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

C. Chuah, D. J. Barnes, M. Kwok, A. Corbin, M. W.N. Deininger, B. J. Druker, J. V. Melo

Research output: Contribution to journalArticle

41 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1896-1904
Number of pages9
JournalLeukemia
Volume19
Issue number11
DOIs
StatePublished - Nov 2005

Keywords

  • Chronic myeloid leukemia
  • Imatinib mesylate
  • Zoledronic acid

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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    Chuah, C., Barnes, D. J., Kwok, M., Corbin, A., Deininger, M. W. N., Druker, B. J., & Melo, J. V. (2005). Zoledronate inhibits proliferation and induces apoptosis of imatinib-resistant chronic myeloid leukaemia cells. Leukemia, 19(11), 1896-1904. https://doi.org/10.1038/sj.leu.2403949