¹Department of Haematology, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, UK

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

Received 1 November 2006; Revised 11 November 2006; Accepted 13 November 2006; Published online 25 January 2007.

Abstract

Imatinib mesylate is a selective inhibitor of the oncogenic tyrosine kinase, Bcr-Abl, and is widely used as a first-line treatment for chronic myeloid leukaemia (CML). Prolonged monotherapy is frequently associated with patients becoming refractory to imatinib. Therefore, there is considerable interest in small molecule inhibitors which may be used either as replacements or as adjuncts to existing imatinib therapy. For this purpose, it is most likely that drugs which do not share imatinib's mechanism of action will be most valuable. We compared two such compounds with different modes of action, adaphostin and 17-allylamino-17-demethoxygeldanamycin (17-AAG), for their cytotoxic effect and ability to induce the downregulation of cellular proteins in a murine haemopoietic cell line transformed with human p210^Bcr-Abl, and two subclones resistant to imatinib owing to an Abl-kinase domain mutation (E255K) or amplification of the BCR-ABL gene, respectively. We found that, whereas 17-AAG selectively killed Bcr-Abl-positive cells and inhibited proteins dependent on heat-shock protein 90 for their stability (p210^Bcr-Abl and Akt), adaphostin induced the downregulation of multiple cell-signalling proteins (p210^Bcr-Abl, Akt, Bcr, Abl and STAT5a) and was cytotoxic to both Bcr-Abl-positive and -negative cells. We suggest that both compounds may prove useful in the treatment of CML but caution that undesirable side-effects may result from the inhibition of multiple cell signalling proteins.