title: Systemic DNA damage accumulation under in vivo tumor growth can be inhibited by the antioxidant Tempol.
abstract: Recently we found that mice bearing subcutaneous non-metastatic tumors exhibited elevated levels of two types of complex DNA damage, i.e., double-strand breaks and oxidatively-induced clustered DNA lesions in various tissues throughout the body, both adjacent to and distant from the tumor site. This DNA damage was dependent on CCL2, a cytokine involved in the recruitment and activation of macrophages, suggesting that this systemic DNA damage was mediated via tumor-induced chronic inflammatory responses involving cytokines, activation of macrophages, and consequent free radical production. If free radicals are involved, then a diet containing an antioxidant may decrease the distant DNA damage. Here we repeated our standard protocol in cohorts of two syngeneic tumor-bearing C57BL/6NCr mice that were on a Tempol-supplemented diet. We show that double-strand break and oxidatively-induced clustered DNA lesion levels were considerably decreased, about two- to three fold, in the majority of tissues studied from the tumor-bearing mice fed the antioxidant Tempol compared to the control tumor-bearing mice. Similar results were also observed in nude mice suggesting that the Tempol effects are independent of functioning adaptive immunity. This is the first in vivo study demonstrating the effect of a dietary antioxidant on abscopal DNA damage in tissues distant from a localized source of genotoxic stress. These findings may be important for understanding the mechanisms of genomic instability and carcinogenesis caused by chronic stress-induced systemic DNA damage and for developing preventative strategies.
authors: Department of Biology, Thomas Harriot College of Arts and Sciences, East Carolina University, Greenville, NC 27858, USA; Department of Physics, National Technical University of Athens, Zografou Campus, Athens GR-15773, Greece.
authors: Alexandros G
authors: AG
authors: Georgakilas
authors: Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors: Christophe E
authors: CE
authors: Redon
authors: Department of Biology, Thomas Harriot College of Arts and Sciences, East Carolina University, Greenville, NC 27858, USA.
authors: Nicholas F
authors: NF
authors: Ferguson
authors: Department of Biology, Thomas Harriot College of Arts and Sciences, East Carolina University, Greenville, NC 27858, USA.
authors: Thomas B
authors: TB
authors: Kryston
authors: Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors: Palak
authors: P
authors: Parekh
authors: Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA; Office of In Vitro Diagnostics, Center for Devices and Radiological Health, Food and Drug Administration, Silver Spring, MD 20993, USA.
authors: Jennifer S
authors: JS
authors: Dickey
authors: Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA; Department of Biological Sciences, Faculty of Science, Ibaraki University, Ibaraki 310-8512, Japan.
authors: Asako J
authors: AJ
authors: Nakamura
authors: Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors: James B
authors: JB
authors: Mitchell
authors: Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors: William M
authors: WM
authors: Bonner
authors: Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA; Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, Vic. 3002, Australia; Laboratory of Molecular Radiation Biology, Peter MacCallum Cancer Centre, Vic. 3002, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Vic. 3002, Australia. Electronic address: olga.martin@petermac.org.
authors: Olga A
authors: OA
authors: Martin
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D018827:Carcinoma, Lewis Lung / Q000235:genetics*; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D053903:DNA Breaks, Double-Stranded; D005260:Female; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000473:pathology; D008546:Melanoma, Experimental / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D017382:Reactive Oxygen Species / Q000378:metabolism; D013113:Spin Labels
chemical_list: D000975:Antioxidants; D003497:Cyclic N-Oxides; D017382:Reactive Oxygen Species; D013113:Spin Labels; C001803:tempol
keywords: Antioxidants; DNA damage; Non-targeted effects; Tempol; Tumor-bearing mice