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The Bcr-Abl kinase inhibitor INNO-406 induces autophagy and different modes of cell death execution in Bcr-Abl-positive leukemias.
- Source :
-
Cell death and differentiation [Cell Death Differ] 2008 Nov; Vol. 15 (11), pp. 1712-22. Date of Electronic Publication: 2008 Jul 11. - Publication Year :
- 2008
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Abstract
- Bcr-Abl tyrosine kinase (TK) inhibitors are promising therapeutic agents for Bcr-Abl-positive (Bcr-Abl(+)) leukemias. Although they are known to promote caspase-mediated apoptosis, it remains unclear whether caspase-independent cell death-inducing mechanisms are also triggered. Here we demonstrated that INNO-406, a second-generation Bcr-Abl TK inhibitor, induces programmed cell death (PCD) in chronic myelogenous leukemia (CML) cell lines through both caspase-mediated and caspase-independent pathways. The latter pathways include caspase-independent apoptosis (CIA) and necrosis-like cell death (CIND), and the cell lines varied regarding which mechanism was elicited upon INNO-406 treatment. We also observed that the propensity toward CIA or CIND in cells was strongly associated with cellular dependency on apoptosome-mediated caspase activity. Cells that undergo CIND have a high apoptosome activity potential whereas cells that undergo CIA tend to have a lower potential. Moreover, we found that INNO-406 promotes autophagy. When autophagy was inhibited with chloroquine or gene knockdown of beclin1 by shRNA, INNO-406-induced cell death was enhanced, which indicates that the autophagic response of the tumor cells is protective. These findings suggest new insights into the biology and therapy of Bcr-Abl(+) leukemias.
- Subjects :
- Animals
Apoptosomes drug effects
Apoptosomes metabolism
Caspases metabolism
Cell Line, Tumor
Chloroquine pharmacology
Cytoprotection drug effects
Disease Models, Animal
Enzyme Activation drug effects
Male
Mice
Mice, SCID
Xenograft Model Antitumor Assays
Autophagy drug effects
Fusion Proteins, bcr-abl antagonists & inhibitors
Leukemia, Myelogenous, Chronic, BCR-ABL Positive enzymology
Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology
Protein Kinase Inhibitors pharmacology
Pyrimidines pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1350-9047
- Volume :
- 15
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Cell death and differentiation
- Publication Type :
- Academic Journal
- Accession number :
- 18617896
- Full Text :
- https://doi.org/10.1038/cdd.2008.107