Correlation of the antibacterial activities of cationic peptide antibiotics and cationic steroid antibiotics
Correlation of the antibacterial activities of cationic peptide antibiotics and cationic steroid antibiotics. breast malignancy cells. Our study provides evidence that both CSA-13 and MNP@CSA-13 decreased viability and inhibit proliferation of MCF-7 and MDA-MB-231 cells despite the protumorigenic properties of LL-37 peptide. Flow cytometry-based analyses revealed that ceragenin treatment results in increases in lifeless and PI-negative/low-viability cells, which was associated with glutathione (GSH) depletion and increased reactive oxygen species (ROS) generation followed by mitochondrial membrane depolarization, caspase activation, and DNA fragmentation. These findings demonstrate that both CSA-13 and MNP@CSA-13 cause disruption of the oxidative balance of cancer cells. This novel mechanism of ceragenin-mediated eradication of cancer cells suggest that these brokers may be developed as a possible treatment of breast cancer. exhibited that administration of CpG oligodeoxynucleotides (CpG-ODNs) in the presence of LL-37 enhanced anti-cancer activity of CpG-ODNs against ovarian cancer despite the protumorigenic activity of human cathelicidin in ovarian cancer tissues . In contrast to reports demonstrating the varied activity of LL-37 peptide in tumor tissues, ceragenins, as mimics of the human cathelicidin amphipathic properties, have been presented as potential pro-apoptotic compounds in the treatment of malignancy [17, 18]. Ceragenins were designed to simulate the facially amphiphilic morphology of antimicrobial peptides with lower costs of production and greater stability under physiological conditions . It is generally accepted that the mechanism of action of ceragenins is due to increases in permeability of the cytoplasmic membranes of pathogens, which is usually driven by their amphiphilic morphology [20, 21]. Given the above observations, it is suggested that a comparable mechanism of action will contribute to the anti-cancer activity of these compounds. To date, results presented by Kuroda indicate that ceragenin CSA-13, one of the best studied of the ceragenin group, exerts anti-tumorigenic activity against colon cancer cells through induction of cell cycle arrest followed by intensification of the apoptosis processes . However, it has not yet been decided if ceragenins, as mimics of LL-37 peptide, exert comparable anti-tumorigenic activity against cancer cells. A recent study by Olekson indicated that ceragenins, including CSA-13, at low concentrations promote human keratinocytes (HaCaT) cell migration and tube formation in an angiogenesis model. It was also suggested LJ570 that CSA-13 acts through vascular endothelial growth LJ570 factor receptor 2 (VEGFR2)-mediated pathway, since ZM323881 (i.e. VEGFR2 inhibitor) blocked its formation. Interestingly, CSA-13-induced release of Ca2+ was only partially limited by this inhibitor, which imply that CSA-13 acts also by other signaling pathways . Considering these observations, we have studied the potential anti-cancer activity of CSA-13 against breast cancer cells and its mechanism of action. In recent years, the rapid development of novel nanotechnology-based therapeutic strategies has provided new tools for treatment of malignancies and created the possibility of overcoming limitations of conventional chemotherapy, including low selectivity of chemotherapeutics and associated toxicity against normal host cells. Moreover, the usefulness of nanostructures in the design of drugs with improved pharmacokinetic properties and having the ability to reverse drug resistance of tumors is becoming a focus of research in modern, personalized oncological therapy . With regard to oncological therapy, the increase in the biological activity of anti-cancer drugs in the presence of nanoparticles as drugs carriers is particularly important . Our previous study on colon cancer cells, employing LL-37 peptide and ceragenin CSA-13 immobilized on the surface of iron oxide magnetic nanoparticles, confirmed that AMP-based nanosystems decrease the viability and proliferation ability of cancer cells . However, the mechanism of this phenomenon is still unclear. Considering the reports described above, we decided to investigate the effects of both ceragenin CSA-13 and its magnetic nanoparticle-based derivative, MNP@CSA-13, on breast malignancy cells lines that are known to increase their growth upon stimulation by human cathelicidin LL-37. The mechanism of action of CSA-13 was also analyzed in order to LJ570 evaluate whether activity of ceragenin-mediated treatment might dependent on different death pathways among various malignancy cell lines. Additionally, Rabbit polyclonal to Myocardin we performed a series of experiments in order to assess whether the development of a nanosystem based on LL-37 might reverse its protumorigenic effect and increase the effect of ROS-generating MNPs. Our study provides.