426120450

Substrate-specific effects of pirinixic acid derivatives on ABCB1-mediated drug transport / Martin Michaelis, Florian Rothweiler, Mario Wurglics, Natalia Aniceto, Michaela Dittrich, Heiko Zettl, Michael Wiese, Mark Wass, Taravat Ghafourian, Manfred Schubert-Zsilavecz, Jindrich Cinatl

Michaelis, Martin [Verfasser] ; Rothweiler, Florian [Verfasser] ; Wurglics, Mario,i1970- [Verfasser] ; Aniceto, Natalia [Verfasser] ; Dittrich, Michaela [Verfasser] ; Zettl, Heiko [Verfasser] ; Wiese, Michael [Verfasser] ; Wass, Mark [Verfasser] ; Ghafourian, Taravat [Verfasser] ; Schubert-Zsilavecz, Manfred [Verfasser] ; Cinatl, Jindrich [Verfasser]

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.

OncoTarget. - [Erscheinungsort nicht ermittelbar] : Impact Journals LLC, 2010-. - Online-Ressource. - ISSN 1949-2553. - Band 7, Heft 10 (2016), Seite 11664-11676

 

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