1. ¹Imperial College London, Hammersmith Hospital, London, UK
2. ²Singapore General Hospital, Singapore, Singapore
3. ³Howard Hughes Medical Institute, Oregon Health & Science University, Portland, OR, USA

Correspondence: Professor JV Melo, Department of Haematology, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK. Fax: +44 20 8742 9335; E-mail: j.melo@imperial.ac.uk

Received 8 August 2005; Accepted 16 August 2005; Published online 15 September 2005.

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.