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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 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.

SUBMITTER: Michaelis M

PROVIDER: S-EPMC4905501 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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

Michaelis Martin M Rothweiler Florian F Wurglics Mario M Aniceto Natália N Dittrich Michaela M Zettl Heiko H Wiese Michael M Wass Mark M Ghafourian Taravat T Schubert-Zsilavecz Manfred M Cinatl Jindrich J

Oncotarget 20160301 10

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 ...[more]

PMID: 26887049

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Dataset Information

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

Publications

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

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