Anticancer effect of caudatin in diethylnitrosamine‑induced hepatocarcinogenesis in rats.

An overwhelming endoplasmic reticulum stress (ERS) and the following unfolded protein response (UPR) can induce hepatic inflammation, fibrosis and hepatocellular carcinoma (HCC). Caudatin, one of the species of C‑21 steroidal glycosides mainly isolated from the roots of Cynanchum bungei Decne, exhibits potent anticancer activities in vivo. However, the effect of caudatin on HCC remains unclear. In the present study, a diethylnitrosamine (DEN)‑induced HCC model was established. Nodules and tumors in rat livers were monitored by T2‑/T1‑weighted‑magnetic resonance imaging (MRI) using a 1.5 T scanner. Caudatin reduced the number and size of nodules and alleviated the inflammatory foci in the liver. In addition, the hepatic pro‑inflammatory levels of interleukin (IL) 6, monocyte chemoattractant protein 1 and IL‑1β were decreased in caudatin‑treated rats. The DEN‑induced surge in malondialdehyde, aspartate aminotransferase, alanine transaminase and TBIL were alleviated following caudatin treatment. The expression of ERS chaperones glucose‑regulated protein, 94 kDa, glucose‑regulated protein, 78 kDa and protein disulfide‑isomerase A4 and the proliferation marker Ki‑67 in liver nodules were all downregulated by caudatin as demonstrated by immunohistochemistry, reverse transcription‑quantitative PCR and western blot analysis. Caudatin reduced the cytoprotective ERS sensor activating transcription factor 6‑mediated signal transduction and inhibited the PKR‑like endoplasmic reticulum kinase/eukaryotic initiation factor 2α/activating transcription factor 4 pathway. However, the effect of caudatin on inositol requiring enzyme 1 signaling was negligible. In conclusion, restoration of the dysregulated UPR program was involved in the antitumor efficacy of caudatin without inducing cumulative hepatotoxicity.