Anti-tumor activities of the host-defense peptide hymenochirin-1B

The hymenochirins are a family of cationic, amphipathic, α-helical host-defense peptides, first isolated from skin secretions of the Congo clawed frog Hymenochirus boettgeri (Pipidae). Of the four hymenochirins tested, hymenochirin-1B (IKLSPETKDNLKKVLKGAIKGAIVAKMV.NH₂) shows the greatest cytotoxic potency against non-small cell lung adenocarcinoma A549 cells (LC₅₀ = 2.5 ± 0.2 μM), breast adenocarcinoma MDA-MB-231 cells (LC₅₀ = 9.0 ± 0.3 μM), colorectal adenocarcinoma HT-29 cells (LC₅₀ = 9.7 ± 0.2 μM), and hepatocarcinoma HepG2 cells (LC₅₀ = 22.5 ± 1.4 μM) with appreciably less hemolytic activity against human erythrocytes (LC₅₀ = 213 ± 18 μM). Structure–activity relationships were investigated by synthesizing analogs of hymenochirin-1B in which Pro⁵, Glu⁶ and Asp⁹on the hydrophilic face of the helix were replaced by one or more L-lysine or D-lysine residues. The [D9K] analog displays the greatest increase in potency against all four cell lines (up to 6 fold) but hemolytic activity also increases (LC₅₀ = 174 ± 12 μM). The [D9k] and [E6k,D9k] analogs retain relatively high cytotoxic potency against the tumor cells (LC₅₀ in the range 2.1–21 μM) but show reduced hemolytic activity (LC₅₀ > 300 μM). The data suggest that hymenochirin-1B has therapeutic potential as a template to generate potent, non-toxic anti-cancer agents.