Sulfur mustard lowers nicotinamide adenine dinucleotide concentrations in human skin grafted to athymic nude mice*1

Sulfur and nitrogen mustards induce characteristic poly(ADP-ribosyl)ation responses in HaCaT keratinocytes with distinctive cellular consequences

“…Based on the rationale that PARP inhibition preserves NAD + levels and counteracts inflammation, PARP inhibitors were tested as potential therapeutic agents for SM exposures. Interest ingly, in several animal models PARP inhibition and/or boosting of NAD + synthesis led to reduced pathological signs upon SM exposure (Cowan et al, 2003;Gross et al, 1985;Mol et al, 1991;Yourick et al, 1991Yourick et al, , 1993Zhang et al, 1995). Despite previous reports on the effect of PARP inhibitors on SM induced NAD + depletion, cell death and pathology, specific reports characterizing the actual PARylation response upon mustard treatment are incomplete and inconsistent.…”

“…Animal experiments showed that PARP inhibition and/or boosting of NAD+ levels can reduce SM induced pathology, suggesting that PARP inhibitors may be used as a medical countermeasure for SM related injuries (Cowan et at., 2003;Gross et al, 1985;Mol et al, 1991 ;Yourick et at., 1991Yourick et at., , 1993Zhang et al, 69 1995 ). Regarding the mechanism of action of such a treatment, it bas been suggestion, that PARP inhibition induces a switch in the mode of cell death by inhibiting necrosis but driving cells into apoptosis, which, in combination with inhibition ofNF KB related gene transcription, counteracts SM induced inflammatory responses (Bai and Virag, 2012a;Kehe et al, 2008;Meier and Millard, 1998;Rosenthal et al, 2001 ).…”

Toxicity of vesicant agents scheduled for destruction by the Chemical Stockpile Disposal Program.

“…Certain enzymes, notably hexokinase, were inhibited when incubated in vitro with very low doses of mustard, although the majority of enzymes so tested were not affected (25). An interesting biochemical hypothesis to account for the generation of mustard-induced skin lesions has been proposed by workers at the U.S. Army Medical Research Institute of Chemical Defense (27,32). This hypothesis links initial chemical binding of mustard to DNA through a complex series of steps to release intracellular enzymes that are responsible for the skin damage and blistering produced by the agent.…”

“…It was known from early biological studies of mustard that this agent produced many cytological abnormalities (31). Because of the similarity of cellular lesions produced by mustard and X-rays, the mustards and other simnilarly acting chemicals are sometimes termed "radiomimetic," that is, imitating the effect of radiation (32,33). Thus, intestinal epithelial damage leading to diarrhea, depression of proliferation of white cell precursors in the bone marrow leading to depressed white blood cell counts, and injury to respiratory epithelium can all be features of mustard poisoning, as they are of radiation injury (30).…”

Immunochemical analysis of poly(ADP-ribosyl)ation in HaCaT keratinocytes induced by the mono-alkylating agent 2-chloroethyl ethyl sulfide (CEES): Impact of experimental conditions

“…It will be interesting to apply the optimized methodology as established in this work to study the PARylation response in cells treated with bifunctional sulfur and nitrogen mustards. This will have significant implica tions towards the question if PARP inhibitors may be used as a therapeutic option to mitigate SM induced pathologies, as suggested by several animal studies (Cowan et al, 2003;Gross et al, 1985;Mol et al, 1991;Yourick et al, 1991Yourick et al, , 1993Zhang et al, 1995) or to sensitize cancer cells to nitrogen mustard treatment, as tested in preclinical and clinical settings (Donawho et al, 2007;Norris et al, 2014). Several of these aspects are addressed in in an accompanying article (c.f.…”