title: Berberine reverses lapatinib resistance of HER2-positive breast cancer cells by increasing the level of ROS.
abstract: Lapatinib, a novel tyrosine kinase inhibitor of HER2/EGFR, is used to treat HER2-positive breast cancer. However, acquired drug resistance has limited the clinical therapeutic efficacy of lapatinib. Our previous study found that inhibition of autophagy can reduce the proliferation, DNA synthesis, and colony-forming capacity of lapatinib-resistant cells. Berberine has attracted extensive attention due to its wide range of biochemical and pharmacological effects in breast cancer treatment. It has been reported that berberine can induce oxidative stress and the mitochondrial-related apoptotic pathway in human breast cancer cells. In our current study, we found that a new combination therapy of berberine with lapatinib overcame lapatinib resistance. Furthermore, we found that berberine induced apoptosis of lapatinib-resistant cells through upregulating the level of ROS. Specially, lapatinib activated both the c-Myc/pro-Nrf2 pathway and GSK-3β signaling to stabilize Nrf2 and maintain a low level of ROS in resistant cells. However, berberine can upset the ROS balance by downregulating c-Myc to reverse the lapatinib resistance. Our finding provides a novel strategy of using berberine to overcome lapatinib resistance.
authors.affiliation: a The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology , The Fourth Military Medical University , Xi'an, Shaanxi , China.|b Department of Hepato-Biliary and Pancreto-Splenic Surgery , Xijing Hospital, The Fourth Military Medical University , Xi'an , China.
authors.forename: Ruohan
authors.initials: R
authors.lastname: Zhang
authors.affiliation: c Department of Cardiology , Xijing Hospital, The Fourth Military Medical University , Xi'an , China.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Qiao
authors.affiliation: d Department of Pharmacy, Xijing Hospital, The Fourth Military Medical University , Xi'an , China.
authors.forename: Suning
authors.initials: S
authors.lastname: Chen
authors.affiliation: e Cadet Brigade of the Fourth Military Medical University, The Fourth Military Medical University , Xi'an , China.
authors.forename: Xu
authors.initials: X
authors.lastname: Chen
authors.affiliation: b Department of Hepato-Biliary and Pancreto-Splenic Surgery , Xijing Hospital, The Fourth Military Medical University , Xi'an , China.
authors.forename: Kefeng
authors.initials: K
authors.lastname: Dou
authors.affiliation: f Department of Obstetrics and Gynecology , Xijing Hospital, The Fourth Military Medical University , Xi'an , China.
authors.forename: Li
authors.initials: L
authors.lastname: Wei
authors.affiliation: a The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology , The Fourth Military Medical University , Xi'an, Shaanxi , China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001599:Berberine / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D045744:Cell Line, Tumor; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D000077341:Lapatinib; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D001599:Berberine; D000077341:Lapatinib; D051267:NF-E2-Related Factor 2; D011799:Quinazolines; D017382:Reactive Oxygen Species; D018719:Erb-b2 Receptor Tyrosine Kinases; C495635:NFE2L2 protein, human; C508053:ERBB2 protein, human
keywords: Berberine; GSK-3β; Lapatinib; Nrf2; ROS; c-Myc; drug resistance