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

The hymenochirins are a family of cationic, amphipathic, alpha-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 center dot NH2) shows the greatest cytotoxic potency against non-small cell lung adenocarcinoma A549 cells (LC50 = 2.5 +/- 0.2 mu M), breast adenocarcinoma MDA-MB-231 cells (LC50 = 9.0 +/- 03 mu M), colorectal adenocarcinoma HT-29 cells (LC50 = 9.7 +/- 0.2 mu M), and hepatocarcinoma HepG2 cells (LC50 = 22.5 +/- 1.4 mu M) with appreciably less hemolytic activity against human erythrocytes (LC50 = 213 +/- 18 mu M). Structure-activity relationships were investigated by synthesizing analogs of hymenochirin-1B in which Pro(5), G1u(6) and Asp(9)on 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 mu M). The [D9k] and [E6k,D9k] analogs retain relatively high cytotoxic potency against the tumor cells (LC50 in the range 2.1-21 mu M) but show reduced hemolytic activity (LC50 > 300 mu M). The data suggest that hymenochirin-1B has therapeutic potential as a template to generate potent, non-toxic anti-cancer agents. (C) 2013 Elsevier B.V. All rights reserved.