ABCG2 impairs the activity of the aurora kinase inhibitor tozasertib but not of alisertib
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% (IC50) was dramatically increased in ABCG2-transduced UKF-NB-3(ABCG2) cells (48.8-fold) compared to UKF-NB-3 cells and vector-transduced control cells. The ABCG2 inhibitor WK-X-34 reduced tozasertib IC50 to the level of non-ABCG2-expressing UKF-NB-3 cells. Furthermore, ABCG2 depletion from UKF-NB-3(ABCG2) cells 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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2015 |
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| Erschienen: |
2015 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:8 |
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| Enthalten in: |
BMC research notes - 8(2015) vom: 28. Sept., Seite 484 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Michaelis, Martin [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 13.06.2016 Date Revised 01.06.2022 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1186/s13104-015-1405-4 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM253187672 |
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| 100 | 1 | |a Michaelis, Martin |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a ABCG2 impairs the activity of the aurora kinase inhibitor tozasertib but not of alisertib |
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| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 520 | |a RESULTS: The tozasertib concentration that reduces cell viability by 50% (IC50) was dramatically increased in ABCG2-transduced UKF-NB-3(ABCG2) cells (48.8-fold) compared to UKF-NB-3 cells and vector-transduced control cells. The ABCG2 inhibitor WK-X-34 reduced tozasertib IC50 to the level of non-ABCG2-expressing UKF-NB-3 cells. Furthermore, ABCG2 depletion from UKF-NB-3(ABCG2) cells 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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
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| 700 | 1 | |a Cinatl, Jindrich |c Jr |e verfasserin |4 aut | |
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