This continuation builds on a research platform continuously funded since 1980 that has focused on the importance of targeting GSH and GST homeostasis in anticancer drug discovery and development.
Aim 1 will address how human pharmacogenetics might influence the multiple functional properties of GSTP, particularly with respect to protein:protein interactions and the catalysis of S-glutathionylation.
Aim 2 seeks to define mechanism(s) of action for a series of nitric oxide (NO) releasing, GSTP activated diazeniumdiolate prodrugs. Structure activity analyses will determine which metabolites of these drugs may act as proximal donors in the S-glutathionylation reaction.
In Aim 3 we will elaborate on preliminary observations that serpina1 and serpina3 are S- glutathionylated in the plasma of drug treated animals and may represent novel biomarkers for drug pharmacodynamics or exposure to reactive oxygen or nitrogen species.
Aim 4 extends Aim 3 into the bone marrow compartment where NOV-002 and Telintra (small molecule myeloproliferative drugs) may impart proliferative effects through S-glutathionylation of the protease inhibitor serpins. Mechanistically, these protein families are subject to redox regulation and have roles in regulation of marrow progenitor cell proliferation and mobilization into the bloodstream. Since some of the drugs under study are in clinical trial, there is a strong translational component to this work. Moreover, drug development is facilitated by goals to develop GST activated prodrugs and define their mechanism(s) of action.

Public Health Relevance

We have initiated projects with an anticancer drug development focus since this is critical in advancing the therapeutic treatment of cancer. Because one side effect of cancer drugs is bone marrow toxicity, we are trying to understand how certain drugs can influence the production of blood cells. The principle goal of the project is to study how oxidant stresses effect these areas of research.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA085660-15
Application #
8468124
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Alley, Michael C
Project Start
2000-04-01
Project End
2015-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
15
Fiscal Year
2013
Total Cost
$295,531
Indirect Cost
$95,171
Name
Medical University of South Carolina
Department
Pharmacology
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Kenche, Harshavardhan; Ye, Zhi-Wei; Vedagiri, Kokilavani et al. (2016) Adverse Outcomes Associated with Cigarette Smoke Radicals Related to Damage to Protein-disulfide Isomerase. J Biol Chem 291:4763-78
Ye, Zhi-Wei; Zhang, Jie; Ancrum, Tiffany et al. (2016) Glutathione S-Transferase P-Mediated Protein S-Glutathionylation of Resident Endoplasmic Reticulum Proteins Influences Sensitivity to Drug-Induced Unfolded Protein Response. Antioxid Redox Signal :
Ye, Zhi-Wei; Zhang, Jie; Townsend, Danyelle M et al. (2015) Oxidative stress, redox regulation and diseases of cellular differentiation. Biochim Biophys Acta 1850:1607-21
Zhang, Jie; Grek, Christina; Ye, Zhi-Wei et al. (2014) Pleiotropic functions of glutathione S-transferase P. Adv Cancer Res 122:143-75
Grek, Christina L; Zhang, Jie; Manevich, Yefim et al. (2013) Causes and consequences of cysteine S-glutathionylation. J Biol Chem 288:26497-504
Manevich, Y; Hutchens, S; Tew, K D et al. (2013) Allelic variants of glutathione S-transferase P1-1 differentially mediate the peroxidase function of peroxiredoxin VI and alter membrane lipid peroxidation. Free Radic Biol Med 54:62-70
Anathy, Vikas; Roberson, Elle; Cunniff, Brian et al. (2012) Oxidative processing of latent Fas in the endoplasmic reticulum controls the strength of apoptosis. Mol Cell Biol 32:3464-78
Mack, Jody T; Brown, Carol B; Garrett, Tracy E et al. (2012) Ablation of the ATP-binding cassette transporter, Abca2 modifies response to estrogen-based therapies. Biomed Pharmacother 66:403-8
Bowers, Robert R; Manevich, Yefim; Townsend, Danyelle M et al. (2012) Sulfiredoxin redox-sensitive interaction with S100A4 and non-muscle myosin IIA regulates cancer cell motility. Biochemistry 51:7740-54
Grek, Christina L; Townsend, Danyelle M; Uys, Joachim D et al. (2012) S-glutathionylated serine proteinase inhibitors as plasma biomarkers in assessing response to redox-modulating drugs. Cancer Res 72:2383-93

Showing the most recent 10 out of 34 publications