Polarization of macrophages towards M1 phenotype by a combination of 2-deoxy-d-glucose and radiation: Implications for tumor therapy.
2-Deoxy-d-glucose (2-DG) has been found to enhance the cytotoxicity of ionizing radiation and chemotherapeutic drugs in several tumor cell lines in vitro. Systemic administration of 2-DG together with localized irradiation of the tumor leads to tumor regression and cure (disease free survival), which correlate with the differential levels of anti-tumor immunity observed in Ehrlich ascites tumor (EAT) bearing mice. Macrophages being a major player of the innate immune system, we investigated the activation status of splenic macrophages during radio-sensitization of EAT in mice as well as in peritoneal macrophages ex vivo and macrophagic cell line (Raw 264.7) in vitro. Results suggest that under in vivo conditions, the combined treatment (2-DG+radiation) restores the M1 phenotype in spleen that correlated with the tumor response. However, 2-DG neither induced significant cytotoxicity nor enhanced radiation-induced cell death in peritoneal macrophages and the macrophage cell line (Raw 264.7). Further, increased arborization and enhanced functional status (expression of MHC class II, CD80, CD86 and phagocytosis) were observed after the combined treatment. Besides this activation, the combined treatment also skewed the macrophages towards M1 phenotype as evidenced by the enhanced secretion of IL-12, IL-2, TNF-α and IFN-γ. These observations suggest that 2-DG not only preserves the survival of normal macrophages during irradiation, but also activates macrophages by polarizing towards M1 phenotype, which is known to be tumoricidal in nature. This study for the first time sheds light on a potential antitumor immune activation by 2-DG involving macrophagic stimulation during in vivo radio-sensitization of tumors, besides the other known antitumor effects of this glucose analogue.
['Farooque|Abdullah|A|', 'Afrin|Farhat|F|', 'Adhikari|Jawahar Singh|JS|', 'Dwarakanath|Bilikere Srinivasa Rao|BS|']
D000818:Animals D018122:B7-1 Antigen D051940:B7-2 Antigen D002286:Carcinoma, Ehrlich Tumor D002454:Cell Differentiation D002460:Cell Line D003847:Deoxyglucose D005720:Gamma Rays D005786:Gene Expression Regulation D000949:Histocompatibility Antigens Class II D007371:Interferon-gamma D018664:Interleukin-12 D007376:Interleukin-2 D017737:Macrophages, Peritoneal D008297:Male D051379:Mice D010587:Phagocytosis D061251:Primary Cell Culture D015398:Signal Transduction D047368:Tumor Burden D014409:Tumor Necrosis Factor-alpha
Macrophages M1 2-Deoxy-d-glucose (2-DG) Radio-sensitization Glycolysis Pro-inflammatory