The anti-angiogenic activity of NSITC, a specific cathepsin L inhibitor.
The anti-angiogenic activity of NSITC, a specific cathepsin L inhibitor.
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发表时间：
2009-11
影响因子：
2
通讯作者：
A. Rebbaa;F. Chu;T. Sudha;C. Gallati;U. Dier;E. Dyskin;M. Yalçın;C. Bianchini;O. Shaker;S. Mousa
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作者：
A. Rebbaa;F. Chu;T. Sudha;C. Gallati;U. Dier;E. Dyskin;M. Yalçın;C. Bianchini;O. Shaker;S. Mousa
新生血管的增加和对化疗的抵抗是侵袭性癌症的特征；因此，开发同时抑制这两个过程的方法是非常必要的。我们实验室以前的研究结果表明，组织蛋白酶L在癌症耐药的发生中起着关键作用，它的抑制逆转了这一现象。本研究的目的是确定靶向组织蛋白酶L是否会抑制血管生成。为此，我们在体外检测了组织蛋白酶L抑制剂纳舒尔-伊莱-色氨酸-CHO(NSITC)对内皮细胞增殖及其与细胞外基质相互作用的影响，并在体内通过检测其对鸡绒毛膜尿囊膜和小鼠Matrigel模型血管生成的影响进行了研究。结果表明，NSITC通过诱导细胞周期停滞于G(0)/G(1)期而抑制内皮细胞的增殖，并抑制细胞与不同底物的黏附。对其机制的研究(S)表明，NSITC能够减少黏附分子αVbeta3整合素的表达，抑制组织蛋白酶L介导的细胞外基质的降解，并干扰促血管生成因子成纤维细胞生长因子和血管内皮生长因子的分泌。在血管生成的CAM和小鼠Matrigel模型中，NSITC在抑制生长因子和肿瘤介导的血管生成方面表现出强大的有效性。NSITC的抗血管生成作用可抑制CAM和裸鼠移植瘤模型中的肿瘤生长。综上所述，这些发现提供了组织蛋白酶L在血管生成中发挥重要作用的证据，并表明NSITC可能是一种治疗侵袭性癌症的潜在药物。
Increased neovasculature and resistance to chemotherapy are hallmarks of aggressive cancer; therefore, the development of approaches to simultaneously inhibit these two processes is highly desirable. Previous findings from our laboratory have demonstrated that cathepsin L plays a key role in the development of drug resistance in cancer, and that its inhibition reversed this phenomenon. The goal of the present study was to determine whether targeting cathepsin L would inhibit angiogenesis. For this, the effects of a specific cathepsin L inhibitor, Napsul-Ile-Trp-CHO (NSITC), were tested in vitro on endothelial cell proliferation and interaction with the extracellular matrix, and also in vivo, by measuring its effect on angiogenesis in the chick chorioallantoic membrane (CAM) and mouse matrigel models. The results indicated that NSITC readily inhibits the proliferation of endothelial cells by inducing cell cycle arrest at the G(0)/G(1) phase, and suppresses cell adhesion to different substrates. Investigation of the underlying mechanism(s) indicated that NSITC was able to reduce expression of the adhesion molecule alphaVbeta3 integrin, inhibit cathepsin L-mediated degradation of the extracellular matrix, and disrupt secretion of the pro-angiogenic factors fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF). NSITC demonstrated potent efficacy in inhibiting growth factor- and tumor mediated-angiogenesis in the CAM and mouse matrigel models of angiogenesis. The anti-angiogenic effects of NSITC resulted in inhibition of tumor growth in the CAM and in nude mouse xenograft models. Together, these findings provide evidence that cathepsin L plays an important role in angiogenesis and suggest that NSITC represents a potential drug for the treatment of aggressive cancer.