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The Small ₅ß₁ Integrin Antagonist, SJ749, Reduces Proliferation and Clonogenicity of Human Astrocytoma Cells

¹ Département de Pharmacologie et Physicochimie and ² Département de Pharmacochimie de la Communication Cellulaire, UMR 7175 Centre National de la Reserche Scientifique, Université Louis Pasteur Strasbourg, Illkirch, France

Requests for reprints: Monique Dontenwill, Département de Pharmacologie et Physicochimie, UMR 7175 Centre National de la Reserche Scientifique, Université Louis Pasteur Strasbourg, BP 60024, 67401 Illkirch, France. Phone: 33-390244267; Fax: 33-390244313; E-mail: monique.dontenwill{at}pharma.u-strasbg.fr.

The potential role of ₅ß₁ integrins in cancer has recently attracted much interest. However, few ₅ß₁-selective antagonists have been developed compared with other integrins. The most specific nonpeptidic ₅ß₁ antagonist described thus far, SJ749, inhibits angiogenesis by affecting adhesion and migration of endothelial cells. We investigated the effects of SJ749 in two human astrocytoma cell lines, A172 and U87, which express different levels of ₅ß₁. SJ749 dose-dependently inhibited adhesion of both cell types on fibronectin. Application of SJ749 to spread cells led to formation of nonadherent spheroids for A172 cells but had no effect on U87 cell morphology. SJ749 also reduced proliferation of A172 cells due to a long lasting G₀-G₁ arrest, whereas U87 cells were only slightly affected. However, under nonadherent culture conditions (soft agar), SJ749 significantly reduced the number of colonies formed only by U87 cells. As U87 cells express more ₅ß₁ than A172 cells, we specifically examined the effect of SJ749 on A172 cells overexpressing ₅. Treatment of ₅-A172 cells with SJ749 decreased colony formation similarly to that observed in U87 cells. Therefore, in nonadherent conditions, the effect of SJ749 on tumor cell growth characteristics depends on the level of ₅ß₁ expression. Our study highlights the importance of ₅ß₁ as an anticancer target and shows for the first time that a small nonpeptidic ₅ß₁-specific antagonist affects proliferation of tumor cells. (Cancer Res 2006; 66(12): 6002-7)

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