Remarkable Effects of a Rhenium(I)-diselenoether Drug on the Production of Cathepsins B and S by Macrophages and their Polarizations

Curr Pharm Des. 2023;29(30):2396-2407. doi: 10.2174/0113816128268963231013074433.

Abstract

Background/objective: Tumor-associated macrophages (TAMs) produce an excessive amount of cysteine proteases, and we aimed to study the effects of anticancer rhenium(I)-diselenoether (Re-diSe) on the production of cathepsins B and S by macrophages. We investigated the effect of Re-diSe on lipopolysaccharides (LPS) induced M1 macrophages, or by interleukin 6 (IL-6) induced M2 macrophages.

Methods: Non-stimulated or prestimulated murine Raw 264 or human THP-1 macrophages were exposed to increasing concentrations of the drug (5, 10, 20, 50 and 100 μM) and viability was assayed by the MTT assay. The amount of cysteine proteases was evaluated by ELISA tests, the number of M1 and M2 macrophages by the expression of CD80 or CD206 biomarkers. The binding of Re-diSe with GSH as a model thiol-containing protein was studied by mass spectrometry.

Results: A dose-dependent decrease in cathepsins B and S was observed in M1 macrophages. There was no effect in non-stimulated cells. The drug induced a dramatic dose-dependent increase in M1 expression in both cells, significantly decreased the M2 expression in Raw 264 and had no effect in non-stimulated macrophages. The binding of the Re atom with the thiols was clearly demonstrated.

Conclusion: The increase in the number of M1 and a decrease in M2 macrophages treated by Re-diSe could be related to the decrease in cysteine proteases upon binding of their thiol residues with the Re atom.

Keywords: Rhenium (Re); cancer.; cysteine proteases; immune resistance; macrophages; rhenium(I)-diselenoether (Re-diSe).

MeSH terms

  • Animals
  • Cathepsins / metabolism
  • Cathepsins / pharmacology
  • Cysteine Proteases* / metabolism
  • Cysteine Proteases* / pharmacology
  • Humans
  • Lipopolysaccharides / pharmacology
  • Macrophages
  • Mice
  • Rhenium* / pharmacology
  • Sulfhydryl Compounds / metabolism
  • Sulfhydryl Compounds / pharmacology

Substances

  • Rhenium
  • Cysteine Proteases
  • Sulfhydryl Compounds
  • Cathepsins
  • Lipopolysaccharides