Intracellular Ca2+ chelators prevent DNA damage and protect hepatoma 1C1C7 cells from quinone-induced cell killing.
Exposure of hepatoma 1c1c7 cells to 2,3-dimethoxy-1,4-naphthoquinone (DMNQ) resulted in a sustained elevation of cytosolic Ca2+, DNA single strand breaks and cell killing. DNA single strand break formation was prevented when cells were preloaded with either of the intracellular Ca2+ chelators, Quin 2 or BAPTA, to buffer the increase in cytosolic Ca2+ concentration induced by the quinone. DMNQ caused marked NAD+ depletion which was prevented when cells were preincubated with 3-aminobenzamide, an inhibitor of nuclear poly-(ADP-ribose)-synthetase activity, or with either of the two Ca2+ chelators. However, 3-aminobenzamide did not protect the hepatoma cells from loss of viability. Our results indicate that quinone-induced DNA damage, NAD+ depletion and cell killing are mediated by a sustained elevation of cytosolic Ca2+.
Dypbukt
J M
JM
Department of Toxicology, Karolinska Institute, Stockholm, Sweden.
Thor
H
H
Nicotera
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D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects*; D002614:Chelating Agents / Q000494:pharmacology*; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004249:DNA Damage; D005978:Glutathione / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D009285:Naphthoquinones / Q000494:pharmacology; D010084:Oxidation-Reduction; D011809:Quinones / Q000037:antagonists & inhibitors* / Q000633:toxicity; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D002614:Chelating Agents; D009285:Naphthoquinones; D011809:Quinones; C063002:2,3-dimethoxy-1,4-naphthoquinone; D005978:Glutathione; D002118:Calcium