title: Auranofin induces apoptosis and necrosis in HeLa cells via oxidative stress and glutathione depletion.
abstract: Auranofin (Au), an inhibitor of thioredoxin reductase, is a known anti‑cancer drug. In the present study, the anti‑growth effect of Au on HeLa cervical cancer cells was examined in association with levels of reactive oxygen species (ROS) and glutathione (GSH). Au inhibited the growth of HeLa cells with an IC50 of ~2 µM at 24 h. This agent induced apoptosis and necrosis, accompanied by the cleavage of poly (ADP‑ribose) polymerase and loss of mitochondrial membrane potential. The pan‑caspase inhibitor, benzyloxycarbonyl‑Val‑Ala‑Asp‑fluoromethylketone, prevented apoptotic cell death and each of the assessed caspase inhibitors inhibited necrotic cell death induced by Au. With respect to the levels of ROS and GSH, Au increased intracellular O2•- in the HeLa cells and induced GSH depletion. The pan‑caspase inhibitor reduced the levels of O2•- and GSH depletion in Au‑treated HeLa cells. The antioxidant, N‑acetyl cysteine, not only attenuated apoptosis and necrosis in the Au‑treated HeLa cells, but also decreased the levels of O2•- and GSH depletion in the cells. By contrast, L‑buthionine sulfoximine, a GSH synthesis inhibitor, intensified cell death O2•- and GSH depletion in the Au‑treated HeLa cells. In conclusion, Au induced apoptosis and necrosis in HeLa cells via the induction of oxidative stress and the depletion of GSH.
authors.affiliation: Department of Physiology, Medical School, Research Institute for Endocrine Sciences, Chonbuk National University, Jeonju, Jeollabuk 561‑180, Republic of Korea.
authors.forename: Bo Ra
authors.initials: BR
authors.lastname: You
authors.affiliation: Department of Physiology, Medical School, Research Institute for Endocrine Sciences, Chonbuk National University, Jeonju, Jeollabuk 561‑180, Republic of Korea.
authors.forename: Hye Rim
authors.initials: HR
authors.lastname: Shin
authors.affiliation: Department of Physiology, Medical School, Research Institute for Endocrine Sciences, Chonbuk National University, Jeonju, Jeollabuk 561‑180, Republic of Korea.
authors.forename: Bo Ram
authors.initials: BR
authors.lastname: Han
authors.affiliation: Department of Physiology, Medical School, Research Institute for Endocrine Sciences, Chonbuk National University, Jeonju, Jeollabuk 561‑180, Republic of Korea.
authors.forename: Suhn Hee
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Department of Physiology, Medical School, Research Institute for Endocrine Sciences, Chonbuk National University, Jeonju, Jeollabuk 561‑180, Republic of Korea.
authors.forename: Woo Hyun
authors.initials: WH
authors.lastname: Park
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001310:Auranofin / Q000494:pharmacology*; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D061945:Caspase Inhibitors / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D005978:Glutathione / Q000032:analysis / Q000172:deficiency / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009336:Necrosis; D009842:Oligopeptides / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D026082:Singlet Oxygen / Q000032:analysis / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D061945:Caspase Inhibitors; D009842:Oligopeptides; C517629:benzyloxycarbonyl-valyl-alanyl-aspartic acid; D026082:Singlet Oxygen; D001310:Auranofin; D019328:Buthionine Sulfoximine; D005978:Glutathione; D000111:Acetylcysteine