O,O'-diethyl-(S,S)-ethylenediamine-N,N'-di-2-(3-cyclohexyl) propanoate dihydrochloride enhances influx of effective NK and NKT cells in murine breast cancer

Milena Jurišević; Nikola Jagić; Nevena Gajović; Aleksandar Arsenijević; Milan Jovanović; Marija Milovanović; Jelena Pantić; Ivan Jovanović; Tibor Sabo; Gordana Radosavljević; Nebojša Arsenijević

doi:10.2298/VSP180723149J

Milena Jurišević University of Kragujevac, Faculty of Medical Sciences, Center for Molecular Medicine and Stem Cell Research
Nikola Jagić University of Kragujevac, Faculty of Medical Sciences, Department of Radiology
Nevena Gajović University of Kragujevac, Faculty of Medical Sciences, Center for Molecular Medicine and Stem Cell Research
Aleksandar Arsenijević University of Kragujevac, Faculty of Medical Sciences, Center for Molecular Medicine and Stem Cell Research
Milan Jovanović Military Medical Academy, Department of Abdominal Surgery; University of Defence, Faculty of Medicine of the Military Medical Academy
Marija Milovanović University of Kragujevac, Faculty of Medical Sciences, Center for Molecular Medicine and Stem Cell Research
Jelena Pantić University of Kragujevac, Faculty of Medical Sciences, Center for Molecular Medicine and Stem Cell Research
Ivan Jovanović University of Kragujevac, Faculty of Medical Sciences, Center for Molecular Medicine and Stem Cell Research
Tibor Sabo University of Belgrade, Faculty of Chemistry
Gordana Radosavljević University of Kragujevac, Faculty of Medical Sciences, Center for Molecular Medicine and Stem Cell Research
Nebojša Arsenijević University of Kragujevac, Faculty of Medical Sciences, Center for Molecular Medicine and Stem Cell Research

DOI: https://doi.org/10.2298/VSP180723149J

Keywords: breast neoplasms;, carcinoma;, mice, inbred balbc;, antineoplastic agents

Abstract

Background/Aim. O,O'-diethyl-(S,S)-ethylenediamine-N,N'-di-2-(3-cyclohexyl)propanoate dihydrochloride (DE-EDCP) has been found to possess promising cytotoxic activity against various tumor cell lines. Also, DE-EDCP reduces tumor progression by several mechanisms such as triggering tumor cell death and inhibition of cell proliferation. The aim of present study was to further evaluate anti-tumor activity of DE-EDCP by investigating effects on migratory potential of tumor cells and anti-tumor immune response. Methods. Migratory potential of DE-EDCP was evaluated by scratch wound assay. Female BALB/c mice were inoculated with 4T1 breast cancer cells and treatment with DE-EDCP started five days following orthotopic tumor implantation. The frequency and phenotype of tumor-infiltrating natural killer (NK) and natural killer T (NKT) cells were analyzed by flow cytometry. Results. DE-EDCP inhibited migratory potential of highly metastatic 4T1 cells. DE-EDCP facilitated accumulation of CD3⁺CD49⁺ NKT cells and CD3^-CD49⁺ NK cells in tumor microenvironment. DE-EDCP treatment led to significant decrement of tumor infiltrating anergic NKT cells expressing cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), killer cell lectin like receptor G1 (KLRG-1) and programmed cell death protein-1 (PD-1). Mice given DE-EDCP had significantly increased percentages of tumoricidal fas ligand (FasL) positive NK cells. Conclusion. DE-EDCP inhibits murine breast cancer progression through direct effects on tumor cells and by facilitating anti-tumor immunity. DE-EDCP enhances accumulation, promotes tumoricidal phenotype and maintenances responsiveness of NK and NKT cells in 4T1 murine breast cancer.

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