Potent interaction of flavopiridol with MRP1

J. H. Hooijberg; H. J. Broxterman; G. L. Scheffer; C. Vrasdonk; M. Heijn; M. C. De Jong; R. J. Scheper; J. Lankelma; H. M. Pinedo

doi:10.1038/sj.bjc.6690687

Potent interaction of flavopiridol with MRP1

J. H. Hooijberg, H. J. Broxterman, G. L. Scheffer, C. Vrasdonk, M. Heijn, M. C. De Jong, R. J. Scheper, J. Lankelma, H. M. Pinedo

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

86 Scopus citations

Abstract

The multidrug resistance protein 1 (MRP1) is an ATP-dependent transport protein for organic anions, as well as neutral or positively charged anticancer agents. In this study we show that flavopiridol, a synthetic flavonoid currently studied in phase 1 trials for its anti-prolifetative characteristics, interacts with MRP1 in a potent way. Flavopiridol, as well as other (iso)flavonoids stimulate the ATPase activity of MRP1 in a dose-dependent way at low micromolar concentrations. A new specific monoclonal antibody against MRP1 (MIB6) inhibits the (iso)flavonoid-induced ATPase activity of plasma membrane vesicles prepared from the MRP1 overexpressing cell line GLC₄/ADR. The accumulation of daunorubicin in GLC₄/ADR cells is increased by flavopiridol and by other non-glycosylated (iso)flavonoids that interact with MRP1 ATPase activity. However, flavopiridol is the only tested compound that affects the daunorubicin accumulation when present at concentrations below 1 μm. Glycosylated (iso)flavonoids do not affect MRP1-mediated transport or ATPase activity. Finally, MRP1 overexpressing and transfected cells are resistant to flavopiridol, but not to other (iso)flavonoids tested. These findings may be of relevance for the development of anticancer therapies with flavopiridol.

Original language	English (US)
Pages (from-to)	269-276
Number of pages	8
Journal	British Journal of Cancer
Volume	81
Issue number	2
DOIs	https://doi.org/10.1038/sj.bjc.6690687
State	Published - 1999
Externally published	Yes

Keywords

(Iso)flavonoids
ATPase
Flavopiridol
MRP1
Multidrug resistance

ASJC Scopus subject areas

Cancer Research
Oncology

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10.1038/sj.bjc.6690687

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title = "Potent interaction of flavopiridol with MRP1",

abstract = "The multidrug resistance protein 1 (MRP1) is an ATP-dependent transport protein for organic anions, as well as neutral or positively charged anticancer agents. In this study we show that flavopiridol, a synthetic flavonoid currently studied in phase 1 trials for its anti-prolifetative characteristics, interacts with MRP1 in a potent way. Flavopiridol, as well as other (iso)flavonoids stimulate the ATPase activity of MRP1 in a dose-dependent way at low micromolar concentrations. A new specific monoclonal antibody against MRP1 (MIB6) inhibits the (iso)flavonoid-induced ATPase activity of plasma membrane vesicles prepared from the MRP1 overexpressing cell line GLC4/ADR. The accumulation of daunorubicin in GLC4/ADR cells is increased by flavopiridol and by other non-glycosylated (iso)flavonoids that interact with MRP1 ATPase activity. However, flavopiridol is the only tested compound that affects the daunorubicin accumulation when present at concentrations below 1 μm. Glycosylated (iso)flavonoids do not affect MRP1-mediated transport or ATPase activity. Finally, MRP1 overexpressing and transfected cells are resistant to flavopiridol, but not to other (iso)flavonoids tested. These findings may be of relevance for the development of anticancer therapies with flavopiridol.",

keywords = "(Iso)flavonoids, ATPase, Flavopiridol, MRP1, Multidrug resistance",

author = "Hooijberg, {J. H.} and Broxterman, {H. J.} and Scheffer, {G. L.} and C. Vrasdonk and M. Heijn and {De Jong}, {M. C.} and Scheper, {R. J.} and J. Lankelma and Pinedo, {H. M.}",

year = "1999",

doi = "10.1038/sj.bjc.6690687",

language = "English (US)",

volume = "81",

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T1 - Potent interaction of flavopiridol with MRP1

AU - Hooijberg, J. H.

AU - Broxterman, H. J.

AU - Scheffer, G. L.

AU - Vrasdonk, C.

AU - Heijn, M.

AU - De Jong, M. C.

AU - Scheper, R. J.

AU - Lankelma, J.

AU - Pinedo, H. M.

PY - 1999

Y1 - 1999

N2 - The multidrug resistance protein 1 (MRP1) is an ATP-dependent transport protein for organic anions, as well as neutral or positively charged anticancer agents. In this study we show that flavopiridol, a synthetic flavonoid currently studied in phase 1 trials for its anti-prolifetative characteristics, interacts with MRP1 in a potent way. Flavopiridol, as well as other (iso)flavonoids stimulate the ATPase activity of MRP1 in a dose-dependent way at low micromolar concentrations. A new specific monoclonal antibody against MRP1 (MIB6) inhibits the (iso)flavonoid-induced ATPase activity of plasma membrane vesicles prepared from the MRP1 overexpressing cell line GLC4/ADR. The accumulation of daunorubicin in GLC4/ADR cells is increased by flavopiridol and by other non-glycosylated (iso)flavonoids that interact with MRP1 ATPase activity. However, flavopiridol is the only tested compound that affects the daunorubicin accumulation when present at concentrations below 1 μm. Glycosylated (iso)flavonoids do not affect MRP1-mediated transport or ATPase activity. Finally, MRP1 overexpressing and transfected cells are resistant to flavopiridol, but not to other (iso)flavonoids tested. These findings may be of relevance for the development of anticancer therapies with flavopiridol.

AB - The multidrug resistance protein 1 (MRP1) is an ATP-dependent transport protein for organic anions, as well as neutral or positively charged anticancer agents. In this study we show that flavopiridol, a synthetic flavonoid currently studied in phase 1 trials for its anti-prolifetative characteristics, interacts with MRP1 in a potent way. Flavopiridol, as well as other (iso)flavonoids stimulate the ATPase activity of MRP1 in a dose-dependent way at low micromolar concentrations. A new specific monoclonal antibody against MRP1 (MIB6) inhibits the (iso)flavonoid-induced ATPase activity of plasma membrane vesicles prepared from the MRP1 overexpressing cell line GLC4/ADR. The accumulation of daunorubicin in GLC4/ADR cells is increased by flavopiridol and by other non-glycosylated (iso)flavonoids that interact with MRP1 ATPase activity. However, flavopiridol is the only tested compound that affects the daunorubicin accumulation when present at concentrations below 1 μm. Glycosylated (iso)flavonoids do not affect MRP1-mediated transport or ATPase activity. Finally, MRP1 overexpressing and transfected cells are resistant to flavopiridol, but not to other (iso)flavonoids tested. These findings may be of relevance for the development of anticancer therapies with flavopiridol.

KW - (Iso)flavonoids

KW - ATPase

KW - Flavopiridol

KW - MRP1

KW - Multidrug resistance

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EP - 276

JO - British Journal of Cancer

JF - British Journal of Cancer

IS - 2

ER -

Potent interaction of flavopiridol with MRP1

Abstract

Keywords

ASJC Scopus subject areas

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