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Phytomedicine. 2015 Jul 15;22(7-8):778-85. doi: 10.1016/j.phymed.2015.05.055. Epub 2015 Jun 5.

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

Author information

1
Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Hwayang-dong, Gwangjin-gu, Seoul 143-701, Republic of Korea.
2
Neuro-Medicine Center, Korea Institute of Science and Technology, 39-1 Hawolgok-dong, Seoungbuk-gu, Seoul 136-791, Republic of Korea. Electronic address: hchoo@kist.re.kr.
3
Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Hwayang-dong, Gwangjin-gu, Seoul 143-701, Republic of Korea. Electronic address: chongy@konkuk.ac.kr.

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

PMID:
26141765
DOI:
10.1016/j.phymed.2015.05.055
[Indexed for MEDLINE]

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