Imatinib mesylate (STI-571) reduces Bcr-Abl-mediated vascular endothelial growth factor secretion in chronic myelogenous leukemia.
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.
Ebos
John M L
JM
Molecular and Cell Biology Research, Sunnybrook and Women's College Health Sciences Centre, Toronto, Ontario, Canada M4N 3M5.
Tran
Jennifer
J
Master
Zubin
Z
Dumont
Daniel
D
Melo
Junia V
JV
Buchdunger
Elisabeth
E
Kerbel
Robert S
RS
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D015153:Blotting, Western; D002455:Cell Division; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D003720:Densitometry; D004305:Dose-Response Relationship, Drug; D016228:Endothelial Growth Factors / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D006801:Humans; D000068877:Imatinib Mesylate; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D007377:Interleukin-3 / Q000378:metabolism; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000378:metabolism; D008222:Lymphokines / Q000378:metabolism*; D051379:Mice; D009389:Neovascularization, Pathologic; D010879:Piperazines / Q000494:pharmacology*; D011233:Precipitin Tests; D011743:Pyrimidines / Q000494:pharmacology*; D013997:Time Factors; D014162:Transfection; D014471:Umbilical Veins / Q000166:cytology; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000970:Antineoplastic Agents; D001549:Benzamides; D017077:Culture Media, Conditioned; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D007377:Interleukin-3; D008222:Lymphokines; D010879:Piperazines; D011743:Pyrimidines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl