Suppression of vascular endothelial growth factor (VEGF) expression by targeting the Bcr-Abl oncogene and protein tyrosine kinase activity in Bcr-Abl-positive leukaemia cells.
Studies have shown that vascular endothelial growth factor (VEGF), a major and potent inducer of angiogenesis, is directly triggered by the disease-related oncogene Bcr-Abl in Bcr-Abl-positive cells. In this study, inhibition of Bcr-Abl tyrosine kinase activity by imatinib significantly decreased VEGF expression in Bcr-Abl-positive K562 cells in vitro. Imatinib treatment in vivo of nude mice xenografted with K562 cells resulted in a significant reduction in tumour size and microvessel density compared with untreated tumours. In addition, interfering with Bcr-Abl oncogene expression with small interfering RNAs (siRNAs) not only induced a specific reduction of Bcr-Abl mRNA and protein expression, but also efficiently inhibited the expression of VEGF in K562 cells. Combined treatment with imatinib and Bcr-Abl-targeting siRNAs resulted in an enhanced effect on VEGF suppression in K562 cells. The combined application of Bcr-Abl-targeting siRNAs and imatinib may provide a potent novel therapeutic approach for chronic myeloid leukaemia.
Li
L
L
The First Affiliated Hospital of Soochow University, Jiangsu Institute of Haematology, Key Laboratory of Thrombosis and Haemostasis, Ministry of Health, Suzhou, China; Suzhou Red Cross Blood Centre, Suzhou, China.
Zhang
R
R
Fang
Z Y
ZY
Chen
J N
JN
Zhu
Z L
ZL
D000818:Animals; D001549:Benzamides; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D016044:Fusion Proteins, bcr-abl / Q000235:genetics* / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000201:enzymology* / Q000235:genetics; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D055806:Microvessels / Q000187:drug effects / Q000473:pathology; D010879:Piperazines / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D034741:RNA, Small Interfering; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl