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.
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Acknowledgements
We thank Bernhard Berkus (German Cancer Research Center, Heidelberg, Germany), Brigitte Geisler and Carmen Hoppstock (both Department of Internal Medicine V, University of Heidelberg) for their excellent technical support, Carina Ittrich (German Cancer Research Center, Heidelberg, Germany) for the statistical calculations, Brigitte Schoell and Heidi Holtgreve-Grez (both Institute of Human Genetics, University of Heidelberg) for chromosome preparation and FISH experiments and Dr E Buchdunger (Novartis, Basel, Switzerland) for providing imatinib mesylate.
This work was supported in part by the Deutsche José Carreras Leukämie Stiftung (Grant DJCLS-R00/03 to SF and WJZ), by the competence network ‘Acute and Chronic Leukemias’ of the Federal Ministry of Education and Research (BMBF Grant 01GI9974 to AJ) and by the Medical Faculty of the University of Heidelberg (Juniorantrag to JT).
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Radujkovic, A., Schad, M., Topaly, J. et al. Synergistic activity of imatinib and 17-AAG in imatinib-resistant CML cells overexpressing BCR-ABL – Inhibition of P-glycoprotein function by 17-AAG. Leukemia 19, 1198–1206 (2005). https://doi.org/10.1038/sj.leu.2403764
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DOI: https://doi.org/10.1038/sj.leu.2403764
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