Angiogenesis inhibitor Z24 induces endothelial cell apoptosis and suppresses tumor growth and metastasis
Angiogenesis inhibitor Z24 induces endothelial cell apoptosis and suppresses tumor growth and metastasis
复制标题
DOI：
10.1254/jphs.fp0040761
复制
发表时间：
2005-04-01
影响因子：
3.5
通讯作者：
Wu, M
中科院分区：
文献类型：
--
作者：
Lu, HY;Lin, C;Wu, M
本实验室设计合成的与SU5416化学结构相似的小分子化合物Z24已被证明是一种血管生成抑制剂。在这项研究中，Z24诱导了人脐静脉内皮细胞(HUVEC)的凋亡，形态学变化证实了Z24的存在，流式细胞仪分析显示明显的亚G1期凋亡峰，琼脂糖凝胶电泳法显示DNA梯带形成，以及TdT介导的X-dUTP缺口末端标记(TUNEL)结果。裸鼠全身应用无毒剂量的Z24对人结肠癌HCT-8皮下肿瘤生长有抑制作用，而在体外对该细胞株无明显抑制作用，对血管内皮细胞的生长抑制率为100倍。免疫组织化学结果显示，Z24组肿瘤组织微血管密度明显低于对照组(P<；0.05)，支持其抗血管生成作用。我们进一步发现，Z24对小鼠肺腺癌LA795的肺转移有抑制作用，与赋形剂组相比，表面肺转移减少(89.6%，P<；0.0001)，肺重量减少(38.5%，P<；0.01)。所有这些发现支持Z24是一种很有前途的血管生成抑制剂，可以限制肿瘤的生长和转移。
Z24, a small molecular compound with similar chemical structure to SU5416 designed and synthesized by our lab, has been proved to be an angiogenesis inhibitor. In this study, Z24 was shown to induce human umbilical venous endothelial cell (HUVEC) apoptosis confirmed by morphologic changes including the presence of apoptotic bodies, significant apoptotic sub-G1 peak upon flow-cytometric analysis, formation of DNA ladders upon agarose gel electrophoresis, and TUNEL (TdT mediated X-dUTP nick-end labeling) results. Systemic administration of Z24 at non-toxic dose in nude mice resulted in inhibition of subcutaneous tumor growth of human colon cancer HCT-8, while it did not inhibit this cell line in vitro, with 100-fold more potent growth-inhibition against endothelial cells. The immunohistochemical results showed that the microvessel density of tumor tissue of the Z24 group was significantly lower than that of the control groups (P < 0.05), which supported its anti-angiogenic property. We further found that Z24 inhibited the pulmonary metastasis of mouse lung adenocarcinoma LA795, with fewer surface lung metastases (89.6%, P < 0.0001) and decreased lung weights (38.5%, P < 0.01) compared to the vehicle group. All these findings support that Z24 is a promising angiogenesis inhibitor for limiting tumor growth and metastasis.