Modulation by (iso)flavonoids of the ATPase activity of the multidrug resistance protein

Hooijberg, Jan Hendrik; Broxterman, H. J.; Heijn, Marc; Fles, D.L.A; Lankelma, J.; Pinedo, H. M.

doi:10.1016/s0014-5793(97)00940-x

Cited by 98 publications

(70 citation statements)

References 31 publications

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“…To get rid of as much of non-MRP1 ATPase activity as possible, we employed a battery of ATPase inhibitors in concentrations that were reported not to affect MRP1 [56]. Although the profile of substances that inhibited/stimulated ATPase activity that we measured in the erythrocyte ghosts was in general agreement with the one reported by other authors for the ATPase activity of MRP1 [9,57,58], there was no guarantee that the ATPase activity recorded from the erythrocyte membranes was pure MRP1 activity without any contribution from other proteins. Despite these caveats, we concluded that morin was likely to influence the ATPase activity of MRP1 in human erythrocytes.…”

Section: Discussionsupporting

confidence: 79%

Perturbation of the lipid phase of a membrane is not involved in the modulation of MRP1 transport activity by flavonoids

Wesołowska

Hendrich

Łania-Pietrzak

et al. 2009

Cellular and Molecular Biology Letters

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The expression of transmembrane transporter multidrug resistance-associated protein 1 (MRP1) confers the multidrug-resistant phenotype (MDR) on cancer cells. Since the activity of the other MDR transporter, P-glycoprotein, is sensitive to membrane perturbation, we aimed to check whether the changes in lipid bilayer properties induced by flavones (apigenin, acacetin) and flavonols (morin, myricetin) were related to their MRP1 inhibitory activity. All the flavonoids inhibited the efflux of MRP1 fluorescent substrate from human erythrocytes and breast cancer cells. Morin was also found to stimulate the ATPase activity of erythrocyte ghosts. All flavonoids intercalated into phosphatidylcholine bilayers as judged by differential scanning calorimetry and fluorescence spectroscopy with the use of two carbocyanine dyes. The model of an intramembrane localization for flavones and flavonols was proposed. No clear relationship was found between the membrane-perturbing activity of flavonoids and their potency to inhibit MRP1. We concluded that mechanisms other than perturbation of the lipid phase of membranes were responsible for inhibition of MRP1 by the flavonoids.

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Section: Discussionsupporting

confidence: 79%

Perturbation of the lipid phase of a membrane is not involved in the modulation of MRP1 transport activity by flavonoids

Wesołowska

Hendrich

Łania-Pietrzak

et al. 2009

Cellular and Molecular Biology Letters

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“…Modulation of MRP1-mediated drug transport may be one way to improve the efficiency of chemotherapeutic treatment of cancer. One class of chemicals that has been reported to interact with MRP1 is the group of (iso)flavonoids (Versantvoort et al, 1993;Hooijberg et al, 1997). The interest in these compounds exceeds their use as MDR modulators, because of their broad spectrum of biochemical activities and their occurrence in our daily food as metabolic products of plants.…”

Section: Discussionmentioning

confidence: 99%

Potent interaction of flavopiridol with MRP1

et al. 1999

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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-proliferative 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 GLC 4 /ADR. The accumulation of daunorubicin in GLC 4 /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 μ M . 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. © 1999 Cancer Research Campaign

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“…51 and 52) of flavopiridol may be due to inhibition of intracellular mechanisms other than CDK activity. These include inhibition of glycogen phosphorylase (26,27), GSK-3␣/␤ (10), and cytosolic aldehyde dehydrogenase (25) as well as interaction with multidrug resistance protein 1 (53,54). Similarly, an affinity chromatography approach recently allowed us to identify Erk2 as a major intracellular target of the CDK inhibitor purvalanol (24).…”

Section: Fig 9 Gwennpaullone-binding Proteins In L Mexicana (A) Anmentioning

confidence: 99%

Intracellular Targets of Paullones

Knockaert¹,

Wieking²,

Schmitt³

et al. 2002

Journal of Biological Chemistry

136

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Numerous inhibitors of cyclin-dependent kinases and glycogen synthase kinase-3 (GSK-3) are being developed in view of their potential applications against cancers and neurodegenerative disorders. Among these, paullones constitute a family of potent and apparently selective cyclin-dependent kinase and GSK-3 inhibitors. However, their actual intracellular targets remain to be identified. To address this issue we have immobilized a paullone, gwennpaullone, on an agarose matrix. Extracts from various cell types and tissues were screened for proteins interacting with this matrix. This approach validated GSK-3␣ and GSK-3␤ as major intracellular paullone targets and also mitochondrial, but not cytoplasmic, malate dehydrogenase (MDH). Mitochondrial MDH was indeed inhibited by micromolar concentrations of paullones. Mitochondrial MDH was the major paullone-binding protein in the parasitic protozoon Leishmania mexicana, and paullones inhibited growth of the parasite. This simple batchwise affinity chromatography approach constitutes a straightforward method for the identification of intracellular targets of this particular class of novel anti-mitotic compounds. It has revealed an unexpected target, mitochondrial MDH, the inhibition of which may participate in the pharmacological effects of paullones.

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Modulation by (iso)flavonoids of the ATPase activity of the multidrug resistance protein

Cited by 98 publications

References 31 publications

Perturbation of the lipid phase of a membrane is not involved in the modulation of MRP1 transport activity by flavonoids

Perturbation of the lipid phase of a membrane is not involved in the modulation of MRP1 transport activity by flavonoids

Potent interaction of flavopiridol with MRP1

Intracellular Targets of Paullones

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