title: Essential oils from Inula japonica and Angelicae dahuricae enhance sensitivity of MCF-7/ADR breast cancer cells to doxorubicin via multiple mechanisms.
abstract: BACKGROUND
  Angelicae dahurica (Hoffm.) Benth. & Hook.f.ex Franch. & Sav combined with Pueraria and Gastrodia elata Bl. combined with Inula japonica Thunb. are widely used in herb-pairs of traditional chinese medicine. Previous studies have shown that Angelicae dahuricae essential oil (ADO) enhanced puerarin internalization into ABCB1-overexpressed Caco-2 cells. These findings suggest the possibility that essential oils may enhance the absorption via certain mechanisms related to ABCB1 and reverse multidrug resistance (MDR).
  
  
  OBJECTIVE
  ADO and essential oils from Inula japonica (IJO) may reverse ABCB1-mediated MDR, but this ability has not been investigated in detail in the well-established cancer cell lines. In this study, the underlying molecular mechanisms were further investigated to examine how IJO and ADO reverse MDR in the resistant human breast cancer cell line of MCF-7/ADR. Also this work may help uncover the conceivable compatibility mechanisms of above herb-pairs involved in ABCB1.
  
  
  METHODS
  The MDR human breast cancer MCF-7/ADR cells were treated with IJO, its sesquiterpene component isoalantolactone (ISO) or ADOat non- cytotoxic concentrations. The MDR ability was examined by measuring the sensitivity to doxorubicin (DOX), DOX accumulation and efflux, ABCB1 ATPase activity, ABCB1 expression, membrane fluidity, and stability and localization of lipid rafts and caveolae. Finally, the molecular modeling was performed to postulate how ISO interacts with ABCB1.
  
  
  RESULTS
  Treating MCF-7/ADR cells with IJ oil, ISO or AD oil reversed MDR 2- to 3-fold, without affecting the sensitivity of the non-MDR parental cell line. Mechanistic studies showed that these oils down-regulated mRNA and protein expression of ABCB1, and reduced the stability of lipid rafts in the cell membrane, which has previously been shown to reduce ABCB1-mediated transport. On the other hand, IJO, ISO and ADO did not inhibit ABCB1 ATPase activity, and fluorescence polarization experiments showed that low concentrations of the oils did not appear to alter membrane fluidity, unlike some MDR-reversing agents, ISO showed a higher docking score than verapamil but lower than dofequidar and tariquidar.
  
  
  CONCLUSIONS
  Our results suggest that IJO, ISO and ADO could reverse MDR by down-regulating ABCB1 expression and reducing lipid raft stability. These findings may be useful for developing safer and effective MDR reversal agents and also help find out the compatibility mechanisms.
authors.affiliation: Department of Biophysics, School of Life Science and Technology, University of Electronic Science and Technology of China, PR China; Department of Pharmacy, Chengdu Medical College, Chengdu 610081, Sichuan, PR China. Electronic address: wuminzhaofeng@126.com.
authors.forename: Min
authors.initials: M
authors.lastname: Wu
authors.affiliation: Department of Biophysics, School of Life Science and Technology, University of Electronic Science and Technology of China, PR China. Electronic address: yhwt2012@163.com.
authors.forename: Tingting
authors.initials: T
authors.lastname: Li
authors.affiliation: Department of Pharmacy, Chengdu Medical College, Chengdu 610081, Sichuan, PR China. Electronic address: 1561956947@qq.com.
authors.forename: Lilan
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Pharmacy, Chengdu Medical College, Chengdu 610081, Sichuan, PR China. Electronic address: 652505364@qq.com.
authors.forename: Sugang
authors.initials: S
authors.lastname: Peng
authors.affiliation: Department of Pharmacy, Chengdu Medical College, Chengdu 610081, Sichuan, PR China. Electronic address: 1339154575@qq.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Liao
authors.affiliation: Department of Pharmacy, Chengdu Medical College, Chengdu 610081, Sichuan, PR China. Electronic address: 446007897@qq.com.
authors.forename: Ruolan
authors.initials: R
authors.lastname: Bai
authors.affiliation: Department of Pharmacy, Chengdu Medical College, Chengdu 610081, Sichuan, PR China. Electronic address: 172932716@qq.com.
authors.forename: Xue
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Biophysics, School of Life Science and Technology, University of Electronic Science and Technology of China, PR China; Center for Information in Biomedicine, University of Electronic Science and Technology of China, Chengdu 610054, Sichuan, PR China. Electronic address: yanghongyh@uestc.edu.cn.
authors.forename: Hong
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Biophysics, School of Life Science and Technology, University of Electronic Science and Technology of China, PR China; Center for Information in Biomedicine, University of Electronic Science and Technology of China, Chengdu 610054, Sichuan, PR China. Electronic address: wuchunhui@uestc.edu.cn.
authors.forename: Chunhui
authors.initials: C
authors.lastname: Wu
authors.affiliation: Department of Biophysics, School of Life Science and Technology, University of Electronic Science and Technology of China, PR China; Center for Information in Biomedicine, University of Electronic Science and Technology of China, Chengdu 610054, Sichuan, PR China. Electronic address: zenghj@uestc.edu.cn.
authors.forename: Hongjuan
authors.initials: H
authors.lastname: Zeng
authors.affiliation: Department of Biophysics, School of Life Science and Technology, University of Electronic Science and Technology of China, PR China; Center for Information in Biomedicine, University of Electronic Science and Technology of China, Chengdu 610054, Sichuan, PR China. Electronic address: liuyiyao@uestc.edu.cn.
authors.forename: Yiyao
authors.initials: Y
authors.lastname: Liu
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000378:metabolism; D029969:Angelica; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D038143:Inula; D061986:MCF-7 Cells; D008560:Membrane Fluidity / Q000187:drug effects; D008958:Models, Molecular; D009822:Oils, Volatile / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology*
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000903:Antibiotics, Antineoplastic; D009822:Oils, Volatile; D012333:RNA, Messenger; D012717:Sesquiterpenes; D004317:Doxorubicin; C032787:isoalantolactone; D000251:Adenosine Triphosphatases
keywords: 1,6-diphenyl-1,3,5-hexatriene (PubChem CID: 5376733); Angelicae dahuricae oil; Chemotherapy; Dofequidar (Pubchem CID: 213040); Doxorubicin (Pubchem CID: 31703); Inula japonica oil; Isoalantolactone; Isoalantolactone (Pubchem CID: 73285); MDR; Reversing mechanism; Tariquidar (Pubchem CID: 148201); Verapamil (Pubchem CID: 2520); sodium orthovanadate (PubChem CID: 61671)