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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Löschmann, Nadine ; Michaelis, Martin ; Rothweiler, Florian ; Zehner, Richard ; Cinatl, Jaroslav ; Voges, Yvonne ; Sharifi, Mohsen ; Riecken, Kristoffer ; Meyer, Jochen ; von Deimling, Andreas ; Fichtner, Iduna ; Ghafourian, Taravat ; Westermann, Frank ; Cinatl Jr, Jindrich (2013)
  • Publisher: Elsevier BV
  • Journal: Translational Oncology, volume 6, issue 6, pages 685-IN18 (issn: 1936-5233)
  • Related identifiers: doi: 10.1593/tlo.13544
  • Subject: RC0254 | RS | Cancer Research | Oncology
    mesheuropmc: animal structures

Novel treatment options are needed for the successful therapy of patients with high-risk neuroblastoma. Here, we investigated the cyclindependent 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.
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