NDLI: Effect of Src kinase inhibition on metastasis and tumor angiogenesis in human pancreatic cancer

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Effect of Src kinase inhibition on metastasis and tumor angiogenesis in human pancreatic cancer

Content Provider	Springer Nature Link
Author	Ischenko, Ivan Guba, Markus Yezhelyev, Maksim Papyan, Armine Schmid, Gerald Green, Tim Fennell, Michael Jauch, Karl Walter Bruns, Christiane J.
Copyright Year	2007
Abstract	Tumor angiogenesis is a process that requires migration, proliferation, and differentiation of endothelial cells. We hypothesized that decrease in pancreatic tumor growth due to inhibition of Src activity is associated with the inability of Src kinase to trigger a network of such signaling processes, which finally leads to endothelial cell death and angiogenesis-restricted tumor dormancy. The therapeutic efficacy of Src kinase inhibitor AZM475271 was tested in nude mice orthotopically xenografted with L3.6pl pancreatic carcinoma cells. No liver metastases and peritoneal carcinosis were detected and a significant effect on the average pancreatic tumor burden was observed following treatment with AZM475271, which in turn correlated with a decrease in cell proliferation and an increase in apoptotic endothelial cells. AZM475271 was shown to significantly inhibit migration of human umbilical vein endothelial cells in an in vitro Boyden Chamber cell migration assay. In a rat aortic ring assay we could demonstrate as well inhibition of endothelial cell migration and sprouting following therapy with Src kinase inhibitor at similar doses. The most conclusive anti-angiogenic activity of AZM475271 was demonstrated in vivo (mouse corneal micropocket assay) by showing a marked inhibition of basic fibroblast growth factor-induced neovascularization in response to systemic administration of AZM475271. Furthermore, we could show reduced proliferation of HUVECs determined with the TACS MTT Cell Viability Assay Kit. The blockade of Src kinase significantly reduced the level of VEGF in L3.6pl medium, the effect which was found also in the cell culture supernate from HUVECs. Inhibition of Src kinase by AZM475271 also showed prevention of survival signaling from VEGF and EGF receptors. Treatment with AZM475271 resulted in VEGF - dependent inhibition of tyrosine phosphorylation of FAK. HUVECs were also examined using propidium iodide staining for cell cycle analysis by FACS. Inhibition of Src kinase promoted HUVEC apoptosis in a dose-dependent manner. Taken together, our results suggest that the Src kinase inhibitor AZM475271, in addition to its effects on tumor cells, suppresses tumor growth and metastasis in vitro and in vivo potentially also by anti-angiogenic mechanisms.
Starting Page	167
Ending Page	182
Page Count	16
File Format	PDF
ISSN	09696970
Journal	Angiogenesis
Volume Number	10
Issue Number	3
e-ISSN	15737209
Language	English
Publisher	Springer Netherlands
Publisher Date	2007-05-08
Publisher Place	Dordrecht
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	AZM475271 Orthotopic tumor model Pancreatic cancer Src kinase inhibition Tumor angiogenesis Oncology Ophthalmology Cardiology Cell Biology Biomedicine general Cancer Research
Content Type	Text
Resource Type	Article
Subject	Physiology Clinical Biochemistry Cancer Research

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