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Antitumor activity of antimicrobial peptides against U937 histiocytic cell line
Patrycja Koszałka1, Elżbieta Kamysz, Magdalena Wejda
1Department of Cell Biology, Faculty of Medical Biotechnology, Medical University of Gdansk, Gdańsk, Poland.
Abstract:
We investigated cytotoxic activity of antimicrobial peptides of different origin (both naturally occurring and synthetic), structure and known mechanisms of action against human histiocytic lymphoma cell line U937. The strongest cytotoxic activity against U937 cell line was shown by Pexiganan MSI-78, followed by Citropin 1.1, Protegrin 1 and a synthetic lipopeptide, N-α-palmitoyl-L-lysyl-L-lysine amide (Pal-Lys-Lys-NH₂). The cytotoxic activity of the peptides was more dependent on the time of incubation than concentration. Only for the lipopeptide, whose mode of action was restricted to disruption of electric potential of the cell membrane, the correlation between cytotoxicity and concentration was almost linear. The high cytotoxicity of Pexiganan MSI-78, Protegrin 1 and the lipopeptide could be basically explained by their membranolytic activity leading to necrosis. However, in the case of Citropin 1.1, the cell membrane integrity was disrupted only slightly and independently of the peptide concentration. Therefore, some other mechanism of action might be responsible for its strong dose-dependent cytotoxic activity, e.g., membranolytic activity leading to apoptosis. Furthermore, TNF-α production due to LPS (lipopolysaccharide) stimulation was suppressed by the presence of Citropin 1.1, Pexiganan MSI-78 or Protegrin 1, but not by Buforin 2 or the lipopeptide. Our experiments have shown that cytotoxic activity is not limited to some specific molecular structure of a peptide, but rather to the length of the peptide chain as it is likely to affect the efficiency of the tumor cell membrane disruption and interaction with LPS.
Insights
Antimicrobial peptides show varying cytotoxic effects on lymphoma cells, with Pexiganan MSI-78 being most potent. Peptide length, not just structure, influences tumor cell membrane disruption and interaction with lipopolysaccharide (LPS).
Area of Science:
- Biochemistry
- Pharmacology
- Cell Biology
Background:
- Antimicrobial peptides (AMPs) are crucial in innate immunity.
- Their cytotoxic potential against cancer cells is an area of active research.
- Understanding AMP mechanisms is key for developing novel therapeutics.
Purpose of the Study:
- To investigate the cytotoxic activity of various antimicrobial peptides against the U937 human histiocytic lymphoma cell line.
- To elucidate the structure-activity relationships and mechanisms of action of these peptides.
- To assess the impact of peptide incubation time and concentration on cytotoxicity.
Main Methods:
- Cytotoxicity assays using the U937 cell line.
- Incubation of cells with different antimicrobial peptides (Pexiganan MSI-78, Citropin 1.1, Protegrin 1, synthetic lipopeptide, Buforin 2).
- Analysis of peptide concentration and incubation time effects on cell death.
- Assessment of tumor necrosis factor-alpha (TNF-α) production following lipopolysaccharide (LPS) stimulation.
Main Results:
- Pexiganan MSI-78 exhibited the strongest cytotoxicity, followed by Citropin 1.1, Protegrin 1, and a synthetic lipopeptide.
- Cytotoxic activity was more dependent on incubation time than peptide concentration.
- High cytotoxicity correlated with membranolytic activity leading to necrosis, except for Citropin 1.1, suggesting apoptosis as a potential mechanism.
- Citropin 1.1, Pexiganan MSI-78, and Protegrin 1 suppressed LPS-induced TNF-α production.
Conclusions:
- Antimicrobial peptide cytotoxicity against U937 cells is influenced by peptide length and its ability to disrupt cell membranes.
- Mechanisms of action vary, including necrosis and potentially apoptosis, with implications for therapeutic development.
- Peptide-mediated suppression of TNF-α production suggests immunomodulatory effects relevant to cancer therapy.
