Abstract
Angiogenesis consists of the proliferation, migration, and differentiation of endothelial cells, although angiogenic factor and integrin-extracellular matrix interaction modulate this process. We report here that a snake venom-derived disintegrin, rhodostomin, inhibited distinct steps in angiogenesis elicited by basic fibroblast growth factor (bFGF), and also suppressed in vivo murine melanoma tumor growth. Rhodostomin dose-dependently inhibited bFGF-induced human umbilical vein endothelial cell (HUVEC) proliferation as examined by cell number count, metabolic activity, and BrdU incorporation assays with submicromolar IC50 values. However, it apparently did not affect the viability of murine B16F10 melanoma cells, even up to 50 μM. Rhodostomin also inhibited HUVEC migration and invasion evoked by bFGF, and tube formation of bFGF-treated HUVECs in Matrigel. Moreover, rhodostomin selectively inhibited bFGF-, but not vascular endothelial growth factor-associated angiogenesis in the chick chorioallantoic membrane model. Furthermore, rhodostomin blocked both bFGF- and B16F10-induced neovascularization in murine Matrigel plug model and suppressed the growth of subcutaneously inoculated B16F10 solid tumor, leading to a prolonged survival of the rhodostomin-treated C57BL/6 mice. The antiangiogenic effect of rhodostomin on bFGF-treated HUVECs is related to the integrin αvβ3 blockade, as evidenced by its selective inhibition on the binding of 7E3, a monoclonal antibody (mAb) raised against αvβ3, but not that of P1F6, an αvβ5 mAb toward both naive and bFGF-primed HUVECs. Moreover, 7E3 specifically blocked fluorescein isothiocyanate-conjugated rhodostomin binding to HUVEC, whereas P1F6 and anti-integrin α2, α3, α4, or α5 mAbs did not.
Footnotes
- Received January 2, 2001.
- Accepted January 31, 2001.
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Send reprint requests to: T. F. Huang, Ph.D., Department of Pharmacology, College of Medicine, National Taiwan University, No.1, Sec. 1, Jen-Ai Rd., Taipei, Taiwan. E-mail:turfu{at}ccms.ntu.edu.tw
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This work was supported by Grant NSC 89–2320-B002–031 from the National Science Council of Taiwan.
- The American Society for Pharmacology and Experimental Therapeutics
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