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

• Verfasst von: Löschmann, Nadine [VerfasserIn]
• Verfasst von: Michaelis, Martin [VerfasserIn]
• Verfasst von: Rothweiler, Florian [VerfasserIn]
• Verfasst von: Zehner, Richard [VerfasserIn]
• Verfasst von: Cinatl, Jaroslav [VerfasserIn]
• Verfasst von: Voges, Yvonne [VerfasserIn]
• Verfasst von: Sharifi, Mohsen [VerfasserIn]
• Verfasst von: Riecken, Kristoffer [VerfasserIn]
• Verfasst von: Meyer, Jochen [VerfasserIn]
• Verfasst von: Deimling, Andreas von [VerfasserIn]
• Verfasst von: Fichtner, Iduna [VerfasserIn]
• Verfasst von: Ghafourian, Taravat [VerfasserIn]
• Verfasst von: Westermann, Frank [VerfasserIn]
• Verfasst von: Cinatl, Jindrich [VerfasserIn]
• Titel: Testing of SNS-032 in a panel of human neuroblastoma cell lines with acquired resistance to a broad range of drugs
• Verf.angabe: Nadine Löschmann, Martin Michaelis, Florian Rothweiler, Richard Zehner, Jaroslav Cinatl, Yvonne Voges, Mohsen Sharifi, Kristoffer Riecken, Jochen Meyer, Andreas von Deimling, Iduna Fichtner, Taravat Ghafourian, Frank Westermann and Jindrich Cinatl
• Jahr: 2013
• Jahr des Originals: 2014
• Umfang: 12 S.
• Fussnoten: Available online 19 February 2014 ; Gesehen am 21.05.2021
• Titel Quelle: Enthalten in: Translational oncology
• Ort Quelle: Ann Arbor, Mich. : [Verlag nicht ermittelbar], 2008
• Jahr Quelle: 2013
• Band/Heft Quelle: 6(2013), 6 vom: Dez., Seite 685-696
• ISSN Quelle: 1936-5233
• DOI: doi:10.1593/tlo.13544
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 175835206X

Abstract

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.