LfcinB-Derived Peptides: Specific and punctual change of an amino acid in monomeric and dimeric sequences increase selective cytotoxicity in colon cancer cell lines

We observed how a change of specific residues in LfcinB dimeric and palindromic sequences caused a notable increase in the cytotoxic activity against CaCo-2 cells while maintaining or even diminishing the level of the cytotoxic effect against normal fibroblast and HEK-293 cells. In both cases, the IC50 of the peptides was reduced by more than half of the concentration, diminishing the IC50 value from 150 µg/mL (101 µM) (LfcinB (21–25)Pal: RWQWRWQWR) to 60 µg/mL (42.8 µM) for the modified palindromic peptide 5[A] LfcinB (21–25)Pal: RWQWAWQWR and the IC50 from 125 µg/mL (LfcinB (20–30)2: (RRWQWRMKKLG)2-K-Ahx to 58 µg/mL (18 µM) for the modified dimeric peptide 26[F] LfcinB (20–30)2: (RRWQWRFKKLG)2-K-Ahx. The cytotoxic effect of 26[F] LfcinB (20–30)2 and LfcinB (21–25)Pal peptides against colon cancer cell line HCT-116 was greater than the cytotoxic effect of these peptides against Caco-2 cells, suggesting that the cytotoxic effect of these peptides is selective for colon cancer cell lines. The cytotoxic effect of the peptides rapidly caused severe damage to the morphology of CaCo-2 cells, while the morphology of the normal fibroblast and HEK-293 cells was not affected. The dimeric modified peptide 26[F] LfcinB (20–30)2 mainly caused death through apoptotic events. As for the palindromic modified peptide 5[A] LfcinB (21–25)Pal, the cell death was induced by both necrotic and apoptotic pathways. All this suggests that specific modification of a single residue in the peptide sequence can improve the anticancer activity of the original monomeric or dimeric peptides, giving place to new potential molecules for the future development of drugs for use against colorectal carcinoma. Our results show that changes to a residue of the anti-cancer peptide sequence may be considered a versatile, feasible, and invaluable strategy for obtaining promising sequences for developing peptide-based cancer treatments.