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
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Ewelina Piktel1, Izabela Prokop2, Urszula Wnorowska1, Grzegorz Król3, Mateusz Cieśluk1, Katarzyna Niemirowicz1, Paul B. Savage4 and Robert Bucki1
1Department of Microbiological and Nanobiomedical Engineering, Medical University of Bialystok, Mickiewicza 2c, Bialystok 15-222, Poland
2Department of Medicinal Chemistry, Medical University of Bialystok, Mickiewicza 2d, Bialystok 15-222, Poland
3Department of Microbiology and Immunology, The Faculty of Health Sciences of the Jan Kochanowski University in Kielce, Aleja IX Wieków Kielc, Kielce 25-317, Poland
4Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah 84604, USA
Robert Bucki, email: [email protected]
Keywords: breast cancer; ceragenin; magnetic nanoparticles; nanotechnology; redox balance
Received: August 03, 2017 Accepted: March 22, 2018 Published: April 24, 2018
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.
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