University Medical Center Hamburg-Eppendorf, Hubertus Wald University Cancer Center Hamburg, Dept. of Oncology/Hematology with sections BMT and Pneumology, Hamburg, Germany.
Invest New Drugs. 2010 Dec;28(6):825-33. doi: 10.1007/s10637-009-9326-5. Epub 2009 Sep 26.
Neoangiogenesis plays an important role in tumor growth and metastasis. Evaluation of new anti-angiogenic targets may broaden the armament for future therapeutic concepts. Focal adhesion kinase (FAK), expressed in endothelial and tumor cells, is essential for adhesion and mobility of adherent cells. In the current study we analyzed the anti-angiogenic properties of the FAK inhibitor TAE226 on the proliferation of blood outgrowth endothelial cell (OEC) and differentiation of endothelial progenitor cells (EPC), derived from peripheral blood CD133(+) cells, tube formation and on neovascularization in a HT29 xenotransplant model. The effects of TAE226 were compared to those of the rapamycin analogue RAD001. The combination of both drugs was also studied. We showed that HT29 tumor cells and OEC were most sensitive to the action of TAE226 compared to EPC in vitro. In contrast, RAD001 affected the proliferation of both types of endothelial cells stronger than that of HT29 cells. Furthermore we could show that TAE226 inhibited tube formation in a dose dependent manner. In a HT29 subcutaneous tumor model TAE226 and RAD001 diminished MVD at commonly employed doses to a similar degree. Combination of both compounds did not show synergy in vitro or in vivo. Since TAE226 has been shown to inhibit the PI3 kinase, Akt kinase, mTor pathway, addition of RAD001 may not increase this effect. In conclusion, we have shown that treatment with TAE leads to a reduction of neoangiogenesis in vitro and in a mouse model. The effects are mediated by inhibition of angiogenesis and vasculogenic OEC and EPC.
新生血管形成在肿瘤生长和转移中起着重要作用。评估新的抗血管生成靶点可能会为未来的治疗概念提供更多的武器。粘着斑激酶（FAK）在血管内皮细胞和肿瘤细胞中表达，对于附着细胞的粘着和迁移是必需的。在本研究中，我们分析了 FAK 抑制剂 TAE226 对血液生长内皮细胞（OEC）增殖和内皮祖细胞（EPC）分化、管形成和 HT29 异种移植模型中新生血管形成的抗血管生成特性。将 TAE226 的作用与雷帕霉素类似物 RAD001 的作用进行了比较，并研究了两种药物的联合作用。我们表明，与 EPC 相比，HT29 肿瘤细胞和 OEC 在体外对 TAE226 的作用最敏感。相比之下，RAD001 对两种类型的内皮细胞的增殖影响比对 HT29 细胞的影响更强。此外，我们还表明，TAE226 以剂量依赖的方式抑制管形成。在 HT29 皮下肿瘤模型中，TAE226 和 RAD001 在常用剂量下使 MVD 减少到相似程度。两种化合物的联合使用在体外和体内均未显示出协同作用。由于 TAE226 已被证明抑制 PI3 激酶、Akt 激酶、mTor 通路，添加 RAD001 可能不会增加这种作用。总之，我们已经表明，TAE 的治疗导致体外和小鼠模型中新生血管形成减少。这种作用是通过抑制血管生成和血管生成的 OEC 和 EPC 介导的。
