2′, 4′-Dihydroxy-6′-methoxy-3′, 5′-dimethylchalcone, a potent Nrf2/ARE pathway inhibitor, reverses drug resistance by decreasing glutathione synthesis and drug efflux in BEL-7402/5-FU cells. (September 2018)

• Record Type: Journal Article
• Authors: Wei, Xing; Mo, Xuejun; An, Faliang; Ji, Xiang; Lu, Yanhua
• Is Part Of: Food and chemical toxicology. Volume 119(2018)
• Page Start: 252
• Page End: 259
• Publication Date: 2018-09
• Subjects: 2′, 4′-Dihydroxy-6′-methoxy-3′, 5′-dimethylchalcone (DMC) -- Glutathione -- Nrf2/ARE pathway -- Drug resistance -- Cancer; Toxicology -- Periodicals; Food poisoning -- Periodicals; Food Poisoning -- Periodicals; Toxicology -- Periodicals; Toxicologie -- Périodiques; Intoxications alimentaires -- Périodiques; Food poisoning; Toxicology; Periodicals; Electronic journals; 615.9
• DOI: 10.1016/j.fct.2018.04.001
• Languages: English
• ISSNs: 0278-6915

Abstract

Abstract: 2′, 4′-Dihydroxy-6′-methoxy-3′, 5′-dimethylchalcone (DMC) is a major active constituent of the buds of Cleistocalyx operculatus (Roxb.) Merr. et Perry (Myrtaceae), a main ingredient of herbal tea in tropical zones. DMC has been reported to significantly reverse drug resistance in BEL-7402/5-FU cells. Glutathione (GSH) and glutathione S-transferase (GST) play important roles in an efflux system that protects the cells from anticancer drugs. In this study, DMC remarkably decreased the intracellular GSH content and GST activity. Furthermore, DMC suppressed the expression of factor erythroid 2-related factor 2 (Nrf2), prevented Nrf2 nuclear translocation, and inhibited the binding of Nrf2 to the antioxidant response element (ARE). The glutamate-cysteine ligase catalytic subunit (GCLC) and glutamate-cysteine ligase modifier subunit (GCLM) were down-regulated by inhibiting Nrf2 with DMC treatment. These results suggested that DMC reduced drug efflux to reverse drug resistance by suppressing the Nrf2/ARE signaling pathway in human hepatocellular carcinoma BEL-7402/5-FU cells. Graphical abstract: Highlights: DMC decreased the intracellular GSH content and GST activity. DMC suppressed the expression of Nrf2, prevented Nrf2 nuclear translocation, and inhibited the binding activity of Nrf2 to ARE. DMC down-regulated the expression of GCLC and GCLM by inhibiting Nrf2. DMC served as the Nrf2/ARE pathway inhibitor, contributed to reversing drug resistance in BEL-7402/5-FU cells.