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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

Item Type:Article
Title:Testing of SNS-032 in a panel of human neuroblastoma cell lines with acquired resistance to a broad range of drugs
Creators Name:Loeschmann, N. and Michaelis, M. and Rothweiler, F. and Zehner, R. and Cinatl, J. and Voges, Y. and Sharifi, M. and Riecken, K. and Meyer, J. and von Deimling, A. and Fichtner, I. and Ghafourian, T. and Westermann, F. and Cinatl Jr., J.
Abstract:Novel treatment options are needed for the successful therapy of high-risk neuroblastoma patients. 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 sub-lines with acquired resistance to 14 different anti-cancer drugs. 73% of the investigated neuroblastoma cell lines and all four investigated primary tumour samples displayed IC50 values in the range of the therapeutic plasma levels reported for SNS-032 (< 754nM). 62% of the cell lines and two of the primary samples displayed IC90 values in this concentration range. SNS-032 also impaired the growth of the multi-drug resistant cisplatin-adapted UKF-NB-3 sub-line UKF-NB-3rCDDP1000 in mice. ABCB1 expression (but not ABCG2 expression) conferred resistance to SNS-032. The anti-neuroblastoma effects of SNS-032 did not depend on functional p53. The anti-neuroblastoma mechanism of SNS-032 included CDK7 and 9 inhibition-mediated suppression of RNA synthesis and subsequent depletion of anti-apoptotic proteins with a fast turnover rate including XIAP, Mcl-1, cIAP1, 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.
Source:Translational Oncology
ISSN:1944-7124
Publisher:Neoplasia Press (U.S.A.)
Volume:6
Number:6
Page Range:685-696
Date:December 2013
Official Publication:https://doi.org/10.1593/tlo.13544
PubMed:View item in PubMed

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