Oncotarget

Research Papers:

Substrate-specific effects of pirinixic acid derivatives on ABCB1-mediated drug transport

Martin Michaelis _, Florian Rothweiler, Mario Wurglics, Natália Aniceto, Michaela Dittrich, Heiko Zettl, Michael Wiese, Mark Wass, Taravat Ghafourian, Manfred Schubert-Zsilavecz, Jindrich Cinatl

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Oncotarget. 2016; 7:11664-11676. https://doi.org/10.18632/oncotarget.7345

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Abstract

Martin Michaelis1,2,7, Florian Rothweiler1, Mario Wurglics3, Natália Aniceto4, Michaela Dittrich3, Heiko Zettl3, Michael Wiese4,5, Mark Wass2, Taravat Ghafourian6, Manfred Schubert-Zsilavecz3, Jindrich Cinatl1

1Institut für Medizinische Virologie, Klinikum der Goethe-Universität, Frankfurt am Main 60596, Germany

2Centre for Molecular Processing and School of Biosciences, University of Kent, Canterbury CT2 7NJ, UK

3Institute for Pharmaceutical Chemistry, Goethe-University, Frankfurt am Main 60438, Germany

4Medway School of Pharmacy, Universities of Kent and Greenwich in Medway, Chatham, Kent ME4 4TB, UK

5Pharmaceutical Institute, University of Bonn, Bonn 53121, Germany

6School of Life Sciences, University of Sussex, Brighton BN1 9QG, UK

7Current address: Centre for Molecular Processing and School of Biosciences, University of Kent, Canterbury CT2 7NJ, UK

Correspondence to:

Jindrich Cinatl, e-mail: Cinatl@em.uni-frankfurt.de

Keywords: pirinixic acid derivative, ABCB1, cancer, drug resistance, pirinixic acid

Received: December 17, 2015     Accepted: January 26, 2016     Published: February 12, 2016

ABSTRACT

Pirinixic acid derivatives, a new class of drug candidates for a range of diseases, interfere with targets including PPARα, PPARγ, 5-lipoxygenase (5-LO), and microsomal prostaglandin and E2 synthase-1 (mPGES1). Since 5-LO, mPGES1, PPARα, and PPARγ represent potential anti-cancer drug targets, we here investigated the effects of 39 pirinixic acid derivatives on prostate cancer (PC-3) and neuroblastoma (UKF-NB-3) cell viability and, subsequently, the effects of selected compounds on drug-resistant neuroblastoma cells. Few compounds affected cancer cell viability in low micromolar concentrations but there was no correlation between the anti-cancer effects and the effects on 5-LO, mPGES1, PPARα, or PPARγ. Most strikingly, pirinixic acid derivatives interfered with drug transport by the ATP-binding cassette (ABC) transporter ABCB1 in a drug-specific fashion. LP117, the compound that exerted the strongest effect on ABCB1, interfered in the investigated concentrations of up to 2μM with the ABCB1-mediated transport of vincristine, vinorelbine, actinomycin D, paclitaxel, and calcein-AM but not of doxorubicin, rhodamine 123, or JC-1. In silico docking studies identified differences in the interaction profiles of the investigated ABCB1 substrates with the known ABCB1 binding sites that may explain the substrate-specific effects of LP117. Thus, pirinixic acid derivatives may offer potential as drug-specific modulators of ABCB1-mediated drug transport.

Author Information

Martin Michaelis
Primary Contact  _

Florian Rothweiler

Mario Wurglics

Natália Aniceto

Michaela Dittrich

Heiko Zettl

Michael Wiese

Mark Wass

Taravat Ghafourian

Manfred Schubert-Zsilavecz

Jindrich Cinatl


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