Arsenic trioxide induces human pulmonary fibroblast cell death via increasing             ROS levels and GSH depletion.
Arsenic trioxide (ATO; As2O3) induces apoptotic cell death in various cancer             cells including lung cancer via the induction of reactive oxygen species (ROS).             However, little is known about the toxicological effects of ATO on normal primary             lung cells. Here, we investigated the effects of N-acetyl cysteine (NAC) and vitamin             C (well-known antioxidants) or L-buthionine sulfoximine (BSO; an inhibitor of             GSH synthesis) on ATO-treated human pulmonary fibroblast (HPF) cells in relation             to cell death, ROS and glutathione (GSH). ATO induced growth inhibition and death             in HPF cells, accompanied by the loss of mitochondrial membrane potential (MMP;             ∆ψm). ATO increased ROS levels including O2•- and GSH depleted cell numbers. NAC             attenuated the growth inhibition, death and MMP (∆ψm) loss in ATO-treated HPF             cells and also decreased the ROS levels in these cells. However, vitamin C enhanced             the growth inhibition, death, MMP (∆ψm) loss and GSH depletion by ATO and even             strongly increased mitochondrial O2•- levels in ATO-treated HPF cells. BSO showed             a strong increase in ROS levels in ATO-treated HPF cells and intensified the growth             inhibition, cell death, MMP (∆ψm) loss and GSH depletion. Moreover, superoxide             dismutase (SOD2) or thioredoxin (TXN) siRNAs attenuated HPF cell death by ATO,             which was not correlated with ROS and GSH level changes. In conclusion, ATO induced             the growth inhibition and death of HPF cells, accompanied by increasing ROS levels             and GSH depletion. NAC attenuated HPF cell death by ATO whereas vitamin C and             BSO enhanced the death.
Department of Physiology, Medical School, Institute for Medical                     Sciences, Chonbuk National University, JeonJu 561-180, Republic of Korea.
Bo Ra
BR
You
Woo Hyun
WH
Park
D000111:Acetylcysteine / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000494:pharmacology; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects*; D005978:Glutathione / Q000172:deficiency / Q000378:metabolism*; D006801:Humans; D008168:Lung / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010087:Oxides / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014162:Transfection
D000970:Antineoplastic Agents; D000975:Antioxidants; D001152:Arsenicals; D010087:Oxides; D017382:Reactive Oxygen Species; D019328:Buthionine Sulfoximine; D005978:Glutathione; D001205:Ascorbic Acid; D000077237:Arsenic Trioxide; D000111:Acetylcysteine