Glutathione and glutathione analogues; Therapeutic potentials

Background: Glutathione (GSH) and related enzymes are critical to cell protection from toxins, both endogenous and environmental, including a number of anti-cancer cytotoxic agents. Scope of review: Enhancing GSH and associated enzymes represents a longtime and persistent aim in the search for cytoprotective strategies against cancer, neurologic degeneration, pulmonary and inflammatory conditions, as well as cardiovascular ailments. The challenge is to identify effective GSH analogues or precursors that generate mimic molecules with glutathione's cellular protective effects. This review will provide an update on these efforts. Much effort has also been directed at depleting cellular GSH and related cytoprotective effects, in order to sensitize established tumors to the cytotoxic effects of anti-cancer agents. Efforts to deplete GSH have been limited by the challenge of selectivity doing so in tumor and not in normal tissue so as to avoid enhancing the toxicity of anti-cancer drugs. This review will also provide an update of efforts at overcoming the challenge of targeting the desired GSH depletion to tumor cells. Major conclusions: This chapter provides a brief background and update of progress in the development and use of GSH analogues in the therapeutic setting, including the pharmacological aspects of these compounds. General significance: This is an area of enormous research activity, and major advances promise the advent of novel therapeutic opportunities in the near future. This article is part of a Special Issue entitled Cellular functions of glutathione. (c) 2012 Elsevier B.V. All rights reserved.