The pan-ErbB tyrosine kinase inhibitor canertinib induces caspase-mediated cell death in human T-cell leukemia (Jurkat) cells.

Abstract

Canertinib is a novel ErbB-receptor inhibitor currently in clinical development for the treatment of solid tumors overexpressing ErbB-receptors. We have recently demonstrated that canertinib displays anti-proliferative and pro-apoptotic effects in human myeloid leukemia cells devoid of ErbB-receptors. The mechanism mediating these effects are however unknown. In this study, we show that canertinib is able to act as a multi-kinase inhibitor by inhibition of several intracellular kinases involved in T-cell signaling such as Akt, Erk1/2 and Zap-70, and reduced Lck protein expression in the human T-cell leukemia cell line Jurkat. Treatment with canertinib at a concentration of 2 μM caused accumulation of Jurkat cells in the G(1) cell cycle phase and increased doses induced apoptosis in a time-dependent manner. Apoptotic signs of treated cells were detected by Annexin V staining and cleavage of PARP, caspase-3, -8, -9, -10 and Bid. A subset of the pro-apoptotic signals mediated by canertinib could be significantly reduced by specific caspase inhibitors. Taken together, these results demonstrate the dual ability of canertinib to downregulate important signaling pathways and to activate caspase-mediated intrinsic apoptosis pathway in human T-cell leukemia cells.

• Authors: Cecilia Trinks, Emelie A Severinsson, Birgitta Holmlund, Anna Gréen, Henrik Gréen, Jan-Ingvar Jönsson, Anna-Lotta Hallbeck, Thomas M Walz
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 410 Issue 3 Pg. 422-7 (Jul 08 2011) ISSN: 1090-2104 [Electronic] United States
• PMID: 21669187 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• Morpholines
• Protein Kinase Inhibitors
• Receptors, Antigen, T-Cell
• Canertinib
• Poly(ADP-ribose) Polymerases
• Receptor Protein-Tyrosine Kinases
• Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
• ZAP-70 Protein-Tyrosine Kinase
• Proto-Oncogene Proteins c-akt
• MAPK1 protein, human
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• Caspases

Topics

• Apoptosis
• Caspases (metabolism)
• Humans
• Jurkat Cells
• Leukemia, T-Cell (enzymology)
• Lymphocyte Specific Protein Tyrosine Kinase p56(lck) (metabolism)
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Morpholines (pharmacology)
• Phosphorylation (drug effects)
• Poly(ADP-ribose) Polymerases (metabolism)
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Receptor Protein-Tyrosine Kinases (antagonists & inhibitors)
• Receptors, Antigen, T-Cell (metabolism)
• ZAP-70 Protein-Tyrosine Kinase (metabolism)