Oxidative stress-related mechanisms are associated with xenobiotics exerting excess toxicity to Fanconi anemia cells.

Pagano, Giovanni; Manini, Paola; Bagchi, Debasis

doi:10.1289/ehp.6229

Cited by 29 publications

(17 citation statements)

References 83 publications

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“…The occurrence of DEB-induced oxidative stress and its cytotoxicity effect has previously been reported (Erexson and Tindall, 2000a;Pagano et al, 2003), although its connection to apoptosis has not been previously reported. Oxidative stress, however, has been implicated in mediating apoptosis induced by various toxicants, including cisplatin and dolichyl phosphate (Rybak et al, 2007;Yokoyama et al, 2007).…”

Section: Discussionmentioning

confidence: 96%

“…An increase in cellular ROS generation has been observed in apoptotic processes triggered by various toxicants in various cell types (Buttke and Sandstrom, 1994). Although, oxidative stress has been implicated in DEB-induced cytotoxicity (Pagano et al, 2003), there have been no reports to indicate whether oxidative stress plays a role in mediating DEB-induced apoptosis in exposed cells.…”

Section: Introductionmentioning

confidence: 99%

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Diepoxybutane activates the mitochondrial apoptotic pathway and mediates apoptosis in human lymphoblasts through oxidative stress

Yadavilli¹,

Martinez‐Ceballos²,

Snowden-Aikens³

et al. 2007

Toxicology in Vitro

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Diepoxybutane (DEB) is the most potent metabolite of the environmental chemical 1, 3-butadiene (BD), which is prevalent in petrochemical industrial areas. BD is a known mutagen and human carcinogen, and possesses multi-systems organ toxicity. We recently reported that DEB-induced cell death in TK6 lymphoblasts was due to the occurrence of apoptosis, and not necrosis. In this study, we investigated the molecular mechanisms responsible for DEB-induced apoptosis in these cells. Bax and Bak were found to be over-expressed and activated, and the mitochondrial trans-membrane potential was attenuated in cells undergoing DEB-induced apoptosis. Cytochrome c was depleted from the mitochondria of TK6 cells undergoing apoptosis, and was released into the cytosol in Jurkat-T lymphoblasts exposed to the same concentrations of DEB. Executioner caspase 3 was deduced to be activated by initiator caspase 9. DEB induced reactive oxygen species (ROS) formation, and the ROS scavenger N-acetyl-L-cysteine effectively blocked DEB-induced apoptosis in TK6 cells.Collectively, these results demonstrate that the mitochondrial apoptotic pathway is activated to mediate DEB-induced apoptosis in human TK6 lymphoblasts. These results further demonstrate that DEB-induced apoptosis is also mediated by the DEB-induced generation of ROS. This is the first report to examine the mechanism of DEB-induced apoptosis in human lymphoblasts.

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Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Diepoxybutane activates the mitochondrial apoptotic pathway and mediates apoptosis in human lymphoblasts through oxidative stress

Yadavilli¹,

Martinez‐Ceballos²,

Snowden-Aikens³

et al. 2007

Toxicology in Vitro

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“…Evidence for excess sensitivity of WS cells to some xenobiotics, such as 4NQ and MMC [5,6], may suggest an impairment of WS cells in redox pathways [7,8], due to the involvement of redox-dependent toxicity mechanisms. Some of these agents (e.g.…”

Section: Discussionmentioning

confidence: 99%

“…Some of these agents (e.g. MMC) have been reported previously to exert excess toxicity in cells from patients with Fanconi anaemia (FA), another cancerprone, oxidative stress-related disease [8].…”

Section: Discussionmentioning

confidence: 99%

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In vivoprooxidant state in Werner syndrome (WS): Results from three WS patients and two WS heterozygotes

Pagano¹,

Zatterale

Degan³

et al. 2005

Free Radical Research

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The hypothesis was tested that Werner syndrome (WS) phenotype might be associated with an in vivo prooxidant state. A set of redox-related endpoints were measured in three WS patients, two of their parents, and 99 controls within a study of some cancer-prone and/or ageing-related genetic disorders. The following analytes were measured: (a) leukocyte 8-hydroxy-2'-deoxyguanosine; (b) glutathione from whole blood, and (c) plasma levels of glyoxal, methylglyoxal, 8-isoprostane, and some plasma antioxidants (uric acid, ascorbic acid, alpha- and gamma-tocopherol). Leukocyte 8-hydroxy-2'-deoxyguanosine levels showed a significant increase in the 3 WS patients vs. 85 controls (p<10(-7)). The disulfide glutathione:glutahione ratio was significantly altered in WS patients (p=0.005). Glyoxal and methylglyoxal levels were significantly increased (p=0.018 and p=0.007, respectively). The plasma levels of uric acid (p=0.002) and ascorbic acid (p=0.003) were also increased significantly in WS patients and in their parents. No significant alterations were found in the plasma levels of alpha- and gamma-tocopherol, nor of 8-isoprostane. This is the first report of in vivo alterations of oxidative stress parameters in WS patients. Further investigations on more extensive study populations are warranted to verify the relevance of an in vivo prooxidant state in WS patients.

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Formation of cyclophosphamide specific DNA adducts in hematological diseases

Johnson

Bhaskar

Tretyakova

et al. 2011

Pediatric Blood & Cancer

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Background Fanconi anemia (FA) patients are hypersensitive to DNA alkylating agents and require lower doses than non-FA patients to minimize serious toxicity. The mechanism by which hypersensitivity occurs is thought to be due to the inability of these individuals to effectively repair drug-induced interstrand DNA-DNA crosslinks. We recently developed a highly sensitive assay for cyclophosphamide specific interstrand DNA-DNA crosslinks (G-NOR-G) and are able to quantify and compare formation of these adducts in the blood of patients. Therefore we sought to determine whether FA patients have higher in vivo exposure to the cyclophosphamide specific interstrand DNA crosslink, G-NOR-G, relative to patients without FA. Procedure Cyclophosphamide interstrand DNA crosslinks were measured with the first dose of cyclophosphamide in FA and non-FA patients receiving a cyclophosphamide based preparative regimen prior to hematopoietic cell transplantation (HCT). FA patients received a lower cyclophosphamide dose than the non-FA patients (5–10 mg/kg/day vs. 50–60 mg/kg/day). Results Despite the lower cyclophosphamide dose and lower plasma concentrations in FA patients, they had G-NOR-G amounts similar to the non-FA patients (area under the curve (AUC)0-∞, 99.8 vs. 144.9 G-NOR-G adducts/10^6 nucleotides*hr, respectively, p=0.47). When G-NOR-G AUC was normalized for cyclophosphamide plasma concentrations, FA study subjects produced 15-fold higher adducts than non-FA patients (p=0.05). Conclusions FA patients are hypersensitive to DNA alkylating agents possibly as a result of greater formation of cyclophosphamide specific interstrand DNA crosslinks and/or diminished capacity for DNA repair. Identification and quantification of these adducts may be important determinant of cyclophosphamide related toxicity.

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Oxidative stress-related mechanisms are associated with xenobiotics exerting excess toxicity to Fanconi anemia cells.

Cited by 29 publications

References 83 publications

Diepoxybutane activates the mitochondrial apoptotic pathway and mediates apoptosis in human lymphoblasts through oxidative stress

Diepoxybutane activates the mitochondrial apoptotic pathway and mediates apoptosis in human lymphoblasts through oxidative stress

In vivoprooxidant state in Werner syndrome (WS): Results from three WS patients and two WS heterozygotes

Formation of cyclophosphamide specific DNA adducts in hematological diseases

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