ABSTRACT
Hypoxia is an important factor in the macrophages microenvironment. Many physiological and pathological processes including solid tumor development are characterized by both low oxygen content and presence of macrophages. Tumor-associated hypoxia causes alternative polarization of macrophages in tumor tissue and transformation of these cells into the allies of a malignant neoplasm. The aim of the work was to investigate the effect of NSC631570, a cancer-selective drug that is known to selectively accumulate in the tumor tissue, on hypoxic macrophage function. Murine peritoneal macrophages (PMs) were subjected to hypoxia (3% O2). Nitrite level was assayed by the Griess reaction. Arginase activity was measured by colorimetric method. ROS generation and phagocytosis was estimated by flow cytometry. O2(-) generation was assayed by the NBT reduction method. HMGB1 expression was determined by ELISA. 42 h hypoxia caused alternative polarization of murine PMs with significant arginase prevalence. NSC631570 repolarized arginine metabolism of hypoxic macrophages to NOS dominant and activated their pro-inflammatory functions: recovered ROS production and increased alarmin release NSC631570 can restore pro-inflammatory functions of macrophages, alternatively polarized by hypoxia.
Subject(s)
Alkaloids/pharmacology , Antineoplastic Agents, Phytogenic/pharmacology , Berberine Alkaloids/pharmacology , Macrophages, Peritoneal/drug effects , Phagocytosis/drug effects , Phenanthridines/pharmacology , Animals , Arginase/genetics , Arginase/metabolism , Cell Hypoxia/drug effects , Cell Hypoxia/genetics , Gene Expression/drug effects , HMGB1 Protein/genetics , HMGB1 Protein/metabolism , Macrophages, Peritoneal/cytology , Macrophages, Peritoneal/physiology , Male , Mice , Nitric Oxide/metabolism , Nitric Oxide Synthase Type II/genetics , Nitric Oxide Synthase Type II/metabolism , Nitrites/metabolism , Phagocytosis/physiology , Primary Cell Culture , Superoxides/metabolismABSTRACT
AIM: To investigate the effect of teichoic acid (TA) from the cell wall of S. aureus on some indices of immunological reactivity in mice bearing Lewis lung carcinoma (LLC). METHODS: The teichoic acid at the doses of 1, 2 and 4 microg/g of body weight has been administered subcutaneously simultaneously with tumor cells transplantation and in 7 days. The cytotoxic activity of peritoneal macrophages has been assessed by NBT-test. The splenocyte cytotoxic activity against the LLC cells has been tested by flow cytometry. The evaluation of tumor infiltration by lymphoid cells was carried out as well. RESULTS: TA had no significant effect on oxidative metabolism of peritoneal macrophages in tumor bearing mice. Upon TA administration, the cytotoxic activity of splenocytes against the LLC cells has been augmented in a dose-dependent manner (at the TA dose of 4 microg/g, 2-fold decrease of tumor growth and metastasis has been registered) and leads to decreased tumor infiltration by mononuclear cells. CONCLUSION: TA caused a dose dependent inhibition of growth and metastasis of LLC. It was supposed that TA can influence the tumor grows by activation of splenocytes cytotoxic activity.
