Penetratin-mediated delivery enhances the antitumor activity of the cationic antimicrobial peptide Magainin II.
Penetratin-mediated delivery enhances the antitumor activity of the cationic antimicrobial peptide Magainin II.
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DOI：
10.1089/cbr.2012.1328
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发表时间：
2013-05
影响因子：
3.4
通讯作者：
Shan Liu;Hao Yang;L. Wan;Jingqiu Cheng;Xiaofeng Lu
中科院分区：
文献类型：
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作者：
Shan Liu;Hao Yang;L. Wan;Jingqiu Cheng;Xiaofeng Lu
具有抗肿瘤活性的阳离子抗菌肽（CAPs）由于其较低的耐药性诱导风险而具有作为新型抗肿瘤药物的潜力。在这些肽中，爪蟾抗菌肽II（MG 2）仅在高浓度下在肿瘤细胞中表现出细胞毒性，这可能是由于MG 2在细胞膜结合和细胞进入中的效率低下。与细胞穿透肽（CPP）结合可能增强MG 2在肿瘤细胞中的细胞毒性。在这里，我们通过将MG 2缀合到CPP穿透蛋白（Antp）的N末端来构建融合肽MG 2A。发现融合肽MG2A在肿瘤细胞杀伤方面比未缀合的MG2更有效。MG2A对测试的肿瘤细胞的IC50比未缀合的MG2的IC50低至少30倍。这些数据表明，与Antp的缀合显著增强了MG 2在肿瘤细胞中的细胞毒性。此外，MG2A对肿瘤细胞的IC50在2至3 μM范围内，比对正常细胞的IC50低约3至5倍。此外，硫酸软骨素（CS）被发现在测试的肿瘤细胞的表面上过表达，并且MG2A的细胞毒性可以通过添加外源CS来抑制。这些结果表明，Antp与肿瘤细胞表面CS的结合可能是MG 2A选择性杀伤肿瘤细胞的重要原因之一。总之，MG 2与Antp的缀合可以显著增强其抗肿瘤活性，并且CAP与Antp的融合可能是癌症靶向治疗的替代方案。
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.