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

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Abstract

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.

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Acknowledgments

We thank Bernhard Berkus, Hans-Jürgen Engel and especially Carmen Hoppstock (German Cancer Research Center, Heidelberg, Germany) for their expert technical assistance and Dr. E. Buchdunger (Novartis, Basel, Switzerland) for supplying nilotinib. We are also grateful to Professor Dr. Junia Melo (Hammersmith Hospital, London, UK) and to Professor Dr. Justus Duyster (Department of Internal Medicine III, Technical University of Munich, Munich, Germany) for providing the imatinib-resistant K562-R/LAMA84-R and Ba/F3 cell lines, respectively.We also thank Dr. Christine Volk for critically reading the manuscript.

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Authors and Affiliations

  1. Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany

    Aleksandar Radujkovic, Anthony D. Ho & Julian Topaly

  2. Center of Tumor Diagnostics and Therapy, Paracelsus Clinic, Am Natruper Holz 69, 49076, Osnabrück, Germany

    Stefan Fruehauf & Julian Topaly

  3. Research Group Pharmacology of Cancer Treatment, German Cancer Research Center, Heidelberg, Germany

    W. Jens Zeller

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  1. Aleksandar Radujkovic
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  2. Stefan Fruehauf
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  3. W. Jens Zeller
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  4. Anthony D. Ho
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  5. Julian Topaly
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Correspondence to Julian Topaly.

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Radujkovic, A., Fruehauf, S., Zeller, W.J. et al. Synergistic activity of nilotinib and established chemotherapeutic drugs in imatinib-sensitive and -resistant BCR-ABL-positive cells. Cancer Chemother Pharmacol 66, 255–264 (2010). https://doi.org/10.1007/s00280-009-1158-7

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