Quercetin-POM (pivaloxymethyl) conjugates: Modulatory activity for P-glycoprotein-based multidrug resistance

Mi Kyoung Kim; Kwang Su Park; Hyunah Choo; Youhoon Chong

doi:10.1016/j.phymed.2015.05.055

Quercetin-POM (pivaloxymethyl) conjugates: Modulatory activity for P-glycoprotein-based multidrug resistance

Mi Kyoung Kim, Kwang Su Park, Hyunah Choo, Youhoon Chong

Research output: Contribution to journal › Article › peer-review

19 Scopus citations

Abstract

Background We previously demonstrated that the bioactivity of quercetin could be improved through conjugation with a hydrolysable pivaloxymethyl (POM) group. Purpose Present study aimed to evaluate MDR (multidrug resistance)-modulatory activity of the quercetin-POM conjugates. Study design/methods MDR-modulatory activity was determined by measuring cytotoxicity of various anticancer agents to MDR MES-SA/Dx5 cell lines upon combination with the quercetin-POM conjugates. Results The quercetin-7-O-POM conjugate (7-O-POM-Q) was significantly more potent than quercetin in reversing MDR, which recovered the cytotoxicity of various anticancer agents with EC₅₀ values of 1.1-1.3 μM. A series of mechanistic studies revealed that 7-O-POM-Q competes with verapamil in binding to the same drug-binding site of the major MDR target, Pgp (P-glycoprotein), and inhibits Pgp-mediated drug efflux with a similar potency as verapamil. The physicochemical properties of 7-O-POM-Q were then evaluated, which confirmed that 7-O-POM-Q has remarkably enhanced cellular uptake and intracellular localization compared with quercetin. Additionally, it is noteworthy that 7-O-POM-Q undergoes slow hydrolysis to quercetin over a prolonged period of time. Conclusion The quercetin-POM conjugate showed significantly improved MDR-reversing activity compared with quercetin, which could be attributed to its capacity to maintain high intracellular concentrations.

Original language	English
Pages (from-to)	778-785
Number of pages	8
Journal	Phytomedicine
Volume	22
Issue number	7-8
DOIs	https://doi.org/10.1016/j.phymed.2015.05.055
State	Published - 22 Jun 2015
Externally published	Yes

Keywords

Modulator
Multidrug resistance (MDR)
P-glycoprotein (Pgp)
Pivaloxymethyl
Quercetin

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10.1016/j.phymed.2015.05.055

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title = "Quercetin-POM (pivaloxymethyl) conjugates: Modulatory activity for P-glycoprotein-based multidrug resistance",

abstract = "Background We previously demonstrated that the bioactivity of quercetin could be improved through conjugation with a hydrolysable pivaloxymethyl (POM) group. Purpose Present study aimed to evaluate MDR (multidrug resistance)-modulatory activity of the quercetin-POM conjugates. Study design/methods MDR-modulatory activity was determined by measuring cytotoxicity of various anticancer agents to MDR MES-SA/Dx5 cell lines upon combination with the quercetin-POM conjugates. Results The quercetin-7-O-POM conjugate (7-O-POM-Q) was significantly more potent than quercetin in reversing MDR, which recovered the cytotoxicity of various anticancer agents with EC50 values of 1.1-1.3 μM. A series of mechanistic studies revealed that 7-O-POM-Q competes with verapamil in binding to the same drug-binding site of the major MDR target, Pgp (P-glycoprotein), and inhibits Pgp-mediated drug efflux with a similar potency as verapamil. The physicochemical properties of 7-O-POM-Q were then evaluated, which confirmed that 7-O-POM-Q has remarkably enhanced cellular uptake and intracellular localization compared with quercetin. Additionally, it is noteworthy that 7-O-POM-Q undergoes slow hydrolysis to quercetin over a prolonged period of time. Conclusion The quercetin-POM conjugate showed significantly improved MDR-reversing activity compared with quercetin, which could be attributed to its capacity to maintain high intracellular concentrations.",

keywords = "Modulator, Multidrug resistance (MDR), P-glycoprotein (Pgp), Pivaloxymethyl, Quercetin",

author = "Kim, {Mi Kyoung} and Park, {Kwang Su} and Hyunah Choo and Youhoon Chong",

year = "2015",

month = jun,

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doi = "10.1016/j.phymed.2015.05.055",

language = "English",

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journal = "Phytomedicine",

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T2 - Modulatory activity for P-glycoprotein-based multidrug resistance

