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 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.

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Author: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
URN:urn:nbn:de:hebis:30:3-759456
DOI:https://doi.org/10.1593/tlo.13544
ISSN:1936-5233
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/24466371
Parent Title (English):Translational oncology
Publisher:Neoplasia Press, Inc
Place of publication:Ann Arbor, Mich.
Document Type:Article
Language:English
Date of Publication (online):2014/04/19
Year of first Publication:2013
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2023/11/06
Volume:6.2013
Issue:6
Page Number:21
First Page:685
Last Page:696
Institutes:Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung-Nicht kommerziell-Keine Bearbeitung 3.0