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: Sen-Ling Feng, Zhong-Wen Yuan, Xiao-Jun Yao, Wen-Zhe Ma, Liang Liu, Zhong-Qiu Liu, Ying Xie
• Journal: Pharmacological research (Pharmacol Res) Vol. 110 Pg. 193-204 (08 2016) ISSN: 1096-1186 [Electronic] Netherlands
• PMID: 27058921 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 Elsevier Ltd. All rights reserved.

Chemical References

• ABCB1 protein, human
• ATP Binding Cassette Transporter, Subfamily B
• Antineoplastic Agents
• Flavones
• Flutax 2
• Taxoids
• Doxorubicin
• tangeretin
• Paclitaxel

Topics

• A549 Cells
• ATP Binding Cassette Transporter, Subfamily B (antagonists & inhibitors, chemistry, genetics, metabolism)
• Antineoplastic Agents (metabolism, pharmacology)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Binding Sites
• Caco-2 Cells
• Cell Survival (drug effects)
• Dose-Response Relationship, Drug
• Doxorubicin (metabolism, pharmacology)
• Drug Resistance, Multiple (drug effects)
• Drug Resistance, Neoplasm (drug effects)
• Flavones (chemistry, metabolism, pharmacology)
• G2 Phase Cell Cycle Checkpoints (drug effects)
• Humans
• Inhibitory Concentration 50
• Molecular Docking Simulation
• Neoplasms (drug therapy, genetics, metabolism)
• Paclitaxel (metabolism, pharmacology)
• Protein Binding
• Protein Conformation
• Structure-Activity Relationship
• Taxoids (metabolism, pharmacology)
• Time Factors