Lao Xingzhen, Liu Meng, Chen Jiao, Zheng Heng
Department of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiang Su Province, PR China.
PLoS One. 2013 Aug 19;8(8):e72242. doi: 10.1371/journal.pone.0072242. eCollection 2013.
A serious limitation of numerous antitumor drugs is the incapacity to penetrate solid tumors. However, addition of an RGD fragment to peptide drugs might solve this problem. In this study, we explored whether the introduction of a permeability-enhancing sequence, such as iRGD (CRGDK/RGPD/EC) fragments, would enhance the activity of thymosin alpha 1 (Tα1). The modified Tα1 (Tα1-iRGD) was successfully expressed and purified, and the in vitro assay showed that Tα1-iRGD presented a similar activity as Tα1 in promoting proliferation of mouse splenocytes. Meanwhile, cell adhesion analysis revealed that Tα1-iRGD exhibited more specific and greater binding with tumor cells compared with Tα1. Furthermore, the iRGD fragment evidently enhanced the basal ability of Tα1 to inhibit proliferation of cancer cells in vitro, particularly of mouse melanoma cell line B16F10 and human lung cancer cell line H460. Our findings indicated that the addition of an iRGD fragment increased the anti-proliferative activity of Tα1 against cancer cells by improving the ability of Tα1 to penetrate the tumor cells. This study highlighted the important roles of an iRGD sequence in the therapeutic strategy of Tα1-iRGD. Thus, Tα1-iRGD could be a novel drug candidate for cancer treatment.
众多抗肿瘤药物的一个严重局限性是无法穿透实体瘤。然而，在肽类药物中添加RGD片段可能会解决这个问题。在本研究中，我们探讨了引入通透性增强序列，如iRGD（CRGDK/RGPD/EC）片段，是否会增强胸腺素α1（Tα1）的活性。修饰后的Tα1（Tα1-iRGD）成功表达并纯化，体外试验表明，Tα1-iRGD在促进小鼠脾细胞增殖方面表现出与Tα1相似的活性。同时，细胞黏附分析显示，与Tα1相比，Tα1-iRGD与肿瘤细胞表现出更特异性且更强的结合。此外，iRGD片段明显增强了Tα1在体外抑制癌细胞增殖的基础能力，尤其是对小鼠黑色素瘤细胞系B16F10和人肺癌细胞系H460。我们的研究结果表明，添加iRGD片段通过提高Tα1穿透肿瘤细胞的能力，增强了Tα1对癌细胞的抗增殖活性。本研究突出了iRGD序列在Tα1-iRGD治疗策略中的重要作用。因此，Tα1-iRGD可能是一种新型的癌症治疗候选药物。
