Oral Administration of Polymyxin B Modulates the Activity of Lipooligosaccharide E. coli B against Lung Metastases in Murine Tumor Models

PLoS One. 2016 Feb 1;11(2):e0148156. doi: 10.1371/journal.pone.0148156. eCollection 2016.

Abstract

Introduction: Polymyxin B (PmB) belongs to the group of cyclic peptide antibiotics, which neutralize the activity of LPS by binding to lipid A. The aim of this study was to analyze the effect of PmB on the biological activity of lipooligosaccharide (LOS E. coli B,rough form of LPS) in vitro and in experimental metastasis models.

Results: Cultures of murine macrophage J774A.1 cells and murine bone marrow-derived dendritic cells (BM-DC) stimulated in vitro with LOS and supplemented with PmB demonstrated a decrease in inflammatory cytokine production (IL-6, IL-10, TNF-α) and down-regulation of CD40, CD80, CD86 and MHC class II molecule expression. Additionally, PmB suspended in drinking water was given to the C57BL/6 mice seven or five days prior to the intravenous injection of B16 or LLC cells and intraperitoneal application of LOS. This strategy of PmB administration was continued throughout the duration of the experiments (29 or 21 days). In B16 model, statistically significant decrease in the number of metastases in mice treated with PmB and LOS (p<0.01) was found on the 14th day of the experiments, whereas the most intensive changes in surface-antigen expression and ex vivo production of IL-6, IL-1β and TNF-α by peritoneal cells were observed 7 days earlier. By contrast, antigen expression and ex vivo production of IL-6, IL-10, IFN-γ by splenocytes remained relatively high and stable. Statistically significant decrease in LLC metastases number was observed after the application of LOS (p<0.01) and in the group of mice preconditioned by PmB and subsequently treated with LOS (LOS + PmB, p<0.01).

Conclusions: In conclusion, prolonged in vivo application of PmB was not able to neutralize the LOS-induced immune cell activity but its presence in the organism of treated mice was important in modulation of the LOS-mediated response against the development of metastases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Carcinoma, Lewis Lung / pathology
  • Concanavalin A
  • Cytokines / biosynthesis
  • Cytokines / blood
  • Dendritic Cells / drug effects
  • Dendritic Cells / metabolism
  • Disease Models, Animal
  • Escherichia coli / chemistry*
  • Female
  • Injections, Intravenous
  • Lipopolysaccharides
  • Lung / pathology
  • Lung Neoplasms / blood
  • Lung Neoplasms / pathology
  • Lung Neoplasms / secondary*
  • Lymphocytes / drug effects
  • Lymphocytes / pathology
  • Macrophages, Peritoneal / drug effects
  • Macrophages, Peritoneal / pathology
  • Melanoma, Experimental / blood
  • Melanoma, Experimental / pathology
  • Mice, Inbred C57BL
  • Phenotype
  • Polymyxin B / administration & dosage*
  • Polymyxin B / pharmacology
  • Polymyxin B / therapeutic use*
  • Spleen / pathology

Substances

  • Cytokines
  • Lipopolysaccharides
  • lipid-linked oligosaccharides
  • Concanavalin A
  • Polymyxin B

Grants and funding

This work was supported by Wroclaw Centre of Biotechnology, Programme The Leading National Research Centre (KNOW) for years 2014–2018 and by the Polish Ministry of Science—The National Centre for Research and Development (http://www.ncbir.pl/en/): "Products of the Gram-negative bacteria lysis as potential anti-tumor agents. Determination of their chemical and biochemical properties as well as biological activities. Development of active substance production technology" (grants no. 13-0089-06/2010). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.