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

Michaelis, Martin, Rothweiler, Florian, Wurglics, Mario, Aniceto, Natália, Dittrich, Michaela, Zettl, Heiko, Wiese, Michael, Wass, Mark N., Ghafourian, Taravat, Schubert-Zsilavecz, Manfred, and others. (2016) Substrate-specific effects of pirinixic acid derivatives on ABCB1-mediated drug transport. Oncotarget, 7 (10). pp. 11664-76. ISSN 1949-2553. (doi:10.18632/oncotarget.7345) (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)

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. (Contact us about this Publication)
Official URL
http://dx.doi.org/10.18632/oncotarget.7345

Abstract

Pirinixic acid derivatives, a new class of drug candidates for a range of diseases, interfere with targets including PPAR?, PPAR?, 5-lipoxygenase (5-LO), and microsomal prostaglandin and E2 synthase-1 (mPGES1). Since 5-LO, mPGES1, PPAR?, and PPAR? 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, PPAR?, or PPAR?. 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 2?M 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.

Item Type: Article
DOI/Identification number: 10.18632/oncotarget.7345
Subjects: R Medicine > RM Therapeutics. Pharmacology
Divisions: Faculties > Sciences > School of Biosciences
Depositing User: Martin Michaelis
Date Deposited: 29 Apr 2016 05:39 UTC
Last Modified: 29 May 2019 17:16 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/55190 (The current URI for this page, for reference purposes)
Michaelis, Martin: https://orcid.org/0000-0002-5710-5888
Wass, Mark N.: https://orcid.org/0000-0001-5428-6479
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