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

Abstract

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.

Scorpion Peptide Smp24 Exhibits a Potent Antitumor Effect on Human Lung Cancer Cells by Damaging the Membrane and Cytoskeleton In Vivo and In Vitro

“…Differently, although Smp24 has significantly lower overall charge (+3) than K 4 F 6 K 4 , the IC 50 value (32.21 μM) of K 4 F 6 K 4 against A549 cells is higher than 4.06 μM of Smp24. It is reported that the net charge need not be as high as possible to improve the anticancer activity, and some mutant peptides with low charge showed strong activity among a series of peptides [ 23 ]. Thus, net charge and anticancer activity are not always positively correlated.…”

Antimicrobial peptides as drugs with double response against Mycobacterium tuberculosis coinfections in lung cancer

“…One of the main problems with the use of AMPs in the treatment of cancer is their cellular non-specificity, which could damage healthy cells at the same time ( Hilchie et al, 2019 ). However, there are already some strategies to improve the peptide sequence by obtaining specific target analogs that could generate better action and fewer side effects ( Yang et al, 2022 ). Table 6 shows the main AMPs that have been relevant in the last three years, with potential anti-Mtb and anticancer activity.…”