1. ¹Research Program Innovative Cancer Diagnostics and Therapy, German Cancer Research Center (DKFZ), Heidelberg, Germany
2. ²Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany
3. ³Department of Radiation Oncology, Mannheim Medical Center, University of Heidelberg, Mannheim, Germany
4. ⁴III. Medizinische Universitätsklinik, Fakultät fur Klinische Medizin Mannheim der Universität Heidelberg, Mannheim, Germany
5. ⁵Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany
6. ⁶Department of Haematology, Imperial College School of Medicine, Hammersmith Hospital, London, UK

Correspondence: Dr. med. S Fruehauf, Department of Internal Medicine V, University of Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany. Fax: +49 6221 566824; E-mail: stefan_fruehauf@med.uni-heidelberg.de

⁷These authors contributed equally to this study.

Received 26 March 2004; Accepted 4 March 2005; Published online 5 May 2005.

Abstract

Overexpression of BCR-ABL and P-glycoprotein (Pgp) are two of the known mechanisms of imatinib resistance. As combination therapy may allow to overcome drug resistance, we investigated the effect of combination treatment with imatinib and 17-allylamino-17-demethoxygeldanamycin (17-AAG), a heat-shock protein 90 (Hsp90) inhibitor, on different imatinib-sensitive and imatinib-resistant CML cell lines. In imatinib-sensitive cells, combination index (CI) values obtained using the method of Chou and Talalay indicated additive (CI=1) or marginally antagonistic (CI>1) effects following simultaneous treatment with imatinib and 17-AAG. In imatinib-resistant cells both drugs acted synergistically (CI<1). In primary chronic-phase CML cells additive or synergistic effects of the combination of imatinib plus 17-AAG were discernible. Annexin V/propidium iodide staining showed that the activity of imatinib plus 17-AAG is mediated by apoptosis. Combination treatment with imatinib plus 17-AAG was more effective in reducing the BCR-ABL protein level than 17-AAG alone. Monotherapy with 17-AAG decreased P-glycoprotein activity, which may increase intracellular imatinib levels and contribute to the sensitization of CML cells to imatinib. The results suggest that combination of imatinib and 17-AAG may be useful to overcome imatinib resistance in a clinical setting.