Liu Shan, Yang Hao, Wan Lin, Cheng Jingqiu, Lu Xiaofeng
Key Lab of Transplant Engineering and Immunology, Ministry of Health, West China Hospital, Sichuan University , Chengdu 610041, China .
Cancer Biother Radiopharm. 2013 May;28(4):289-97. doi: 10.1089/cbr.2012.1328. Epub 2013 Jan 3.
Cationic antimicrobial peptides (CAPs) with antitumor activity have potential for use as novel antitumor agents because of their lower risk for induction of resistance. Of these peptides, magainin II (MG2) exhibited cytotoxicity in tumor cells only at high concentrations, likely due to the inefficiency of MG2 in cell membrane binding and cell entry. Conjugation to a cell-penetrating peptide (CPP) might enhance the cytotoxicity of MG2 in tumor cells. Here, we constructed a fusion peptide MG2A by conjugating MG2 to the N-terminus of the CPP penetratin (Antp). It was found that the fusion peptide MG2A is more potent than unconjugated MG2 at tumor cell killing. The IC50s of MG2A for the tumor cells tested were at least 30 times lower than the IC50s of unconjugated MG2. These data indicate that conjugation to Antp significantly enhanced the cytotoxicity of MG2 in tumor cells. Moreover, the IC50s of MG2A for tumor cells are within 2 to 3 μM, which are about three to five times lower than the IC50 for normal cells. Furthermore, chondroitin sulfate (CS) was found to be overexpressed on the surface of the tested tumor cells, and the cytotoxicity of MG2A could be inhibited by the addition of exogenous CS. These results suggest that binding of Antp to CS on tumor cells might be one important cause for the selective cytotoxicity of MG2A in tumor cells. Taken together, conjugation of MG2 to Antp can significantly enhance its antitumor activity, and the fusion of CAP to Antp might be an alternative for cancer-targeted therapy.
具有抗肿瘤活性的阳离子抗菌肽（CAPs）因其诱导耐药性的风险较低而有潜力用作新型抗肿瘤药物。在这些肽中，蛙皮素II（MG2）仅在高浓度时才对肿瘤细胞表现出细胞毒性，这可能是由于MG2在细胞膜结合和进入细胞方面效率低下所致。与细胞穿透肽（CPP）偶联可能会增强MG2在肿瘤细胞中的细胞毒性。在此，我们通过将MG2与CPP穿膜肽（Antp）的N端偶联构建了融合肽MG2A。结果发现，融合肽MG2A在杀伤肿瘤细胞方面比未偶联的MG2更有效。MG2A对所测试肿瘤细胞的半数抑制浓度（IC50）比未偶联的MG2的IC50至少低30倍。这些数据表明，与Antp偶联显著增强了MG2在肿瘤细胞中的细胞毒性。此外，MG2A对肿瘤细胞的IC50在2至3μM范围内，比正常细胞的IC50低约三至五倍。此外，发现硫酸软骨素（CS）在所测试肿瘤细胞表面过表达，添加外源性CS可抑制MG2A的细胞毒性。这些结果表明，Antp与肿瘤细胞表面CS的结合可能是MG2A在肿瘤细胞中具有选择性细胞毒性的一个重要原因。综上所述，MG2与Antp偶联可显著增强其抗肿瘤活性，CAP与Antp融合可能是癌症靶向治疗的一种替代方法。
