ACTIVITY OF NOVEL HYBRID SYNTHETIC ANTITUMOR PEPTIDES CABUCR AND CALTX IN VIVO IN THE MURINE EHRLICH ASCITES CARCINOMA MODEL

AbstractCationic amphipathic peptides of the innate immune system that are able to selectively bind to and damage cancer cell membranes are considered promising candidates for broadening the arsenal of chemotherapeutics to combat drug-resistant tumors. The current research was aimed at evaluating antitumor activity of novel synthetic hybrid peptides CaBuCr and CaLTX in vivo, using a mouse 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 (in the case of CaBuCr), or with a sequence based on 2 lysine – 2 tryptophan repeats similar to that of the synthetic peptide LTX-315 (in the case of CaLTX). Previously, these peptides were found to be highly active against 6 tumor cell lines and demonstrated low hemolytic activity toward human erythrocytes in vitro. The development of ascites tumor in male F1 CBA × C57BL/6 mice was initiated by intraperitoneal injection of 1 million EAC cells. The animals were injected with peptides at a dose of 1.3 mg/kg daily for 10 days. We analyzed survival curves, as well as a number of parameters calculated based on sacrificing 3 animals from each group on the 11th day since the tumor inoculation: the volume of ascites, the total number and concentration of EAC cells, and the leukocytes’ concentration in mice blood. Results were compared to the control group that received injections of saline. Both peptides showed the ability to reduce the total number of cells in ascites by more than 40% and significantly increased the concentration of leukocytes in the blood. CaBuCr demonstrated a more pronounced effect on the lifespan of tumor-bearing mice, the average survival time increased by 24 % compared with the control group, while CaLTX was able to provide only the increase by 13 %. Comparison with the cytolytic peptide protegrin 1, previously studied in the EAC model, suggests that not only direct cytotoxic activity, but also immunomodulatory effects may contribute to the observed action of the peptides of interest.