title: Polarization of macrophages towards M1 phenotype by a combination of 2-deoxy-d-glucose and radiation: Implications for tumor therapy.
abstract: 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.
authors.affiliation: Division of Radiation Biosciences, Institute of Nuclear Medicine and Allied Sciences, Brig. S.K. Mazumdar Marg, Delhi 110054, India.
authors.forename: Abdullah
authors.initials: A
authors.lastname: Farooque
authors.affiliation: Department of Biotechnology, Jamia Hamdard (Hamdard University), New Delhi 110062, India.
authors.forename: Farhat
authors.initials: F
authors.lastname: Afrin
authors.affiliation: Division of Radiation Biosciences, Institute of Nuclear Medicine and Allied Sciences, Brig. S.K. Mazumdar Marg, Delhi 110054, India.
authors.forename: Jawahar Singh
authors.initials: JS
authors.lastname: Adhikari
authors.affiliation: Division of Radiation Biosciences, Institute of Nuclear Medicine and Allied Sciences, Brig. S.K. Mazumdar Marg, Delhi 110054, India. Electronic address: dwarakanathdrbs@gmail.com.
authors.forename: Bilikere Srinivasa Rao
authors.initials: BS
authors.lastname: Dwarakanath
mesh_terms: D000818:Animals; D018122:B7-1 Antigen / Q000235:genetics / Q000276:immunology; D051940:B7-2 Antigen / Q000235:genetics / Q000276:immunology; D002286:Carcinoma, Ehrlich Tumor / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D002454:Cell Differentiation / Q000187:drug effects / Q000528:radiation effects; D002460:Cell Line; D003847:Deoxyglucose / Q000494:pharmacology*; D005720:Gamma Rays / Q000627:therapeutic use*; D005786:Gene Expression Regulation; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000276:immunology / Q000473:pathology / Q000528:radiation effects*; D008297:Male; D051379:Mice; D010587:Phagocytosis / Q000187:drug effects / Q000528:radiation effects; D061251:Primary Cell Culture; D015398:Signal Transduction; D047368:Tumor Burden / Q000187:drug effects / Q000528:radiation effects; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
chemical_list: D018122:B7-1 Antigen; D051940:B7-2 Antigen; C497965:Cd86 protein, mouse; D000949:Histocompatibility Antigens Class II; D007376:Interleukin-2; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D007371:Interferon-gamma; D003847:Deoxyglucose
keywords: 2-Deoxy-d-glucose (2-DG); Glycolysis; M1; Macrophages; Pro-inflammatory; Radio-sensitization