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Synergistic activity of nilotinib and established chemotherapeutic drugs in imatinib-sensitive and -resistant BCR-ABL-positive cells

We investigated various combination treatment regimens employing nilotinib with established chemotherapeutic agents (daunorubicin, mitoxantrone, etoposide and cytarabine) in imatinib-sensitive and -resistant BCR-ABL-positive cells. Mitoxantrone or cytarabine showed synergism (CI < 1) in combinati...

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Main Authors: Radujković, Aleksandar (Author) , Fruehauf, Stefan (Author) , Zeller, W. Jens (Author) , Ho, Anthony Dick (Author) , Topaly, Julian (Author)
Format: Article (Journal)
Language:English
Published: 2010
In: Cancer chemotherapy and pharmacology
Year: 2010, Volume: 66, Issue: 2, Pages: 255-264
ISSN:1432-0843
DOI:10.1007/s00280-009-1158-7
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1007/s00280-009-1158-7
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Author Notes:Aleksandar Radujkovic, Stefan Fruehauf, W. Jens Zeller, Anthony D. Ho, Julian Topaly
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Summary:We investigated various combination treatment regimens employing nilotinib with established chemotherapeutic agents (daunorubicin, mitoxantrone, etoposide and cytarabine) in imatinib-sensitive and -resistant BCR-ABL-positive cells. Mitoxantrone or cytarabine showed synergism (CI < 1) in combination with nilotinib in imatinib-sensitive LAMA84 cells, whereas in imatinib-resistant LAMA84-R cells synergistic effects could be assessed for daunorubicin, mitoxantrone and etoposide when combined with nilotinib. In both imatinib-sensitive and -resistant K562 cells daunorubicin, mitoxantrone and etoposide demonstrated synergism in combination with nilotinib. Moreover, both daunorubicin and mitoxantrone led to synergistic antiproliferative effects when combined with nilotinib in imatinib-resistant Ba/F3 cells carrying point mutations in the ABL TK domain (E255K, E255V and T315I). Annexin V/propidium iodide staining revealed a significant enhancement of nilotinib-induced apoptosis in imatinib-resistant Ba/F3T315I and LAMA84-R cells upon combination with daunorubicin and mitoxantrone, respectively. Our results demonstrate the efficacy of combination treatment regimens employing nilotinib and established chemotherapeutic agents in improving antileukemic effects in imatinib-sensitive and imatinib-resistant cells. This may be the foundation for further study on the potential of the applied combinations in a clinical setting.
Item Description:Online veröffentlicht: 28. Oktober 2009
Gesehen am 09.05.2023
Physical Description:Online Resource
ISSN:1432-0843
DOI:10.1007/s00280-009-1158-7

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