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Open AccessArticle

Taxifolin Resensitizes Multidrug Resistance Cancer Cells via Uncompetitive Inhibition of P-Glycoprotein Function

1
Department of Pharmacy, College of Pharmacy, China Medical University, 91 Hsueh-Shih Road, Taichung 40402, Taiwan
2
Research Assistant Center, Show Chwan Health Care System, 542, Sec 1, Chung-shan Rd., Changhua 500, Taiwan
3
Department of Medical Research and Development, Chang Bing Show Chwan Memorial Hospital, No.6, Lugong Rd., Lugang Town, Changhua 505, Taiwan
4
School of Medicine, College of Medicine, Fu Jen Catholic University, No.510, Zhongzheng Rd., Xinzhuang Dist., New Taipei City 24205, Taiwan
5
Department of Surgery, Show Chwan Memorial Hospital, 542, Sec 1, Chung-shan Rd., Changhua 500, Taiwan
6
Department of Surgery, Chang Bing Show Chwan Memorial Hospital, No.6, Lugong Rd. Lugang Town, Changhua 505, Taiwan
7
Department of Bioinformatics and Medical Engineering, Asia University, 500, Lioufeng Rd., Wufeng, Taichung 41354, Taiwan
8
Department of Internal Medicine, Taipei Medical University Hospital, No. 252, Wuxing St, Xinyi District, Taipei City 110, Taiwan
9
Department of Pharmacy, China Medical University Hospital, 2 Yude Road, Taichung 40447, Taiwan
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this paper.
Molecules 2018, 23(12), 3055; https://doi.org/10.3390/molecules23123055
Received: 5 November 2018 / Revised: 19 November 2018 / Accepted: 20 November 2018 / Published: 22 November 2018
P-glycoprotein (P-gp) effluxes lots of chemotherapeutic agents and leads to multidrug resistance (MDR) in cancer treatments. The development of P-gp inhibitors from natural products provide a potential strategy for the beneficial clinical outcomes. This study aimed to evaluate the effects of the natural flavonoid taxifolin, luteolin, (−)-gallocatechin, and (−)-catechin on human P-gp activity. The kinetic interactions and underlying mechanisms of taxifolin-mediated transporter inhibition were further investigated. The transporter inhibition ability was evaluated in human P-gp stable expression cells (ABCB1/Flp-InTM-293) by calcein-AM uptake assays. The kinetics study for P-gp inhibition was evaluated by doxorubicin and rhodamine123 efflux assays. The MDR reversal ability of taxifolin were performed by SRB assays to detect the cell viability in sensitive cancer cell line (HeLaS3), and resistant cancer cell line (KB-vin). Cell cycle analysis and ABCB1 real-time RT-PCR were used for mechanical exploration. The results demonstrated that taxifolin decreased ABCB1 expression in a concentration-dependent manner. The function of P-gp was inhibited by taxifolin through uncompetitive inhibition of rhodamine 123 and doxorubicin efflux. The combination of taxifolin significantly resensitized MDR cancer cells to chemotherapeutic agents. These results suggested that taxifolin may be considered as a potential P-gp modulator for synergistic treatment of MDR cancers. View Full-Text
Keywords: taxifolin; quercetin; P-glycoprotein; multidrug resistance; kinetic mechanism taxifolin; quercetin; P-glycoprotein; multidrug resistance; kinetic mechanism
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MDPI and ACS Style

Chen, H.-J.; Chung, Y.-L.; Li, C.-Y.; Chang, Y.-T.; Wang, C.C.N.; Lee, H.-Y.; Lin, H.-Y.; Hung, C.-C. Taxifolin Resensitizes Multidrug Resistance Cancer Cells via Uncompetitive Inhibition of P-Glycoprotein Function. Molecules 2018, 23, 3055.

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