UPM-MAKNA Cancer Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, Serdang, 43400 UPM Serdang, Selangor, Malaysia.
Chem Biol Interact. 2010 Aug 5;186(3):295-305. doi: 10.1016/j.cbi.2010.04.029. Epub 2010 May 7.
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.
姜烯（ZER），一种在亚热带生姜（Zingiber zerumbet Smith）中发现的单倍体萜烯，对包括宫颈癌、皮肤癌和结肠癌在内的几种癌细胞系具有抗增殖作用。在这项研究中，用单次腹腔注射二乙基亚硝胺（DEN，200mg/kg）和饮食 2-乙酰氨基芴（AAF）（0.02%）诱导大鼠肝癌，评估 ZER 的抗肿瘤作用。大鼠还在 DEN 注射后第四周开始每周两次接受腹腔注射 ZER，剂量为 15、30 或 60mg/kg 体重。阳性对照（DEN/AAF）大鼠的肝细胞体积较小，核染色质深，细胞质颗粒化，胞质内有紫色物质，这是肝癌发生的特征。组织病理学评价表明，ZER 可保护大鼠肝脏免受 DEN 和 AAF 的致癌作用。血清丙氨酸转氨酶（ALT）、天冬氨酸转氨酶（AST）、碱性磷酸酶（AP）和甲胎蛋白（AFP）在接受 ZER 治疗的肝癌大鼠中明显低于未治疗的大鼠（P<0.05）。未治疗的 DEN/AAF 大鼠的肝丙二醛（MDA）浓度明显升高（P<0.05），表明肝脂质过氧化。肝组织谷胱甘肽（GSH）浓度也显著降低（P<0.05）。未治疗的 DEN/AAF 大鼠肝组织切片还显示大量增殖细胞核抗原（PCNA），而 ZER 治疗组的抗原表达明显降低（P<0.05）。通过 TUNEL 检测，用 ZER 治疗的 DEN/AAF 大鼠的凋亡细胞数量明显高于未治疗的大鼠（P<0.05）。ZER 治疗还增加了 DEN/AAF 大鼠肝脏中 Bax 的表达，降低了 Bcl-2 蛋白的表达，提示细胞凋亡增加。即使在 ZER 治疗 11 周后，正常大鼠的肝脏也没有异常迹象。这项研究表明，ZER 可降低氧化应激，抑制增殖，诱导线粒体调控的细胞凋亡，从而最大限度地减少 DEN/AAF 诱导的大鼠肝癌发生。因此，ZER 在肝癌治疗方面具有巨大潜力。
