A novel alpha(v)beta (3)-blocking disintegrin containing the RGD motive, DisBa-01, inhibits bFGF-induced angiogenesis and melanoma metastasis

Clin Exp Metastasis. 2008;25(1):53-64. doi: 10.1007/s10585-007-9101-y. Epub 2007 Oct 19.


The integrin alpha(v)beta(3) is involved in multiple aspects of malignant cancer, including tumor angiogenesis and metastasis, which makes the receptor a key target for the development of anti-cancer therapies. We report here on the production, the characterization and the in vivo anti-angiogenic and anti-metastatic properties of a novel alpha(v)beta(3)-binding disintegrin, DisBa-01, isolated from a cDNA library made with RNAs from the venom gland of Bothrops alternatus. The 11,637 Da-recombinant monomeric form of DisBa-01 displayed an RGD motif and interacted with purified alpha(v)beta(3) integrin in surface plasmon resonance studies, in a dose-dependent and cation sensitive manner. A three-dimensional molecular model of DisBa-01 in complex with alpha(v)beta(3) predicted a large surface of contacts with the beta(3) subunit. DisBa-01 inhibited the adhesion of alpha(v)beta(3)-expressing human microvascular endothelial cell line-1 (HMEC-1) and murine melanoma cell line B16F10 to vitronectin (IC(50) = 555 nM and 225 nM, respectively), and transiently inhibited their proliferation without direct cell toxicity, but did not affect the binding nor the proliferation of a human breast cancer-derived cell line (MDA-MB-231) not expressing alpha(v)beta(3). In vivo, DisBa-01 dose-dependently decreased bFGF-induced angiogenesis in a matrigel plug assay in athymic nude mice (IC(50) = 83 nM). When injected intravenously to C57BL/6 mice together with B16F10 melanoma cells, DisBa-01 time- and dose-dependently inhibited lung metastasis monitored by bioluminescent imaging. We conclude that DisBa-01 is a potent new inhibitor of alpha(v)beta(3)-dependent adherence mechanisms involved in neo-vascularization and tumor metastasis processes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Base Sequence
  • Bothrops
  • Cell Adhesion / drug effects
  • Cloning, Molecular
  • Crotalid Venoms / chemistry
  • Crotalid Venoms / pharmacology*
  • Disintegrins / chemistry
  • Disintegrins / genetics
  • Disintegrins / pharmacology*
  • Fibroblast Growth Factors / metabolism
  • Humans
  • Integrin alphaVbeta3 / antagonists & inhibitors*
  • Integrin alphaVbeta3 / drug effects
  • Melanoma, Experimental / drug therapy*
  • Mice
  • Molecular Sequence Data
  • Neoplasm Metastasis / drug therapy*
  • Neovascularization, Pathologic / drug therapy*
  • Polymerase Chain Reaction
  • Protein Conformation
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / pharmacology


  • Antineoplastic Agents
  • Crotalid Venoms
  • Disintegrins
  • Integrin alphaVbeta3
  • Recombinant Proteins
  • Fibroblast Growth Factors