A novel αvβ3-blocking disintegrin containing the RGD motive, DisBa-01, inhibits bFGF-induced angiogenesis and melanoma metastasis

Oscar H.P. Ramos, Alexandre Kauskot, Márcia R. Cominetti, Iga Bechyne, Carmen L. Salla Pontes, Fabrice Chareyre, Jan Manent, Roger Vassy, Marco Giovannini, Chantal Legrand, Heloisa S. Selistre-De-Araujo, Michel Crépin, Arnaud Bonnefoy

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63 Citations (Scopus)

Abstract

The integrin αvβ3 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 α vβ3-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 αvβ3 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 αvβ3 predicted a large surface of contacts with the β3 subunit. DisBa-01 inhibited the adhesion of αvβ3-expressing human microvascular endothelial cell line-1 (HMEC-1) and murine melanoma cell line B16F10 to vitronectin (IC50 = 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 αvβ3. In vivo, DisBa-01 dose-dependently decreased bFGF-induced angiogenesis in a matrigel plug assay in athymic nude mice (IC50 = 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 αvβ 3-dependent adherence mechanisms involved in neo-vascularization and tumor metastasis processes.

Original languageEnglish
Pages (from-to)53-64
Number of pages12
JournalClinical and Experimental Metastasis
Volume25
Issue number1
DOIs
Publication statusPublished - 1 Mar 2008
Externally publishedYes

Keywords

  • αβ
  • Angiogenesis
  • Bioluminescent imaging
  • Disintegrin
  • Metastasis

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