The Pharmaceutical Research Institute at Albany, Albany College of Pharmacy and Health Sciences, Rensselaer, NY 12144, USA.
Anticancer Res. 2009 Nov;29(11):4473-81.
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.
新生血管形成和对化疗的耐药性是侵袭性癌症的标志；因此，开发同时抑制这两个过程的方法是非常需要的。我们实验室的先前研究结果表明，组织蛋白酶 L 在癌症耐药性的发展中起着关键作用，其抑制作用逆转了这种现象。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，在体外测试了一种特定的组织蛋白酶 L 抑制剂 Napsul-Ile-Trp-CHO（NSITC）对内皮细胞增殖和与细胞外基质相互作用的影响，并且还在体内通过测量其对鸡胚绒毛尿囊膜（CAM）和小鼠基质胶模型中的血管生成的影响来进行。结果表明，NSITC 通过诱导细胞周期停滞在 G(0)/G(1)期，很容易抑制内皮细胞的增殖，并抑制细胞粘附到不同的基质上。对潜在机制的研究表明，NSITC 能够降低粘附分子 αVβ3 整联蛋白的表达，抑制组织蛋白酶 L 介导的细胞外基质降解，并破坏促血管生成因子成纤维细胞生长因子（FGF）和血管内皮生长因子（VEGF）的分泌。NSITC 在 CAM 和小鼠基质胶血管生成模型中表现出抑制生长因子和肿瘤介导的血管生成的强大功效。NSITC 的抗血管生成作用导致在 CAM 和裸鼠异种移植模型中肿瘤生长的抑制。总之，这些发现提供了证据表明组织蛋白酶 L 在血管生成中起着重要作用，并表明 NSITC 代表了治疗侵袭性癌症的潜在药物。
