Abstract
The present study was designed to determine the effects of NIK-333, a synthetic acyclic retinoid, on N-diethylnitrosamine (DEN)-induced hepatocarcinogenesis in male F344 rats. Animals were given DEN dissolved in drinking water at a concentration of 40 p.p.m. for 5 weeks and then provided with drinking water free of DEN for 15 weeks to induce hepatocellular neoplasms. NIK-333 was administered orally (once a day) to rats at doses of 10, 40 and 80 mg/kg body wt for 14 weeks, starting 1 week after the completion of administration of DEN. At 20 weeks after the start of DEN administration, histopathological evaluation was carried out on all animals. The effects of NIK-333 on the cell proliferation activity of non-tumorous areas and liver tumor cells and the immunohistochemical expression of transforming growth factor-alpha (TGF-alpha) were also evaluated. NIK-333 at 40 and 80 mg/kg body wt significantly inhibited hepatocarcinogenesis (P < 0.05). In addition, NIK-333 at the same doses decreased DEN-induced overexpression of TGF-alpha in hepatocellular neoplasms (adenomas and carcinomas) and their surrounding tissue. Furthermore, NIK-333 significantly inhibited cell proliferation activity in the lesions and in non-tumorous areas (P < 0.01). Our results suggest that NIK-333 inhibits DEN-induced hepatocarcinogenesis through suppression of TGF-alpha expression and cell proliferation.
Highlights
Hepatocellular carcinoma (HCC) develops through chronic hepatitis/hepatic cirrhosis caused by persistent infection with hepatitis viruses C (HCV) and B (HBV)
Burr et al reported that administration of DEN to rats increased the transforming growth factor-a (TGF-a) level in the whole liver and immunohistological staining revealed TGF-a expression in hepatocytes surrounding the centrilobular vein [12]
The reason why expression of TGF-a is increased in hepatocytes by treatment with DEN is not yet known, it is likely that dedifferentiation of mature hepatocytes is induced by the hepatocarcinogen
Summary
Hepatocellular carcinoma (HCC) develops through chronic hepatitis/hepatic cirrhosis caused by persistent infection with hepatitis viruses C (HCV) and B (HBV). Considerable advances have recently been made in various treatments for HCC, but high recurrence rates are still observed in patients with this malignancy and it still has a poor prognosis. Inhibition of hepatocarcinogenesis at the chronic hepatitis/liver cirrhosis stage and inhibition of recurrence of Abbreviations: AgNORs, argyrophilic nucleolar organizer regions; DEN, N-diethylnitrosamine; HBV, hepatitis virus B; HCC, hepatocellular carcinoma; HCV, hepatitis virus C; RA, retinoic acid; TGF-a, transforming growth factor-a. NIK-333 is a drug with a high safety profile that does not cause impaired liver function or any other of the side-effects induced by other retinoids
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