title: Nilotinib exerts equipotent antiproliferative effects to imatinib and does not induce apoptosis in CD34+ CML cells.
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 microM. CML CD34(+) cells were still able to expand over 72 hours with 5 microM of either drug, although there was a concentration-dependent restriction of amplification. As for IM, the most primitive cells (CFSE(max)) 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.
authors.affiliation: Section of Experimental Haematology, Division of Cancer Sciences and Molecular Pathology, University of Glasgow, 10 Alexandra Parade, Glasgow, UK.
authors.forename: Heather G
authors.initials: HG
authors.lastname: Jørgensen
authors.forename: Elaine K
authors.initials: EK
authors.lastname: Allan
authors.forename: Niove E
authors.initials: NE
authors.lastname: Jordanides
authors.forename: Joanne C
authors.initials: JC
authors.lastname: Mountford
authors.forename: Tessa L
authors.initials: TL
authors.lastname: Holyoake
mesh_terms: D018952:Antigens, CD34; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000201:enzymology*; D014411:Neoplastic Stem Cells / Q000201:enzymology*; D010879:Piperazines / Q000819:agonists / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000819:agonists / Q000494:pharmacology*; D011743:Pyrimidines / Q000819:agonists / Q000494:pharmacology*; D013997:Time Factors; D014410:Tumor Stem Cell Assay
chemical_list: D018952:Antigens, CD34; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; C498826:nilotinib