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
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
Date of Publication (online):2014/04/19
Year of first Publication:2013
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2023/11/06
Page Number:21
First Page:685
Last Page:696
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung-Nicht kommerziell-Keine Bearbeitung 3.0