title: The pan-ErbB receptor tyrosine kinase inhibitor canertinib induces ErbB-independent apoptosis in human leukemia (HL-60 and U-937) cells.
abstract: Epidermal growth factor (EGF) receptor tyrosine kinase inhibitors have recently been shown to display anti-neoplastic effects in human malignant myeloid cells. Our study was initiated in order to determine the effect of the pan-ErbB receptor tyrosine kinase inhibitor, canertinib (CI-1033), on growth and survival of human leukemia (HL-60 and U-937) cells. We show that treatment of HL-60 and U-937 cells with canertinib significantly inhibits growth of both cell lines in a dose-dependent manner; half maximal effective dose (IC(50)) in HL-60 and U-937 cells was approximately 2.5 microM and 1.0 microM, respectively. Treatment with 2 microM canertinib promoted a G(1) cell cycle arrest, whereas doses of 5 microM or more induced apoptosis as determined by the Annexin V method and cleavage of poly-(ADP-ribose) polymerase (PARP). HL-60 and U-937 cells lacked EGF-receptor transcript but expressed ErbB2-4 mRNA as determined by RT-PCR. However, none of the corresponding ErbB-receptor proteins could be detected by Western blot analysis. We conclude that canertinib induces apoptosis in HL-60 and U-937 cells devoid of functional ErbB1-4 receptors. Our results suggest that canertinib could be of potential clinical interest in the treatment of acute myeloid leukemia.
authors.affiliation: Division of Oncology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, S-581 85 Linköping, Sweden. cecilia.trinks@liu.se
authors.forename: Cecilia
authors.initials: C
authors.lastname: Trinks
authors.forename: Emelie A
authors.initials: EA
authors.lastname: Djerf
authors.forename: Anna-Lotta
authors.initials: AL
authors.lastname: Hallbeck
authors.forename: Jan-Ingvar
authors.initials: JI
authors.lastname: Jönsson
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Walz
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D016193:G1 Phase / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology*; D009025:Morpholines / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D009025:Morpholines; D011065:Poly(ADP-ribose) Polymerases; D047428:Protein Kinase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; C420268:Canertinib