Mechanisms of Chemoprevention by Isothiocyanates

异硫氰酸酯（ITCs）及其缀合物在动物模型中是有效的肺肿瘤发生抑制剂。ITCs的化学预防活性主要归因于选择性抑制细胞色素p450和诱导II期酶。近年来，细胞培养研究发现了ITCs抑制肿瘤的潜在重要新机制，包括通过激活信号转导通路诱导细胞凋亡和细胞周期阻滞。这些研究表明，如果在起始后阶段给药，ITCs可能会抑制肿瘤发生。事实上，我们已经证明，在苯并[a]芘治疗后，在饮食中给予苯乙基和苯基ITCs的n -乙酰半胱氨酸偶联物可以显著抑制a /J小鼠肺肿瘤的形成。此外，我们已经展示了第一个

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.