Overcoming the Drug Resistance in Breast Cancer Cells by Rational Design of Efficient Glutathione <i>S</i>-Transferase Inhibitors

Li, Wen‐Shan; Lam, Wing See; Liu, Kung-Cheng; Wang, Chie‐Hong; Chang, Claire H.C.; Jen, Ya Ching; Hsu, Yu-Ting; Shivatare, Sachin S.; Jao, Shu-Chuan

doi:10.1021/ol902298s

Cited by 18 publications

(10 citation statements)

References 26 publications

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“…Only GST-p expression has been investigated in relation to the radiotherapy response in breast cancer and head-and-neck cancer patients but no significance to response was observed (42,43). Inhibitors directed against GSTs have shown synergistic effects with chemotherapy drugs in breast cancer cell lines, some of which produce ROS as a byproduct of their action (44). A general GST inhibitor that has shown radiosensitization in the MCF-7 breast cancer cell line is ethacrynic acid, a well-known diuretic (45).…”

Section: Discussionmentioning

confidence: 99%

Redox Protein Expression Predicts Radiotherapeutic Response in Early-Stage Invasive Breast Cancer Patients

Al‐Attar

Storr

Ellis

et al. 2011

International Journal of Radiation Oncology*Biology*Physics

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Section: Discussionmentioning

confidence: 99%

Redox Protein Expression Predicts Radiotherapeutic Response in Early-Stage Invasive Breast Cancer Patients

Al‐Attar

Storr

Ellis

et al. 2011

International Journal of Radiation Oncology*Biology*Physics

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“…Considerable effort has been expended in the development of GST (particularly GSTP) inhibitors, largely to overcome GST-dependent drug resistance (for reviews, see van Bladeren and van Ommen 1991; Tew et al 1997;Burg and Mulder 2002;Townsend and Tew 2003;Mahajan and Atkins 2005;Mathew et al 2006;Zhao and Wang 2006;Li et al 2010;Thurairatnam 2012;Wu and Batist 2013;Mohana and Achary 2017). Inhibitors of the several classes of cytosolic GSTs are discussed below.…”

Section: Inhibitorsmentioning

confidence: 99%

The mercapturic acid pathway

Hanna

Anders

2019

Critical Reviews in Toxicology

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The mercapturic acid pathway is a major route for the biotransformation of xenobiotic and endobiotic electrophilic compounds and their metabolites. Mercapturic acids (N-acetyl-L-cysteine S-conjugates) are formed by the sequential action of the glutathione transferases, c-glutamyltransferases, dipeptidases, and cysteine S-conjugate N-acetyltransferase to yield glutathione S-conjugates, L-cysteinylglycine S-conjugates, L-cysteine S-conjugates, and mercapturic acids; these metabolites constitute a "mercapturomic" profile. Aminoacylases catalyze the hydrolysis of mercapturic acids to form cysteine S-conjugates. Several renal transport systems facilitate the urinary elimination of mercapturic acids; urinary mercapturic acids may serve as biomarkers for exposure to chemicals. Although mercapturic acid formation and elimination is a detoxication reaction, L-cysteine S-conjugates may undergo bioactivation by cysteine Sconjugate b-lyase. Moreover, some L-cysteine S-conjugates, particularly L-cysteinyl-leukotrienes, exert significant pathophysiological effects. Finally, some enzymes of the mercapturic acid pathway are described as the so-called "moonlighting proteins," catalytic proteins that exert multiple biochemical or biophysical functions apart from catalysis.

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“…We have previously developed thiol conjugate addition DCLs directed towards GST inhibition, and successfully interfaced the enzyme with small molecules so that it controlled library evolution27. The GSTs are well suited to exploration using DCC methods, being well-characterized, robust proteins having nascent medicinal chemistry application46,47. There are relatively few ligands reported in the literature for GST binding—a plus point, as it would enable us to use DCC as a genuine discovery tool for new binding motifs, rather than as a proof-of-principle process for confirming the binding ability of known ligands.…”

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confidence: 99%

Nucleophilic catalysis of acylhydrazone equilibration for protein-directed dynamic covalent chemistry

et al. 2010

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Dynamic covalent chemistry uses reversible chemical reactions to set up an equilibrating network of molecules at thermodynamic equilibrium, which can adjust its composition in response to any agent capable of altering the free energy of the system. When the target is a biological macromolecule, such as a protein, the process corresponds to the protein directing the synthesis of its own best ligand. Here, we demonstrate that reversible acylhydrazone formation is an effective chemistry for biological dynamic combinatorial library formation. In the presence of aniline as a nucleophilic catalyst, dynamic combinatorial libraries equilibrate rapidly at pH 6.2, are fully reversible, and may be switched on or off by means of a change in pH. We have interfaced these hydrazone dynamic combinatorial libraries with two isozymes from the glutathione S-transferase class of enzyme, and observed divergent amplification effects, where each protein selects the best-fitting hydrazone for the hydrophobic region of its active site.

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Overcoming the Drug Resistance in Breast Cancer Cells by Rational Design of Efficient Glutathione S-Transferase Inhibitors

Abstract: A new type of competitive human GST inhibitors has been developed via the bioisostere and structure activity profile strategies; we report their discovery, preparation, inhibitory activity, and synergetic effect in combination with chemotherapy drugs against breast cancer cells.

Cited by 18 publications

References 26 publications

Redox Protein Expression Predicts Radiotherapeutic Response in Early-Stage Invasive Breast Cancer Patients

Redox Protein Expression Predicts Radiotherapeutic Response in Early-Stage Invasive Breast Cancer Patients

The mercapturic acid pathway

Nucleophilic catalysis of acylhydrazone equilibration for protein-directed dynamic covalent chemistry

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