Redox Pathways as a Platform in Drug Development
Redox homeostasis is frequently aberrantly regulated in human diseases such as cancer and neurological disorders. Partly as a consequence, there is optimism in validating and extending redox controlling pathways as a platform for the discovery/development of drugs, particularly in cancer. As the primary redox buffer, cellular thiols have been variously therapeutically targeted. N-acetylcysteine is the simplest pharmaceutical version of a bioavailable redox equivalent. It has uses in a number of disparate human pathologies. Other agents have redox active centers primarily as a function of nucleophilic centers associated with the variable valence states of sulfur. Redox homeostasis is aberrantly regulated in cancer cells and this has provided an opportunity to advance treatment concepts that attempt to produce a beneficial therapeutic index. A component of the approaches to prevent cancer is based upon the possibility that thiols provide a way of detoxifying environmental electrophiles prior to enacting damage to DNA that could progress a cell towards a cancerous phenotype. Further, therapies designed to enhance myeloproliferation, hematopoietic progenitor cell mobilization and immune response also have a foundation in modulation of redox pathways within the bone marrow compartment. As a consequence of these principles, a number of “redox modulating” drugs are under development and progressing towards FDA review.
KeywordsChronic Lymphocytic Leukemia Redox Homeostasis Arsenic Trioxide Ethacrynic Acid Diallyl Disulfide
This work was supported by grants from the National Institutes of Health (ES017453, CA08660 and CA117259) and support from the South Carolina Centers of Excellence program. We thank the Drug Metabolism and Pharmacokinetics and Proteomics Core Facilities at the Medical University of South Carolina. This work was conducted in a facility constructed with support from the National Institutes of Health, Grant Number C06 RR015455 from the Extramural Research Facilities Program of the National Center for Research Resources.
- Lyons RM, Wilks ST, Young S, Brown GL (2011) Oral ezatiostat HCl (Telintra(R), TLK199) and idiopathic chronic neutropenia (ICN): a case report of complete response of a patient with G-CSF resistant ICN following teatment with ezatiostat, a glutathione S-transferase P1-1 (GSTP1-1) inhibitor. J Hematol Oncol 4:43PubMedCentralPubMedCrossRefGoogle Scholar
- Xinhua J (2008) Structure-based design of anticancer prodrug PABA/NO. Drug Des Devel Ther 2:123Google Scholar