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.
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.
|Ye, Zhi-Wei; Zhang, Jie; Ancrum, Tiffany et al. (2017) Glutathione S-Transferase P-Mediated Protein S-Glutathionylation of Resident Endoplasmic Reticulum Proteins Influences Sensitivity to Drug-Induced Unfolded Protein Response. Antioxid Redox Signal 26:247-261|
|Jones, Jane T; Qian, Xi; van der Velden, Jos L J et al. (2016) Glutathione S-transferase pi modulates NF-?B activation and pro-inflammatory responses in lung epithelial cells. Redox Biol 8:375-82|
|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; 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|
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