Isothiocyanates and plant polyphenols as inhibitors of lung and esophageal cancer
Isothiocyanates and plant polyphenols as inhibitors of lung and esophageal cancer
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DOI：
10.1016/s0304-3835(97)04639-9
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发表时间：
1997-03-19
期刊：
影响因子：
9.7
通讯作者：
Morse, MA
中科院分区：
文献类型：
--
作者：
Stoner, GD;Morse, MA
测试了一组异硫氰酸芳基烷基酯抑制 A/J 小鼠肺中烟草特异性亚硝胺 NNK 和 F344 大鼠食道中食道特异性致癌物 NMBA 诱导的致瘤性和 DNA 甲基化的能力。此外，还测试了鞣花酸抑制 NMBA 诱导的食管肿瘤发生的能力。在A株肺肿瘤模型中，PEITC在5μmol剂量下可有效抑制NNK诱导的肺肿瘤，但在较低剂量下则无抑制作用。 PPITC、PBITC、PPeITC 和 PHITC 都是比 PEITC 更有效的 NNK 肺肿瘤发生抑制剂，而 PHITC 是其中最有效的抑制剂。因此，在A株肺肿瘤模型中，随着烷基链长度的增加，异硫氰酸芳基烷基酯的抑制效力有增加的趋势。在F344大鼠食管肿瘤模型中，PPITC明显比PEITC更有效，BITC和PBITC对食管肿瘤发生几乎没有抑制作用，并且在单独的实验中，PHITC实际上增强了食管肿瘤发生。因此，异硫氰酸芳基烷基酯抑制肿瘤发生的结构-活性关系在两种动物模型中显着不同。然而，在任一模型中，异硫氰酸盐对肿瘤发生的影响与其对 DNA 加合物形成的影响密切相关。这些异硫氰酸盐抑制肿瘤发生的最可能机制是通过抑制负责激活小鼠肺中的 NNK 或大鼠食道中的 NMBA 的细胞色素 p450 酶。鞣花酸是食管肿瘤发生的有效抑制剂，但不如 PEITC 或 PPITC 有效。与异硫氰酸盐一样，鞣花酸抑制细胞色素 p450 介导的 NMBA 激活。 (C) 1997 爱思唯尔科学爱尔兰有限公司
A group of arylalkyl isothiocyanates were tested for their abilities to inhibit tumorigenicity and DNA methylation induced by both the tobacco-specific nitrosamine, NNK, in A/J mouse lung and the esophageal-specific carcinogen, NMBA, in F344 rat esophagus. In addition, ellagic acid was tested for its ability to inhibit NMBA-induced esophageal tumorigenesis. In the strain A lung tumor model, PEITC effectively inhibited NNK-induced lung tumors at a dose of 5 mu mol, but was not inhibitory at lower doses. PPITC, PBITC, PPeITC, and PHITC were all considerably more potent inhibitors of NNK lung tumorigenesis than PEITC, and PHITC was the most potent inhibitor of all. Thus, in the strain A lung tumor model, there was a trend of increased inhibitory efficacy among arylalkyl isothiocyanates with increased alkyl chain length. In the F344 rat esophageal tumor model, PPITC was clearly more potent than PEITC, BITC and PBITC had little inhibitory effect on esophageal tumorigenesis, and in a separate experiment, PHITC actually enhanced esophageal tumorigenesis. Thus, the structure-activity relationships for inhibition of tumorigenesis by arylalkyl isothiocyanates were considerably different in the two animal models. However, the effects of the isothiocyanates on tumorigenesis were well-correlated to their effects on DNA adduct formation in either model. The most likely mechanism of inhibition of tumorigenesis by these isothiocyanates is via inhibition of the cytochrome p450 enzymes responsible for activation of NNK in mouse lung or NMBA in rat esophagus. Ellagic acid was an effective inhibitor of esophageal tumorigenesis, although not as potent as PEITC or PPITC. Like the isothiocyanates, ellagic acid inhibits cytochrome p450-mediated activation of NMBA. (C) 1997 Elsevier Science Ireland Ltd.