title: The MEK inhibitor PD184352 enhances BMS-214662-induced apoptosis in CD34+ CML stem/progenitor cells.
abstract: The cytotoxic farnesyl transferase inhibitor BMS-214662 has been shown to potently induce mitochondrial apoptosis in primitive CD34+ chronic myeloid leukaemia (CML) stem/progenitor cells. Here, to enhance the BMS-214662 apoptotic effect, we further targeted the extracellular signal-regulated kinase (ERK) pathway, downstream of BCR-ABL, by treating CD34+ CML stem/progenitor cells with a highly selective adenosine triphosphate (ATP) non-competitive MEK inhibitor, PD184352. PD184352 increased the apoptotic effect of BMS-214662 in a CML blast crisis cell line, K562, and in primary chronic phase CD34+ CML cells. Compared with BMS-214662, after combination treatment we observed inhibition of ERK phosphorylation, increased Annexin-V levels, caspase-3, -8 and -9 activation and potentiated mitochondrial damage, associated with decreased levels of anti-apoptotic BCL-2 family protein MCL-1. Inhibition of K-RAS function by a dominant-negative mutant resulted in CML cell death and this process was further enhanced by the addition of BMS-214662 and PD184352. Together, these findings suggest that the addition of a MEK inhibitor improves the ability of BMS-214662 to selectively target CML stem/progenitor cells, notoriously insensitive to tyrosine kinase inhibitor treatment and presumed to be responsible for the persistence and relapse of the disease.
authors.affiliation: Paul O'Gorman Leukaemia Research Centre, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
authors.forename: F
authors.initials: F
authors.lastname: Pellicano
authors.forename: P
authors.initials: P
authors.lastname: Simara
authors.forename: A
authors.initials: A
authors.lastname: Sinclair
authors.forename: G V
authors.initials: GV
authors.lastname: Helgason
authors.forename: M
authors.initials: M
authors.lastname: Copland
authors.forename: S
authors.initials: S
authors.lastname: Grant
authors.forename: T L
authors.initials: TL
authors.lastname: Holyoake
mesh_terms: D018952:Antigens, CD34 / Q000032:analysis; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology*; D001752:Blast Crisis / Q000201:enzymology / Q000473:pathology*; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D005799:Genes, Dominant; D011905:Genes, ras; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D020014:K562 Cells / Q000187:drug effects / Q000201:enzymology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000201:enzymology / Q000473:pathology*; D015466:Leukemia, Myeloid, Chronic-Phase / Q000201:enzymology / Q000473:pathology*; D048369:MAP Kinase Kinase 1 / Q000235:genetics; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000201:enzymology; D015689:Oncogene Protein p21(ras) / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology
chemical_list: C120227:2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide; D018952:Antigens, CD34; D001549:Benzamides; D004791:Enzyme Inhibitors; D007093:Imidazoles; D009363:Neoplasm Proteins; D011993:Recombinant Fusion Proteins; D001569:Benzodiazepines; D051231:Farnesyltranstransferase; D020930:MAP Kinase Kinase Kinases; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D015689:Oncogene Protein p21(ras); C415151:7-cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine