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.
|Tew, Kenneth D; Townsend, Danyelle M (2011) Redox platforms in cancer drug discovery and development. Curr Opin Chem Biol 15:156-61|
|Hutchens, Steven; Manevich, Yefim; He, Lin et al. (2011) Cellular resistance to a nitric oxide releasing glutathione S-transferase P-activated prodrug, PABA/NO. Invest New Drugs 29:719-29|
|Grek, Christina L; Townsend, Danyelle M; Tew, Kenneth D (2011) The impact of redox and thiol status on the bone marrow: Pharmacological intervention strategies. Pharmacol Ther 129:172-84|
|Mack, Jody T; Helke, Kristi L; Normand, Gabrielle et al. (2011) ABCA2 transporter deficiency reduces incidence of TRAMP prostate tumor metastasis and cellular chemotactic migration. Cancer Lett 300:154-61|
|Grek, Christina L; Tew, Kenneth D (2010) Redox metabolism and malignancy. Curr Opin Pharmacol 10:362-8|
|Uys, J D; Manevich, Y; Devane, L C et al. (2010) Preclinical pharmacokinetic analysis of NOV-002, a glutathione disulfide mimetic. Biomed Pharmacother 64:493-8|
|Jenderny, Sara; Lin, He; Garrett, Tracy et al. (2010) Protective effects of a glutathione disulfide mimetic (NOV-002) against cisplatin induced kidney toxicity. Biomed Pharmacother 64:73-6|
|Townsend, Danyelle M; Tew, Kenneth D (2009) Pharmacology of a mimetic of glutathione disulfide, NOV-002. Biomed Pharmacother 63:75-8|
|Townsend, Danyelle M; Manevich, Yefim; He, Lin et al. (2009) Nitrosative stress-induced s-glutathionylation of protein disulfide isomerase leads to activation of the unfolded protein response. Cancer Res 69:7626-34|
|Townsend, Danyelle M; Tew, Kenneth D; He, Lin et al. (2009) Role of glutathione S-transferase Pi in cisplatin-induced nephrotoxicity. Biomed Pharmacother 63:79-85|
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