Glutathione transferases (
GSTs) are a family of Phase II detoxification
enzymes that are involved in the development of the multidrug resistance (MDR) mechanism in
cancer cells and therefore affect the clinical outcome of
cancer chemotherapy. The discovery of nontoxic natural compounds as inhibitors for
GSTs is a promising approach for chemosensitizing and reversing MDR.
Fisetin (7,3',4'-flavon-3-ol) is a plant
flavonol present in many plants and fruits. In the present work, the interaction of
fisetin with human
glutathione transferase A1-1 (hGSTA1-1) was investigated. Kinetic analysis revealed that
fisetin is a reversible inhibitor for hGSTA1-1 with IC50 1.2 ± 0.1 μΜ. It functions as a mixed-type inhibitor toward
glutathione (GSH) and as a noncompetitive inhibitor toward the electrophile substrate
1-chloro-2,4-dinitrobenzene (CDNB). In silico molecular modeling and docking predicted that
fisetin binds at a distinct location, in the
solvent channel of the
enzyme, and occupies the entrance of the substrate-binding sites. Treatment of proliferating human epithelial colorectal
adenocarcinoma cells (CaCo-2) with
fisetin causes a reduction in the expression of hGSTA1-1 at the
mRNA and
protein levels. In addition,
fisetin inhibits GST activity in CaCo-2 cell
crude extract with an IC50 (2.5 ± 0.1 μΜ), comparable to that measured using purified recombinant hGSTA1-1. These actions of
fisetin can provide a synergistic role toward the suppression and chemosensitization of
cancer cells. The results of the present study provide insights into the development of safe and effective GST-targeted
cancer chemosensitizers.