Ceragenin CSA-13 as free molecules and attached to magnetic nanoparticle surfaces induce caspase-dependent apoptosis in human breast cancer cells via disruption of cell oxidative balance

Abstract

Natural antimicrobial peptides and ceragenins, as non-peptide amphipathic mimics, have been proposed as anti-cancer agents. To date, it has been confirmed that cathelicidin LL-37 and ceragenin CSA-13, both in free form and immobilized on the surface of magnetic nanoparticles (MNP@LL-37, MNP@CSA-13) induce apoptosis in colon cancer cells. Nevertheless, the question remains whether ceragenins, as synthetic analogs of LL-37 peptide and mimicking a number of its properties, act as antineoplastic agents in breast cancer cells, where LL-37 peptide stimulates oncogenesis. Considering potential anticancer activity, we determined whether CSA-13 and MNP@CSA-13 might be effective against breast cancer 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 dead 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 agents may be developed as a possible treatment of breast cancer.

Antimicrobial Peptides as Anticancer Agents: Functional Properties and Biological Activities

“…More recently, Piktel et al observed that MNP-CSA-13 reduced the viability and inhibited proliferation of MCF-7 and MDA-MB-231 breast cancer cells through the disruption of the oxidative balance. The ultimate result of the increased reactive oxygen species (ROS) generation is cell membrane disorganization and induction of caspase-dependent apoptosis via mitochondrial membrane depolarization [ 81 ].…”

Nanoantibiotics containing membrane-active human cathelicidin LL-37 or synthetic ceragenins attached to the surface of magnetic nanoparticles as novel and innovative therapeutic tools: current status and potential future applications

“…In relation to studies describing antimicrobial activities, fewer reports have been published describing the therapeutic value of LL-37 or cerageninn-containing nanosystems as anti-cancer agents. Nevertheless, promising data have been reported with colon [136] and breast cancer [137]. To date, detailed investigation of the anti-tumor mechanism of LL-37 action in colon cancer has shown that human cathelicidin-derived peptide (similarly to its modified versions—FK-16 [i.e.…”

“…Similar improvement of anti-cancer activity of CSA-13, through generation of MNP, was reported for ceragenin-mediated breast cancer treatment. Recently, Piktel et al reported that ceragenin CSA-13 exerts significant anti-cancer activity against breast cancer MCF-7 and MDA-MB-231 cells lines, which results from a novel mechanism involving cell membrane disorganization and induction of caspase-dependent apoptosis via increased reactive oxygen species (ROS) generation followed by mitochondrial membrane depolarization [137]. This oxidative balance disruption-mediated effect was noted to be further strengthen due to attachment of CSA-13 to the surface of MNPs, leading to improvement of cellular internalization of membrane-active compounds into breast cancer cells and most likely, intensification of oxidative stress due to ROS-generating abilities of uncoated nanoparticles [143].…”

“…This oxidative balance disruption-mediated effect was noted to be further strengthen due to attachment of CSA-13 to the surface of MNPs, leading to improvement of cellular internalization of membrane-active compounds into breast cancer cells and most likely, intensification of oxidative stress due to ROS-generating abilities of uncoated nanoparticles [143]. This uptake results in damage to cellular proteins, disruption of mitochondrial membrane polarization and cell death [137]. One of the novel nano-based approaches tested to date assumed that attachment of LL-37, as a compound with variable receptor-dependent activity against cancer cells and considerable membrane-permeabilizing properties [118], on the surface of magnetic nanoparticles characterized by well-described anti-cancer activity [144] would provide means of reversing pro-tumorigenic activity of the human cathelicidin and allow for creation of a nanosystem with anti-cancer features and high biocompatibility.…”

<p>NDM-1 Carbapenemase-Producing Enterobacteriaceae are Highly Susceptible to Ceragenins CSA-13, CSA-44, and CSA-131</p>

“…20 Apart from antibacterial effects, these molecules also display antibiofilm, sporicidal, antiviral, antiparasitic, and anticancer activities. [21][22][23][24] The therapeutic potential of CSAs is also underlined by their low toxicity, good stability under physiological conditions, and relatively inexpensive production. 20,25 Because of promising therapeutic properties of CSAs, we investigated antibacterial features of CSA-13, CSA-44, and CSA-131 against rods belonging to Enterobacteriaceae family producing NDM-1.…”