Martin Michaelis, Florian Rothweiler, Mario Wurglics, Natalia Aniceto, Michaela Dittrich, Heiko Zettl, Michael Wiese, Mark N. Wass, Taravat Ghafourian, Manfred Schubert-Zsilavecz, Jindrich Cinatl
- 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.
MetadatenAuthor: | Martin MichaelisORCiDGND, Florian RothweilerGND, Mario WurglicsGND, Natalia Aniceto, Michaela Dittrich, Heiko Zettl, Michael WieseORCiD, Mark N. WassORCiD, Taravat GhafourianORCiD, Manfred Schubert-ZsilaveczGND, Jindrich CinatlORCiDGND |
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URN: | urn:nbn:de:hebis:30:3-452279 |
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DOI: | https://doi.org/10.18632/oncotarget.7345 |
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ISSN: | 1949-2553 |
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Pubmed Id: | https://pubmed.ncbi.nlm.nih.gov/26887049 |
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Parent Title (English): | OncoTarget |
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Publisher: | Impact Journals LLC |
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Place of publication: | [s. l.] |
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Document Type: | Article |
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Language: | English |
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Year of Completion: | 2016 |
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Date of first Publication: | 2016/02/12 |
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Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
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Release Date: | 2017/12/12 |
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Tag: | ABCB1; cancer; drug resistance; pirinixic acid; pirinixic acid derivative |
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Volume: | 7 |
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Issue: | 10 |
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Page Number: | 13 |
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First Page: | 11664 |
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Last Page: | 11676 |
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Note: | All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License. |
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HeBIS-PPN: | 426120450 |
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Institutes: | Biochemie, Chemie und Pharmazie / Pharmazie |
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| Medizin / Medizin |
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Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
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Sammlungen: | Universitätspublikationen |
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Licence (German): | Creative Commons - Namensnennung 3.0 |
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