Mangiferin activates Nrf2-antioxidant response element signaling without reducing the sensitivity to etoposide of human myeloid leukemia cells in vitro

Abstract

Aim: Mangiferin is glucosylxanthone extracted from plants of the Anacardia ceae and Gentianaceae families. The aim of this study was to investigate the effects of mangiferin on Nrf2-antioxidant response element (ARE) signaling and the sensitivity to etoposide of human myeloid leukemia cells in vitro. Methods: Human HL-60 myeloid leukemia cells and mononuclear human umbilical cord blood cells (MNCs) were examined. Nrf2 protein was detected using immunofluorescence staining and Western blotting. Binding of Nrf2 to ARE was examined with electrophoretic mobility shift assay. The level of NQO1 was assessed with real-time RT-PCR and Western blotting. DCFH-DA was used to evaluate intracellular ROS level. Cell proliferation and apoptosis were analyzed using MTT and flow cytometry, respectively. Results: Mangiferin (50 µmol/L) significantly increased Nrf2 protein accumulation in HL-60 cells, particularly in the nucleus. Mangiferin also enhanced the binding of Nrf2 to an ARE, significantly up-regulated NQO1 expression and reduced intracellular ROS in HL60 cells. Mangiferin alone dose-dependently inhibited the proliferation of HL-60 cells. Mangiferin (50 mol/L) did not attenuate etoposide-induced cytotoxicity in HL-60 cells, and combined treatment of mangiferin with low concentration of etoposide (0.8 μg/mL) even increased the cell inhibition rate. Nor did mangiferin change the rate of etoposide-induced apoptosis in HL-60 cells. In MNCs, mangiferin significantly relieved oxidative stress, but attenuated etoposide-induced cytotoxicity. Conclusion: Mangiferin is a novel Nrf2 activator that reduces oxidative stress and protects normal cells without reducing the sensitivity to etoposide of HL-60 leukemia cells in vitro. Mangiferin may be a potential chemotherapy adjuvant.

Mangiferin: a natural miracle bioactive compound against lifestyle related disorders

“…It also relieved oxidative stress and attenuated etoposide-induced cytotoxicity in mononuclear human umbilical cord blood cells [48]. …”

Mangiferin-Loaded Polymeric Nanoparticles: Optical Characterization, Effect of Anti-topoisomerase I, and Cytotoxicity

“…However, it has been shown that encapsulation can ensure that the amount of compound released can have a direct effect, without undergoing possible alterations during the process to reach the target cells. Mangiferin studies at a concentration of 50 µM have demonstrated an antiproliferative effect on cancer cells without affecting healthy cells; this is due to the activation of Nrf2-ARE signaling cascades [42], the controlled release of the phytochemical contributes to the inhibition of the topoisomerase enzyme, when mangiferin is expelled during the different phases of the cellular reproduction of the yeast, promoting cell death due to encapsulation [43]. A similar behavior was observed in the encapsulation of topotecan, which is a selective topoisomerase II inhibitor.…”

Mangiferin increases Nrf2 protein stability by inhibiting its ubiquitination and degradation in human HL60 myeloid leukemia cells

“…Furthermore, MA has been shown to increase Nrf2 expression in D-galactosamine intoxicated rat liver (29). Moreover, in our previous study, we found that MA activated Nrf2-ARE signaling in human HL60 myeloid leukemia cells (30). However, to the best of our knowledge, the mechanisms by which MA increases Nrf2 expression have not been documented to date.…”

“…Previous stuides have revealed that MA induces Nrf2mediated antioxidant response, which provides an explanation for its antioxidant activity (29,30). It has been reported that MA enhances the expression of several detoxification and antioxidant enzymes, including NQO1, GST, HO-1, superoxide dismutase (SOD) and uridin 5'-diphosphate-glucuronosyl transferase (UDP-GT) (33)(34)(35)(36).…”