title: Pro-oxidants ameliorate radiation-induced apoptosis through activation of the calcium-ERK1/2-Nrf2 pathway.
abstract: There are no reports describing the ability of pro-oxidants to protect against radiation-induced apoptosis. Activation of the redox-sensitive transcription factor Nrf2 by low levels of ROS is known to protect against oxidative stress-induced cell death. In this study, hydrogen peroxide, diethylmaleate, and 1,4-naphthoquinone (NQ) exhibited complete protection against radiation-induced cell death in lymphocytes as estimated by propidium iodide staining. Radioprotection by NQ was demonstrated by inhibition of caspase activation, decrease in cell size, DNA fragmentation, nuclear blebbing, and clonogenic assay. Interestingly, NQ offered protection to lymphocytes even when added to cells postirradiation. NQ increased intracellular ROS levels and decreased GSH levels. NQ activated Nrf2 and increased the expression of the cytoprotective gene heme oxygenase-1 in lymphocytes. NQ increased ERK phosphorylation, which is upstream of Nrf2, and this ERK activation was through increased intracellular calcium levels. Administration of NQ to mice offered protection against whole-body irradiation (WBI)-induced apoptosis in splenic lymphocytes and loss of viability of spleen and bone marrow cells. It restored WBI-mediated changes in hematological parameters and functional responses of lymphocytes. Importantly, NQ rescued mice against WBI-induced mortality. These results demonstrated that a pro-oxidant such as NQ can protect against radiation-induced apoptosis by activation of multiple prosurvival mechanisms including activation of the calcium-ERK1/2-Nrf2 pathway.
authors.affiliation: Bio-Medical Group, Radiation Biology & Health Sciences Division, Bhabha Atomic Research Centre, Mumbai 400085, India.
authors.forename: Nazir M
authors.initials: NM
authors.lastname: Khan
authors.forename: Santosh K
authors.initials: SK
authors.lastname: Sandur
authors.forename: Rahul
authors.initials: R
authors.lastname: Checker
authors.forename: Deepak
authors.initials: D
authors.lastname: Sharma
authors.forename: T B
authors.initials: TB
authors.lastname: Poduval
authors.forename: Krishna B
authors.initials: KB
authors.lastname: Sainis
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000528:radiation effects*; D020013:Calcium Signaling / Q000187:drug effects*; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008298:Maleates / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009285:Naphthoquinones / Q000378:metabolism / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D008298:Maleates; D051267:NF-E2-Related Factor 2; D009285:Naphthoquinones; C495636:Nfe2l2 protein, mouse; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C014476:diethyl maleate; C035342:1,4-naphthoquinone