Arsenic, mode of action at biologically plausible low doses: What are the implications for low dose cancer risk?

Snow, ET; Sýkora, Peter; Durham, TR; Klein, CB

doi:10.1016/j.taap.2005.01.048

Cited by 147 publications

(116 citation statements)

References 29 publications

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“…Interestingly, low dose arsenic exposure decreases the incidence of cancer in humans (Lamm et al, 2004;Snow et al, 2005). This low-dose protective mechanism of arsenic has been confirmed in experimental models (Pott et al, 1998;Romach et al, 2000;Bae et al, 2002;Mahata et al, 2004;Snow et al, 2005). We also observed an increased proliferation in response to low doses of arsenic exposure (Wang et al, 2007).…”

Section: Introductionsupporting

confidence: 77%

“…Arsenic has been demonstrated to activate the Nrf2-dependent response in various cell types (Pi et al, 2003;He et al, 2006;Kimura et al, 2006;Massrieh et al, 2006). Interestingly, low dose arsenic exposure decreases the incidence of cancer in humans (Lamm et al, 2004;Snow et al, 2005). This low-dose protective mechanism of arsenic has been confirmed in experimental models (Pott et al, 1998;Romach et al, 2000;Bae et al, 2002;Mahata et al, 2004;Snow et al, 2005).…”

Section: Introductionmentioning

confidence: 81%

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Activation of Nrf2 by arsenite and monomethylarsonous acid is independent of Keap1-C151: enhanced Keap1–Cul3 interaction

Wang

Sun

Chen

et al. 2008

Toxicology and Applied Pharmacology

127

101

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Drinking water contaminated with arsenic, a human carcinogen, is a worldwide health issue. An understanding of cellular signaling events in response to arsenic exposure and rational designing of strategies to reduce arsenic damages by modulating signaling events are important to fight against arsenic-induced diseases. Previously, we reported that activation of the Nrf2-mediated cellular defense pathway confers protection against toxic effects induced by sodium arsenite [As(III)] or monomethylarsonous acid [MMA(III)]. Paradoxically, arsenic has been reported to induce the Nrf2-dependent signaling pathway. Here, we report the unique mechanism of Nrf2 induction by arsenic. Similar to tert-butylhydroquinone (tBHQ) or sulforaphane (SF), arsenic induced the Nrf2-dependent response through enhancing Nrf2 protein levels by inhibiting Nrf2 ubiquitination and degradation. However, the detailed action of arsenic in Nrf2 induction is different from that of tBHQ or SF. Arsenic markedly enhanced the interaction between Keap1 and Cul3, subunits of the E3 ubiquitin ligase for Nrf2, which led to impaired dynamic assembly/disassembly of the E3 ubiquitin ligase and thus decreased its ligase activity. Furthermore, induction of Nrf2 by arsenic is independent of the previously identified C151 residue in Keap1 that is required for Nrf2 activation by tBHQ or SF. Distinct mechanisms of Nrf2 activation by seemingly harmful and beneficial reagents provide a molecular basis to design Nrf2-activating agents for therapeutic intervention.

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Section: Introductionsupporting

confidence: 77%

Section: Introductionmentioning

confidence: 81%

Activation of Nrf2 by arsenite and monomethylarsonous acid is independent of Keap1-C151: enhanced Keap1–Cul3 interaction

Wang

Sun

Chen

et al. 2008

Toxicology and Applied Pharmacology

127

101

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show abstract

“…It is reported that AS has a dual effect on cancer, i.e., it promotes cell proliferation at low concentration, whereas inhibits it at high ones. 22 It has also been reported that chronic exposure to AS caused EMT during AS-induced malignant transformation; 23,24 however, the significance of EMT in AS induced carcinogenesis remains incompletely defined. In our study, we demonstrated that EMT is involved in AS-transformed colon cells.…”

Section: Discussionmentioning

confidence: 99%

Arsenite promotes intestinal tumor cell proliferation and invasion by stimulating epithelial-to-mesenchymal transition

Sun

Chen

et al. 2014

Cancer Biology & Therapy

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“…44 Of relevance to the study presented in figure 6, the natural intracellular glutathione (GSH) level of…”

Section: Variability: Cell Lines and Assaysmentioning

confidence: 99%

Numerical simulations of in vitro nanoparticle toxicity – The case of poly(amido amine) dendrimers

Maher¹,

Naha²,

Mukherjee³

et al. 2014

Toxicology in Vitro

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A phenomenological rate equation model is constructed to numerically simulate nanoparticle uptake and subsequent cellular response. Polyamidoamine dendrimers (generations 4-6) are modelled and the temporal evolution of the intracellular cascade of; increased levels of reactive oxygen species, intracellular antioxidant species, caspase activation, mitochondrial membrane potential decay, tumour necrosis factor and interleukin generation is simulated, based on experimental observations. The model serves as a tool to interpolate and visualise the range of dose and temporal dependences and elucidate the mechanisms underlying the in vitro cytotoxic response to nanoparticle exposure and describes the interaction in terms of independent nanoparticle properties and cellular parameters, based on reaction rates. Such an approach could be a valid alternative to that of effective concentrations for classification of nanotoxicity and may lay the foundation for future quantitative structure activity relationships and predictive nanotoxicity models.3

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Arsenic, mode of action at biologically plausible low doses: What are the implications for low dose cancer risk?

Cited by 147 publications

References 29 publications

Activation of Nrf2 by arsenite and monomethylarsonous acid is independent of Keap1-C151: enhanced Keap1–Cul3 interaction

Activation of Nrf2 by arsenite and monomethylarsonous acid is independent of Keap1-C151: enhanced Keap1–Cul3 interaction

Arsenite promotes intestinal tumor cell proliferation and invasion by stimulating epithelial-to-mesenchymal transition

Numerical simulations of in vitro nanoparticle toxicity – The case of poly(amido amine) dendrimers

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