Myricetin as a Potential Adjuvant in Chemotherapy: Studies on the Inhibition of Human Glutathione Transferase A1–1

Abstract

Glutathione transferases (GSTs) are a family of Phase II detoxification enzymes that are involved in the development of multi-drug resistance (MDR) phenomena toward chemotherapeutic agents. GST inhibitors are considered candidate compounds able to chemomodulate and reverse MDR. The natural flavonoid myricetin (MYR) has been shown to exhibit a wide range of pharmacological functions, including antitumor activity. In the present work, the interaction of MYR with human glutathione transferase A1–1 (hGSTA1–1) was investigated by kinetics inhibition analysis and molecular modeling studies. The results showed that MYR binds with high affinity to hGSTA1–1 (IC50 2.1 ± 0.2 μΜ). It functions as a non-competitive inhibitor towards the electrophile substrate 1-chloro−2,4-dinitrobenzene (CDNB) and as a competitive inhibitor towards glutathione (GSH). Chemical modification studies with the irreversible inhibitor phenethyl isothiocyanate (PEITC), in combination with in silico molecular docking studies allowed the prediction of the MYR binding site. MYR appears to bind at a distinct location, partially overlapping the GSH binding site (G-site). The results of the present study show that MYR is a potent inhibitor of hGSTA1–1 that can be further exploited towards the development of natural, safe, and effective GST-targeted cancer chemosensitizers.

Overexpression of Glutathione S-Transferases in Human Diseases: Drug Targets and Therapeutic Implications

“…Furthermore, different 2,2 -dihydroxybenzophenones and their carbonyl N-analogs showed distinct GSTA1 and GSTP1 isozymes inhibition specificity, with disubstituted benzophenones exhibited a minimal inhibition to GSTP1, whereas the inhibition potency to GSTA1 was still adequate [200]. In addition, natural flavonoids fisetin and myricetin are effective inhibitors of GSTA1, with IC 50 values of 1.2 ± 0.1 µM and 2.1 ± 0.2 µM, respectively (Figure 10C,D) [201,202]. Fisetin not only inhibits the activity of GSTA1 in Caco-2 cells but also reduces the expression levels of GSTA1 mRNA and protein.…”

“…ts 2023, 12, x FOR PEER REVIEW was still adequate [200]. In addition, natural flavonoids fisetin and myricetin are e inhibitors of GSTA1, with IC50 values of 1.2 ± 0.1 µM and 2.1 ± 0.2 µM, respectively 10C,D) [201,202]. Fisetin not only inhibits the activity of GSTA1 in Caco-2 cells b reduces the expression levels of GSTA1 mRNA and protein.…”

A Monocarbonyl Curcuminoid Derivative Inhibits the Activity of Human Glutathione Transferase A4-4 and Chemosensitizes Glioblastoma Cells to Temozolomide

“…Similarly, some 2,2′-dihydroxybenzophenones were shown to have significant hGSTA1-1 inhibitory activity, which was also found to be related to their cytotoxicity against human colon adenocarcinoma [ 27 , 28 ]. Additionally, the natural flavonoids fisetin and myricetin have been reported to act as effective hGSTA1-1 inhibitors [ 29 , 30 ]. Finally, a series of 34 monocarbonyl curcumin analogues, including 2,6-dibenzylidenecyclohexanones, 2,5-dibenzylidenecyclopentanones, and 1,4-pentadiene-3-ones, were evaluated as potential human GST inhibitors against hGSTA1-1, hGSTM1-1, and hGSTP1-1 isoenzymes [ 31 ].…”