Perspective approach for cutaneous melanoma treatment by cationic peptides

Abstract

Background: Metastatic cutaneous melanoma is the most aggressive skin cancer with poor prognosis. As a rule, metastatic melanoma tumors with various localization have not complete recovery. Effective therapy of disseminated cutaneous melanoma remains an acute problem, in spite of the recent advances in immunotherapy and targeted molecular therapy. This paper describes a preliminary data obtained from the analysis of cytotoxicity and antitumor activity of some cationic peptides (CPs), in metastatic cutaneous melanoma cell lines generated from the biopsies and subcutaneous cutaneous melanoma xenografts in immunodeficient mice. Molecular mechanisms for CP selective cytotoxicity and specific antitumor effect are related with functional inhibition of chaperone proteins nucleolin and nucleophosmin followed by nucleolar stress. Objective: Evaluation of cytotoxicity and antitumor activities of some cationic peptides using in vitro and in vivo cell and mice xenograft models. Material and methods: Three cutaneus melanoma cell lines generated from metastatic lymph nodes were used for in vitro analysis of cytotoxicity of 4 cationic peptides by MTT assay. Antitumor activity of the peptides was studied in vivo using subcutaneous xenografts generated from MelCher melanoma cell line. Flow cytometry and molecular docking were used for analysis of molecular mechanisms of cell death induced by peptides under study. Results: The use of cationic peptides (CPs) with specific molecular structure for inducing selective tumor cell death, namely cutaneous melanoma, seems to solve a problem of melanoma resistance to standard treatment. Suchcationic dendritic peptides: have some advantages (1) low toxicity fornormal cells, (2) rapid penetration through cell membranes, (3) the interaction with specific surface and intracellular targets in tumor cells, including, cell surface nucleolin (NCL). This chaperone protein is highly expressed in solid tumors and trigger ligand internalization, including cationic peptides. Nucleolin and nucleophosmin (NPM) control the most important cell functions - DNA transcription, RNA translation, ribosome biogenesis, chromatin remodeling, cell signaling, differentiation, invasion, angiogenesis and carcinogenesis. However, NCL/NPM expression in normal tissues is significantly lower. Differential expression levels of NCL and NPM in tumor and normal cells allows to use these proteins as a targets for selective inhibition of tumor growth. Molecular mechanisms for CP selective cytotoxicity and specific antitumor effect are related with functional inhibition of NCL/NPM followed by nucleolar stress this idea was proven by in vivo experiments using melChermice subcutaneous xenografts. Conclusion: Tumor growth suppression up to 85% was induced by two tested cationic peptides (CPs) in MelCher xenografts. High selective cytotoxicity of PCs tested for three cutaneous melanoma cell lines was also revealed invitro . Molecular docking results indicate high possibility for NCL/NPM interactions with CP molecule as cell targets and ligands with significant glide scores. Thus, CPs might consider as perspective anticancer agents.