This renewal requests support for years 25-30 to extend studies on drug development within the framework of glutathione (GSH), glutathione S-transferases (GST) and pathways that maintain thiol homeostasis. Attachment of GS- to acceptor cysteine residues (glutathionylation) is becoming recognized as a post-translational modification that can alter the structure and function of proteins in a significant manner. We have found that a novel glutathione S-transferase (GST) activated pro-drug, (PABA/NO) releases nitric oxide, inducing cytotoxicity and causing glutathionylation of a number of cellular proteins. We wish to identify these and determine their relevance to the drug's mechanism of action. Extending our goal to develop new cancer drugs, we have included approaches that will assist in pre-clinical development of PABA/NO and of platinum stabilized form of oxidized glutathione (NOV-002). These will include in vitro and rodent studies, particularly for determination of mechanism of action and pharmacokinetics. Drug resistant cell lines will be created and subject to gene expression studies using our amplified differential gene expression microarray technology (ADGE-microarray). Data from these lines will be used to confirm and extend drug target identification and validation. GST and other thiol based cell constituents (such as thioredoxin) play a leading role in regulating critical kinase signaling molecules. We will clone and characterize mammalian sulfiredoxin, a gene that has, until now, only been identified in yeast. What role this protein has in intracellular redox cycling and the regulation of drug response and signaling pathways will be the topic of one aim. Extension of our GST/JNK work will include large-scale purification and crystallization of the complex and will seek to extend the observation that bone marrow cells from GSTpi null mice have enhanced proliferation rates associated with altered expression of JAK-STAT and certain cellular phosphatases (SHP-1 and -2). We will attempt to solidify this connection as a means of consolidating these pathways. Overall, we seek to enhance the collective appreciation of the importance of GSH/GST and associated pathways in controlling cellular homeostasis and develop drugs that target these pathways.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA085660-07
Application #
6921064
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Song, Min-Kyung H
Project Start
2000-04-01
Project End
2010-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
7
Fiscal Year
2005
Total Cost
$328,500
Indirect Cost
Name
Medical University of South Carolina
Department
Pharmacology
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Zhang, Jie; Ye, Zhi-Wei; Chen, Wei et al. (2018) S-Glutathionylation of estrogen receptor ? affects dendritic cell function. J Biol Chem 293:4366-4380
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
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
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

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