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 i s based on a recent epidemiological study showing that ITC intake is highly protective in individuals with GSTM1 and GSTT1 null genotypes.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA100853-05
Application #
7454947
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Perloff, Marjorie
Project Start
2004-09-01
Project End
2009-06-30
Budget Start
2008-07-23
Budget End
2009-06-30
Support Year
5
Fiscal Year
2008
Total Cost
$338,193
Indirect Cost
Name
Georgetown University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
Fu, Ying; Mi, Lixin; Sanda, Miloslav et al. (2014) A Click Chemistry Approach to Identify Protein Targets of Cancer Chemopreventive Phenethyl Isothiocyanate. RSC Adv 4:3920-3923
Xiao, Zhen; Mi, Lixin; Chung, Fung-Lung et al. (2012) Proteomic analysis of covalent modifications of tubulins by isothiocyanates. J Nutr 142:1377S-81S
Mi, Lixin; Xiao, Zhen; Veenstra, Timothy D et al. (2011) Proteomic identification of binding targets of isothiocyanates: A perspective on techniques. J Proteomics 74:1036-44
Mi, Lixin; Gan, Nanqin; Chung, Fung-Lung (2011) Isothiocyanates inhibit proteasome activity and proliferation of multiple myeloma cells. Carcinogenesis 32:216-23
Wang, Xiantao; Govind, Sudha; Sajankila, Shyama P et al. (2011) Phenethyl isothiocyanate sensitizes human cervical cancer cells to apoptosis induced by cisplatin. Mol Nutr Food Res 55:1572-81
Wang, Xiantao; Di Pasqua, Anthony J; Govind, Sudha et al. (2011) Selective depletion of mutant p53 by cancer chemopreventive isothiocyanates and their structure-activity relationships. J Med Chem 54:809-16
Sun, Xiaoyun; Mi, Lixin; Liu, Jin et al. (2011) Sulforaphane prevents microcystin-LR-induced oxidative damage and apoptosis in BALB/c mice. Toxicol Appl Pharmacol 255:9-17
Mi, Lixin; Hood, Brian L; Stewart, Nicolas A et al. (2011) Identification of potential protein targets of isothiocyanates by proteomics. Chem Res Toxicol 24:1735-43
Mi, Lixin; Di Pasqua, Anthony J; Chung, Fung-Lung (2011) Proteins as binding targets of isothiocyanates in cancer prevention. Carcinogenesis 32:1405-13
Mi, Lixin; Sirajuddin, Paul; Gan, Nanqin et al. (2010) A cautionary note on using N-acetylcysteine as an antagonist to assess isothiocyanate-induced reactive oxygen species-mediated apoptosis. Anal Biochem 405:269-71

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