Tangeretin, a citrus pentamethoxyflavone, antagonizes ABCB1-mediated multidrug resistance by inhibiting its transport function. (August 2016)

• Record Type: Journal Article
• Authors: Feng, Sen-Ling; Yuan, Zhong-Wen; Yao, Xiao-Jun; Ma, Wen-Zhe; Liu, Liang; Liu, Zhong-Qiu; Xie, Ying
• Is Part Of: Pharmacological research. Volume 110(2016:Aug.)
• Page Start: 193
• Page End: 204
• Publication Date: 2016-08
• Subjects: MDR Multidrug resistance -- P-gp glycoprotein P -- ABC ATP-binding cassette -- PTX paclitaxel -- DOX doxorubicin -- NSCLC non-small cell lung cancer -- CI combination index -- Rho 123 rhodamin123; Tangeretin (PubChem CID: 69077) -- Paclitaxel (PubChem CID: 36314) -- Doxorubicin (PubChem CID: 31703) -- Docetaxel (PubChem CID: 148124) -- Daunorubicin (PubChem CID: 30323) -- 5-Fluorouracil (PubChem CID: 3385); Tangeretin -- Citrus flavonoid -- Multidrug resistance -- ABCB1/P-glycoprotein; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2016.04.003
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: 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.