Glutathione And Glutathionestransferase In Anticancer Drug Resistance

Glutathione (GSH) is a ubiquitous cysteine-containing tripeptide that is the predominant cellular thiol. GSH is a radical scavenger through its transformation to the disulphide derivative, but it is also a nucleophile that reacts with electrophiles to form deactivated conjugates readily excreted by a glutathione synthase (GS)-conjugated export pump, in a reaction that may occur spontaneously or with the help of the enzyme glutathione-S-transferase (GST).4 In addition, GSH may directly or indirectly participate in DNA repair because it modulates the expression of transcription factors that potentially affect DNA repair and apoptosis, such as c-fos and c-jun,48 and may protect tumor cells against apoptotic cell death through the preservation of protein mercapto groups in a reduced state because of its antioxidant properties.49 Owing to its reactivity and high intracellular concentrations, glutathione (GSH) has been implicated in resistance of several chemothera-peutic agents, such as platinum-containing compounds,50 alkylating agents,51 and anthracyclines,52 and research efforts have been directed to find compounds that modulate its activity.

2.1. Inhibitors of glutathione biosynthesis

Glutathione is synthesized in two steps from amino acid precursors: the first step, where glutamic acid and cysteine are joined, is catalyzed by g-glutamylcysteine synthetase (g-GCS), while addition of glycine takes place at the second step by the catalysis of GS (Fig. 12.5).

Since g-GCS is the enzyme involved in the rate-limiting step of the GSH synthesis, depletion of intracellular GSH levels has been pursued by using inhibitors of this enzyme. Among these inhibitors, diazenes and ethacrynic acid have been preclinically evaluated, while l-buthionine-(S,R)-sulfoximine (l-BSO) has been further studied.53

L-Glutamate + L-Cysteine

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