2. Academic Validation
  3. Structure-activity relationship and mechanism of flavonoids on the inhibitory activity of P-glycoprotein (P-gp)-mediated transport of rhodamine123 and daunorubicin in P-gp overexpressed human mouth epidermal carcinoma (KB/MDR) cells

Structure-activity relationship and mechanism of flavonoids on the inhibitory activity of P-glycoprotein (P-gp)-mediated transport of rhodamine123 and daunorubicin in P-gp overexpressed human mouth epidermal carcinoma (KB/MDR) cells

  • Food Chem Toxicol. 2021 Sep:155:112381. doi: 10.1016/j.fct.2021.112381.
Yajing Fang 1,  Fuqiang Liang 2,  Mengmeng Xia 3,  Weiwei Cao 4,  Siyi Pan 5,  Ting Wu 6,  Xiaoyun Xu 7
Affiliations

Affiliations

  • 1 Key Laboratory of Environment Correlative Dietology (Huazhong Agricultural University), Ministry of Education, Wuhan, 430070, PR China; Department of Food Science, Faculty of Science, University of Copenhagen, DK-1958 Frederiksberg C, Denmark. Electronic address: [email protected].
  • 2 College of Food Science and Engineering, Nanjing University of Finance and Economics, Nanjing 210023, PR China. Electronic address: [email protected].
  • 3 Key Laboratory of Environment Correlative Dietology (Huazhong Agricultural University), Ministry of Education, Wuhan, 430070, PR China. Electronic address: [email protected].
  • 4 College of Food and Bioengineering, Henan University of Science and Technology, Luoyang, 471023, PR China. Electronic address: [email protected].
  • 5 Key Laboratory of Environment Correlative Dietology (Huazhong Agricultural University), Ministry of Education, Wuhan, 430070, PR China. Electronic address: [email protected].
  • 6 Key Laboratory of Environment Correlative Dietology (Huazhong Agricultural University), Ministry of Education, Wuhan, 430070, PR China. Electronic address: [email protected].
  • 7 Key Laboratory of Environment Correlative Dietology (Huazhong Agricultural University), Ministry of Education, Wuhan, 430070, PR China. Electronic address: [email protected].
PMID: 34217736 DOI: 10.1016/j.fct.2021.112381
Abstract

This study was aimed to investigate the inhibitory activity of Flavonoids on P-glycoprotein (P-gp). Effects of 39 Flavonoids on the cellular uptake (CU) of rhodamine123 (Rho) and daunomycin (DNR) were investigated in both parental KB and P-gp overexpressed KB/MDR cells. The inhibition mechanism of selected Flavonoids was further investigated by measuring the ATPase activity and expression level of P-gp. Twelve Flavonoids improved the uptake of Rho (↑RhoF) and nineteen Flavonoids increased the uptake of DNR (↑DNRF) in KB/MDR cells with nine Flavonoids overlapped. Structure-activity relationship (SAR) indicated that 8-OCH3, and 2'-OH have a negative effect on Rho and DNR transport. Whereas 5-OH, 5-OCH3, 6-OH, 7-OCH3, 3'-OH, and 4'-OH, are essential for inhibition of Flavonoids on P-gp and reversing the resistance of Rho and DNR. Eleven selected Flavonoids significantly induced the basal P-gp-ATPase activity but much lower than that induced by verapamil. Tangeretin, galangin, kaempferol, quercetin, and morin significantly reversed the ATPase activity stimulated by verapamil. Six of eleven Flavonoids significantly decreased P-gp expression, whereas three Flavonoids slightly increased P-gp expression. These results provide valuable information that Flavonoids can effectively reverse multidrug resistance of P-gp-mediated transport of nutraceutical and drugs by co-administration.

Keywords

Cellular uptake; Flavonoids; KB/MDR cells; P-glycoprotein inhibitors; P-glycoprotein substrates; Structure-activity relationship.

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