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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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Main Authors: Löschmann, Nadine (Author) , Michaelis, Martin (Author) , Rothweiler, Florian (Author) , Zehner, Richard (Author) , Cinatl, Jaroslav (Author) , Voges, Yvonne (Author) , Sharifi, Mohsen (Author) , Riecken, Kristoffer (Author) , Meyer, Jochen (Author) , Deimling, Andreas von (Author) , Fichtner, Iduna (Author) , Ghafourian, Taravat (Author) , Westermann, Frank (Author) , Cinatl, Jindrich (Author)
Format: Article (Journal)
Language:English
Published: 2013
In: Translational oncology
Year: 2014, Volume: 6, Issue: 6, Pages: 685-696
ISSN:1936-5233
DOI:10.1593/tlo.13544
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1593/tlo.13544
Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S1936523313800083
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Author Notes: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
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Summary: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.
Item Description:Available online 19 February 2014
Gesehen am 21.05.2021
Physical Description:Online Resource
ISSN:1936-5233
DOI:10.1593/tlo.13544

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