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

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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., Michaelis, M., Rothweiler, F., Zehner, R., Cinatl, J., Voges, Y., Sharifi, M., Riecken, K., Meyer, J., von Deimling, A., Fichtner, I., Ghafourian, T., 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.
Keywords:	Animals, Mice
Source:	Translational Oncology
ISSN:	1944-7124
Publisher:	Neoplasia Press
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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