Antitumor activity of antimicrobial peptides against U937 histiocytic cell line.

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.

Current scenario of peptide-based drugs: the key roles of cationic antitumor and antiviral peptides

“…It has been shown that the cytotoxic activity of buforin II is low when compared with citropin 1.1, pexiganan MSI-78 and protegrin 1, and that it does not permanently disrupt the cell membrane like other molecules, i.e., its antitumor activity corroborates with the mechanism described above (Koszalka et al, 2011). A synthetic analog of buforin II named buforin IIb has shown greater cytolytic activity against cancer cells (leukemia, breast cancer, non-small cell lung cancer, CNS cancer, melanoma, renal, ovarian, prostate, and colon cancer) than buforin II (Lee et al, 2008).…”

Antimicrobial Peptides: Versatile Biological Properties

“…Certain AMPs such as pexiganan MSI-78, citropin 1.1, protegrin 1, synthetic lipopeptide, and N- α -palmitoyl-L-lysine–L-lysine amide (Pal-Lys-Lys-NH 2 ) showed cytotoxic activity against U937 histiocytic cell line. Of these, pexiganan MSI-78, protegrin 1, and lipopeptide showed increased tumoricidal activity due to their stronger membranolytic activity that leads to necrosis [120]. Cecropins A and B showed selective inhibitory and antiproliferative efficacy against bladder tumour cells lines, RT4, 647V, J82, 486P, and benign fibroblast cell line, 3T6 [101].…”

Host-Defense Peptides with Therapeutic Potential from Skin Secretions of Frogs from the Family Pipidae

“…Out of a range of antimicrobial peptides tested, the magainin-2 analog, pexiganan shows the greatest cytotoxic activity against the U937 human histiocytic lymphoma cell line [70]. The anti-tumor activity of protease-resistant all D-amino acid magainin-2 amide (MSI-238) is markedly superior to the parent compound displaying high potency in vitro against non-small cell lung adenocarcinoma A549 cells and in vivo against P388 leukemia, S180 ascites, and a spontaneous ovarian tumor [71].…”