Chemopreventive effect of saikosaponin-d on diethylinitrosamine-induced hepatocarcinogenesis: Involvement of CCAAT/enhancer binding protein�β and cyclooxygenase-2

Abstract

Abstract. Cyclooxygenase-2 (COX-2) and CCAAT/enhancer binding protein β (C/EBPβ) have been shown to be involved in inflammation and carcinogenesis, and our previous study revealed that they were co-overexpressed in human hepatocellular carcinoma (HCC) tissue and a positive correlation was found. Saikosaponin-d (SSD), a triterpene saponin extracted from Bupleurum falcatum L. (Umbelliferae), is known to exert inhibitory effects on COX-2 expression, together with inflammation and hepatic fibrosis. These findings prompted us to investigate the chemopreventive potential of SSD against hepatocarcinogenesis and its possible molecular mechanism in vivo. An experimental model with diethylinitrosamine (DEN)-treated Sprague Dawley rats was used in the present study. DEN (50 mg/kg body weight) and SSD (2 mg/kg body weight) were intraperitoneally injected weekly and daily, respectively. Administration of SSD alone had no side effects. The liver nodule formation, tumorous invasion to surrounding organs and increased cellular atypia induced by DEN were markedly reduced by SSD in the SSD + DEN group compared with the DEN group. On the other hand, immunohistochemical staining demonstrated that the expression of COX-2 and C/ EBPβ proteins was significantly increased in tumor cells and macrophages of liver tissue from DEN-treated rats, whereas the expression of the two proteins was markedly lowered in the SSD + DEN group. Overall, our results suggest that SSD prevents DEN-induced hepatocarcinogenesis in rats through inhibition of C/EBPβ and COX-2, providing indispensable experimental evidence for the clinical application of SSD as a novel chemopreventive agent against HCC in the future.

HCV NS5A Up-Regulates COX-2 Expression via IL-8-Mediated Activation of the ERK/JNK MAPK Pathway

“…In general, C/EBP activation is considered an important factors promoting liver fibrosis [ 39 ]. In this regard, it is noteworthy that our results are consistent with the findings of overexpression of C/EBP and COX-2 in the liver biopsy data from patients with HCC [ 40 ] and in vivo study [ 41 ]. In addition, both overexpression of NS5A and activation of C/EBP affect the insulin pathway, lipid modulation, and liver steatosis [ 42 ].…”

Vinegar amount in the process affected the components of vinegar-baked Radix Bupleuri and its hepatoprotective effect

“…The results showed that the native saponins (saikosaponin a, c, d) decreased, and the secondary saponin (saikosaponin b 2 ) increased gradually with the increasing proportion of vinegar. Modern research considered that native saponins (saikosaponin a, c, d) were the main effective compounds of Radix Bupleuri, so these saponins usually used as the index components of Radix Bupleuri [25–27]. However, similar with our results, other study also showed that secondary saponins (saikosaponin b 1 , b 2 ) were increased, while the saikosaponin a, saikosaponin c, and saikosaponin d were decreased after the vinegar-baking process [28, 29], and a higher saikosaponin b content also follow a better hepatoprotective effect [17], in spite of that the model they used is CCl 4 induced liver injury.…”

Current Understanding on Antihepatocarcinoma Effects of Xiao Chai Hu Tang and Its Constituents

“…SSa may inhibit HepG2 growth by increasing the levels of p-15INK4a and p-16INK4b (cyclin-dependent kinase inhibitors) in a protein kinase C (PKC) [33] and/or extracellular signal-regulated kinase (ERK) signaling pathway-dependent manner [34]. SSd markedly reduced the liver nodule, tumor cell invasion while increased cellular atypia in xenograft model [35]. It appeared that SSd exerted its action by diminishing the expression of highly expressed cyclooxygenase 2 (COX-2) and CCAAT/enhancer-binding protein β (C/EBPβ) in tumor cells and macrophages of liver tumors [35].…”

“…SSd markedly reduced the liver nodule, tumor cell invasion while increased cellular atypia in xenograft model [35]. It appeared that SSd exerted its action by diminishing the expression of highly expressed cyclooxygenase 2 (COX-2) and CCAAT/enhancer-binding protein β (C/EBPβ) in tumor cells and macrophages of liver tumors [35]. In a study reported by Zhu et al [36], SSd was shown capable of reversing the malignant phenotype of HepG2 cells.…”