Mechanistic Insights into the Anticancer Activity of the Crotalicidin-Derived Ctn-2 Peptide in Triple-Negative Breast Cancer

Triple-negative breast cancer is the subtype with the worst prognosis and has limited treatment options. Bioactive peptides are a promising alternative, having demonstrated antitumor properties with a mechanism of action involving the cell membrane. In this study, we evaluated the Ctn-2 peptide, a fragment of crotalicidin (Ctn), which has shown antitumor activity with highly lytic characteristics but is not selective in non-tumor cells. We evaluated the antitumor activity of the peptide Ctn-2 in triple-negative breast cancer cells and its selectivity over non-tumoral cells. Comparative analyses with LTX-315 and biophysical studies on model membranes indicate that Ctn-2 preferentially interacts with cancer-associated lipids. Functional assays further show that its action involves controlled membrane disruption and associated cellular responses. We also examined the combined effect of Ctn-2 and doxorubicin, finding that Ctn-2 selectively enhanced cytotoxicity in tumor cells and potentiated the activity of conventional chemotherapy. Overall, the results indicate that Ctn-2 is a membrane-active peptide with selective antitumor potential and the ability to improve chemotherapeutic efficacy.