Zerumbone, a sesquiterpene in subtropical ginger, suppresses skin tumor initiation and promotion stages in ICR mice
Zerumbone, a sesquiterpene in subtropical ginger, suppresses skin tumor initiation and promotion stages in ICR mice
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DOI：
10.1002/ijc.20175
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发表时间：
2004-07-01
影响因子：
6.4
通讯作者：
Ohigashi, H
中科院分区：
文献类型：
--
作者：
Murakami, A;Tanaka, T;Ohigashi, H
我们最近发现，zerumbone，一种在亚热带生姜中发现的倍半萜，抑制大鼠结肠肿瘤标志物的形成，并诱导结肠癌细胞系的凋亡。在我们目前的研究中，Zerumbone在小鼠皮肤中的抗肿瘤启动和促进活性使用传统的2阶段致癌模型进行了评估。在应用二甲基苯并[a]蒽（0.2 μ mol）前24小时，对小鼠皮肤进行单次局部预处理（2 μ mol），可显著抑制肿瘤发生率60%和肿瘤数量80%/小鼠。在起始后阶段每周两次重复预处理（16 nmol）可使12-O-十四烷酰基佛波醇-13-乙酸酯（TPA，1.6 nmol）诱导的肿瘤数量减少83%，直径减少57%。多重逆转录酶（RT）PCR实验表明，zerumbone（2 μ mol）提高锰超氧化物歧化酶，谷胱甘肽过氧化物酶-1，谷胱甘肽S-转移酶-P1和NAD（P）H醌氧化还原酶在表皮中的mRNA表达水平，但不是细胞色素P450 1A1或1B1。此外，它减少了TPA诱导的环氧合酶-2蛋白表达和细胞外信号调节激酶1/2的磷酸化，而预处理，无论是在引发或激活阶段或两者，减少了双TPA应用诱导的过氧化氢形成和水肿诱导，分别为29%至86%。组织学检查显示，zerumbone预处理抑制了白细胞浸润，并降低了增殖细胞核抗原标记指数。总之，我们的研究结果表明，zerumbone是一个有前途的代理预防肿瘤启动和促进过程，通过诱导抗氧化和II期药物代谢酶以及衰减促炎信号通路。(C)2004 Wiley-Liss，Inc.
We recently showed that zerumbone, a sesquiterpene found in subtropical ginger, suppresses colonic tumor marker formation in rats and induces apoptosis in colon cancer cell lines. In our present study, the anti-tumor initiating and promoting activities of zerumbone in mouse skin were evaluated using a conventional 2-stage carcinogenesis model. A single topical pretreatment to mouse skin (2 mumol) 24 hr before application of dimethylbenz[a]anthracene (0.2 mumol) markedly suppressed tumor incidence by 60% and the number of tumors by 80% per mouse. Repeated pretreatment (16 nmol) twice weekly during the post-initiation phase reduced the number of 12-O-tetradecanoylphorbol-13-acetate (TPA, 1.6 nmol)-induced tumors by 83% as well as their diameter by 57%. Multiple reverse transcriptase (RT) PCR experiments revealed that zerumbone (2 mumol) enhanced the mRNA expression level of manganese superoxide dismutase, glutathione peroxidase-1, glutathione S-transferase-P1 and NAD(P)H quinone oxidoreductase in the epidermis, but not that of cytochrome P450 1A1 or 1B1. Further, it diminished TPA-induced cyclooxygenase-2 protein expression and phosphorylation of extracellular signal-regulated kinase 1/2, while pretreatment(s), in either the priming or activation stage or both, reduced double TPA application-induced hydrogen peroxide formation and edema induction by 29% to 86%, respectively. Histologic examination revealed that pretreatment(s) with zerumbone suppressed leukocyte infiltration and reduced proliferating cell nuclear antigen-labeling indices. Together, our results indicate that zerumbone is a promising agent for the prevention of both tumor initiating and promoting processes, through induction of anti-oxidative and phase II drug metabolizing enzymes as well as attenuation of proinflammatory signaling pathways. (C) 2004 Wiley-Liss, Inc.