title: Drug resistance associates with activation of Nrf2 in MCF-7/DOX cells, and wogonin reverses it by down-regulating Nrf2-mediated cellular defense response.
abstract: 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.
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Jiangsu, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhong
authors.forename: Fengyi
authors.initials: F
authors.lastname: Zhang
authors.forename: Zhongying
authors.initials: Z
authors.lastname: Sun
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.forename: Zhi-Yu
authors.initials: ZY
authors.lastname: Li
authors.forename: Qi-Dong
authors.initials: QD
authors.lastname: You
authors.forename: Qing-Long
authors.initials: QL
authors.lastname: Guo
authors.forename: Rong
authors.initials: R
authors.lastname: Hu
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004365:Drugs, Chinese Herbal; D005260:Female; D044950:Flavanones / Q000494:pharmacology*; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: D000903:Antibiotics, Antineoplastic; D004365:Drugs, Chinese Herbal; D044950:Flavanones; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D004317:Doxorubicin; C085514:wogonin