Xanthorrhizol inhibits 12-O-tetradecanoylphorbol-13-acetate-induced acute inflammation and two-stage mouse skin carcinogenesis by blocking the expression of ornithine decarboxylase, cyclooxygenase-2 and inducible nitric oxide synthase through mitogen-activated protein kinases and/or the nuclear factor-κB
Xanthorrhizol inhibits 12-O-tetradecanoylphorbol-13-acetate-induced acute inflammation and two-stage mouse skin carcinogenesis by blocking the expression of ornithine decarboxylase, cyclooxygenase-2 and inducible nitric oxide synthase through mitogen-activated protein kinases and/or the nuclear factor-κB
复制标题
DOI：
10.1093/carcin/bgm005
复制
发表时间：
2007-06-01
期刊：
影响因子：
4.7
通讯作者：
Park, Kwang Kyun
中科院分区：
文献类型：
--
作者：
Chung, Won Yoon;Park, Jae Hee;Park, Kwang Kyun
黄根醇是从黄姜中分离得到的一种有效成分。(姜科)在印度尼西亚传统上用于医药目的。在本研究中，我们发现，在12-O-十四烷基佛波醇(TPA)治疗前局部应用黄曲根醇可显著抑制TPA诱导的小鼠耳肿胀和TPA诱导的7，12-二甲基苯并[a]菲(DNMA)诱导的ICR小鼠皮肤肿瘤形成。在TPA诱导的增殖和异型增生的乳头状瘤诱导后，局部应用xanthorRhol也降低了DMBA引发的小鼠皮肤中肿瘤的多发性和发病率。为了进一步阐明黄曲根醇抗肿瘤作用的分子机制，我们在小鼠皮肤中研究了其对TPA诱导的鸟氨酸脱羧酶(ODC)、环氧合酶-2(COX-2)和诱导型一氧化氮合酶(NOS)表达的影响以及控制这些蛋白表达的上游信号分子。在TPA诱导的小鼠急性炎症皮肤和TPA促进的DMBA诱导的小鼠皮肤中，黄曲根醇预处理19周均能抑制ODC、NOS和COX-2蛋白的表达和核因子-kappaB的激活。在TPA诱导的小鼠皮肤乳头状瘤形成后进行皮肤治疗时，赞松根醇显著抑制ODC、NOS和COX-2的表达，并抑制核因子-kappa B的激活。此外，Western印迹分析显示，在诱导小鼠乳头状瘤后局部应用6周后，赞松根醇抑制了细胞外信号调节蛋白激酶、p38、c-Jun-N末端激酶和Akt的激活。综上所述，本研究表明，黄索根醇不仅延缓或抑制肿瘤的形成，而且通过降低受核因子-kappa B、丝裂原活化蛋白激酶和/或Akt调控的ODC、MOS和COX-2的蛋白水平，逆转癌前阶段的致癌过程。
Xanthorrhizol is an active component isolated from Curcuma xanthorrhiza Roxb. (Zingiberaceae) that is traditionally used in Indonesia for medicinal purposes. In the present study, we found that the topical application of xanthorrhizol before 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment significantly inhibits TPA-induced mouse ear edema and TPA-induced tumor promotion in 7,12-dimethylbenz[a]anthracene (DNMA)-initiated ICR mouse skin. The topical application of xanthorrhizol following the induction of papillomas with TPA-induced hyperplasia and dysplasia also reduced tumor multiplicity and incidence in DMBA-initiated mouse skin. To further elucidate the molecular mechanisms underlying the antitumor-promoting activity of xanthorrhizol, its effect on the TPA-induced expression of ornithine decarboxylase (ODC), cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (NOS) and the upstream signaling molecules controlling these proteins were explored in mouse skin. The pre-treatment with xanthorrhizol inhibited the expression of ODC, NOS and COX-2 proteins and nuclear factor-kappa B (NF-kappa B) activation in both mouse skin with TPA-induced acute inflammation and DMBA-initiated mouse skin promoted by TPA for 19 weeks. When mouse skin was treated after TPA-induced production of papillomas, xanthorrhizol remarkably suppressed the expression of ODC, NOS and COX-2 and inhibited the activation of NF-kappa B. Furthermore, western blot analysis showed that xanthorrhizol suppressed the activation of extracellular signal-regulated protein kinase, p38, c-jun-N-terminal kinase and Akt in mice after topical application for 6 weeks following the induction of papillomas. Taken together, the present study demonstrates that xanthorrhizol not only delays or inhibits tumor formation, but also reverses the carcinogenic process at premalignant stages by reducing the protein levels of ODC, MOS and COX-2 regulated by the NF-kappa B, mitogen-activated protein kinases and/or Akt.