TY  - JOUR
A1  - Löschmann, Nadine
A1  - Michaelis, Martin
A1  - Rothweiler, Florian
A1  - Zehner, Richard
A1  - Cinatl, Jaroslav
A1  - Voges, Yvonne
A1  - Sharifi, Mohsen
A1  - Riecken, Kristoffer
A1  - Meyer, Jochen
A1  - Deimling, Andreas von
A1  - Fichtner, Iduna
A1  - Ghafourian, Taravat
A1  - Westermann, Frank
A1  - Cinatl, Jindrich
T1  - Testing of SNS-032 in a panel of human neuroblastoma cell lines with acquired resistance to a broad range of drugs
T2  - Translational oncology
N2  - 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.
Y1  - 2014
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/75945
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-759456
SN  - 1936-5233
VL  - 6.2013
IS  - 6
SP  - 685
EP  - 696
PB  - Neoplasia Press, Inc
CY  - Ann Arbor, Mich.
ER  -