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

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

Item Type: Article
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: 06 Jun 2017 11:20 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
  • Depositors only (login required):