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Testing of SNS-032 in a panel of human neuroblastoma cell lines with acquired resistance to a broad range of drugs

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 t...

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Hauptverfasser: Löschmann, Nadine (VerfasserIn) , Michaelis, Martin (VerfasserIn) , Rothweiler, Florian (VerfasserIn) , Zehner, Richard (VerfasserIn) , Cinatl, Jaroslav (VerfasserIn) , Voges, Yvonne (VerfasserIn) , Sharifi, Mohsen (VerfasserIn) , Riecken, Kristoffer (VerfasserIn) , Meyer, Jochen (VerfasserIn) , Deimling, Andreas von (VerfasserIn) , Fichtner, Iduna (VerfasserIn) , Ghafourian, Taravat (VerfasserIn) , Westermann, Frank (VerfasserIn) , Cinatl, Jindrich (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: 2013
In: Translational oncology
Year: 2014, Jahrgang: 6, Heft: 6, Pages: 685-696
ISSN:1936-5233
DOI:10.1593/tlo.13544
Online-Zugang:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1593/tlo.13544
Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S1936523313800083
Volltext
Verfasserangaben: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 and Jindrich Cinatl
Beschreibung
Zusammenfassung: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.
Beschreibung:Available online 19 February 2014
Gesehen am 21.05.2021
Beschreibung:Online Resource
ISSN:1936-5233
DOI:10.1593/tlo.13544

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