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Sulfonamide Derivative, E7820, Is a Unique Angiogenesis Inhibitor Suppressing an Expression of Integrin 2 Subunit on Endothelium

Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan 300-2635

In the process of angiogenesis, endothelial adhesion molecules play a significant role in vascular morphogenesis, in coordination with angiogenic factor signaling. Here we report that a novel angiogenesis inhibitor, E7820 (an aromatic sulfonamide derivative), inhibited in vitro proliferation and tube formation of human umbilical vascular endothelial cell (HUVEC). E7820 decreased integrin 2, 3, 5, and ß1 in confluent culture of HUVEC, and integrin 2 was initially suppressed in mRNA level, followed by decrement of integrins 3, 5, and ß1. The inhibition of integrin 2 expression in HUVEC showed dose dependence but did not alter the level of CD31. Up-regulation of integrin 2 by phorbol 12-myristate 13-acetate abrogated the inhibitory effect of E7820 on tube formation within type I collagen gel, whereas addition of antibody against integrin 2 canceled the phorbol 12-myristate 13-acetate effect. These results suggest that E7820 inhibited tube formation through the suppression of integrin 2. Oral administration of E7820 remarkably resulted in inhibition of tumor-induced angiogenesis in mouse dorsal air sac model, and tumor growth of human colorectal tumor cell lines (WiDr and LoVo) was inhibited in xenotransplanted model in mice. This is the first time that a small molecule has been shown to modulate integrins, and this finding may provide the basis for a new approach to antiangiogenic therapy through the suppression of integrin 2 on endothelium.