Pterostilbene Is More Potent than Resveratrol in Preventing Azoxymethane (AOM)-Induced Colon Tumorigenesis via Activation of the NF-E2-Related Factor 2 (Nrf2)-Mediated Antioxidant Signaling Pathway
Pterostilbene Is More Potent than Resveratrol in Preventing Azoxymethane (AOM)-Induced Colon Tumorigenesis via Activation of the NF-E2-Related Factor 2 (Nrf2)-Mediated Antioxidant Signaling Pathway
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DOI：
10.1021/jf2000103
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发表时间：
2011-03-23
影响因子：
6.1
通讯作者：
Pan, Min-Hsiung
中科院分区：
文献类型：
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作者：
Chiou, Yi-Siou;Tsai, Mei-Ling;Pan, Min-Hsiung
炎症性肠病一直是结直肠癌（CRC）的危险因素。由炎症细胞产生的活性氧（ROS）产生氧化应激，并有助于肿瘤转化，增殖，甚至转移。以前，白藜芦醇（RS）和紫檀芪（PS）已被报道，以防止化学诱导的结肠癌的抗炎和促凋亡的特性。本研究旨在探讨RS和PS是否能通过抗氧化作用预防氧化偶氮甲烷（AOM）诱导的结肠肿瘤发生，并探讨其可能的分子机制。给雄性BALB/c小鼠注射AOM（5 mg/kg体重），含或不含RS或PS，在方案结束时，对所有小鼠实施安乐死并分析结肠。PS给药在减少AOM诱导的异常隐窝病灶（ACF）、淋巴结（LN）和肿瘤形成方面可能比RS更有效。我们还发现，PS比RS更有效地通过抑制蛋白激酶C-β 2（PKC-β 2）的磷酸化和降低下游靶基因的表达来降低核因子-κ B（NF-κ B B）的激活，包括诱导型一氧化氮合酶（iNOS），环氧合酶-2（考克斯-2）和醛糖还原酶（AR）在AOM刺激的小鼠结肠中的表达。此外，RS和PS给药6周显著增强抗氧化酶的表达，如血红素加氧酶-1（HO-1）和谷胱甘肽还原酶（GR），通过激活NF-E2相关因子2（Nrf 2）信号传导。当上述发现结合在一起时，他们表明两种芪类通过诱导HO-1和GR阻断细胞炎症和氧化应激，从而防止AOM诱导的结肠癌发生。相比之下，PS是一个更有效的化学预防剂比RS预防结肠癌。这也是第一项证明PS在AOM处理的结肠癌发生模型中是Nrf 2诱导剂和AR抑制剂的研究。
Inflammatory bowel diseases have been a risk factor of colorectal cancer (CRC). The reactive oxygen species (ROS) generated by inflammatory cells create oxidative stress and contribute to neoplastic transformation, proliferation, and even metastasis. Previously, resveratrol (RS) and pterostilbene (PS) had been reported to prevent chemical-induced colon carcinogenesis by anti-inflammatory and pro-apoptotic properties. In this study, we investigated whether RS and PS could prevent the azoxymethane (AOM)-induced colon tumorigenesis via antioxidant action and to explore possible molecular mechanisms. Male BALB/c mice were injected with AOM (5 mg/kg of body weight) with or without RS or PS, and at the end of the protocol, all of the mice were euthanized and colons were analyzed. Administrations of PS can be more effective than RS in reducing AOM-induced formation of aberrant crypt foci (ACF), lymphoid nodules (LNs), and tumors. We also find that PS is functioning more effectively than RS to reduce nuclear factor-kappa B (NF-kappa B) activation by inhibiting the phosphorylation of protein kinase C-beta 2 (PKC-beta 2) and decreasing downstream target gene expression, including inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and aldose reductase (AR) in mouse colon stimulated by AOM. Moreover, administration of RS and PS for 6 weeks significantly enhanced expression of antioxidant enzymes, such as heme oxygenase-1 (HO-1) and glutathione reductase (GR), via activation of NF-E2-related factor 2 (Nrf2) signaling. When the above findings are taken together, they suggest that both stilbenes block cellular inflammation and oxidative stress through induction of HO-1 and GR, thereby preventing AOM-induced colon carcinogenesis. In comparison, PS was a more potent chemopreventive agent than RS for the prevention of colon cancer. This is also the first study to demonstrate that PS is a Nrf2 inducer and AR inhibitor in the AOM-treated colon carcinogenesis model.