Yan Zhong and Fengyi Zhang contributed equally to this study.
Drug resistance associates with activation of Nrf2 in MCF-7/DOX cells, and wogonin reverses it by down-regulating Nrf2-mediated cellular defense response
Article first published online: 16 MAY 2012
© 2012 Wiley Periodicals, Inc.
Volume 52, Issue 10, pages 824–834, October 2013
How to Cite
Zhong, Y., Zhang, F., Sun, Z., Zhou, W., Li, Z.-Y., You, Q.-D., Guo, Q.-L. and Hu, R. (2013), Drug resistance associates with activation of Nrf2 in MCF-7/DOX cells, and wogonin reverses it by down-regulating Nrf2-mediated cellular defense response. Mol. Carcinog., 52: 824–834. doi: 10.1002/mc.21921
- Issue published online: 19 SEP 2013
- Article first published online: 16 MAY 2012
- Manuscript Accepted: 10 APR 2012
- Manuscript Received: 28 FEB 2012
- Natural Science Foundation of China. Grant Numbers: 30801410, 30973556, 91029744, 81173086, 81173087
- Natural Science Foundation of Jiangsu Province, China. Grant Number: BK2009297
- Project Program of State Key Laboratory of Natural Medicines, China Pharmaceutical University. Grant Number: ZJ11173
- drug resistance;
Acquired resistance to doxorubicin (DOX) is a serious therapeutic problem in breast cancer patients. In this study, we investigated whether nuclear factor erythroid 2-related factor 2 (Nrf2) was associated with drug resistant in DOX resistant MCF-7 (MCF-7/DOX) cells, and if wogonin, a flavonoid isolated from the root of Scutellaria baicalensis Georgi, could reverse drug resistance in MCF-7/DOX cells. We found that the endogenous expression of Nrf2 as well as its target proteins heme oxygenase-1 (HO-1), NADP(H):quinone oxidoreductase (NQO) in MCF-7/DOX cells was higher than that in MCF-7 cells. Tert-butylhydroquinone treatment increased the expression Nrf2, HO-1, and NQO-1, and enhanced resistance of MCF-7 cells to DOX. Similarly, intracellular Nrf2 protein level was significantly decreased in MCF-7/DOX cells and DOX resistance was partially reversed by Nrf2 siRNA. Wogonin downregulated the Nrf2-dependent response and partly reversed DOX resistance in MCF-7/DOX cells. These results suggested that activation of Nrf2 was associated with drug resistance in MCF-7/DOX cells. Wogonin reversed drug resistance and its reversal mechanism might be due to the suppression of Nrf2 signaling pathway, indicating the feasibility of using Nrf2 inhibitors to increase efficacy of chemotherapeutic drugs. © 2012 Wiley Periodicals, Inc.