TY  - JOUR
A1  - Michaelis, Martin
A1  - Rothweiler, Florian
A1  - Wurglics, Mario
A1  - Aniceto, Natalia
A1  - Dittrich, Michaela
A1  - Zettl, Heiko
A1  - Wiese, Michael
A1  - Wass, Mark N.
A1  - Ghafourian, Taravat
A1  - Schubert-Zsilavecz, Manfred
A1  - Cinatl, Jindrich
T1  - Substrate-specific effects of pirinixic acid derivatives on ABCB1-mediated drug transport
T2  - OncoTarget
N2  - 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.
KW  - pirinixic acid derivative
KW  - ABCB1
KW  - cancer
KW  - drug resistance
KW  - pirinixic acid
Y1  - 2016
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/45227
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-452279
SN  - 1949-2553
N1  - All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
VL  - 7
IS  - 10
SP  - 11664
EP  - 11676
PB  - Impact Journals LLC
CY  - [s. l.]
ER  -