DNA damage, signalling and repair after exposure of cells to the sulphur mustard analogue 2-chloroethyl ethyl sulphide

Jowsey, Paul A.; Williams, Faith M.; Blain, Peter G.

doi:10.1016/j.tox.2008.12.001

Cited by 49 publications

(50 citation statements)

References 36 publications

(35 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The mono functional alkylating agent CEES is widely used as such a substitute, because it represents the mono functional analogue to SM [ Fig. 1, Jain et al, 2011;Jowsey et al, 2009;Sayer et al, 2010;Wang et al, 2012)]. In addition, the bi functional nitrogen mustard is used as a surrogate agent, because it takes into account the bi functional reaction mechanism of SM [ Fig.…”

Section: (I) Cees and Hn2 As Sm Surrogatesmentioning

confidence: 99%

“…HR was reported to be the major repair pathway protecting cells against acute SM and HN2 toxicity, with NER and NHEJ also contributing to cell survival (Inturi et al, 2014;Jowsey et al, 2010Jowsey et al, , 2012Moller et al, 2000;Muller et al, 2000). In contrast, repair of CEES induced DNA monoadducts seem to rely mostly on BER and NER pathways (Jowsey et al, 2009;Matijasevic et al, 2001). Thus, even though mustards do not induce DNA strand breaks directly, strand breaks can occur in response to mustard treatment by enzymatic processes that actively introduce them in the course of DNA repair processes.…”

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

confidence: 99%

“…Statistical evaluation was performed using two-way ANOVA testing followed by Sidak's multiple comparison testing. *P < 0.05. mustard treatment (Debiak et al, 2011 ;lnturi et al, 2011;Jain et at., 2011;jowsey et al, 2009, 2012 (Fig. S3).…”

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

confidence: 99%

“…It has to be noted that cytotoxicity in these studies was measured by dye exclusion and by this method only necrotic cells are scored as dead cells. Others did not observe such an effect (Kehe et al, 2008;Lin et al, 1994;Rosenthal et al, 2001;Smith et al, 1990), or even showed a sensitization of CEES induced cell death in the presence of PARP inhibitor treatment (Jowsey et al, 2009). Furthermore, it has been suggested that PARP inhibition induces a switch in the mode of cell death by inhibiting necrosis but driving cells into apoptosis (Kehe et al, 2008;Meier and Millard, 1998;Rosenthal et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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: (I) Cees and Hn2 As Sm Surrogatesmentioning

confidence: 99%

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

confidence: 99%

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

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

“…Alternatively, different PARy lation dynamics may be a direct consequences of the different types of DNA lesions formed, i.e., H 2 O 2 induces mainly oxidative damage and strand breaks, while CEES induces mainly DNA alkylation, without being thought to induce DNA strand breaks directly. Previous reports showed that CEES induced DNA mono adducts are predominantly repaired by BER and NER pathways (Jowsey et al, 2009;Matijasevic et al, 2001). PARylation plays an active role in both repair pathway, potentially by being activated through DNA strand breaks introduced by endonucleases as intermediates during the repair processes (Fischer et al, 2014;Pines et al, 2013Pines et al, , 2012Robert et al, 2013).…”

Section: Application Of the Optimized Cees Treatment Prototocol For Tmentioning

confidence: 99%

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

et al. 2016

View full text Add to dashboard Cite

Biological effects of CEES treated cells are significantly influenced by treatment protocol. Optimized protocol for the treatment of HaCaT cells with CEES. CEES induces a dose and time dependent PARylation response in HaCaT cells. CEES induced PAR formation is predominantly due to the activation of PARP1. Keywords:Poly(ADP-ribose) Poly(ADP-ribose) polymerases Sulfur mustard CEES HaCaT keratinocytes Solvent A B S T R A C T Sulfur mustard (SM) is a bifunctional alkylating agent with a long history of use as a chemical weapon. Although its last military use is dated for the eighties of the last century, a potential use in terroristic attacks against civilians remains a significant threat. Thus, improving medical therapy of mustard exposed individuals is still of particular interest. PARP inhibitors were recently brought into the focus as a potential countermeasure for mustard induced pathologies, supported by the availability of efficient compounds successfully tested in cancer therapy.PARP activation after SM treatment was reported in several cell types and tissues under various conditions; however, a detailed characterization of this phenomenon is still missing. This study provides the basis for such studies by developing and optimizing experimental conditions to investigate poly(ADP ribosyl)ation (PARylation) in HaCaT keratinocytes upon treatment with the monofunctional alkylating agent 2 chloroethyl ethyl sulfide ("half mustard", CEES). By using an immunofluorescence based approach, we show that optimization of experimental conditions with regards to the type of solvent, dilution factors and treatment procedure is essential to obtain a homogenous PAR staining in HaCaT cell cultures. Furthermore, we demonstrate that different CEES treatment protocols significantly influence the cytotoxicity profiles of treated cells. Using an optimized treatment protocol, our data reveals that CEES induces a dose and time dependent dynamic PARylation response in HaCaT cells that could be completely blocked by treating cells with the clinically relevant pharmacological PARP inhibitor ABT888 (also known as veliparib). Finally, siRNA experiments show that CEES induced PAR formation is predominantly due to the activation of PARP1. In conclusion, this study provides a detailed analysis of the CEES induced PARylation response in HaCaT keratinocytes, which forms an experimental basis to study the molecular mechanism of PARP1 activation and its functional consequences after mustard treatment in general.

show abstract

LW-213 induces G2/M cell cycle arrest through AKT/GSK3β/β-catenin signaling pathway in human breast cancer cells

Zhao

Hua

et al. 2015

Mol. Carcinog.

View full text Add to dashboard Cite

LW-213 is a derivative of Wogonin and the anticancer activities of Wogonin have been reported. To study whether LW-213 inhibits cancer cells and explore a possible mechanism, we investigate the compound in several cancer cell lines. We found LW-213 arrests G2/M cycle in breast cancer cells by suppression of Akt/Gsk3β/β-catenin signaling pathway. In compound treated cells, cell cycle-related proteins cyclin A, cyclin B1, p-CDK1, p-Cdc25C, and p-Chk2 (Thr68) were upregulated, and β-catenin nuclear translocation was inhibited. Electrophoretic mobility shift assay revealed LW-213 inhibits binding of β-catenin/LEF complex to DNA. GSK3β inhibitor LiCl and siRNA against GSK3β partially reversed G2/M arrest in breast cancer MCF-7 cells. These results suggest LW-213 triggered G2/M cell cycle arrest through suppression of β-catenin signaling. In BALB/c mice, growth of xenotransplanted MCF-7 tumor was also inhibited after treatment of LW-213. Regulation of cyclin A, cyclin B1, and β-catenin by LW-213 in vivo was the same as in vitro study. In conclusion, we found LW-213 exerts its anticancer effect on cell proliferation and cell cycle through repression of Akt/Gsk3β/β-catenin signaling pathway. LW-213 could be a potential candidate for anticancer drug development.

show abstract

DNA damage, signalling and repair after exposure of cells to the sulphur mustard analogue 2-chloroethyl ethyl sulphide

Cited by 49 publications

References 36 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

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

LW-213 induces G2/M cell cycle arrest through AKT/GSK3β/β-catenin signaling pathway in human breast cancer cells

Contact Info

Product

Resources

About