Mechanisms of Chemoprevention by Isothiocyanates

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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.