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Development of antimicrobial peptides (AMPs) as highly effective and selective anticancer agents would represent great progress in cancer treatment. Here we show that myristoyl-CM4, a new synthetic analog generated by N-myristoylation of AMPs CM4, had anticancer activity against MCF-7, MDA-MB-231, MX-1 breast cancer cells (IC 50  of 3–6 μM) and MDA-MB-231 xenograft tumors. The improved activity was attributed to the effect of myristoyl on the cell membrane. Flow cytometry and confocal laser scanning microscopy results showed that N-myristoylation significantly increased the membrane affinity toward breast cancer cells and also effectively mediated cellular entry. Despite increasing cytotoxicity against HEK293 and NIH3T3 cells and erythrocytes associated with its anticancer activity, myristoyl-CM4 maintained a certain selectivity toward breast cancer cells. Accordingly, the membrane affinity toward breast cancer cells was two to threefold higher than that of normal cells. Glycosylation analysis showed that sialic acid-containing oligosaccharides (including  O -mucin and gangliosides) were important targets for myristoyl-CM4 binding to breast cancer cells. After internalization, co-localization analysis revealed that myristoyl-CM4 targeted mitochondria and induced mitochondrial dysfunction, including alterations in mitochondrial transmembrane potential, reactive oxygen species (ROS) generation and cytochrome c release. Activation of caspase 9, caspase 3 and cleavage of PARP were observed in MX-1, MCF-7, and MDA-MB-231 cells after myristoyl-CM4 treatment. The current work indicates that increasing hydrophobicity by myristoylation to modulate peptide-membrane interactions and then target mitochondria is a good strategy to develop AMPs as anticancer agents in the future.

frontiers in pharmacology

N-myristoylation of Antimicrobial Peptide CM4 Enhances Its Anticancer Activity by Interacting With Cell Membrane and Targeting Mitochondria in Breast Cancer Cells