Nilotinib exerts equipotent antiproliferative effects to imatinib and does not induce apoptosis in CD34⁺ CML cells

Allan, E.K., Holyoake, T.L., Jordanides, N.E., Jorgensen, H.G. and Mountford, J.C. (2007) Nilotinib exerts equipotent antiproliferative effects to imatinib and does not induce apoptosis in CD34⁺ CML cells. Blood, 109(9), pp. 4016-4019. (doi: 10.1182/blood-2006-11-057521)

Abstract

Chronic myeloid leukemia (CML) stem and progenitor cells overexpress BcrAbl and are insensitive to imatinib mesylate (IM). We therefore investigated whether these cells were efficiently targeted by nilotinib. In K562, the inhibitory concentration (IC50) of nilotinib was 30 nM versus 600 nM for IM, consistent with its reported 20-fold-higher potency. However, in primary CD34⁺ CML cells, nilotinib and IM were equipotent for inhibition of BcrAbl activity, producing equivalent but incomplete reduction in CrkL phosphorylation at 5 mu M. CML CD34⁺ cells were still able to expand over 72 hours with 5 mu M of either drug, although there was a concentration-dependent restriction of amplification. As for IM, the most primitive cells (CFSEmax) persisted and accumulated over 72 hours with nilotinib and remained caspase-3 negative. Furthermore, nilotinib with IM led to further accumulation of this population, suggesting at least additive antiproliferative effects. These results confirmed that, like IM, the predominant effect of nilotinib is antiproliferative rather than proapoptotic.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Jordanides, Ms Niove and Holyoake, Professor Tessa and Mountford, Dr Joanne and Allan, Mrs Elaine and Jorgensen, Dr Heather
• Authors: Allan, E.K., Holyoake, T.L., Jordanides, N.E., Jorgensen, H.G., and Mountford, J.C.
• College/School: College of Medical Veterinary and Life Sciences > School of Life Sciences; College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing; College of Medical Veterinary and Life Sciences > School of Cancer Sciences; College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience
• Journal Name: Blood
• ISSN: 0006-4971