학술논문
NAD + Acts as a Protective Factor in Cellular Stress Response to DNA Alkylating Agents.
Document Type
Academic Journal
Author
Ruszkiewicz J; Molecular Toxicology Group, Department of Biology, University of Konstanz, 78457 Konstanz, Germany.; Papatheodorou Y; Molecular Toxicology Group, Department of Biology, University of Konstanz, 78457 Konstanz, Germany.; Jäck N; Molecular Toxicology Group, Department of Biology, University of Konstanz, 78457 Konstanz, Germany.; Melzig J; Molecular Toxicology Group, Department of Biology, University of Konstanz, 78457 Konstanz, Germany.; Eble F; Molecular Toxicology Group, Department of Biology, University of Konstanz, 78457 Konstanz, Germany.; Pirker A; Molecular Toxicology Group, Department of Biology, University of Konstanz, 78457 Konstanz, Germany.; Thomann M; Molecular Toxicology Group, Department of Biology, University of Konstanz, 78457 Konstanz, Germany.; Haberer A; Molecular Toxicology Group, Department of Biology, University of Konstanz, 78457 Konstanz, Germany.; Rothmiller S; Bundeswehr Institute of Pharmacology and Toxicology, 80937 Munich, Germany.; Bürkle A; Molecular Toxicology Group, Department of Biology, University of Konstanz, 78457 Konstanz, Germany.; Mangerich A; Molecular Toxicology Group, Department of Biology, University of Konstanz, 78457 Konstanz, Germany.; Nutritional Toxicology, Institute Nutritional Science, University of Potsdam, 14469 Potsdam, Germany.
Source
Publisher: MDPI Country of Publication: Switzerland NLM ID: 101600052 Publication Model: Electronic Cited Medium: Internet ISSN: 2073-4409 (Electronic) Linking ISSN: 20734409 NLM ISO Abbreviation: Cells Subsets: MEDLINE
Subject
Language
English
Abstract
Sulfur mustard (SM) and its derivatives are potent genotoxic agents, which have been shown to trigger the activation of poly (ADP-ribose) polymerases (PARPs) and the depletion of their substrate, nicotinamide adenine dinucleotide (NAD + ). NAD + is an essential molecule involved in numerous cellular pathways, including genome integrity and DNA repair, and thus, NAD + supplementation might be beneficial for mitigating mustard-induced (geno)toxicity. In this study, the role of NAD + depletion and elevation in the genotoxic stress response to SM derivatives, i.e., the monofunctional agent 2-chloroethyl-ethyl sulfide (CEES) and the crosslinking agent mechlorethamine (HN2), was investigated with the use of NAD + booster nicotinamide riboside (NR) and NAD + synthesis inhibitor FK866. The effects were analyzed in immortalized human keratinocytes (HaCaT) or monocyte-like cell line THP-1. In HaCaT cells, NR supplementation, increased NAD + levels, and elevated PAR response, however, did not affect ATP levels or DNA damage repair, nor did it attenuate long- and short-term cytotoxicities. On the other hand, the depletion of cellular NAD + via FK866 sensitized HaCaT cells to genotoxic stress, particularly CEES exposure, whereas NR supplementation, by increasing cellular NAD + levels, rescued the sensitizing FK866 effect. Intriguingly, in THP-1 cells, the NR-induced elevation of cellular NAD + levels did attenuate toxicity of the mustard compounds, especially upon CEES exposure. Together, our results reveal that NAD + is an important molecule in the pathomechanism of SM derivatives, exhibiting compound-specificity. Moreover, the cell line-dependent protective effects of NR are indicative of system-specificity of the application of this NAD + booster.