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INTRODUCTION
The glutathione S-transferases (GSTs) are members of a large family of enzymes expressed in most living organisms. GSTs catalyze the conjugation of glutathione (GSH) with a variety of electrophilic compounds and are involved in the detoxification of xenobiotics. GSTs can also modulate cell-signaling pathways by direct protein-protein interaction with important proteins. As a result of these interactions, GSTs have been found to be involved in the acquisition of resistance to chemotherapeutic agents and in the regulation of signaling pathways that control cancer cell survival and cell death.
GSTP1-1 AND CANCER
The majority of human tumor cell lines resistant to chemotherapeutic agents overexpress class pi GST (GSTP1-1). Significant quantitative correlations among enzyme activity, total enzyme protein, and mRNA have been shown for GSTP1-1, particularly in those cell lines selected for resistance to alkylating agents such as melphalan, chlorambucil, cyclophosphamide, BCNU, and cisplatin.
A variety of human cancers, including breast, colon, kidney, lung and ovarian, usually express high levels of GSTP1-1 compared to the surrounding tissues. High expression of GSTP1-1 has been associated with disease progression and with drug resistance in patients undergoing chemotherapy.
GSTP1-1 has been shown to inhibit c-Jun N-terminal kinase (JNK) through direct protein-protein interaction. JNK is a mitogen-activated protein kinase (MAPK) involved in cellular differentiation and proliferation, apoptosis, and inflammation. Activated JNK phosphorylates c-Jun, a component of the Activator Protein-1 ( AP-1) transcription factor. This activation causes induction of AP-1-dependent target genes that lead to cell proliferation or cell death.
GSTP1-1 has also been reported to associate with tumor necrosis factor receptor-associated factor 2 (TRAF2) and inhibit TRAF2-induced activation of both JNK and p38-MAPK. GSTP1-1 inhibited TRAF2-enhanced apoptosis signal-regulating kinase 1 (ASK1) autophosphorylation and TRAF2-ASK1-induced cell apoptosis.
Most anticancer agents induce cancer cell death or apoptosis by activation of the MAPK pathways, in particular those involving JNK and p38-MAPK. The role of GSTP1-1 as an endogenous inhibitor of JNK activation may inhibit those signaling pathways. Therefore, inhibition of GSTP1-1 is a promising strategy for the treatment of cancer.
REFERENCES
1. Ruscoe, J. E.; Rosario, L. A.; Wang, T.; Gaté, L.; Arifoglu, P.; Wolf, C. R.; Henderson, C. J.; Ronai, Z.; Tew, K. D. Pharmacologic or genetic manipulation of glutathione S-transferase P1-1 (GSTpi) influences cell proliferation pathways. J Pharmacol Exp Ther 2001;298(1):339-345.
2. Gaté, L.; Tew, K. D. Glutathione S-transferases as emerging therapeutic targets. Expert Opin Ther Targets. 2001;5(4):477-489.
3. Hayes, J. D.; Flanagan, J. U.; Jowsey, I. R. Glutathione Transferases. Annu Rev Pharmacol Toxicol 2005;45:51-88.
4. Zhao, G.; Wang, X. Advance in antitumor agents targeting glutathione-S-transferase. Curr Med Chem 2006;13(12):1461-1471.
5. Morales, G. A.; Laborde, E. Small-Molecule Inhibitors of Glutathione S-Transferase P1-1 as Anticancer Therapeutic Agents. Ann Rep Med Chem 2007;42:321-335.
6. Ruzza, P.; Rosato, A.; Rossi, C. R.; Floreani, M. Quintieri, L. Glutathione Transferases as Targets for Cancer Therapy. Anti-Cancer Agents Med Chem 2009;9:763-777.
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