title: The pan-ErbB receptor tyrosine kinase inhibitor canertinib promotes apoptosis of malignant melanoma in vitro and displays anti-tumor activity in vivo.
abstract: The ErbB receptor family has been suggested to constitute a therapeutic target for tumor-specific treatment of malignant melanoma. Here we investigate the effect of the pan-ErbB tyrosine kinase inhibitor canertinib on cell growth and survival in human melanoma cells in vitro and in vivo. Canertinib significantly inhibited growth of cultured melanoma cells, RaH3 and RaH5, in a dose-dependent manner as determined by cell counting. Half-maximum growth inhibitory dose (IC(50)) was approximately 0.8 μM and by 5 μM both cell lines were completely growth-arrested within 72 h of treatment. Incubation of exponentially growing RaH3 and RaH5 with 1 μM canertinib accumulated the cells in the G(1)-phase of the cell cycle within 24h of treatment without induction of apoptosis as determined by flow cytometry. Immunoblot analysis showed that 1 μM canertinib inhibited ErbB1-3 receptor phosphorylation with a concomitant decrease of Akt-, Erk1/2- and Stat3 activity in both cell lines. In contrast to the cytostatic effect observed at doses ≤ 5μM canertinib, higher concentrations induced apoptosis as demonstrated by the Annexin V method and Western blot analysis of PARP cleavage. Furthermore, canertinib significantly inhibited growth of RaH3 and RaH5 melanoma xenografts in nude mice. Pharmacological targeting of the ErbB receptors may prove successful in the treatment of patients with metastatic melanoma.
authors: Division of Oncology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, S-581 85 Linköping, Sweden. Emelie.severinsson@liu.se
authors: Emelie A
authors: EA
authors: Djerf Severinsson
authors: Cecilia
authors: C
authors: Trinks
authors: Henrik
authors: H
authors: Gréen
authors: Avni
authors: A
authors: Abdiu
authors: Anna-Lotta
authors: AL
authors: Hallbeck
authors: Olle
authors: O
authors: Stål
authors: Thomas M
authors: TM
authors: Walz
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors; D009025:Morpholines / Q000627:therapeutic use*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors; D050796:STAT3 Transcription Factor / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D009025:Morpholines; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D050796:STAT3 Transcription Factor; C420268:Canertinib; C535150:MAPK1 protein, human