The long term goal of this proposal is to understand the detailed molecular basis for the cancer chemopreventitive effects of 1,2-dithiole-3-thiones and 1,2-dithiole-3-ones. One promising member of this class is oltipraz which is in Phase 2 clinical trials in the People's Republic of China. There is currently much investigation by a number of groups about the mode of action of these compounds at the biochemical, cellular and organismal level. The general picture to date is that these compounds preferentially stimulate the induction of Phase 2 metabolic enzymes that protect against electrophilic assault. However, a major area of uncertainty is the molecular nature of the initiation steps involved in Phase 2 enzyme induction. As elaborated in this proposal, this is in part due to the dearth of information regarding the chemistry and metabolism of this class of compounds. One posits the notion that these compounds, or the products of their decomposition, act as electrophiles which form adducts with protein messengers, possibly transcription factors, that subsequently activate expression. The alternative is that these compounds, or the products of their decomposition, generate reactive oxygen species (ROS) that interact with redox sensitive transcription factors that then give rise to induction. Resolving this dichotomy is absolutely required before a detailed analysis of the chemical mechanism of the key process can be undertaken. Resolution of this problem will also greatly aid in focusing efforts to find the target biomolecules of the electorphiles of ROS. Finally, understanding the chemical basis for induction of Phase 2 enzyme induction is essentially for thinking about constructing new cancer chemopreventitives with enhanced potency and efficacy.
| Holland, Ryan; Navamal, Mettachit; Velayutham, Murugesan et al. (2009) Hydrogen peroxide is a second messenger in phase 2 enzyme induction by cancer chemopreventive dithiolethiones. Chem Res Toxicol 22:1427-34 |
| Holland, Ryan; Hawkins, Arie E; Eggler, Aimee L et al. (2008) Prospective type 1 and type 2 disulfides of Keap1 protein. Chem Res Toxicol 21:2051-60 |
| Velayutham, Murugesan; Villamena, Frederick A; Fishbein, James C et al. (2005) Cancer chemopreventive oltipraz generates superoxide anion radical. Arch Biochem Biophys 435:83-8 |
| Velayutham, Murugesan; Villamena, Frederick A; Navamal, Mettachit et al. (2005) Glutathione-mediated formation of oxygen free radicals by the major metabolite of oltipraz. Chem Res Toxicol 18:970-5 |
| Navamal, Mettachit; McGrath, Colleen; Stewart, Jennifer et al. (2002) Thiolytic chemistry of alternative precursors to the major metabolite of the cancer chemopreventive oltipraz. J Org Chem 67:9406-13 |
