Kim Mihye, Miyamoto Shingo, Yasui Yumiko, Oyama Takeru, Murakami Akira, Tanaka Takuji
Department of Oncologic Pathology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa, Japan.
Int J Cancer. 2009 Jan 15;124(2):264-71. doi: 10.1002/ijc.23923.
Zerumbone (ZER), present in subtropical ginger Zingiber zerumbet Smith, possesses anti-growth and anti-inflammatory properties in several human cancer cell lines. ZER also down-regulates the cyclooxygenase-2 and inducible nitric oxide synthase expression via modulation of nuclear factor (NF)-kappaB activation in cell culture systems. These findings led us to investigate whether ZER is able to inhibit carcinogenesis in the colon and lung, using 2 different preclinical mouse models. In Exp. 1, a total of 85 male ICR mice were initiated using a single intraperitoneal (i.p.) injection with azoxymethane (AOM, 10 mg/kg bw) and promoted by 1.5% dextran sulfate sodium (DSS) in drinking water for 7 days for rapid induction of colonic neoplasms. Animals were then fed the diet containing 100, 250 or 500 ppm ZER for 17 weeks. In Exp. 2, a total of 50 female A/J mice were given a single i.p. injection of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (10 micromol/mouse) to induce lung proliferative lesions. They were then fed the diet mixed with 100, 250 or 500 ppm ZER for 21 weeks. At the termination of the experiments (wk 20 of Exp. 1 and wk 22 of Exp. 2), all animals were subjected to complete necropsy examination to determine the pathological lesions in both tissues. Oral administration of ZER at 100, 250 and 500 ppm significantly inhibited the multiplicity of colonic adenocarcinomas. The treatment also suppressed colonic inflammation. In the lung carcinogenesis, ZER feeding at 250 and 500 ppm significantly inhibited the multiplicity of lung adenomas in a dose-dependent manner. Feeding with ZER resulted in inhibition of proliferation, induction of apoptosis, and suppression of NFkappaB and heme oxygenase (HO)-1 expression in tumors developed in both tissues. Our findings suggest that dietary administration of ZER effectively suppresses mouse colon and lung carcinogenesis through multiple modulatory mechanisms of growth, apoptosis, inflammation and expression of NFkappaB and HO-1 that are involved in carcinogenesis in the colon and lung.
姜酮（ZER）存在于亚热带姜科植物红球姜（Zingiber zerumbet Smith）中，在多种人类癌细胞系中具有抗生长和抗炎特性。在细胞培养系统中，ZER还通过调节核因子（NF）-κB的激活来下调环氧化酶-2和诱导型一氧化氮合酶的表达。这些发现促使我们使用两种不同的临床前小鼠模型来研究ZER是否能够抑制结肠癌和肺癌的发生。在实验1中，总共85只雄性ICR小鼠通过腹腔内（i.p.）单次注射10 mg/kg体重的氧化偶氮甲烷（AOM）启动造模，并通过在饮用水中添加1.5%的葡聚糖硫酸钠（DSS）持续7天来促进结肠肿瘤的快速诱导。然后给动物喂食含100、250或500 ppm ZER的饲料，持续17周。在实验2中，总共50只雌性A/J小鼠通过腹腔内单次注射4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮（10 μmol/小鼠）来诱导肺部增殖性病变。然后给它们喂食混合了100、250或500 ppm ZER的饲料，持续21周。在实验结束时（实验1的第20周和实验2的第22周），对所有动物进行完整的尸检检查，以确定两个组织中的病理病变。口服100、250和500 ppm的ZER可显著抑制结肠腺癌的数量。该治疗还抑制了结肠炎症。在肺癌发生过程中，喂食250和500 ppm的ZER可显著剂量依赖性地抑制肺腺瘤的数量。喂食ZER导致在两个组织中发生的肿瘤中增殖受到抑制、细胞凋亡被诱导，并且NFκB和血红素加氧酶（HO）-1的表达受到抑制。我们的研究结果表明，通过饮食给予ZER可通过生长、细胞凋亡、炎症以及参与结肠癌和肺癌发生的NFκB和HO-1表达的多种调节机制，有效抑制小鼠结肠癌和肺癌的发生。
