Abstract
The CDK inhibitor SNS-032 had previously exerted promising anti-neuroblastoma activity via CDK7 and 9 inhibition. ABCB1 expression was identified as major determinant of SNS-032 resistance. Here, we investigated the role of ABCB1 in acquired SNS-032 resistance. In contrast to ABCB1-expressing UKF-NB-3 sub-lines resistant to other ABCB1 substrates, SNS-032-adapted UKF-NB-3 (UKF-NB-3rSNS- 032300nM) cells remained sensitive to the non-ABCB1 substrate cisplatin and were completely re-sensitized to cytotoxic ABCB1 substrates by ABCB1 inhibition. Moreover, UKF-NB-3rSNS-032300nM cells remained similarly sensitive to CDK7 and 9 inhibition as UKF-NB-3 cells. In contrast, SHEPrSNS-0322000nM, the SNS-032-resistant sub-line of the neuroblastoma cell line SHEP, displayed low level SNS-032 resistance also when ABCB1 was inhibited. This discrepancy may be explained by the higher SNS-032 concentrations that were used to establish SHEPrSNS-0322000nM cells, since SHEP cells intrinsically express ABCB1 and are less sensitive to SNS-032 (IC50 912 nM) than UKF-NB-3 cells (IC50 153 nM). In conclusion, we show that ABCB1 expression represents the primary (sometimes exclusive) resistance mechanism in neuroblastoma cells with acquired resistance to SNS-032. Thus, ABCB1 inhibitors may increase the SNS-032 efficacy in ABCB1-expressing cells and prolong or avoid resistance formation.
Keywords:
ABCB1; CDK inhibitor; cancer; multi-drug resistance; neuroblastoma.
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B / genetics
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ATP Binding Cassette Transporter, Subfamily B / metabolism
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ATP Binding Cassette Transporter, Subfamily G, Member 2 / genetics
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ATP Binding Cassette Transporter, Subfamily G, Member 2 / metabolism
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Antineoplastic Agents / pharmacology*
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Antineoplastic Agents / therapeutic use
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Cell Line, Tumor
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Cyclin-Dependent Kinase 2 / antagonists & inhibitors
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Cyclin-Dependent Kinase 9 / antagonists & inhibitors
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Cyclin-Dependent Kinase-Activating Kinase
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Cyclin-Dependent Kinases / antagonists & inhibitors
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Drug Resistance, Neoplasm*
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Humans
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Inhibitory Concentration 50
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Multidrug Resistance-Associated Proteins / genetics
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Multidrug Resistance-Associated Proteins / metabolism
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism
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Neuroblastoma / drug therapy*
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Neuroblastoma / pathology
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Oxazoles / pharmacology*
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Oxazoles / therapeutic use
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Protein Kinase Inhibitors / pharmacology*
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Protein Kinase Inhibitors / therapeutic use
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Pyrazoles / pharmacology
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Pyrimidines / pharmacology
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RNA Interference
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RNA, Small Interfering / metabolism
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Sulfonamides / pharmacology
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Thiazoles / pharmacology*
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Thiazoles / therapeutic use
Substances
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3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide
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ABCB1 protein, human
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ABCG2 protein, human
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ATP Binding Cassette Transporter, Subfamily B
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ATP Binding Cassette Transporter, Subfamily G, Member 2
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Antineoplastic Agents
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Multidrug Resistance-Associated Proteins
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N-(5-(((5-(1,1-dimethylethyl)-2-oxazolyl)methyl)thio)-2-thiazolyl)-4-piperidinecarboxamide
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Neoplasm Proteins
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Oxazoles
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Protein Kinase Inhibitors
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Pyrazoles
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Pyrimidines
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RNA, Small Interfering
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Sulfonamides
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Thiazoles
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BS-181
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CDK2 protein, human
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CDK9 protein, human
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinase 9
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Cyclin-Dependent Kinases
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multidrug resistance-associated protein 1
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Cyclin-Dependent Kinase-Activating Kinase
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CDK7 protein, human