Document Detail


Autophagy and autophagic cell death are next targets for elimination of the resistance to tyrosine kinase inhibitors.
MedLine Citation:
PMID:  18823378     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Autophagy, a cellular degradation system has been demonstrated in some hematopoietic malignant cell lines, but there is much still remaining to be known about its role and the mechanisms. We observed the excessive autophagy in chronic myelogenous leukemia (CML) cell line, K562, associated with treatment of 12-O-tetradecanoyl-phorbol-13-acetate (TPA), which can induce K562 cells to differentiate into megakaryocytic lineage. Confocal microscopic analysis demonstrated that autophagic cells did not express a megakaryocyte marker, the CD41 molecule, indicating that the autophagy was independent of megakaryocytic differentiation. After remarkable autophagic degradation, the cells finally underwent autophagic cell death (APCD). On the other hand, a block of TPA-induced autophagy by chloroquine rapidly promoted cell death that was not APCD. This result suggested that autophagy regulated two mechanisms in K562 cells: both the cell survival system and APCD. To confirm that autophagy regulates the cell survival system in K562 cells, imatinib was used to induce cell death in K562 cells. Autophagy has not been considered during imatinib treatment; nonetheless, co-treatment with imatinib and chloroquine markedly enhanced imatinib-induced cell death, compared to K562 cells treated only with imatinib. Furthermore, imatinib-resistant cell lines, BaF3/T315I and BaF3/E255K, also underwent cell death by co-treatment with imatinib and chloroquine. From these data, we concluded that autophagy is deeply related to the cell survival system and that inhibition of autophagy accelerates TPA- or imatinib-induced cell death. The block of autophagy could be a new strategy in the treatment of CML.
Authors:
Yuko Mishima; Yasuhito Terui; Yuji Mishima; Akiko Taniyama; Ryoko Kuniyoshi; Toshihiro Takizawa; Shinya Kimura; Keiya Ozawa; Kiyohiko Hatake
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Publication Detail:
Type:  Journal Article     Date:  2008-09-22
Journal Detail:
Title:  Cancer science     Volume:  99     ISSN:  1349-7006     ISO Abbreviation:  Cancer Sci.     Publication Date:  2008 Nov 
Date Detail:
Created Date:  2008-11-28     Completed Date:  2009-01-23     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  101168776     Medline TA:  Cancer Sci     Country:  England    
Other Details:
Languages:  eng     Pagination:  2200-8     Citation Subset:  IM    
Affiliation:
Department of Clinical Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
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MeSH Terms
Descriptor/Qualifier:
Autophagy / drug effects*
Cell Death
Cell Differentiation
Cell Line, Tumor
Drug Resistance, Neoplasm*
Humans
K562 Cells
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy,  pathology
Protein Kinase Inhibitors / pharmacology*,  therapeutic use
Protein-Tyrosine Kinases / antagonists & inhibitors*
Tetradecanoylphorbol Acetate / pharmacology,  therapeutic use
Chemical
Reg. No./Substance:
0/Protein Kinase Inhibitors; 16561-29-8/Tetradecanoylphorbol Acetate; EC 2.7.10.1/Protein-Tyrosine Kinases

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