Role of poly(ADP-ribose) polymerase (PARP) in DNA repair in sulfur mustard-exposed normal human epidermal keratinocytes (NHEK)†‡

Bhat, K. R.; Benton, Betty; Rosenthal, Dean S.; Smulson, Mark E.; Ray, Radharaman

doi:10.1002/1099-1263(200012)20:1+<::aid-jat695>3.0.co;2-g

Cited by 11 publications

(7 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Consistent with this, studies by Bhat et at. suggested a role of PARylation in mustard induced DNA repair by stabilizing DNA ligase I, consistent with a decreased half life of ligase I and reduced DNA repair in PARP deficient keratinocytes (Bhat et al, 2006(Bhat et al, , 2000. Future studies are required to define the exact molecular basis for PARP activation during mustard induced genotoxic stress response and to unravel the down stream signaling effects of mustard induced PARylation.…”

Section: (Ii) Parylation Actively Participates In the Mustard Inducedmentioning

confidence: 86%

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

et al. 2016

View full text Add to dashboard Cite

Letters ; 244 (2016). -S. 56-71 https://dx.doi.org/10.1016/j.toxlet.2015In particular, we recorded substance specific as well as dose and time dependent PARylation responses using independent bioanalytical methods based on single cell immuno fluorescence microscopy and quantitative isotope dilution mass spectrometry. Furthermore, we analyzed if and how PARylation contributes to mustard induced toxicity by treating HaCaT cells with CEES, SM, and HN2 in combination with the clinically relevant PARP inhibitor ABT888. As evaluated by a novel immunofluorescence based protocol for the detection of N7 ETE guanine DNA adducts, the excision rate of CEES induced DNA adducts was not affected by PARP inhibition. Furthermore, while CEES induced moderate changes in cellular NAD + levels, annexin V/PI flow cytometry analysis revealed that these changes did not affect CEES induced short term cytotoxicity 24 h after treatment. In contrast, PARP inhibition impaired cell proliferation and clonogenic survival, and potentiated micronuclei formation of HaCaT cells upon CEES treatment. Similarly, PARP inhibition affected clonogenic survival of cells treated with bi functional mustards such as SM and HN2.In conclusion, we demonstrate that PARylation plays a functional role in mustard induced cellular stress response with substance specific differences. Since PARP inhibitors exhibit therapeutic potential to treat SM related pathologies and to sensitize cancer cells for mustard based chemotherapy, potential long term effects of PARP inhibition on genomic stability and carcinogenesis should be carefully considered when pursuing such a strategy.

show abstract

Section: (Ii) Parylation Actively Participates In the Mustard Inducedmentioning

confidence: 86%

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

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Following activation, PARP binds to DNA and (ADP-ribosyl)ates itself, as well as many other proteins involved in DNA repair and chromatin remodeling. Previous studies have shown that PARP is rapidly activated by sulfur mustard and CEES in guinea pig skin and in cultured keratinocytes (Hinshaw et al , 1999; Bhat et al , 2000; Kan et al , 2003; Bhat et al , 2006; Tewari-Singh et al , 2010). Moreover, inhibition of PARP suppresses DNA repair in sulfur mustard-treated human keratinocytes, demonstrating that activation of this enzyme is involved in this process.…”

Section: Discussionmentioning

confidence: 99%

Expression of proliferative and inflammatory markers in a full-thickness human skin equivalent following exposure to the model sulfur mustard vesicant, 2-chloroethyl ethyl sulfide

Black

Hayden

Casillas

et al. 2010

Toxicology and Applied Pharmacology

View full text Add to dashboard Cite

Sulfur mustard is a potent vesicant that induces inflammation, edema and blistering following dermal exposure. To assess molecular mechanisms mediating these responses, we analyzed the effects of the model sulfur mustard vesicant, 2-chloroethyl ethyl sulfide, on EpiDerm-FT™, a commercially available full-thickness human skin equivalent. CEES (100–1000 μM) caused a concentration-dependent increase in pyknotic nuclei and vacuolization in basal keratinocytes; at high concentrations (300–1000 μM), CEES also disrupted keratin filament architecture in the stratum corneum. This was associated with time-dependent increases in expression of proliferating cell nuclear antigen, a marker of cell proliferation, and poly(ADP-ribose) polymerase (PARP) and phosphorylated histone H2AX, markers of DNA damage. Concentration- and time-dependent increases in mRNA and protein expression of eicosanoid biosynthetic enzymes including COX-2, 5-lipoxygenase, microsomal PGE2 synthases, leukotriene (LT) A4 hydrolase and LTC4 synthase were observed in CEES-treated skin equivalents, as well as in antioxidant enzymes, glutathione S-transferases A1–2 (GSTA1–2), GSTA3 and GSTA4. These data demonstrate that CEES induces rapid cellular damage, cytotoxicity and inflammation in full-thickness skin equivalents. These effects are similar to human responses to vesicants in vivo and suggest that the full thickness skin equivalent is a useful in vitro model to characterize the biological effects of mustards and to develop potential therapeutics.

show abstract

“…The cellular mechanisms involved in mustard toxicity are well established and include oxidative stress, DNA damage, and the overactivation of PARP-1 (5,25,26). The goal of the present research was to determine if the selected test compounds could reduce the toxicity of a sulphur mustard surrogate in vitro.…”

Section: Discussionmentioning

confidence: 99%

Ebselen Analogues Reduce 2-chloroethyl Ethyl Sulphide Toxicity in A-431 Cells

Pino

Pįętka-Ottlik

Billack

2013

Archives of Industrial Hygiene and Toxicology

View full text Add to dashboard Cite

Vesicants are potent blistering agents. The prototype vesicant is sulphur mustard gas, fi rst used in World War I, which still has no effective antidote. We used a mustard gas surrogate 2-chloroethyl ethyl sulphide (CEES) to study the ability of resveratrol (RES) and pterostilbene (PTS), two well-established stilbene antioxidants, ebselen (EB-1), an organoselenium compound, and three EB-1 analogues (EB-2, EB-3, and EB-4) to reduce CEES toxicity in human epidermoid carcinoma cells (A-431). Following a 24-hour incubation of a toxic concentration of CEES (1000 μmol L ) did not decrease cell viability. Treatment with CEES and test antioxidants for 24 h showed that only EB-1 and its analogues EB-2, EB-3, and EB-4 but not the stilbene compounds could rescue the cells from death. EB-1 and EB-4 were the most effective at reducing CEES cytotoxicity and did so in a concentration-dependent manner, while EB-2 and EB-3 demonstrated the least protective effect. In summary, the data described herein indicate that organoselenium antioxidants, especially EB-4, may prove useful as countermeasures to blistering agents.

show abstract

Role of poly(ADP-ribose) polymerase (PARP) in DNA repair in sulfur mustard-exposed normal human epidermal keratinocytes (NHEK)†‡

Cited by 11 publications

References 16 publications

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

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

Expression of proliferative and inflammatory markers in a full-thickness human skin equivalent following exposure to the model sulfur mustard vesicant, 2-chloroethyl ethyl sulfide

Ebselen Analogues Reduce 2-chloroethyl Ethyl Sulphide Toxicity in A-431 Cells

Contact Info

Product

Resources

About