Mechanisms of Chemoprevention by Isothiocyanates

异硫氰酸酯（ITC）及其缀合物是动物模型中抗肺肿瘤发生的有效抑制剂。ITCs的化学预防活性主要归因于细胞色素P450的选择性抑制和II相酶的诱导。近年来，细胞培养研究显示了ITCs抑制肿瘤的一个潜在的重要新机制，涉及通过激活信号转导途径介导的凋亡诱导和细胞周期阻滞。这些研究表明，ITC可以抑制肿瘤发生时，在启动后阶段的管理。事实上，我们已经证明，苯并[a]芘治疗后，在饮食中给予苯乙基和苄基ITC的N-乙酰半胱氨酸缀合物显著抑制A/J小鼠的肺肿瘤形成。此外，我们已经证明了第一个 在肿瘤生物测定条件下，这些药物通过激活MAP激酶、JNK、AP- 1和p53磷酸化诱导小鼠肺细胞凋亡，这是一组与培养细胞中观察到的相似的分子反应。在这个项目中，作为细胞培养和动物研究的延伸，我们的主要目标是研究人肺细胞中ITCs的分子和细胞机制，将其与动物中的ITCs进行比较，并研究其活性的化学基础。我们推测ITCs通过与特定靶蛋白结合和/或通过与谷胱甘肽结合改变氧化还原电位来激活人肺细胞中的信号转导途径，从而诱导细胞凋亡。在一个单独的目标中，我们将调查 谷胱甘肽转移酶（GST）多态性在人类ITC代谢中的作用。这一目标是基于最近的流行病学研究表明，ITC摄入量是高度保护与GSTM 1和GSTT 1无效基因型的个人。

Isothiocyanates (ITCs) and their conjugates are effective inhibitors against lung tumorigenesis in animal models. The chemopreventive activities of ITCs have been attributed mainly to selective inhibition of cytochrome-P450s and induction of phase II enzymes. In recent years, studies in cell culture showed a potentially important new mechanism of tumor inhibition by ITCs, involving induction of apoptosis and cell cycle arrest mediated through activation of signal transduction pathways. These studies suggested that ITCs may inhibit tumorigenesis when administered during post-initiation phases. Indeed, we have demonstrated that the N-acetylcysteine conjugates of phenethyl and benzyl ITCs given in the diet after benzo[a]pyrene treatment significantly inhibit lung tumor formation in A/J mice. Furthermore, we have shown for the first time in vivo, under the tumor bioassay conditions, that these agents induce apoptosis in mouse lung by activating MAP kinases, JNK, AP- 1 and p53 phosphorylation, a set of molecular responses similar to those seen in cultured cells. In this project, as an extension of cell culture and animal studies, our primary goals are to examine the molecular and cellular mechanisms of ITCs in human lung cells, comparing them to that in animals, and to investigate the chemical basis for their activities. We hypothesize that ITCs induce apoptosis by activating signal transduction pathways in human lung cells through binding to specific target proteins and/or altering redox potential by conjugating with glutathione. In a separate goal, we will investigate the role of glutathione transferase (GST) polymorphism in ITC metabolism by humans. This aim is based on a recent epidemiological study showing that ITC intake is highly protective in individuals with GSTM1 and GSTT1 null genotypes.