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.
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Abbreviations
- AIF:
-
apoptosis-inducing factor
- ALL:
-
acute lymphoblastic leukemia
- Apaf-1:
-
apoptotic protease-activating factor-1
- BC:
-
blast crisis
- BM:
-
bone marrow
- CIA:
-
caspase-independent apoptosis
- CIND:
-
caspase-independent necrosis-like cell death
- CML:
-
chronic myelogenous leukemia
- CQ:
-
chloroquine
- cyt:
-
cytochrome
- DiOC6(3):
-
3,3′-dihexyloxacarbocyanine iodide
- EM:
-
electron microscopy
- HE:
-
hematoxilin–eosin
- IAP:
-
inhibitors of apoptosis protein
- IF:
-
immunofluorescent
- IgG:
-
immunoglobulin G
- IHC:
-
immunohistochemical
- LC3:
-
light chain 3
- LM:
-
light microscopy
- MOMP:
-
mitochondrial outer membrane permeabilization
- PB:
-
peripheral blood
- PCD:
-
programmed cell death
- Ph:
-
Philadelphia
- PI:
-
propidium iodide
- PI3K:
-
phosphoinositide-3-kinase
- STAT5:
-
signal transducer and activator of transcription
- TK:
-
tyrosine kinase
- WB:
-
western blotting
- XIAP:
-
X-linked inhibitor of apoptosis protein
- zVAD:
-
zVAD-fmk
- 3-MA:
-
3-methyladenine
- sh:
-
short hairpin
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Acknowledgements
We are grateful to Professor T Yoshimori (Osaka University), Drs T Mashima (Cancer Chemotherapy Center, Japanese Foundation for Cancer Research), DC Huang (The Walter and Eliza Hall Institute of Medical Research), T Heike, YW Lin, Y Toda, M Fujioka, Y Nakagawa (Kyoto University), Y Kobayashi (Kyoto Second Red Cross Hospital), C Shimazaki (Kyoto Prefectural University of Medicine) and H Segawa (Shiga University of Medical Science) for their technical support, scientific advice, and gifts. This work was partly supported by Grants-in-Aids for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to TN and TM).
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Kamitsuji, Y., Kuroda, J., Kimura, S. et al. The Bcr-Abl kinase inhibitor INNO-406 induces autophagy and different modes of cell death execution in Bcr-Abl-positive leukemias. Cell Death Differ 15, 1712–1722 (2008). https://doi.org/10.1038/cdd.2008.107
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DOI: https://doi.org/10.1038/cdd.2008.107
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