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Because of their unique properties, antimicrobial peptides (AMPs) represent a potential reservoir of novel anticancer therapeutic agents. However, only a few AMPs can kill tumors with high efficiency, and obtaining inexpensive anticancer AMPs with strong activity is still a challenge. In our previous work, a series of original short amphiphilic triblock AMP (KnFmKn) analogues were developed which were demonstrated to exert excellent effects on bacterial infection, both in vitro and in vivo. Herein, the overall objectives were to assess the potent tumoricidal capacities of these analogues against human lung cancer cell line A549 and the underlying mechanism. The results of the CCK-8 assay revealed that the precise modification of the peptides’ primary sequences could modulate their tumoricidal potency. In the tumoricidal progress, positive charge and hydrophobicity were the key driving forces. Among these peptides, K4F6K4 displayed the most remarkable tumoricidal activity. Furthermore, the excellent anticancer capacity of K4F6K4 was proven by the live/dead cell staining, colony formation assay, and tumor growth observations on xenografted mice, which indicated that K4F6K4 might be a promising drug candidate for lung cancer, with no significant adverse effects in vitro or in vivo. In addition, the cell apoptosis assay using flow cytometry, the morphology observations using the optical microscope, confocal microscopy using CellMask™ Deep Red staining, and scanning electron microscope suggested that membrane disruption was the primary mechanism of its antitumor action. Through analyzing the structure–activity relationship, it was found that the amount of positive charge required for KnFmKn to exert its optimal tumoricidal effect was more than that needed for the antimicrobial activity, while the optimal proportion of hydrophobicity was less. Our findings suggest that further analysis of the structure–activity relationship of AMPs’ primary sequence variations will be beneficial. Hopefully, this work can provide guiding principles in designing peptide-based therapeutics for lung cancer.

Therapeutic Effects of Synthetic Triblock Amphiphilic Short Antimicrobial Peptides on Human Lung Adenocarcinoma