naphthoquinones and diethyl-maleate

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.

Topics: Animals; Apoptosis; Calcium Signaling; Cell Line; Enzyme Activation; Humans; Hydrogen Peroxide; Maleates; MAP Kinase Signaling System; Mice; Mice, Inbred BALB C; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Naphthoquinones; NF-E2-Related Factor 2; Oxidative Stress; Phosphorylation; Reactive Oxygen Species

Sixteen naphthoquinones with various substituents were tested for cytotoxicity toward cultured resting leukemia L1210 cells. The cytotoxicity of all the naphthoquinones examined was not affected at all by the treatment in combination with diethyl maleate, a glutathione-specific SH-blocking agent in the cells. Depending on the characteristics of the response to the treatment in combination with iodoacetamide (IAA) and glutathione (GSH), these naphthoquinones were tentatively classified into three groups. The chemicals of Group I, which include naphthoquinones carrying an electron-donating group(s) other than an OH group on the quinone ring moiety, showed synergistic cytotoxicity with IAA and no reduction in cytotoxicity with GSH. Those of Group II, which include naphthoquinones without an electron-donating group on the quinone ring moiety, showed no synergy with IAA but appreciable reductions in cytotoxicity with GSH. Group III includes 2-hydroxylated naphthoquinones, which showed neither synergy with IAA nor cytotoxicity reduction with GSH. Cytotoxicity was discussed in terms of the electron-deficiency of the quinone ring moiety. It is suggested that the cytotoxicity of Group I quinones comes from the active oxygen generation which follows semiquinone formation, whereas that of the other groups of quinones is not likely caused simply by either SH-blocking of biomolecules or active oxygen-related mechanism.

Topics: Alkylating Agents; Animals; Cell Survival; Culture Media; Drug Interactions; Glutathione; Iodoacetamide; Leukemia L1210; Maleates; Mice; Naphthoquinones; Tumor Cells, Cultured