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CME, BCR/ABL Studies and Myeloproliferative Disorders

Zoledronate inhibits proliferation and induces apoptosis of imatinib-resistant chronic myeloid leukaemia cells

Leukemia volume 19, pages 1896–1904 (2005)Cite this article

Abstract

Although imatinib mesylate has revolutionized the treatment of chronic myeloid leukaemia (CML), resistance to the drug, manifesting as relapse after an initial response or persistence of disease, remains a therapeutic challenge. In order to overcome this, alternative or additional targeting of signaling pathways downstream of Bcr-Abl may provide the best option for improving clinical response. Bisphosphonates, such as zoledronate, have been shown to inhibit the oncogenicity of Ras, an important downstream effector of Bcr-Abl. In this study, we show that zoledronate is equally effective in inhibiting the proliferation and clonogenicity of both imatinib-sensitive and -resistant CML cells, regardless of their mechanism of resistance. This is achieved by the induction of S-phase cell cycle arrest and apoptosis, through the inhibition of prenylation of Ras and Ras-related proteins by zoledronate. The combination of imatinib and zoledronate also augmented the activity of either drug alone and this occurred in imatinib-resistant CML cells as well. Since zoledronate is already available for clinical use, these results suggest that it may be an effective addition to the armamentarium of drugs for the treatment of CML.

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Acknowledgements

We are grateful to Dr Elisabeth Buchdunger and Dr Jonathan Green (Novartis, Switzerland) for their kind gift of IM and ZOL, respectively, and to Dr Alex Tipping, Ms Christalla Dimitriadis and Ms Kara Johnson for their advice and technical assistance. This work was supported by the Leukaemia Research Fund, United Kingdom; Singapore General Hospital Medical Fellowship and National Medical Research Council-Totalisator Board Medical Research Fellowship, Singapore.

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Authors and Affiliations

  1. Imperial College London, Hammersmith Hospital, London, UK

    C Chuah, D J Barnes, M Kwok & J V Melo

  2. Singapore General Hospital, Singapore, Singapore

    C Chuah

  3. Howard Hughes Medical Institute, Oregon Health & Science University, Portland, OR, USA

    A Corbin, M W N Deininger & B J Druker

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Correspondence to J V Melo.

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Chuah, C., Barnes, D., Kwok, M. et al. Zoledronate inhibits proliferation and induces apoptosis of imatinib-resistant chronic myeloid leukaemia cells. Leukemia 19, 1896–1904 (2005). https://doi.org/10.1038/sj.leu.2403949

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