Inhibition of chronic ulcerative colitis-associated colorectal adenocarcinoma development in a murine model by N-acetylcysteine
Inhibition of chronic ulcerative colitis-associated colorectal adenocarcinoma development in a murine model by N-acetylcysteine
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DOI：
10.1093/carcin/23.6.993
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发表时间：
2002-06-01
期刊：
影响因子：
4.7
通讯作者：
Yang, GY
中科院分区：
文献类型：
--
作者：
Seril, DN;Liao, J;Yang, GY
长期溃疡性结肠炎（UC）患者患结直肠癌的风险增加。为了开发预防UC相关致癌的策略，我们研究了抗氧化剂N-乙酰半胱氨酸（NAC）对小鼠模型中UC相关癌症发展的影响。对雌性C57 BL/6 J小鼠进行长期施用葡聚糖硫酸钠（DSS）的饮用液和2倍铁富集的AIN 76 A饮食，有或没有NAC。在DSS加2倍铁阳性对照组中，12个DSS周期（1个DSS周期= 7天DSS治疗期，随后为10天恢复期）后，大体肿瘤发生率为88.5%（23/26只小鼠）。肿瘤多样性为2.1 +/- 0.2个肿瘤/荷瘤小鼠，肿瘤体积为0.054 +/- 0.019 cm（3）。在0.2%NAC给药的情况下，肿瘤发生率显著降低（68%，17/25只小鼠; P < 0.05），肿瘤多样性也是如此（1.5 +/-0.1个肿瘤/荷瘤小鼠; P < 0.05）。肿瘤体积较低（0.014 +/- 0.004 cm（3）），但没有显著减少。非癌上皮细胞的增殖指数显著降低（48.5 +/-6.0%vs 32.0 +/- 3.7%; P < 0.05），但肿瘤细胞中没有。NAC可显著诱导非癌上皮细胞和结直肠腺癌细胞凋亡。在NAC治疗的小鼠的非癌粘膜中，硝基酪氨酸免疫染色阳性的细胞数量显著减少（102.4 +/-16.6阳性细胞/mm（2）粘膜vs 53.6 +/-14.9细胞/mm（2）粘膜; P < 0.05）。此外，诱导型一氧化氮合酶（iNOS）阳性的炎症细胞在远端结肠的非癌粘膜的数量显着减少NAC。这项研究表明，抗氧化剂NAC可能通过抑制细胞增殖和亚硝化应激引起的细胞损伤，有可能作为UC相关结直肠癌的预防剂。
Long-term ulcerative colitis (UC) patients are at increased risk for developing colorectal cancer. In order to develop strategies for preventing UC-associated carcinogenesis, we studied the effect of the antioxidant N-acetylcysteine (NAC) on UC-associated cancer development in a mouse model. Female C57BL/6J mice were subjected to long-term administration of dextran sulfate sodium (DSS) in the drinking fluid and 2-fold iron-enriched AIN76A diet, with or without NAC. In the DSS-plus-2-fold iron positive control group, gross tumor incidence was 88.5% (23/26 mice) after 12 DSS cycles (1 DSS cycle = 7 day DSS treatment period followed by 10 day recovery period). The tumor multiplicity was 2.1 +/- 0.2 tumors/tumor-bearing mouse, and the tumor volume was 0.054 +/- 0.019 cm(3). With 0.2% NAC administration, tumor incidence was significantly reduced (68%, 17/25 mice; P < 0.05), as was the tumor multiplicity (1.5 +/- 0.1 tumors/tumor-bearing mouse; P < 0.05). The tumor volume was lower (0.014 +/- 0.004 cm(3)), but not significantly decreased. The proliferation index was significantly decreased in non-cancerous epithelia (48.5 +/- 6.0% vs 32.0 +/- 3.7%; P < 0.05), but not in tumor cells. NAC significantly induced apoptosis in both non-cancerous epithelia and colorectal adenocarcinoma. The number of cells immunostained-positive for nitrotyrosine was markedly decreased in the non-cancerous mucosa of NAC-treated mice (102.4 +/-16.6 positive cells/mm(2) mucosa vs 53.6 +/- 14.9 cells/mm(2); P < 0.05). In addition, the number of inducible nitric oxide synthase (iNOS)-positive inflammatory cells in the non-cancerous mucosa of the distal colon was markedly decreased by NAC. This study indicates that the antioxidant NAC has the potential to serve as a preventive agent for UC-associated colorectal cancer, possibly via inhibition of cellular proliferation and nitrosative stress-caused cellular damage.