Quercetin Selectively Inhibits Bioreduction and Enhances Apoptosis in Melanoma Cells That Overexpress Tyrosinase

Abstract

Tyrosinase is expressed in melanoma cells and catalyzes the formation of 3,3′,4′,5,7-pentahydroxyflavone (quercetin) into reactive quinone species and subsequent glutathionyl adducts. Therefore, we examined the effect of quercetin metabolism on the glutathione (GSH) bioreduction pathway and cell viability in DB-1 melanoma cells that express varying levels of tyrosinase (Tyr⁺). In a cell-free system, GSH was significantly decreased by quercetin, which coincided with the formation of glutathionyl adducts. In Tyr⁺ clones, quercetin decreased bioreduction capacity and increased reactive oxygen species (ROS) to a greater degree compared to control cells. The antioxidant/electrophile response element-induced enzymes, glutathione-S-transferase (GST), and nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase 1 were expressed at high levels in Tyr⁺ cells and contributed to pro-oxidant quercetin metabolism. The basal level of ROS and apoptosis was higher in Tyr⁺ cells and were selectively increased after exposure to quercetin. The increase in apoptosis following quercetin exposure was p53/Bax mediated and correlated with a decrease in GST-driven bioreduction capacity and an increase in ROS. In conclusion, quercetin can selectively sensitize Tyr⁺ expressing melanoma cells to apoptosis and may serve as an adjuvant to chemotherapy by enhancing cell death and interfering with GST-mediated drug resistance.

Acknowledgments and Notes

The authors wish to thank the technical assistance rendered by Geoffrey Mitchell and Yoon Joo Shin, Department of Nutritional Sciences, University of Arizona and Donna Fath, Thomas Jefferson University, Philadelphia. This study was supported by a grant from the American Institute for Cancer Research (Grant # 03B113-REV).