Identification of a novel lytic peptide for the treatment of solid tumours
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https://doi.org/10.18632/genesandcancer.18
Claudia Szczepanski1, Olav Tenstad3, Anne Baumann4, Aurora Martinez4, Reidar Myklebust1, Rolf Bjerkvig1,2,*and Lars Prestegarden1,5,*
1 NorLux Neuro-Oncology, Dept. of Biomedicine, University of Bergen, Norway
2 Centre de Recherche Public de la Santé, Luxembourg, Luxemburg
3 Cardiovascular Research Group, Dept. of Biomedicine, University of Bergen, Norway
4 Biorecognition Group, Dept. of Biomedicine, University of Bergen, Norway
5 Dept. of Dermatology, Haukeland University Hospital, Bergen, Norway
* These authors contributed equally
Correspondence:
Lars Prestegarden, email:
Keywords: Antimicrobal lytic peptides, cationic lytic peptides, cancer treatment, membrane disruption.
Received: April 16, 2014 Accepted: June 26, 2014 Published: June 27, 2014
Abstract
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.
