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-NH₂), 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 (AMP) 在癌症治疗中显示出巨大的潜力。用脂肪酸进行修饰是提高 AMP 活性的一种简单有效的方法。在本研究中，我们研究了脂肪酸链长对 CAMEL (CM15, KWKLFKKIGAVLKVL-NH ₂ ) 的抗癌活性、自组装和作用机制的影响，CAMEL 是一种具有 15 个氨基酸的两亲性 AMP。脂肪酸共轭能明显改善体外CAMEL 的抗癌活性。在测试的肽中，C12-CAMEL 显示出最高的抗癌活性，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拉紧的纳米纤维。此外，坏死和坏死性凋亡而非细胞凋亡是 CAMEL、C12-CAMEL 和 C16-CAMEL 抗癌活性的主要机制，这意味着用脂肪酸修饰并没有明显改变 CAMEL 的作用机制。值得注意的是，C12-CAMEL 具有高和快速的细胞杀伤活性，在体内表现出显着更强抗癌活性优于 CAMEL 和 C16-CAMEL。总体而言，目前的工作表明，选择合适的脂肪酸进行结构修饰对于提高 AMP 的抗癌活性是必要的。