Abstract
BackgroundAnti-angiogenesis remains an attractive strategy for cancer therapy. Some anti-angiogenic reagents have bell-shape dose-response curves with higher than the effective doses yielding lower anti-angiogenic effects. In this study, two different types of anti-angiogenic reagents, a receptor tyrosine kinase inhibitor Sunitinib and an integrin antagonist peptide HM-3, were selected and their effects on tumor angiogenesis and metastasis were compared. The involved molecular mechanisms were investigated.MethodsThe effect of high dose Sunitinib and HM-3 on tumor angiogenesis and metastasis was investigated with two animal models: metastasis of B16F10 cells in syngeneic mice and metastasis of human MDA-MB-231 cells in nude mice. Furthermore, mechanistic studies were performed with cell migration and invasion assays and with biochemical pull-down assays of intracellular RhoGTPases. Distribution of integrin αvβ3, α5β1, VEGFR2 and the complex of integrin αvβ3 and VEGFR2 inside or outside of lipid rafts was detected with lipid raft isolation and Western-blot analysis.ResultsBoth Sunitinib and HM-3 showed a bell-shape dose-response curve on tumor angiogenesis and metastasis in both animal models. The effects of Sunitinib and HM-3 on endothelial cell and tumor cell proliferation and migration were characterized. Activation of intracellular RhoGTPases and actin stress fiber formation in endothelial and cancer cells following Sunitinib and HM-3 treatment correlated with cell migration analysis. Mechanistic studies confirmed that HM-3 and Sunitinib regulated distribution of integrin αvβ3, α5β1, VEGFR2 and αvβ3-VEGFR2 complexes, both inside and outside of the lipid raft regions to regulate endothelial cell migration and intracellular RhoGTPase activities.ConclusionsThese data confirmed that a general non-linear dose-effect relationship for these anti-angiogenic drugs exists and their mechanisms are correlative. It also suggests that the effective dose of an anti-angiogenic drug may have to be strictly defined to achieve its optimal clinical effects.
Highlights
Anti-angiogenesis remains an attractive strategy for cancer therapy
Activation of intracellular RhoGTPases and actin stress fiber formation in endothelial and cancer cells following Sunitinib and HM-3 treatment correlated with cell migration analysis
Sunitinib is a second-generation tyrosine Integrins αvβ3 and α5β1 can be recruited into lipid rafts kinase inhibitor that targets multiple tyrosine kinases, in- where they interact with local kinases and phosphatases to cluding the vascular endothelial growth factor receptors promote downstream signaling [21]
Summary
Anti-angiogenesis remains an attractive strategy for cancer therapy. R have bell-shape dose-response curves with higher than the effective doses yielding lower anti-angiogenic effects. Two different types of anti-angiogenic reagents, a receptor tyrosine kinase inhibitor Sunitinib and an integrin. A antagonist peptide HM-3, were selected and their effects on tumor angiogenesis and metastasis were compared.
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