the selected doses of carfilzomib produced a significant protection against hepatic cancer. The present results claimed that chosen doses of carfilzomib succeeded in suppressing serum tumor markers level AFP and CEA. Furthermore, the drug reduced the elevated level of hepatic growth factors, MMP-2 and TIMP-1 induced by the carcinogen. The antitumor effect of carfilzomib was also accompanied by augmentation of hepatic content of endostatin and metallothionein. Histopathological examination of liver tissues also correlated with the biochemical observations. It could be concluded that treatment with carfilzomib confers a possible antitumor effect against hepatocellular carcinoma induced by DENA model in rats.

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