In vivo activity of novel hybrid synthetic antitumor peptides CaBuCr and CaLTX in murine model of Ehrlich ascites carcinoma

Cationic amphipathic peptides of the innate immune system that are able to selectively bind to and damage cancer cell membranes are considered promising candidates for extending the pipeline of chemotherapeutics in order to combat drug-resistant malignancies. The current research was aimed at evaluating antitumor activity of novel synthetic hybrid peptides CaBuCr and CaLTX in vivo, using a murine Ehrlich ascites carcinoma (EAC) model. These peptides are chimeric sequences based on the N-terminal fragment (1-8) of cecropin A combined with the regularized proline- and tryptophan-rich sequence of water buffalo’s cathelicidin 4 buCATHL4D (abbrev. name CaBuCr), or with a sequence based on 2 lysine – 2 tryptophan repeats similar to that of the synthetic peptide LTX-315 (abbrev. name CaLTX). These peptides were found to be highly active against 6 tumor cell lines and demonstrated low hemolytic activity towards human erythrocytes in vitro. The ascites tumors were initiated in male F1 CBA × C57BL/6 mice by intraperitoneal injection of 1 million EAC cells. The animals were injected with tested peptides at a dose of 1.3 mg/kg daily for 10 days. We analyzed survival curves, as well as a number of estimated parameters based on sacrificing 3 animals from each group on the 11^th day since the tumor inoculation, i.e., volume of ascite tumors, total number and concentration of EAC cells, and leukocyte counts in murine blood. The experimental results were compared to the control mice that received injections of physiological saline. Both peptides showed the ability of reducing total number of ascites cells by > 40% and significantly increased the leukocyte counts in peripheral blood. CaBuCr demonstrated a more pronounced effect on the lifespan of tumor-bearing mice: the average survival time increased by 24% compared with control group, whereas CaLTX was able to provide only an increase of 13%. Comparison with cytolytic peptide protegrin 1, being previously studied in EAC model, suggests that besides direct cytotoxic action, immunomodulatory effects may also contribute to observed in vivo activity of the peptides of interest.