Substrate-specific effects of pirinixic acid derivatives on ABCB1-mediated drug transport
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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
Jindrich Cinatl, e-mail: [email protected]
Keywords: pirinixic acid derivative, ABCB1, cancer, drug resistance, pirinixic acid
Received: December 17, 2015 Accepted: January 26, 2016 Published: February 12, 2016
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.
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