FDA-approved drugs and other compounds tested as inhibitors of human glutathione transferase P1-1

Musdal, Yaman; Hegazy, Usama M.; Aksoy, Yasemin; Mannervik, Bengt

doi:10.1016/j.cbi.2013.06.003

Cited by 41 publications

(37 citation statements)

References 42 publications

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“…37 Chlorophyllin is a potent GST P1-1 inhibitor with 2.3 µM IC 50 value. 13 There are many reports on GST P1-1 inhibitor, such as ethacrynic acid, TLK series, and others tested in a variety of cancers, but their usage is limited due to toxicity. 38 However, chlorophyllin, also known as E141, is commonly used as a food dye and additive in canned foods, in a water-soluble sodium-copper form without any toxic effect.…”

Section: Discussionmentioning

confidence: 99%

Dual actions of the antioxidant chlorophyllin, a glutathione transferase P1‐1 inhibitor, in tumorigenesis and tumor progression

Özcan

Esendağlı

Musdal

et al. 2018

J of Cellular Biochemistry

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Glutathione (GSH) and enzymes related to this antioxidant molecule are often overexpressed in tumor cells and may contribute to drug resistance. Blockade of glutathione transferases (GSTs) has been proposed to potentiate the efficacy of chemotherapeutic drugs in cancer. The aim of this study was to evaluate the effect of chlorophyllin that has antioxidant properties, and also interferes with the activity of GST P1‐1, on breast cancers in vitro and in vivo. The in vivo studies were conducted using an N‐methyl‐ N‐nitrosourea (MNU)‐induced chemical carcinogenesis model in laboratory rats. DNA damage, GST activity, and GSH levels were determined in liver and tumor tissues. Treatment with chlorophyllin increased the GSH levels in the liver and significantly decreased DNA damage in the blood, liver, and tumor tissues. Even though tumorigenesis was delayed in rats receiving chlorophyllin before MNU injections, once the tumors emerged, the progression of tumor appeared to be faster than in the animals that received the carcinogen only. Out of nine breast cell lines, GST P1‐1 expression was detected in MCF‐12A, MDA‐MB‐231, and HCC38. Concomitant incubation with chlorophyllin and docetaxel did not significantly affect cell proliferation and viability. Chlorophyllin displayed genoprotective effects that initially delayed tumorigenesis. However, once the tumors were established, it may act as a promoter that facilitates tumor growth, potentially by a mechanism independent of cell proliferation and viability. Our results underline the pros and cons of antioxidant treatment in cancer, even if it has a capacity to inhibit GST P1‐1.

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Section: Discussionmentioning

confidence: 99%

Dual actions of the antioxidant chlorophyllin, a glutathione transferase P1‐1 inhibitor, in tumorigenesis and tumor progression

Özcan

Esendağlı

Musdal

et al. 2018

J of Cellular Biochemistry

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“…GST inhibitors are useful as therapeutic agents [ 25 ] and many GST inhibitors are known [ 26 ]. As AfGST is a possible target for the control of aflatoxin production, aflatoxin production inhibitors might be obtained from GST inhibitors and compounds identified by conducting a screening search for AfGST inhibitors.…”

Section: Discussionmentioning

confidence: 99%

The Mode of Action of Cyclo(l-Ala-l-Pro) in Inhibiting Aflatoxin Production of Aspergillus flavus

Iimura

Furukawa

Yamamoto

et al. 2017

Toxins

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Cyclo(l-Ala-l-Pro) inhibits aflatoxin production in aflatoxigenic fungi without affecting fungal growth. The mode of action of cyclo(l-Ala-l-Pro) in inhibiting aflatoxin production of Aspergillus flavus was investigated. A glutathione S-transferase (GST) of the fungus, designated AfGST, was identified as a binding protein of cyclo(l-Ala-l-Pro) in an experiment performed using cyclo(l-Ala-l-Pro)-immobilized Sepharose beads. Cyclo(l-Ala-l-Pro) specifically bound to recombinant AfGST and inhibited its GST activity. Ethacrynic acid, a known GST inhibitor, inhibited the GST activity of recombinant AfGST and aflatoxin production of the fungus. Ethacrynic acid reduced the expression level of AflR, a key regulatory protein for aflatoxin production, similar to cyclo(l-Ala-l-Pro). These results suggest that cyclo(l-Ala-l-Pro) inhibits aflatoxin production by affecting GST function in A. flavus, and that AfGST inhibitors are possible candidates as selective aflatoxin production inhibitors.

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“…IC 50 values of the coumarin derivatives were determined with CDNB as electrophilic substrate on an Epoch UV Plate Reader (BioTek, Winooski, VT, USA) using a series of inhibitor concentrations. Briefly, various concentrations of inhibitor compounds (final concentration 5–50 µM, 20 µL) were incubated with the GST enzyme from human placenta (0.65 U/mL, 20 µL) and Dulbecco's phosphate buffered saline (DPBS) (pH 6.6, 60 µL) in a 96‐well microplate for 30 min at room temperature and a substrate solution containing 2 mM GSH and 1 mM CDNB in DPBS (100 µL) was added to start the reaction . Reaction mixture was mixed well by gentle shaking for a few seconds and absorbance in the Epoch UV Plate Reader (BioTek) was measured at 340 nm after immediately preparing the reaction tests for 6 min (the extinction coefficient; ϵ = 5.3/M/cm).…”

Section: Methodsmentioning

confidence: 99%

In Vitro Inhibition of Human Placental Glutathione S‐Transferase by 3‐Arylcoumarin Derivatives

Alparslan

Danış

2015

Archiv der Pharmazie

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Glutathione S-transferases (EC: 2.5.1.18, GSTs) are phase II detoxification enzymes that catalyze the conjugation of various electrophilic compounds to glutathione (GSH), thus usually producing less reactive and more water soluble compounds. However, there is evidence that elevated expression of GSTs, especially GSTP1, is involved in the resistance of tumor cells against chemotherapeutic agents. In this study, we synthesized and investigated the inhibitory effects of differently substituted 3-arylcoumarin derivatives on human placental GST, identified as GSTP1-1, using 1-chloro-2,4-dinitrobenzene as a substrate. A known potent inhibitor of GST, ethacrynic acid was used as a positive control. Among the tested compounds, 6,7-dihydroxy substituted coumarin derivatives exhibited the highest inhibitory activity (IC50 = 13.50-20.83 μM). These results suggest that 6,7-dihydroxy-3-arylcoumarins may represent a new promising scaffold to discover potent GST inhibitors.

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FDA-approved drugs and other compounds tested as inhibitors of human glutathione transferase P1-1

Cited by 41 publications

References 42 publications

Dual actions of the antioxidant chlorophyllin, a glutathione transferase P1‐1 inhibitor, in tumorigenesis and tumor progression

Dual actions of the antioxidant chlorophyllin, a glutathione transferase P1‐1 inhibitor, in tumorigenesis and tumor progression

The Mode of Action of Cyclo(l-Ala-l-Pro) in Inhibiting Aflatoxin Production of Aspergillus flavus

In Vitro Inhibition of Human Placental Glutathione S‐Transferase by 3‐Arylcoumarin Derivatives

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