Abstract

The mechanisms involved in detoxification of drugs and poisons are important to cancer biology. The ability of a cell or tissue to detoxify xenobiotic poisons are associated with the emergence of anti-cancer drug resistance in tumors. In normal tissues, this detoxification activity influences the outcome of exposure to carcinogens and other toxins. A long term goal of the studies proposed is to understand the mechanisms by which the drug conjugating system, glutathione (GSH) and glutathione transferase (GST) and glutathione transferase (GST), and the toxin efflux transporters, MRP1 and MRP2, operate together to confer protection from anti-cancer drugs or carcinogens. This knowledge will improve the ability to predict the responses of particular tissues and tumors to toxin exposure including the risk of developing cancer in normal tissues or the likelihood of develop drug resistance in cancer. Moreover, this knowledge can be used to device more effect ant-cancer treatment or chemopreventive strategies.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA070338-05
Application #
6342007
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Song, Min-Kyung H
Project Start
1996-05-10
Project End
2004-12-31
Budget Start
2001-01-01
Budget End
2001-12-31
Support Year
5
Fiscal Year
2001
Total Cost
$225,193
Indirect Cost

  Institution

Name
Wake Forest University Health Sciences
Department
Biochemistry
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157

  Publications

Bates, Darcy J P; Smitherman, Pamela K; Townsend, Alan J et al. (2011) Nitroalkene fatty acids mediate activation of Nrf2/ARE-dependent and PPARýý-dependent transcription by distinct signaling pathways and with significantly different potencies. Biochemistry 50:7765-73
Rudd, Lisa P; Kabler, Sandra L; Morrow, Charles S et al. (2011) Enhanced glutathione depletion, protein adduct formation, and cytotoxicity following exposure to 4-hydroxy-2-nonenal (HNE) in cells expressing human multidrug resistance protein-1 (MRP1) together with human glutathione S-transferase-M1 (GSTM1). Chem Biol Interact 194:113-9
Bates, Darcy J P; Lively, Mark O; Gorczynski, Michael J et al. (2009) Noncatalytic interactions between glutathione S-transferases and nitroalkene fatty acids modulate nitroalkene-mediated activation of peroxisomal proliferator-activated receptor gamma. Biochemistry 48:4159-69
Alexander, Richard L; Wright, Marcus W; Gorczynski, Michael J et al. (2009) Differential potencies of naturally occurring regioisomers of nitrolinoleic acid in PPARgamma activation. Biochemistry 48:492-8
Gorczynski, Michael J; Smitherman, Pamela K; Akiyama, Taro E et al. (2009) Activation of peroxisome proliferator-activated receptor gamma (PPARgamma) by nitroalkene fatty acids: importance of nitration position and degree of unsaturation. J Med Chem 52:4631-9
Peklak-Scott, Christina; Smitherman, Pamela K; Townsend, Alan J et al. (2008) Role of glutathione S-transferase P1-1 in the cellular detoxification of cisplatin. Mol Cancer Ther 7:3247-55
Sibhatu, Mebrahtu B; Smitherman, Pamela K; Townsend, Alan J et al. (2008) Expression of MRP1 and GSTP1-1 modulate the acute cellular response to treatment with the chemopreventive isothiocyanate, sulforaphane. Carcinogenesis 29:807-15
Alexander, Richard L; Bates, Darcy J P; Wright, Marcus W et al. (2006) Modulation of nitrated lipid signaling by multidrug resistance protein 1 (MRP1): glutathione conjugation and MRP1-mediated efflux inhibit nitrolinoleic acid-induced, PPARgamma-dependent transcription activation. Biochemistry 45:7889-96
Morrow, Charles S; Peklak-Scott, Christina; Bishwokarma, Bimjhana et al. (2006) Multidrug resistance protein 1 (MRP1, ABCC1) mediates resistance to mitoxantrone via glutathione-dependent drug efflux. Mol Pharmacol 69:1499-505
O'Flaherty, Joseph T; Rogers, LeAnn C; Paumi, Christian M et al. (2005) 5-Oxo-ETE analogs and the proliferation of cancer cells. Biochim Biophys Acta 1736:228-36

Showing the most recent 10 out of 24 publications