title: Tangeretin, a citrus pentamethoxyflavone, antagonizes ABCB1-mediated multidrug resistance by inhibiting its transport function.
abstract: Multidrug resistance (MDR) and tumor metastasis are the main causes of chemotherapeutic treatment failure and mortality in cancer patients. In this study, at achievable nontoxic plasma concentrations, citrus flavonoid tangeretin has been shown to reverse ABCB1-mediated cancer resistance to a variety of chemotherapeutic agents effectively. Co-treatment of cells with tangeretin and paclitaxel activated apoptosis as well as arrested cell cycle at G2/M-phase. Tangeretin profoundly inhibited the ABCB1 transporter activity since it significantly increased the intracellular accumulation of doxorubicin, and flutax-2 in A2780/T cells and decreased the efflux of ABCB1 substrates in Caco2 cells without altering the expression of ABCB1. Moreover, it stimulated the ATPase activity and inhibited verapamil-stimulated ATPase activity in a concentration-dependent manner, indicating a direct interaction with the transporter. The molecular docking results indicated a favorable binding of tangeretin with the transmemberane region site 1 of homology modeled ABCB1 transporter. The overall results demonstrated that tangeretin could sensitize ABCB1-overexpressing cancer cells to chemotherapeutical agents by directly inhibiting ABCB1 transporter function, which encouraged further animal and clinical studies in the treatment of resistant cancers.
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute For Applied Research in Medicine and Health, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau (SAR), China.
authors.forename: Sen-Ling
authors.initials: SL
authors.lastname: Feng
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute For Applied Research in Medicine and Health, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau (SAR), China.
authors.forename: Zhong-Wen
authors.initials: ZW
authors.lastname: Yuan
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute For Applied Research in Medicine and Health, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau (SAR), China.
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Yao
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute For Applied Research in Medicine and Health, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau (SAR), China.
authors.forename: Wen-Zhe
authors.initials: WZ
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute For Applied Research in Medicine and Health, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau (SAR), China.
authors.forename: Liang
authors.initials: L
authors.lastname: Liu
authors.affiliation: International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, China.
authors.forename: Zhong-Qiu
authors.initials: ZQ
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute For Applied Research in Medicine and Health, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau (SAR), China. Electronic address: yxie@must.edu.mo.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xie
mesh_terms: D000072283:A549 Cells; D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D018938:Caco-2 Cells; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000378:metabolism / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D047309:Flavones / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D017239:Paclitaxel / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D043823:Taxoids / Q000378:metabolism / Q000494:pharmacology; D013997:Time Factors
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D047309:Flavones; C413450:Flutax 2; D043823:Taxoids; D004317:Doxorubicin; C059006:tangeretin; D017239:Paclitaxel
keywords: 5-Fluorouracil (PubChem CID: 3385); ABCB1/P-glycoprotein; Citrus flavonoid; Daunorubicin (PubChem CID: 30323); Docetaxel (PubChem CID: 148124); Doxorubicin (PubChem CID: 31703); Multidrug resistance; Paclitaxel (PubChem CID: 36314); Tangeretin; Tangeretin (PubChem CID: 69077)