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-3(r)CDDP(1000) 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.
Institut für Medizinische Virologie, Klinikum der Goethe-Universität, Frankfurt am Main, Germany.
Nadine
N
Löschmann
Centre for Molecular Processing and School of Biosciences, University of Kent, Canterbury, United Kingdom.
Martin
M
Michaelis
Institut für Medizinische Virologie, Klinikum der Goethe-Universität, Frankfurt am Main, Germany.
Florian
F
Rothweiler
Institut für Rechtsmedizin, Klinikum der Goethe-Universität, Frankfurt am Main, Germany.
Richard
R
Zehner
Institut für Medizinische Virologie, Klinikum der Goethe-Universität, Frankfurt am Main, Germany.
Jaroslav
J
Cinatl
Institut für Medizinische Virologie, Klinikum der Goethe-Universität, Frankfurt am Main, Germany.
Yvonne
Y
Voges
Medway School of Pharmacy, Universities of Kent and Greenwich, Kent, United Kingdom.
Mohsen
M
Sharifi
Forschungsabteilung Zell- und Gentherapie, Interdisziplinäre Klinik und Poliklinik für Stammzelltransplantation, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
Kristoffer
K
Riecken
Department of Neuropathology, Ruprecht-Karls-University Heidelberg and Deutsches Krebsforschungszentrum, Heidelberg, Germany.
Jochen
J
Meyer
Department of Neuropathology, Ruprecht-Karls-University Heidelberg and Deutsches Krebsforschungszentrum, Heidelberg, Germany.
Andreas
A
von Deimling
Max Delbrück Center for Molecular Medicine, Berlin, Germany.
Iduna
I
Fichtner
Medway School of Pharmacy, Universities of Kent and Greenwich, Kent, United Kingdom.
Taravat
T
Ghafourian
Division of Tumor Genetics (B030), German Cancer Research Center, Heidelberg, Germany.
Frank
F
Westermann
Institut für Medizinische Virologie, Klinikum der Goethe-Universität, Frankfurt am Main, Germany.
Jindrich
J
Cinatl