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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 GSAO and subsequent activity on endothelial cell proliferation. (A) GSAO activation by γGT and peptidase. (B) Pancreatic tumor cell γGT activity positively correlates with GSAO-mediated proliferation arrest of endothelial cells in a transwell model. Pancreatic adenocarcinoma cells are represented by circles and normal and tumor-activated pancreatic stellate cells by squares. BxPC-3 pancreatic tumor cells transfected with γGT are represented as triangles. (C) Model of GSAO activation by tumor γGT (from Ramsay et al., 2014).
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Figure 3: Activation process of GSAO and subsequent activity on endothelial cell proliferation. (A) GSAO activation by γGT and peptidase. (B) Pancreatic tumor cell γGT activity positively correlates with GSAO-mediated proliferation arrest of endothelial cells in a transwell model. Pancreatic adenocarcinoma cells are represented by circles and normal and tumor-activated pancreatic stellate cells by squares. BxPC-3 pancreatic tumor cells transfected with γGT are represented as triangles. (C) Model of GSAO activation by tumor γGT (from Ramsay et al., 2014).

Mentions: 4-(N-(S-glutathionylacetyl)amino)phenylarsonous acid consists of a phenylarsenoxide moiety attached by an N-acetyl linker to the cysteine thiol of reduced GSH (Figure 3). The phenylarsenoxide group is the active moiety, imparting to GSAO its activity by crosslinking closely spaced protein thiols and forming a high affinity ring structure between its arsenic and the thiols (Donoghue et al., 2000). GSAO specifically targets proliferative endothelial cells, which consequently starves the tumor of the nutrients required to support its expanding growth (Don et al., 2003; Dilda et al., 2005b). The GSH moiety contributes to the transport of GSAO in and out of the cell (Dilda et al., 2008, 2005b).


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

Ramsay EE, Dilda PJ - Front Pharmacol (2014)

Activation process of GSAO and subsequent activity on endothelial cell proliferation. (A) GSAO activation by γGT and peptidase. (B) Pancreatic tumor cell γGT activity positively correlates with GSAO-mediated proliferation arrest of endothelial cells in a transwell model. Pancreatic adenocarcinoma cells are represented by circles and normal and tumor-activated pancreatic stellate cells by squares. BxPC-3 pancreatic tumor cells transfected with γGT are represented as triangles. (C) Model of GSAO activation by tumor γGT (from Ramsay et al., 2014).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Activation process of GSAO and subsequent activity on endothelial cell proliferation. (A) GSAO activation by γGT and peptidase. (B) Pancreatic tumor cell γGT activity positively correlates with GSAO-mediated proliferation arrest of endothelial cells in a transwell model. Pancreatic adenocarcinoma cells are represented by circles and normal and tumor-activated pancreatic stellate cells by squares. BxPC-3 pancreatic tumor cells transfected with γGT are represented as triangles. (C) Model of GSAO activation by tumor γGT (from Ramsay et al., 2014).
Mentions: 4-(N-(S-glutathionylacetyl)amino)phenylarsonous acid consists of a phenylarsenoxide moiety attached by an N-acetyl linker to the cysteine thiol of reduced GSH (Figure 3). The phenylarsenoxide group is the active moiety, imparting to GSAO its activity by crosslinking closely spaced protein thiols and forming a high affinity ring structure between its arsenic and the thiols (Donoghue et al., 2000). GSAO specifically targets proliferative endothelial cells, which consequently starves the tumor of the nutrients required to support its expanding growth (Don et al., 2003; Dilda et al., 2005b). The GSH moiety contributes to the transport of GSAO in and out of the cell (Dilda et al., 2008, 2005b).

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