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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Bibliographic Details
Published in:Cancer chemotherapy and pharmacology 2010-07, Vol.66 (2), p.255-264
Main Authors: Radujkovic, Aleksandar, Fruehauf, Stefan, Zeller, W. Jens, Ho, Anthony D, Topaly, Julian
Format: Article
Language:English
Subjects:
Antineoplastic agents
Antineoplastic Agents - pharmacology
Apoptosis - drug effects
BCR-ABL
Benzamides
Biological and medical sciences
Cancer Research
Cell Line, Tumor
Cell Proliferation - drug effects
Chromosome aberrations
Combination treatment
Drug Interactions
Drug Resistance, Neoplasm
Drug Synergism
Fusion Proteins, bcr-abl - metabolism
Humans
Imatinib Mesylate
Imatinib resistance
K562 Cells
Medical genetics
Medical sciences
Medicine
Medicine & Public Health
Nilotinib
Oncology
Original Article
Pharmacology. Drug treatments
Pharmacology/Toxicology
Piperazines - pharmacology
Pyrimidines - pharmacology
synergism
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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.
ISSN:0344-5704
1432-0843
DOI:10.1007/s00280-009-1158-7