Glutathione S-conjugates as prodrugs to target drug-resistant tumors.

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Ramsay EE, Dilda PJ

Glutathione S-conjugates as prodrugs to target drug-resistant tumors.

Front Pharmacol. 2014 Aug 11;5:181. doi: 10.3389/fphar.2014.00181. eCollection 2014.

PubMed ID

25157234 [ View in PubMed

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Abstract

Living organisms are continuously exposed to xenobiotics. The major phase of enzymatic detoxification in many species is the conjugation of activated xenobiotics to reduced glutathione (GSH) catalyzed by the glutathione-S-transferase (GST). It has been reported that some compounds, once transformed into glutathione S-conjugates, enter the mercapturic acid pathway whose end products are highly reactive and toxic for the cell responsible for their production. The cytotoxicity of these GSH conjugates depends essentially on GST and gamma-glutamyl transferases (gammaGT), the enzymes which initiate the mercapturic acid synthesis pathway. Numerous studies support the view that the expression of GST and gammaGT in cancer cells represents an important factor in the appearance of a more aggressive and resistant phenotype. High levels of tumor GST and gammaGT expression were employed to selectively target tumor with GST- or gammaGT-activated drugs. This strategy, explored over the last two decades, has recently been successful using GST-activated nitrogen mustard (TLK286) and gammaGT-activated arsenic-based (GSAO and Darinaparsin) prodrugs confirming the potential of GSH-conjugates as anticancer drugs.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
S-benzylglutathione	Glutathione S-transferase A1	Protein	Humans	Unknown	Ligand	Details