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

Michaelis, Martin, Rothweiler, Florian, Wurglics, Mario, Aniceto, Natália, Dittrich, Michael, Zettl, Heiko, Wiese, Michael, Wass, Mark, Ghafourian, Taravat, Schubert-Zsilavecz, Manfred and Cinatl, Jindrich (2016) Substrate-specific effects of pirinixic acid derivatives on ABCB1-mediated drug transport. Oncotarget, 7 (10). pp. 11664-11676. ISSN 1949-2553

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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
Keywords: antineoplastic agent; arachidonate 5 lipoxygenase; calcein; calcein AM; cisplatin; dactinomycin; doxorubicin; hz 123; hz 51; lp 117; microsome enzyme; multidrug resistance protein 1; navelbine; paclitaxel; peroxisome proliferator activated receptor alpha; peroxisome proliferator activated receptor gamma; pirinixic acid; pirinixic acid derivative; prostaglandin and E2 synthase 1; rhodamine 123; unclassified drug; verapamil; vincristine; ys 71; ys80, antineoplastic activity; Article; binding site; cancer resistance; cell viability; chemosensitivity; concentration (parameters); controlled study; drug effect; drug transport; human; human cell; IC50; male; molecular docking; neuroblastoma cell; PC 3 cell line; prostate cancer cell line; sensitivity analysis; UKF NB 3 cell line
Schools and Departments: School of Life Sciences > Biochemistry
Depositing User: Taravat Ghafourian
Date Deposited: 11 Oct 2016 09:50
Last Modified: 07 Mar 2017 05:08
URI: http://sro.sussex.ac.uk/id/eprint/64122

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