title: Substrate-specific effects of pirinixic acid derivatives on ABCB1-mediated drug transport.
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.
authors.affiliation: Institut für Medizinische Virologie, Klinikum der Goethe-Universität, Frankfurt am Main 60596, Germany.|Centre for Molecular Processing and School of Biosciences, University of Kent, Canterbury CT2 7NJ, UK.|Current address: Centre for Molecular Processing and School of Biosciences, University of Kent, Canterbury CT2 7NJ, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Michaelis
authors.affiliation: Institut für Medizinische Virologie, Klinikum der Goethe-Universität, Frankfurt am Main 60596, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Rothweiler
authors.affiliation: Institute for Pharmaceutical Chemistry, Goethe-University, Frankfurt am Main 60438, Germany.
authors.forename: Mario
authors.initials: M
authors.lastname: Wurglics
authors.affiliation: Medway School of Pharmacy, Universities of Kent and Greenwich in Medway, Chatham, Kent ME4 4TB, UK.
authors.forename: Natália
authors.initials: N
authors.lastname: Aniceto
authors.affiliation: Institute for Pharmaceutical Chemistry, Goethe-University, Frankfurt am Main 60438, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Dittrich
authors.affiliation: Institute for Pharmaceutical Chemistry, Goethe-University, Frankfurt am Main 60438, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Zettl
authors.affiliation: Medway School of Pharmacy, Universities of Kent and Greenwich in Medway, Chatham, Kent ME4 4TB, UK.|Pharmaceutical Institute, University of Bonn, Bonn 53121, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Wiese
authors.affiliation: Centre for Molecular Processing and School of Biosciences, University of Kent, Canterbury CT2 7NJ, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Wass
authors.affiliation: School of Life Sciences, University of Sussex, Brighton BN1 9QG, UK.
authors.forename: Taravat
authors.initials: T
authors.lastname: Ghafourian
authors.affiliation: Institute for Pharmaceutical Chemistry, Goethe-University, Frankfurt am Main 60438, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Schubert-Zsilavecz
authors.affiliation: Institut für Medizinische Virologie, Klinikum der Goethe-Universität, Frankfurt am Main 60596, Germany.
authors.forename: Jindrich
authors.initials: J
authors.lastname: Cinatl
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008297:Male; D062105:Molecular Docking Simulation; D009447:Neuroblastoma / Q000188:drug therapy / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D013379:Substrate Specificity; D014750:Vincristine / Q000494:pharmacology
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D011743:Pyrimidines; D014750:Vincristine; C006253:pirinixic acid
keywords: ABCB1; cancer; drug resistance; pirinixic acid; pirinixic acid derivative