This application builds on previous work carried out under the auspices of the OIG awarded to the Principal Investigator. Significant Progress has been instrumental in defining a role for glutathione (GSH) and associated enzymes in detoxification and drug resistance. Our most recent work has provided a framework for assigning novel ways of viewing how glutathione S-transferase pi (GST pi) influences cell response to external stimuli. The present application seeks to extend our efforts in four complementary areas. (i) Determine how acute and chronic drug exposure influences expression of protective stress response genes, with emphasis on drugs which directly influence GSH and related pathways. (ii) Determine how GSH, as a major contributor to thiol: disulfide homeostasis impacts on S-thiolation and glutathionylation of targeted proteins. Altered function of certain enzymes with active cysteine residues will be considered. (iii) Our recent data identify GSTpi as a ligand binding protein and suppressor of C-jun NH2-terminal kinase (JNK). This property may explain the high levels of GSTpi in many solid tumors and drug resistant cell lines, where no obvious catalytic role for GSTpi exists. Experiments are designed to consider a role for GSTPI in cell proliferation and how GSH/GST may impact upon stress kinase biology. Mouse embryo fibroblast cell lines from wild type (GST+/+) and GSTpi knock out (GST-/-) will be used as model cell systems for these studies. The cause/effect relationships between GSTpi inhibitor and an aminothiol drug cause myeloproliferation, part of this study will focus on drug effects on thiol metabolism in bone marrow cells from wild type and GST-/- mice. (iv) Pharmacological characterization of two novel therapeutics which target GST pi will be carried out. In addition to the GSTpi was designed to have an enhanced therapeutic index in tumors with high GSTpi levels. Overall, the main emphasis of the present application will be to generate data which link GSH and GST pathways with cellular determinants of stress response and proliferation, and to provide a rationale, preclinical approach to the development of GSTpi targeting drugs.
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