Tyrosine kinase inhibitor AG1024 exerts antileukaemic effects on STI571-resistant Bcr-Abl expressing cells and decreases AKT phosphorylation.

Details

Serval ID
serval:BIB_DA6835983ED6
Type
Article: article from journal or magazin.
Collection
Publications
Title
Tyrosine kinase inhibitor AG1024 exerts antileukaemic effects on STI571-resistant Bcr-Abl expressing cells and decreases AKT phosphorylation.
Journal
British journal of cancer
Author(s)
Deutsch E., Maggiorella L., Wen B., Bonnet M.L., Khanfir K., Frascogna V., Turhan A.G., Bourhis J.
ISSN
0007-0920 (Print)
ISSN-L
0007-0920
Publication state
Published
Issued date
01/11/2004
Peer-reviewed
Oui
Volume
91
Number
9
Pages
1735-1741
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
Chronic myelogenous leukaemia (CML) is a clonal malignancy of the pluripotent haematopoietic stem cell, characterised by an uncontrolled proliferation and expansion of myeloid progenitors expressing a fusion oncogene, BCR-ABL, the molecular counterpart of the Ph1 chromosome. The tyrosine kinase (TK) activity of BCR-ABL is known to activate several major signalling pathways in malignant cells, including Ras, JAK/STAT and PI3K/Akt with evidence of proteasome-mediated degradation of other targets such as the DNA repair protein DNA-PKcs and cyclin-dependent kinases inhibitor p27. Targeting these abnormalities by blocking TK of BCR-ABL with STI571 provided a promising approach for the therapy of CML. The recent development of resistance to STI571 illustrates, however, that the use of other TK inhibitors could be of major interest for therapeutic purposes. To this end, the TK inhibitor Tyrphostin AG1024 was used to evaluate effect on regulation of BCR-ABL expression, inhibition of cell proliferation and tumour formation in vivo in human and murine BCR-ABL expressing cell lines. Tyrphostin AG1024 was shown to downregulate expression of BCR-ABL and P-Akt, and to upregulate DNA-PKcs expression. In addition, Tyrphostin AG1024 was able to inhibit cell proliferation, and delay tumour growth in vivo. Thus, AG1024 is able to interfere with three major targets of BCR-ABL in leukaemic cells. Interestingly, Tyrphostin AG1024 was also effective against cells resistant to STI571 by distinct mechanisms including Bcr-Abl mutation. Therefore, these data suggest that Tyrphostin AG1024 could represent the basis of a novel therapy for STI571 refractory CML.
Keywords
Animals, Antineoplastic Agents/therapeutic use, Benzamides, Cell Proliferation/drug effects, DNA-Activated Protein Kinase, DNA-Binding Proteins/antagonists & inhibitors, Drug Resistance, Neoplasm, Enzyme Inhibitors/therapeutic use, Fusion Proteins, bcr-abl, Gene Expression Regulation, Leukemic, Humans, Imatinib Mesylate, Leukemia, Erythroblastic, Acute/drug therapy, Leukemia, Erythroblastic, Acute/metabolism, Mice, Mice, Nude, Neoplasm Recurrence, Local/drug therapy, Neoplasm Recurrence, Local/metabolism, Neoplasm Recurrence, Local/pathology, Nuclear Proteins, Phosphorylation, Piperazines/pharmacology, Protein-Serine-Threonine Kinases/antagonists & inhibitors, Protein-Serine-Threonine Kinases/metabolism, Protein-Tyrosine Kinases/antagonists & inhibitors, Protein-Tyrosine Kinases/metabolism, Proto-Oncogene Proteins/metabolism, Proto-Oncogene Proteins c-akt, Pyrimidines/pharmacology, Tumor Cells, Cultured, Tyrphostins/therapeutic use
Pubmed
Web of science
Open Access
Yes
Create date
16/08/2019 16:01
Last modification date
21/08/2019 5:34
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