Department of Bioengineering, Zhengzhou University, Science Road 100, Zhengzhou 450001, China.
Peptides. 2010 May;31(5):850-64. doi: 10.1016/j.peptides.2010.01.007. Epub 2010 Feb 2.
In recent years, many endogenous peptides have been identified by screening combinatory phage display peptide library, which play important roles in the process of angiogenesis. A heptapeptide, ATWLPPR, binds specifically to NRP-1 and selectively inhibits VEGF165 binding to VEGFR-2. Another heptapeptide, NLLMAAS, blocks both Ang-1 and Ang-2 binding to Tie-2 in a dose-dependent manner. In the present study, we aimed to connect ATWLPPR (V1) with NLLMAAS (V2) via a flexible linker, Ala-Ala, to reconstruct a novel peptide ATWLPPRAANLLMAAS (V3). We firstly investigated the anti-tumor and anti-angiogenic effects of peptide V3 on sarcoma S180 and hepatoma H22 bearing BALB/c nude mice. Mice were continuously subcutaneously administrated with normal saline, V1 (320microg/kg/d), V2 (320microg/kg/d), V1+V2 (320microg/kg/d), and V3 (160, 320 and 480microg/kg/d), for 7 days. Treatment with peptide V3 could significantly reduce the tumor weight and volume. Pathological examination showed that the tumors treated with peptide V3 had a larger region of necrosis than that of peptide V1, V2, and V1+V2 at the same dose. A significant decrease of microvessel density (MVD) in a dose-dependent manner was observed in each group of peptide V3. The results of pathological examination on normal tissue, lung, heart, liver, spleen, kidney and white blood cells showed that peptide V3 might have no significant toxicity. In conclusion, our results demonstrated that peptide V3 could be more effective on inhibiting tumor growth and angiogenesis than that of V1, V2, and V1+V2. Peptide V3 could be considered as a novel chimeric peptide with potent anti-tumor activity.
近年来，通过筛选组合噬菌体展示肽文库，已经鉴定出许多内源性肽，它们在血管生成过程中发挥重要作用。一个七肽 ATWLPPR 特异性结合 NRP-1，并选择性抑制 VEGF165 与 VEGFR-2 的结合。另一个七肽 NLLMAAS 以剂量依赖性方式阻断 Ang-1 和 Ang-2 与 Tie-2 的结合。在本研究中，我们旨在通过柔性接头 Ala-Ala 将 ATWLPPR（V1）与 NLLMAAS（V2）连接起来，构建一个新的肽 ATWLPPRAANLLMAAS（V3）。我们首先研究了肽 V3 对荷肉瘤 S180 和肝癌 H22 的 BALB/c 裸鼠的抗肿瘤和抗血管生成作用。小鼠连续皮下给予生理盐水、V1（320μg/kg/d）、V2（320μg/kg/d）、V1+V2（320μg/kg/d）和 V3（160、320 和 480μg/kg/d），连续 7 天。用肽 V3 治疗可显著降低肿瘤重量和体积。病理检查显示，用肽 V3 治疗的肿瘤在相同剂量下比肽 V1、V2 和 V1+V2 的坏死区域更大。肽 V3 组的微血管密度（MVD）呈剂量依赖性显著降低。对正常组织、肺、心、肝、脾、肾和白细胞的病理检查结果表明，肽 V3 可能没有明显的毒性。总之，我们的结果表明，肽 V3 对抑制肿瘤生长和血管生成的效果比 V1、V2 和 V1+V2 更有效。肽 V3 可被视为一种具有潜在抗肿瘤活性的新型嵌合肽。
