Originally known as host defence
peptides for their substantial bacteriotoxic effects, many
cationic antimicrobial peptides also exhibit a potent cytotoxic activity against
cancer cells. Their mode of action is characterized mostly by electrostatic interactions with the plasma membrane, leading to membrane disruption and rapid necrotic cell death. In this work, we have designed a novel cationic
peptide of 27
amino acids (Cypep-1), which shows efficacy against a number of
cancer cell types, both in vitro and in vivo, while normal human fibroblasts were significantly less affected. Surface plasmon resonance experiments as well as
liposome leakage assays monitored by fluorescence spectroscopy revealed a substantial binding affinity of Cypep-1 to negatively charged
liposomes and induced significant leakage of
liposome content after exposure to the
peptide. The observed membranolytic effect of Cypep-1 was confirmed by scanning electron microscopy (SEM) as well as by time-lapse confocal microscopy. Pharmacokinetic profiling of Cypep-1 in rats showed a short plasma half-life after i.v. injection, followed mainly by retention in the liver, spleen and kidneys. Extremely low concentrations within the organs of the central nervous system indicated that Cypep-1 did not pass the blood-brain-barrier. Local treatment of 4T1 murine mammary
carcinoma allografts by means of a single local bolus injection of Cypep-1 led to a significant reduction of tumour growth in the following weeks and prolonged survival. Detailed histological analysis of the treated tumours revealed large areas of
necrosis. In sum, our findings show that the novel cationic
peptide Cypep-1 displays a strong cytolytic activity against
cancer cells both in vitro and in vivo and thus holds a substantial therapeutic potential.