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Cancer is a frequently occurring disease in humans causing over seven million deaths per year worldwide and showing increasing morbidity. Therapy is challenging, as the disease is not curable in its advanced stages, and, in addition, medication causes severe side effects or becomes ineffective due to an increase of drug-resistant cancer types. Antimicrobial peptides (AMPs) became the focus of research, as the search of new and effective anti-cancer agents intensified. These peptides are part of the innate immune system of mammals, some showing anti-cancer activity besides targeting pathogens. To investigate the potential of AMPs as anti-cancer drugs, the present study aimed at determining the activity of a selection of natural AMPs and fragments thereof against an equine sarcoid and a human prostate cancer cell line, and to elucidate the mode of action of the selected peptides. Cytotoxicity assays and sensor-chip-based real-time measurements made evident a potent activity of the tested AMPs against both cancer cell lines. Derivates of peptide NK-2 were documented to exhibit improved anti-cancer potency, thus becoming promising candidates for future drug development. Peptides’ mode of action was investigated with respect to killing kinetics, peptide-to-peptide-interaction, target structures on cell surfaces, and cancer cell selectivity. The cationic AMPs are believed to target cells via an anionic membrane surface, which several cancer cells have. The AMPs mainly inflict cell death via direct membrane destruction. It is suggested that AMPs might aggregate, especially during membrane interaction, and gel electrophoresis performed in this study supports this assumption. Cytotoxicity assays, fluorescent microscopy, and sensor-chip-based real-time measurements showed a fast cell-killing process by the tested peptides. Inhibition tests and enzymatic treatment of the cell surface evidenced that AMPs can distinguish different anionic cell surface structures. They bind sulfated carbohydrates rather than sialic acids or sialylated proteins. The anionic membrane lipid PS interacts in varying degrees with individual AMPs, pointing to different target preferences. While peptides exhibit selectivity for the prostate cancer cell line over a healthy cell line, no selectivity was seen for the equine sarcoid cell line over its healthy counterpart. This difference could be explained by a lack of anionic surface in the latter cancer cells.