Potential chemoprevention of diethylnitrosamine-initiated and 2-acetylaminofluorene-promoted hepatocarcinogenesis by zerumbone from the rhizomes of the subtropical ginger (Zingiber zerumbet)

Abstract

Zerumbone (ZER), a monosesquiterpene found in the subtropical ginger (Zingiber zerumbet Smith), possesses antiproliferative properties to several cancer cells lines, including the cervical, skin and colon cancers. In this study, the antitumourigenic effects of ZER were assessed in rats induced to develop liver cancer with a single intraperitoneal injection of diethylnitrosamine (DEN, 200 mg/kg) and dietary 2-acetylaminofluorene (AAF) (0.02%). The rats also received intraperitoneal ZER injections at 15, 30 or 60 mg/kg body wt. twice a week for 11 weeks, beginning week four post-DEN injection. The hepatocytes of positive control (DEN/AAF) rats were smaller with larger hyperchromatic nuclei than normal, showing cytoplasmic granulation and intracytoplasmic violaceous material, which were characteristics of hepatocarcinogenesis. Histopathological evaluations showed that ZER protects the rat liver from the carcinogenic effects of DEN and AAF. Serum alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (AP) and alpha-fetoprotein (AFP) were significantly lower (P<0.05) in ZER-treated than untreated rats with liver cancer. The liver malondialdehyde (MDA) concentrations significantly (P<0.05) increased in the untreated DEN/AAF rats indicating hepatic lipid peroxidation. There was also significant (P<0.05) reduction in the hepatic tissue glutathione (GSH) concentrations. The liver sections of untreated DEN/AAF rats also showed abundant proliferating cell nuclear antigen (PCNA), while in ZER-treated rats the expression of this antigen was significantly (P<0.05) lowered. By the TUNEL assay, there were significantly (P<0.05) higher numbers of apoptotic cells in DEN/AAF rats treated with ZER than those untreated. Zerumbone treatment had also increased Bax and decreased Bcl-2 protein expression in the livers of DEN/AAF rats, which suggested increased apoptosis. Even after 11 weeks of ZER treatment, there was no evidence of abnormality in the liver of normal rats. This study suggests that ZER reduces oxidative stress, inhibits proliferation, induces mitochondria-regulated apoptosis, thus minimising DEN/AAF-induced carcinogenesis in rat liver. Therefore, ZER has great potential in the treatment of liver cancers.

Cytotoxicity and genotoxicity of zingiberene on different neuron cell lines in vitro

“…Also, Wang et al (2001) revealed that artesunate showed evident cytotoxicity to human hepatocarcinoma SMMC-7721 cells. In addition, Taha et al (2010) demonstrated that zerumbone (a monosesquiterpene found in the subtropical ginger), showed a strong cytotoxic effect in rat liver (DEN/AAF-induced) cancer cell lines. These results suggest a dose-dependent cytotoxic and antiproliferative effect of ZBN on neuron and N2a-NB cell cultures.…”

Key cell signaling pathways modulated by zerumbone: Role in the prevention and treatment of cancer

“…Anti-tumorigenic effects of zerumbone were also reported on diethylnitrosamine (DEN) (single injected dose) and dietary 2-acetylaminoflurene (AAF)-induced liver tumors in rats [70]. The sesquiterpene was reported to protect rat liver from carcinogenic effects of DEN and AAF.…”

Terpenoids as potential chemopreventive and therapeutic agents in liver cancer

“…Reduced the number of GSTp foci initiated by DENA and promoted by NASH in male Sprague-Dawley rats ↓PCNA; ↓cyclinD1; ↓TNF-α; ↓IL-1β; ↓IL-12; ↓lipid peroxidation; ↓CYP2E1; ↓pERK; ↓NF-κB 250 mg/kg per day; 6 wk Diet Wang et al [184] Sesquiterpenoids [124] Farnesol Suppressed the development of GSTp foci and nodules initiated with DENA and promoted by 2-AAF in male Wistar rats ↓cell proliferation; ↓DNA damage; ↓plasma cholesterol; ↓HMG-CoA reductase 250 mg/kg; 8 wk po Ong et al [129] Zerumbone Reduced DENA/2-AAF-induced hepatocarcinogenesis in Sprague-Dawley rats ↓ALP; ↓ALT; ↓AST; ↓AFP; ↓lipid peroxidation; ↓GSH; ↓PCNA; ↑Bax; ↓Bcl-2 15, 30 or 60 mg/kg; twice a week for 11 wk ip Taha et al [186] and similar study by Cardozo et al [130] observed the same chemopreventive benefits of geraniol in male Wistar rats initiated with DENA promoted by phenobarbital (PB). Geraniol was found to suppress liver carcinogenesis by inhibiting the promotion phase through induction of apoptosis and reduction of hepatic membrane protein RhoA.…”

“…ZER treatment also reduced oxidative stress and proliferation accompanied with apoptosis. An increase in Bax and decrease in Bcl-2 protein expression have been postulated as the mechanistic basis of proapoptotic properties of ZER during experimental hepatocarcinogenesis [186] .…”