The Institute of Pharmacology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, China.
Institute of Physiology, Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, China.
Eur J Med Chem. 2022 Sep 5;239:114557. doi: 10.1016/j.ejmech.2022.114557. Epub 2022 Jun 23.
Antimicrobial peptides (AMPs) display promising potential in cancer therapy. Modification with fatty acids is a simple and effective approach to improve the activity of AMPs. In the present study, we investigated the effects of fatty acid chain lengths on the anticancer activity, self-assembly and mechanism of action of CAMEL (CM15, KWKLFKKIGAVLKVL-NH), an amphipathic AMP with 15 amino acids. Conjugation of fatty acids could obviously improve the in vitro anticancer activity of CAMEL. Among the tested peptides, C12-CAMEL showed the highest anticancer activity, while C16-CAMEL killed cancer cells with the slowest kinetics. This may be related to the self-assembly of C12-CAMEL and C16-CAMEL, which could form spherical nanoparticles and tightened nanofibers, respectively. In addition, necrosis and necroptosis rather than apoptosis were the major mechanisms underlying the anticancer activity of CAMEL, C12-CAMEL and C16-CAMEL, implying that modification with fatty acids did not obviously alter the mechanism of action of CAMEL. Notably, C12-CAMEL, with high and rapid cell-killing activity, exhibited significantly stronger in vivo anticancer activity than CAMEL and C16-CAMEL. Overall, the present work suggests that the choice of a suitable fatty acid for structural modification is necessary for improving the anticancer activity of AMPs.
抗菌肽 (AMPs) 在癌症治疗中显示出有前景的潜力。脂肪酸修饰是提高 AMPs 活性的一种简单而有效的方法。在本研究中，我们研究了脂肪酸链长对具有 15 个氨基酸的两亲性 AMP CAMEL（CM15，KWKLFKKIGAVLKVL-NH）的抗癌活性、自组装和作用机制的影响。脂肪酸的缀合可以明显提高 CAMEL 的体外抗癌活性。在测试的肽中，C12-CAMEL 表现出最高的抗癌活性，而 C16-CAMEL 以最慢的动力学杀死癌细胞。这可能与 C12-CAMEL 和 C16-CAMEL 的自组装有关，它们可以分别形成球形纳米颗粒和紧密的纳米纤维。此外，坏死和 necroptosis 而不是细胞凋亡是 CAMEL、C12-CAMEL 和 C16-CAMEL 抗癌活性的主要机制，这意味着脂肪酸修饰并没有明显改变 CAMEL 的作用机制。值得注意的是，具有高和快速细胞杀伤活性的 C12-CAMEL 表现出比 CAMEL 和 C16-CAMEL 更强的体内抗癌活性。总的来说，本工作表明，选择合适的脂肪酸进行结构修饰对于提高 AMPs 的抗癌活性是必要的。
