Mitochondrial and nuclear DNA damage induced by sulphur mustard in keratinocytes

Shahin, Susan; Cullinane, Carleen; Gray, Peter J.

doi:10.1016/s0009-2797(01)00275-7

Cited by 41 publications

(20 citation statements)

References 36 publications

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“…The mitochondrion seems to play a dual role in apoptosis, both in cell detachment and in the execution of apoptosis in detached cells with obvious signs of MMP in detached cells such as (i) opening of the PTPC, (ii) dissipation of m and (iii) mitochondrial release of cytochrome c (but neither AIF nor EndoG relocalization), specifying previous results obtained in other cell types [7]. The absence of HN2 effects on isolated mitochondria indicates that mustards do not directly affect this organelle suggesting that MMP may be mediated by the modulation of pro-or anti-apoptotic factor of the Bcl-2 family.…”

Section: Discussionsupporting

confidence: 87%

“…SM remains a significant threat as there are still no effective medical countermeasures available to prevent severe lesions in exposed skin, lungs and eyes [1][2][3][4]. Common cellular mechanisms of toxicity have been brought to light in different studies, mainly concerning keratinocytes, involving PARP (poly (ADP-ribose) polymerase) activation [5], NAD depletion, ATP decrease, cell death [6], DNA-alkylation and DNA-damaging properties [7]. Oxidative stress [8], calcium imbalance [9] and inflammatory process [10] have also been incriminated in SM acute toxicity.…”

Section: Introductionmentioning

confidence: 99%

“…All these mechanisms can independently trigger cell death. Thus, apoptosis was proposed as a final event by which SM could exert its cytotoxic effects [5] as different studies showed that SM induced early DNA lesions [5,7] and an increase in the apoptotic sub-G0/G1 fraction of the cellular cycle [7,12]. Activation of the apoptotic mitochondrial pathway requires membrane permeabilization and release of pro-apoptotic mitochondrial proteins resulting in the activation of caspases (e.g.…”

Section: Introductionmentioning

confidence: 99%

“…The mitochondrial permeabilization can be achieved by the opening of the permeability transition pore complex (PTPC), a large proteinaceous complex, regulated by members of the Bcl-2 family [16,17]. In keratinocytes, SM was also shown to up regulate p53 and reduce the levels of Bcl-2 protein [9], activate caspase-3 [18], and target the mitochondrion [7].…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of caspase-dependent mitochondrial permeability transition protects airway epithelial cells against mustard-induced apoptosis

et al. 2006

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In the present study, the toxicity of yperite, SM, and its structural analogue mechlorethamine, HN2, was investigated in a human bronchial epithelial cell line 16HBE. Cell detachment was initiated by caspase-2 activation, down-regulation of Bcl-2 and loss of mitochondrial membrane potential. Only in detached cells, mustards induced apoptosis associated with increase in p53 expression, Bax activation, decrease in Bcl-2 expression, opening of the mitochondrial permeability transition pore, release of cytochrome c, caspase-2, -3, -8, -9 and -13 activation and DNA fragmentation. Apoptosis, occurring only in detached cells, could be recognized as anoikis and the mitochondrion, involved both in cell detachment and subsequent cell death, appears to be a crucial checkpoint. Based on our understanding of the apoptotic pathway triggered by mustards, we demonstrated that inhibition of the mitochondrial pathway by ebselen, melatonin and cyclosporine A markedly prevented mustard-induced anoikis, pointing to these drugs as interesting candidates for the treatment of mustard-induced airway epithelial lesions.

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Section: Discussionsupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Inhibition of caspase-dependent mitochondrial permeability transition protects airway epithelial cells against mustard-induced apoptosis

et al. 2006

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“…The pellet was resuspended in Tris/EDTA buffer (10 mM Tris, pH 8.0, 1 mM EDTA) and the final DNA concentration recovered was determined as described above. Quantitative PCR of an 1858-bp fragment in the DHFR gene was performed as described previously (Shahin et al, 2001). Briefly, each PCR amplification mixture (25 l) consisted of 100 ng of total genomic DNA and contained 0.625 U of Taq polymerase (Promega, Madison, WI), primers (0.5 M for each primer; sense primer, 5Ј-AAACGTAGCTCGTCCTCAAA; antisense primer, 5Ј-TTCCAGTCTACGGGAAGCC), dNTPs (0.2 mM of each dNTP), 1ϫ QIAGEN PCR buffer, 1ϫ Q solution (QIAGEN), 2.6 mM MgCl 2 , and made up to 25 l with Milli-Q water.…”

mentioning

confidence: 99%

Gemcitabine Potentiates Cisplatin Cytotoxicity and Inhibits Repair of Cisplatin-DNA Damage in Ovarian Cancer Cell Lines

Moufarij¹,

Phillips²,

Cullinane³

2003

Mol Pharmacol

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Synergistic cytotoxicity between cisplatin and the nucleoside analog gemcitabine was observed in a panel of cisplatin-sensitive (2008, A2780) and -resistant (2008/C13*5.25, A2780/ CP70) human ovarian cell lines. Previous studies have suggested a role for DNA repair in the mechanism of synergy between the two drugs. We therefore further investigated the hypothesis that the synergistic cytotoxicity between gemcitabine and cisplatin in these cell lines may be caused by gemcitabine-mediated inhibition of cisplatin intrastrand adduct (IA) and interstand cross-link (ICL) repair. The effect of gemcitabine on the accumulation and repair of cisplatin IA and ICL in each cell line was then measured directly using gene-specific quantitative polymerase chain reaction and denaturation/renaturation techniques, respectively. Pretreatment of 2008 cells with 1 M gemcitabine for 2 h before exposure to cisplatin for 7 h enhanced the accumulation of cisplatin IA and ICL by 50 and 40%, respectively (P Ͻ 0.05), above that induced by cisplatin alone. To investigate the possibility that the increased accumulation of cisplatin lesions was caused by inhibition of removal of cisplatin damage, 2008 cells were incubated with 200 M cisplatin for 5 h in the presence and absence of gemcitabine and then a further 8 h in the absence of cisplatin. Only 57% IA were removed in the combination treated cells compared with 74% in cisplatin control cells. Similarly, repair of cisplatin ICL was inhibited in the gemcitabine-treated cells compared with the cells treated with cisplatin only (60 versus 72%). These findings demonstrate a direct inhibitory effect of gemcitabine on the repair of cisplatin IA and ICL and suggest a mechanistic basis for the cytotoxic synergy between the two drugs.

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Sulfur Mustard

Steinritz¹,

Thiermann²

2017

Critical Care Toxicology

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Mitochondrial and nuclear DNA damage induced by sulphur mustard in keratinocytes

Cited by 41 publications

References 36 publications

Inhibition of caspase-dependent mitochondrial permeability transition protects airway epithelial cells against mustard-induced apoptosis

Inhibition of caspase-dependent mitochondrial permeability transition protects airway epithelial cells against mustard-induced apoptosis

Gemcitabine Potentiates Cisplatin Cytotoxicity and Inhibits Repair of Cisplatin-DNA Damage in Ovarian Cancer Cell Lines

Sulfur Mustard

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