Plenary Lecture

Plenary Lecture

Disintegrins as Prototypes for Drug Design Targeting Adhesion Receptors for Anti-Metastatic Therapy

Professor Heloisa Sobreiro Selistre de Araujo
UFSCar, Sao Carlos
SP, Brazil

Abstract: Metastasis is a key characteristic of malignant cells, which must reach the bloodstream to colonize distant target organs. Once in the circulation, tumor cells must attach to vascular endothelial cells, platelets or components of the vessel wall and invade through them until reach the target organs. Most of these steps are mediated by specific adhesive functions of tumor cell receptors such as the integrins. Disintegrins are small integrin-ligand molecules that specifically inhibit cell adhesion to natural substrates found in the extracellular matrix. Disintegrin structural variations result in the specificity of integrin recognition. Most disintegrins have an RGD motif that is relevant for ‚3 (ŠIIb‚3, platelet fibrinogen receptor, and Šv‚3, vitronectin receptor) and ‚1 integrin binding (Š5‚1, fibronectin receptor). DisBa-01, a recombinant RGD-disintegrin derived from the venom glands of Bothrops alternatus inhibited the adhesion of ?v?3-expressing human microvascular endothelial cell line-1 (HMEC-1) and murine melanoma cell line B16F10 to vitronectin (IC50 = 555 nM and 225 nM, respectively), but it did not affect the binding of a human breast cancer-derived cell line (MDA-MB-231) not expressing Šv‚3. 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. DisBa-01 also inhibited chemotactic migration of 4T1BM2 cell migration towards serum or vitronectin. Molecular modelling of the interaction between DisBa-01 and the ?v?3 integrin showed that the N-terminal region of the disintegrin was not involved in receptor binding. Deletion of the first 36 residues of the N-terminal region of DisBa-01 did not affect significantly the cell adhesion properties of the molecule. On the other hand, ADAM9D, a recombinant disintegrin domain from a human homologue, was able to support tumor cell adhesion through binding to the ?1 integrin subunit. In a dynamic flow assay ADAM9D inhibited about 60% and 55% of MDA-MB-231 tumor cells and platelet adhesion to collagen, respectively. In conclusion, disintegrins are useful tools for the design of selective inhibitors against the adhesion and extravasation of cancer cells.
Support: FAPESP, CAPES e CNPq (Brazil).

Brief Biography of the Speaker:
I received my PhD in Biochemistry from the University of Sao Paulo, in Ribeirao Preto, SP, Brazil in 1988. I subsequently joined the Department of Physiological Sciences at Federal University of Sao Carlos (UFSCar), in Sao Carlos, SP, Brazil, as Professor of Biochemistry and Biophysics. Between 1993 and 1995, I was a visiting scientist fellow at the Venom Research Group at the Department of Physiological Sciences of the College of Veterinary Medicine of the Oklahoma State University, Ok, USA, collaborating with Dr. Charlotte L. Ownby. Back to the Federal University of Sao Carlos in 1995, I started the research group in integrin binding proteins from snake venoms and their applications in prevention of metastasis. Currently, I am the team leader of the Biochemistry and Molecular Biology Laboratory at UFSCar, which focus on integrin-dependent cell adhesion and migration, extracellular matrix interactions and intracellular signaling of metastatic cells.



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