ABCB1 as predominant resistance mechanism in cells with acquired SNS-032 resistance
- 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.
Author: | Nadine LöschmannGND, Martin MichaelisORCiDGND, Florian RothweilerGND, Yvonne Voges, Barbora Balónová, Barry A. Blight, Jindrich CinatlORCiDGND |
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URN: | urn:nbn:de:hebis:30:3-441326 |
URL: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5295411 |
DOI: | https://doi.org/10.18632/oncotarget.11160 |
ISSN: | 1949-2553 |
Pubmed Id: | https://pubmed.ncbi.nlm.nih.gov/27517323 |
Parent Title (English): | OncoTarget |
Publisher: | Impact Journals LLC |
Place of publication: | [s. l.] |
Document Type: | Article |
Language: | English |
Date of Publication (online): | 2017/04/06 |
Year of first Publication: | 2016 |
Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
Release Date: | 2017/04/06 |
Tag: | ABCB1; CDK inhibitor; cancer; multi-drug resistance; neuroblastoma |
Volume: | 7 |
Issue: | 36 |
Page Number: | 14 |
First Page: | 58051 |
Last Page: | 58064 |
Note: | All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License. |
HeBIS-PPN: | 421385596 |
Institutes: | Medizin / Medizin |
Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
Sammlungen: | Universitätspublikationen |
Licence (German): | Creative Commons - Namensnennung 3.0 |