AU - Kim, Mi Kyoung

AU - Park, Kwang Su

AU - Choo, Hyunah

AU - Chong, Youhoon

PY - 2015/6/22

Y1 - 2015/6/22

N2 - Background We previously demonstrated that the bioactivity of quercetin could be improved through conjugation with a hydrolysable pivaloxymethyl (POM) group. Purpose Present study aimed to evaluate MDR (multidrug resistance)-modulatory activity of the quercetin-POM conjugates. Study design/methods MDR-modulatory activity was determined by measuring cytotoxicity of various anticancer agents to MDR MES-SA/Dx5 cell lines upon combination with the quercetin-POM conjugates. Results The quercetin-7-O-POM conjugate (7-O-POM-Q) was significantly more potent than quercetin in reversing MDR, which recovered the cytotoxicity of various anticancer agents with EC50 values of 1.1-1.3 μM. A series of mechanistic studies revealed that 7-O-POM-Q competes with verapamil in binding to the same drug-binding site of the major MDR target, Pgp (P-glycoprotein), and inhibits Pgp-mediated drug efflux with a similar potency as verapamil. The physicochemical properties of 7-O-POM-Q were then evaluated, which confirmed that 7-O-POM-Q has remarkably enhanced cellular uptake and intracellular localization compared with quercetin. Additionally, it is noteworthy that 7-O-POM-Q undergoes slow hydrolysis to quercetin over a prolonged period of time. Conclusion The quercetin-POM conjugate showed significantly improved MDR-reversing activity compared with quercetin, which could be attributed to its capacity to maintain high intracellular concentrations.

AB - Background We previously demonstrated that the bioactivity of quercetin could be improved through conjugation with a hydrolysable pivaloxymethyl (POM) group. Purpose Present study aimed to evaluate MDR (multidrug resistance)-modulatory activity of the quercetin-POM conjugates. Study design/methods MDR-modulatory activity was determined by measuring cytotoxicity of various anticancer agents to MDR MES-SA/Dx5 cell lines upon combination with the quercetin-POM conjugates. Results The quercetin-7-O-POM conjugate (7-O-POM-Q) was significantly more potent than quercetin in reversing MDR, which recovered the cytotoxicity of various anticancer agents with EC50 values of 1.1-1.3 μM. A series of mechanistic studies revealed that 7-O-POM-Q competes with verapamil in binding to the same drug-binding site of the major MDR target, Pgp (P-glycoprotein), and inhibits Pgp-mediated drug efflux with a similar potency as verapamil. The physicochemical properties of 7-O-POM-Q were then evaluated, which confirmed that 7-O-POM-Q has remarkably enhanced cellular uptake and intracellular localization compared with quercetin. Additionally, it is noteworthy that 7-O-POM-Q undergoes slow hydrolysis to quercetin over a prolonged period of time. Conclusion The quercetin-POM conjugate showed significantly improved MDR-reversing activity compared with quercetin, which could be attributed to its capacity to maintain high intracellular concentrations.

KW - Modulator

KW - Multidrug resistance (MDR)

KW - P-glycoprotein (Pgp)

KW - Pivaloxymethyl

KW - Quercetin

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ER -

Quercetin-POM (pivaloxymethyl) conjugates: Modulatory activity for P-glycoprotein-based multidrug resistance

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Keywords

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