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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

Activation process of Darinaparsin.
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Figure 4: Activation process of Darinaparsin.

Mentions: Darinaparsin belongs to the class of organic arsenical compounds that are generally considered less toxic than inorganic ones (Waxman and Anderson, 2001; Dilda and Hogg, 2007). It was synthesized by conjugating GSH to dimethyl arsenic (Figure 4). Darinaparsin shares some characteristics with other arsenicals but has also unique properties. As do other arsenicals, it induces G2/M cell cycle arrest and triggers apoptosis through disruption of mitochondrial functions and JNK activation and is responsible for reactive oxygen species production (Diaz et al., 2008). However, unlike arsenic trioxide, GSAO (Dilda et al., 2005b) or PENAO (Dilda et al., 2009), Darinaparsin activity is unaffected by the expression of ABCC1 (MRP-1), modulation of GSH levels (Diaz et al., 2008) and heme-oxygenase inhibition (Garnier et al., 2013).


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

Ramsay EE, Dilda PJ - Front Pharmacol (2014)

Activation process of Darinaparsin.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Activation process of Darinaparsin.
Mentions: Darinaparsin belongs to the class of organic arsenical compounds that are generally considered less toxic than inorganic ones (Waxman and Anderson, 2001; Dilda and Hogg, 2007). It was synthesized by conjugating GSH to dimethyl arsenic (Figure 4). Darinaparsin shares some characteristics with other arsenicals but has also unique properties. As do other arsenicals, it induces G2/M cell cycle arrest and triggers apoptosis through disruption of mitochondrial functions and JNK activation and is responsible for reactive oxygen species production (Diaz et al., 2008). However, unlike arsenic trioxide, GSAO (Dilda et al., 2005b) or PENAO (Dilda et al., 2009), Darinaparsin activity is unaffected by the expression of ABCC1 (MRP-1), modulation of GSH levels (Diaz et al., 2008) and heme-oxygenase inhibition (Garnier et al., 2013).

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