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Reversal of P-glycoprotein-Mediated Multidrug Resistance by the Murine Double Minute 2 Antagonist Nutlin-3

Michaelis, Martin, Rothweiler, Florian, Klassert, Denise, von Deimling, Andreas, Weber, Kristoffer, Fehse, Boris, Kammerer, Bernd, Doerr, Hans Wilhelm, Cinatl, Jindrich (2009) Reversal of P-glycoprotein-Mediated Multidrug Resistance by the Murine Double Minute 2 Antagonist Nutlin-3. Cancer Research, 69 (2). pp. 416-421. ISSN 0008-5472. (doi:10.1158/0008-5472.CAN-08-1856) (The full text of this publication is not currently available from this repository. You may be able to access a copy if URLs are provided)

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Official URL
http://dx.doi.org/10.1158/0008-5472.CAN-08-1856

Abstract

Murine double minute 2(MDM2)negatively regulates the activity of the tumor suppressor protein p53. Nutlin-3 is a MDM2 inhibitor under preclinical investigation as nongenotoxic activator of the p53 pathway for cancer therapy. Here, nutlin-3 was evaluated for its activity alone or in combination with established chemotherapeutic drugs for antitumor action in chemosensitive and chemoresistant neuroblastoma and rhabdomyosarcoma cell lines. Effects of nutlin-3 single treatment were much more pronounced in p53 wild-type cell lines (IC50s <3 ?mol/L) than in p53-mutated cell lines (IC50s >17 ?mol/L). In sharp contrast to the expectations, nutlin-3 concentrations that did not affect viability of p53-mutated cell lines strongly increased the efficacy of vincristine in p53-mutated, P-glycoprotein (P-gp)–overexpressing cell lines (decrease in IC50s 92- to 3,434-fold). Similar results were obtained for other P-gp substrates. Moreover, nutlin-3 reduced efflux of rhodamine 123 and other fluorescence dyes that are effluxed by P-gp. Investigation of Madin-Darby canine kidney (MDCK) II cells stably transfected with plasmids encoding for P-gp (MDCKII MDR1) or multidrug resistance protein 1 (MRP-1, MDCKII MRP1) revealed that nutlin-3 not only interferes with P-gp but also affects MRP-1–mediated efflux. Kinetic studies and investigation of P-gp-ATPase activity showed that nutlin-3 is likely to act as a P-gp transport substrate. Examination of the nutlin-3 enantiomers nutlin-3a and nutlin-3b revealed that, in contrast to MDM2-inhibitory activity that is limited to nutlin-3a, both enantiomers similarly interfere with P-gp–mediated drug efflux. In conclusion, nutlin-3–induced inhibition of P-gp and MRP-1 was discovered as a novel anticancer mechanism of the substance in this report. [Cancer Res 2009;69(2):416–21]

Item Type: Article
DOI/Identification number: 10.1158/0008-5472.CAN-08-1856
Uncontrolled keywords: nutlin-3; p53; multidrug resistance; P-glycoprotein; ABC transporters
Subjects: Q Science
Divisions: Faculties > Sciences > School of Biosciences
Depositing User: Sue Davies
Date Deposited: 08 Oct 2012 13:55 UTC
Last Modified: 22 Jan 2020 04:04 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/31387 (The current URI for this page, for reference purposes)
Michaelis, Martin: https://orcid.org/0000-0002-5710-5888
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