Nadine Löschmann, Martin Michaelis, Florian Rothweiler, Richard Zehner, Jaroslav Cinatl, Yvonne Voges, Mohsen Sharifi, Kristoffer Riecken, Jochen Meyer, Andreas von Deimling, Iduna Fichtner, Taravat Ghafourian, Frank Westermann, Jindrich Cinatl
- Novel treatment options are needed for the successful therapy of patients with high-risk neuroblastoma. Here, we investigated the cyclin-dependent kinase (CDK) inhibitor SNS-032 in a panel of 109 neuroblastoma cell lines consisting of 19 parental cell lines and 90 sublines with acquired resistance to 14 different anticancer drugs. Seventy-three percent of the investigated neuroblastoma cell lines and all four investigated primary tumor samples displayed concentrations that reduce cell viability by 50% in the range of the therapeutic plasma levels reported for SNS-032 (<754 nM). Sixty-two percent of the cell lines and two of the primary samples displayed concentrations that reduce cell viability by 90% in this concentration range. SNS-032 also impaired the growth of the multidrug-resistant cisplatin-adapted UKF-NB-3 subline UKF-NB-3rCDDP1000 in mice. ABCB1 expression (but not ABCG2 expression) conferred resistance to SNS-032. The antineuroblastoma effects of SNS-032 did not depend on functional p53. The antineuroblastoma mechanism of SNS-032 included CDK7 and CDK9 inhibition-mediated suppression of RNA synthesis and subsequent depletion of antiapoptotic proteins with a fast turnover rate including X-linked inhibitor of apoptosis (XIAP), myeloid cell leukemia sequence 1 (Mcl-1), baculoviral IAP repeat containing 2 (BIRC2; cIAP-1), and survivin. In conclusion, CDK7 and CDK9 represent promising drug targets and SNS-032 represents a potential treatment option for neuroblastoma including therapy-refractory cases.
MetadatenVerfasserangaben: | Nadine LöschmannGND, Martin MichaelisORCiDGND, Florian RothweilerGND, Richard ZehnerORCiDGND, Jaroslav Cinatl, Yvonne Voges, Mohsen SharifiORCiD, Kristoffer RieckenORCiDGND, Jochen MeyerGND, Andreas von DeimlingORCiDGND, Iduna Fichtner, Taravat GhafourianORCiD, Frank WestermannORCiDGND, Jindrich CinatlORCiDGND |
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URN: | urn:nbn:de:hebis:30:3-759456 |
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DOI: | https://doi.org/10.1593/tlo.13544 |
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ISSN: | 1936-5233 |
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Pubmed-Id: | https://pubmed.ncbi.nlm.nih.gov/24466371 |
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Titel des übergeordneten Werkes (Englisch): | Translational oncology |
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Verlag: | Neoplasia Press, Inc |
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Verlagsort: | Ann Arbor, Mich. |
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Dokumentart: | Wissenschaftlicher Artikel |
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Sprache: | Englisch |
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Datum der Veröffentlichung (online): | 19.04.2014 |
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Jahr der Erstveröffentlichung: | 2013 |
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Veröffentlichende Institution: | Universitätsbibliothek Johann Christian Senckenberg |
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Datum der Freischaltung: | 06.11.2023 |
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Jahrgang: | 6.2013 |
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Ausgabe / Heft: | 6 |
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Seitenzahl: | 21 |
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Erste Seite: | 685 |
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Letzte Seite: | 696 |
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HeBIS-PPN: | 517175169 |
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Institute: | Medizin |
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DDC-Klassifikation: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
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Sammlungen: | Universitätspublikationen |
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Lizenz (Deutsch): | Creative Commons - Namensnennung-Nicht kommerziell-Keine Bearbeitung 3.0 |
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