ABCG2 impairs the activity of the aurora kinase inhibitor tozasertib but not of alisertib

BMC Research Notes

Jindrich Cinatl³  Michael Wiese¹  Florian Rothweiler³  Florian Selt²  Martin Michaelis⁴ 

[1] Pharmaceutical Institute, University of Bonn, An der Immenburg 4, Bonn, 53121, Germany;Deutsches Krebsforschungszentrum (DKFZ), Klinische Kooperationseinheit Pädiatrische Onkologie (G340) and Pädiatrie III, Zentrum für Kinder- und Jugendmedizin, Im Neuenheimer Feld 280, Heidelberg, 69120, Germany;Institut für Medizinische Virologie, Klinikum der Goethe-Universität, Paul Ehrlich-Str. 40, Frankfurt Am Main, 60596, Germany;Centre for Molecular Processing and School of Biosciences, University of Kent, Canterbury CT2 7NJ, UK

关键词: MLN8237;    Alisertib;    MK-0457;    VX680;    Tozasertib;    Aurora kinase inhibitor;    Drug resistance;    ABCG2;   

Others  :  1229969
DOI  :  10.1186/s13104-015-1405-4

 received in 2015-07-18, accepted in 2015-08-31,  发布年份 2015

【 摘 要 】

Background

Recently, we have shown that the ATP-binding cassette (ABC) transporter ABCB1 interferes with the anti-cancer activity of the pan-aurora kinase inhibitor tozasertib (VX680, MK-0457) but not of the aurora kinase A and B inhibitor alisertib (MLN8237). Preliminary data had suggested tozasertib also to be a substrate of the ABC transporter ABCG2, another ABC transporter potentially involved in cancer cell drug resistance. Here, we studied the effect of ABCG2 on the activity of tozasertib and alisertib.

Results

The tozasertib concentration that reduces cell viability by 50 % (IC ₅₀ ) was dramatically increased in ABCG2-transduced UKF-NB-3 ^ABCG2cells (48.8-fold) compared to UKF-NB-3 cells and vector-transduced control cells. The ABCG2 inhibitor WK-X-34 reduced tozasertib IC ₅₀to the level of non-ABCG2-expressing UKF-NB-3 cells. Furthermore, ABCG2 depletion from UKF-NB-3 ^ABCG2cells using another lentiviral vector expressing an shRNA against the bicistronic mRNA of ABCG2 and eGFP largely re-sensitised these cells to tozasertib. In contrast, alisertib activity was not affected by ABCG2 expression.

Conclusions

Tozasertib but not alisertib activity is affected by ABCG2 expression. This should be considered within the design and analysis of experiments and clinical trials investigating these compounds.

【 授权许可】

   
2015 Michaelis et al.

【 图 表 】

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