Cancer Research Institute, The Catholic University of Korea, Seoul, Republic of Korea.
Cancer Lett. 2010 Feb 28;288(2):251-60. doi: 10.1016/j.canlet.2009.07.008. Epub 2009 Aug 6.
The kringle domain of urokinase-type plasminogen activator (UK1) has anti-angiogenic and anti-tumor effects. Celecoxib, an inhibitor of cyclooxygenase type 2, also suppresses angiogenesis and tumor growth. To look for potential additive effects in their activities, we examined the anti-angiogenic and anti-tumor effects of the combination of UK1 and celecoxib for malignant gliomas. In vitro, the combination of UK1 and celecoxib enhanced inhibition of proliferation, migration, and tube formation of endothelial cells, although showing no enhancement of inhibition of U87 cell growth. However, in vivo models, combination treatment of intracerebral U87 malignant glioma xenografts in nude mice with UK1 (10mg/kg/day) and celecoxib (10mg/kg/day) at lower doses resulted in even more potent inhibition of tumor growth than each monotherapy (by 81% compared to untreated tumors), with drastic decrease of the expression of angiogenesis-related factors and increase of apoptosis in the tumor tissues. Interestingly, UK1 inhibited VEGF or bFGF-induced phosphorylation of ERK1/2 in ECs, whereas celecoxib showed no such effects. However, celecoxib inhibited U87 cell growth and directly suppressed their VEGF production. Therefore, our data suggest that combined use at low doses of UK1 and celecoxib with different anti-angiogenic mechanisms provides a desirable strategy for anti-glioma therapy.
尿激酶型纤溶酶原激活物（uPA）的kringle 结构域具有抗血管生成和抗肿瘤作用。环氧化酶 2 抑制剂塞来昔布也能抑制血管生成和肿瘤生长。为了寻找它们活性的潜在协同作用，我们研究了 UK1 和塞来昔布联合应用对恶性胶质瘤的抗血管生成和抗肿瘤作用。在体外，UK1 和塞来昔布联合应用增强了对内皮细胞增殖、迁移和管形成的抑制作用，尽管对 U87 细胞生长的抑制没有增强。然而，在体内模型中，联合应用 UK1（10mg/kg/天）和塞来昔布（10mg/kg/天）在较低剂量下治疗裸鼠脑内 U87 恶性胶质瘤异种移植物，比单独用药更能有效地抑制肿瘤生长（与未治疗的肿瘤相比抑制率为 81%），肿瘤组织中血管生成相关因子的表达明显下降，细胞凋亡增加。有趣的是，UK1 抑制了 ECs 中 VEGF 或 bFGF 诱导的 ERK1/2 磷酸化，而塞来昔布则没有这种作用。然而，塞来昔布抑制了 U87 细胞的生长，并直接抑制了它们的 VEGF 产生。因此，我们的数据表明，低剂量 UK1 和塞来昔布联合应用具有不同的抗血管生成机制，为抗胶质瘤治疗提供了一种理想的策略。
