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Imatinib mesylate (STI-571) reduces Bcr-Abl-mediated vascular endothelial growth factor secretion in chronic myelogenous leukemia.
- Source :
-
Molecular cancer research : MCR [Mol Cancer Res] 2002 Dec; Vol. 1 (2), pp. 89-95. - Publication Year :
- 2002
-
Abstract
- A large and diverse spectrum of oncogenes has been implicated as a contributor to angiogenesis in solid tumors based, in part, on its ability to induce proangiogenic growth factors such as vascular endothelial growth factor (VEGF), and the fact that various anti-oncogenic signaling inhibitor drugs have been shown to reverse such proangiogenic effects both in vitro and in vivo. Because leukemias are now also considered to be angiogenesis-dependent malignancies, we asked whether a similar paradigm might exist for the BCR-ABL oncogene and the Bcr-Abl targeting drug, STI-571 (imatinib mesylate), in the context of chronic myelogenous leukemia (CML) cells. We found that levels of VEGF expression in BCR-ABL-positive K562 cells were reduced in vitro by treatment with STI-571 in a dose-dependent fashion. Transfection of BCR-ABL into murine myeloid 32D and human megakaryocyte MO7e hematopoietic cells resulted in enhanced VEGF expression, which could be further elevated by the exposure to cytokines such as interleukin 3 and granulocyte macrophage colony-stimulating factor. We also found that conditioned media taken from 32D-p210-transfected cells could stimulate human umbilical vein endothelial cells by increasing phosphorylation of VEGF-R2/KDR and the downstream serine/threonine kinase PKB/Akt, an important regulator of endothelial cell survival. Moreover, amplification of BCR-ABL in STI-571-resistant cells was associated with elevated VEGF expression levels which could be reversed by treatment with higher concentrations of STI-571. Taken together, our results implicate BCR-ABL as a possible regulator of CML angiogenesis and raise the possibility that STI-571 could mediate some of its anti-CML properties in vivo through an angiogenesis-dependent mechanism.
- Subjects :
- Animals
Benzamides
Blotting, Western
Cell Division
Cells, Cultured
Culture Media, Conditioned pharmacology
Densitometry
Dose-Response Relationship, Drug
Endothelium, Vascular metabolism
Humans
Imatinib Mesylate
Interleukin-3 metabolism
K562 Cells
Leukemia, Myelogenous, Chronic, BCR-ABL Positive metabolism
Mice
Neovascularization, Pathologic
Precipitin Tests
Time Factors
Transfection
Umbilical Veins cytology
Up-Regulation
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factors
Antineoplastic Agents pharmacology
Endothelial Growth Factors metabolism
Fusion Proteins, bcr-abl metabolism
Intercellular Signaling Peptides and Proteins metabolism
Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy
Lymphokines metabolism
Piperazines pharmacology
Pyrimidines pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1541-7786
- Volume :
- 1
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Molecular cancer research : MCR
- Publication Type :
- Academic Journal
- Accession number :
- 12496355