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Reversal of in vitro cellular MRP1 and MRP2 mediated vincristine resistance by the flavonoid myricetin

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Author: Zanden, J.J. van · Mul, A. de · Wortelboer, H.M. · Usta, M. · Bladeren, P.J. van · Rietjens, I.M.C.M. · Cnubben, N.H.P.
Type:article
Date:2005
Institution: TNO Kwaliteit van Leven
Source:Biochemical Pharmacology, 11, 69, 1657-1665
Identifier: 238540
doi: doi:10.1016/j.bcp.2005.03.001
Keywords: Biology · Physiological Sciences · Flavonoids · MRP1 · MRP2 · Multidrug resistance · Myricetin · Vincristine · antineoplastic agent · flavonoid · multidrug resistance protein 1 · multidrug resistance protein 2 · myricetin · vincristine · animal cell · article · cell line · cell proliferation · chemotherapy · concentration (parameters) · controlled study · drug resistance · drug transport · genetic transfection · IC 50 · in vitro study · nonhuman · priority journal · Animals · Cell Line · Cell Proliferation · Dogs · Dose-Response Relationship, Drug · Drug Resistance, Neoplasm · Flavonoids · Humans · Membrane Transport Modulators · Membrane Transport Proteins · Multidrug Resistance-Associated Proteins · Vincristine

Abstract

In the present study, the effects of myricetin on either MRP1 or MRP2 mediated vincristine resistance in transfected MDCKII cells were examined. The results obtained show that myricetin can inhibit both MRP1 and MRP2 mediated vincristine efflux in a concentration dependent manner. The IC50 values for cellular vincristine transport inhibition by myricetin were 30.5 ± 1.7 μM for MRP1 and 24.6 ± 1.3 μM for MRP2 containing MDCKII cells. Cell proliferation analysis showed that the MDCKII control cells are very sensitive towards vincristine toxicity with an IC50 value of 1.1 ± 0.1 μM. The MDCKII MRP1 and MRP2 cells are less sensitive towards vincristine toxicity with IC50 values of 33.1 ± 1.9 and 22.2 ± 1.4 μM, respectively. In both the MRP1 and MRP2 cells, exposure to 25 μM myricetin enhances the sensitivity of the cells towards vincristine toxicity to IC50 values of 7.6 ± 0.5 and 5.8 ± 0.5 μM, respectively. The increase of sensitivity represents a reversal of the resistance towards vincristine as a result of MRP1 and MRP2 inhibition. Thus, the present study demonstrates the ability of the flavonoid myricetin to modulate MRP1 and MRP2 mediated resistance to the anticancer drug vincristine in transfected cells, indicating that flavonoids might be a valuable adjunct to chemotherapy to block MRP mediated resistance. © 2005 Elsevier Inc. All rights reserved.