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

Ramsay EE, Dilda PJ - Front Pharmacol (2014)

Bottom Line: The cytotoxicity of these GSH conjugates depends essentially on GST and gamma-glutamyl transferases (γGT), the enzymes which initiate the mercapturic acid synthesis pathway.Numerous studies support the view that the expression of GST and γGT in cancer cells represents an important factor in the appearance of a more aggressive and resistant phenotype.This strategy, explored over the last two decades, has recently been successful using GST-activated nitrogen mustard (TLK286) and γGT-activated arsenic-based (GSAO and Darinaparsin) prodrugs confirming the potential of GSH-conjugates as anticancer drugs.

View Article: PubMed Central - PubMed

Affiliation: Tumour Metabolism Group, Adult Cancer Program, Lowy Cancer Research Centre and Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales Sydney, NSW, Australia.

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 (γGT), the enzymes which initiate the mercapturic acid synthesis pathway. Numerous studies support the view that the expression of GST and γGT in cancer cells represents an important factor in the appearance of a more aggressive and resistant phenotype. High levels of tumor GST and γGT expression were employed to selectively target tumor with GST- or γGT-activated drugs. This strategy, explored over the last two decades, has recently been successful using GST-activated nitrogen mustard (TLK286) and γGT-activated arsenic-based (GSAO and Darinaparsin) prodrugs confirming the potential of GSH-conjugates as anticancer drugs.

No MeSH data available.


Related in: MedlinePlus

γ-glutamyl conjugates and β-lyase substrates. Activation of N-hydroxyguanidines (A) and glutamylated phenolic amines (B) by γGT. (C) examples of cysteine- and selenocysteine-conjugates activated by β-elimination catalyzed by β-lyase.
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Figure 5: γ-glutamyl conjugates and β-lyase substrates. Activation of N-hydroxyguanidines (A) and glutamylated phenolic amines (B) by γGT. (C) examples of cysteine- and selenocysteine-conjugates activated by β-elimination catalyzed by β-lyase.

Mentions: In terms of potential antitumor activity, γ-glutamyl-protected N-hydroxyguanidines (NHGs) have been developed to explore the ability to deliver NO to the kidney (Figure 5A). The NHGs include Nw-hydroxy-L-arginine, which is an intermediate in the NO synthase synthesis of NO (Zhang et al., 2013b). Whilst promising results were seen, there was a propensity for the potential compounds to cyclize (Zhang et al., 2013a,b) suggesting that NHG conjugation to GSH may be more stable. (Zhang et al., 2013a). As described above for PABA/NO, JS-K, and GSNO, the NHGs, in accordance with γGT expression patterns, contribute to chemotherapy by producing locally high levels of NO which can rapidly react with O2⋅- to generate the potent oxidant peroxynitrite that, in turn causes extensive cellular damage, including the nitration of protein tyrosine residues (Kirsch et al., 2001).


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

Ramsay EE, Dilda PJ - Front Pharmacol (2014)

γ-glutamyl conjugates and β-lyase substrates. Activation of N-hydroxyguanidines (A) and glutamylated phenolic amines (B) by γGT. (C) examples of cysteine- and selenocysteine-conjugates activated by β-elimination catalyzed by β-lyase.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4127970&req=5

Figure 5: γ-glutamyl conjugates and β-lyase substrates. Activation of N-hydroxyguanidines (A) and glutamylated phenolic amines (B) by γGT. (C) examples of cysteine- and selenocysteine-conjugates activated by β-elimination catalyzed by β-lyase.
Mentions: In terms of potential antitumor activity, γ-glutamyl-protected N-hydroxyguanidines (NHGs) have been developed to explore the ability to deliver NO to the kidney (Figure 5A). The NHGs include Nw-hydroxy-L-arginine, which is an intermediate in the NO synthase synthesis of NO (Zhang et al., 2013b). Whilst promising results were seen, there was a propensity for the potential compounds to cyclize (Zhang et al., 2013a,b) suggesting that NHG conjugation to GSH may be more stable. (Zhang et al., 2013a). As described above for PABA/NO, JS-K, and GSNO, the NHGs, in accordance with γGT expression patterns, contribute to chemotherapy by producing locally high levels of NO which can rapidly react with O2⋅- to generate the potent oxidant peroxynitrite that, in turn causes extensive cellular damage, including the nitration of protein tyrosine residues (Kirsch et al., 2001).

Bottom Line: The cytotoxicity of these GSH conjugates depends essentially on GST and gamma-glutamyl transferases (γGT), the enzymes which initiate the mercapturic acid synthesis pathway.Numerous studies support the view that the expression of GST and γGT in cancer cells represents an important factor in the appearance of a more aggressive and resistant phenotype.This strategy, explored over the last two decades, has recently been successful using GST-activated nitrogen mustard (TLK286) and γGT-activated arsenic-based (GSAO and Darinaparsin) prodrugs confirming the potential of GSH-conjugates as anticancer drugs.

View Article: PubMed Central - PubMed

Affiliation: Tumour Metabolism Group, Adult Cancer Program, Lowy Cancer Research Centre and Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales Sydney, NSW, Australia.

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 (γGT), the enzymes which initiate the mercapturic acid synthesis pathway. Numerous studies support the view that the expression of GST and γGT in cancer cells represents an important factor in the appearance of a more aggressive and resistant phenotype. High levels of tumor GST and γGT expression were employed to selectively target tumor with GST- or γGT-activated drugs. This strategy, explored over the last two decades, has recently been successful using GST-activated nitrogen mustard (TLK286) and γGT-activated arsenic-based (GSAO and Darinaparsin) prodrugs confirming the potential of GSH-conjugates as anticancer drugs.

No MeSH data available.


Related in: MedlinePlus