Potent interaction of flavopiridol with MRP1

Hooijberg, Jan Hendrik; Broxterman, Henk J.; Scheffer, George L.; Vrasdonk, C.; Heijn, Marc; Jong, Mariska C. de; Scheper, Rik J.; Lankelma, J.; Pinedo, H. M.

doi:10.1038/sj.bjc.6690687

Cited by 70 publications

(63 citation statements)

References 42 publications

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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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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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“…We and others have previously reported that a wide range of flavonoids can inhibit the conjugated organic anion transport properties and modulate the ATPase activity of MRP1 (Hooijberg et al, 1997(Hooijberg et al, , 1999(Hooijberg et al, , 2000Leslie et al, 2001a). Thus a number of bioflavonoids were found to be potent inhibitors of LTC 4 and 17␤-estradiol 17-(␤-D-glucuronide) transport by MRP1-enriched membrane vesicles (Leslie et al, 2001a).…”

mentioning

confidence: 99%

Bioflavonoid Stimulation of Glutathione Transport by the 190-kDa Multidrug Resistance Protein 1 (MRP1)

Leslie¹,

Deeley²,

Cole³

2003

Drug Metab Dispos

114

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ABSTRACT:In tumor cells, the human multidrug resistance protein 1 (MRP1), confers resistance to a broad spectrum of anticancer agents. MRP1 is also expressed in many normal tissues where it acts as an ATP-dependent transporter of organic anions. , respectively. Chemosensitivity assays with control-transfected and MRP1-transfected HeLa cell lines showed that the IC 50 values for apigenin, naringenin, genistein, and quercetin were similar, demonstrating that overexpression of MRP1 does not confer resistance to these bioflavonoids. Our results suggest that flavonoids stimulate MRP1-mediated GSH transport by increasing the apparent affinity of the transporter for GSH but provide no evidence that a cotransport mechanism is involved.

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“…Such apparently contradictory effects were previously also observed for other flavonoids, e.g. kaempferol, apigenin and flavopiridol [9,59]. At present, there is no satisfactory explanation of such observations (see Leslie et al [9] and discussion within).…”

Section: Discussionmentioning

confidence: 56%

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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Potent interaction of flavopiridol with MRP1

Cited by 70 publications

References 42 publications

Intracellular Targets of Paullones

Intracellular Targets of Paullones

Bioflavonoid Stimulation of Glutathione Transport by the 190-kDa Multidrug Resistance Protein 1 (MRP1)

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

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