title: Arsenic trioxide-induced cytotoxicity in small cell lung cancer via altered redox homeostasis and mitochondrial integrity.
abstract: Arsenic trioxide (ATO) has demonstrated anticancer activity in different malignancies, especially acute promyelocytic leukemia, with a wide array of putative mechanisms. In this study, we aimed to elucidate the activity and mechanisms of ATO in small cell lung cancer (SCLC). A panel of SCLC cell lines (H841, DMS79, H526, H69 and H187) was employed to demonstrate the activity of ATO. Cell viability, apoptosis and mitochondrial membrane depolarization were assessed. Western blotting was performed to determine the alteration of pro-apoptotic and anti-apoptotic mediators. Reactive oxygen species (ROS) (hydrogen peroxide and superoxide) and intracellular glutathione (GSH) were measured. Antioxidants, N-acetyl-L-cysteine (NAC) and butylated hydroxyanisole (BHA), were applied to restore GSH content and reduce production of ROS. All SCLC cell lines were relatively sensitive to ATO with IC50 values below 10 µM. ATO induced cell death mainly through apoptosis in H841 cells in a dose-dependent manner. Hydrogen peroxide was the major ROS in SCLC cells induced by ATO. Along with GSH depletion and Bcl-2 downregulation, mitochondrial membrane permeabilization was enhanced, followed by release of AIF and SMAC from mitochondria to initiate different cell death pathways. NAC reversed cell death and molecular changes induced by ATO via restoring GSH and reducing ROS content. BHA inhibited hydrogen peroxide production completely and partially restored GSH content accounting for partial reversal of cell inhibition and mitochondrial dysfunction. Nonetheless, ATO reduced both reduced and oxidized form of thioredoxin 1 (Trx1) with no effect on Trx1 redox potential. ATO led to cell death in SCLC mainly through mitochondrial dysfunction, resulting from altered cellular redox homeostasis, namely, hydrogen peroxide generation, GSH depletion and Trx1 downregulation.
authors.affiliation: Division of Respiratory Medicine, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, SAR, P.R. China.
authors.forename: Chun-Yan
authors.initials: CY
authors.lastname: Zheng
authors.affiliation: Division of Respiratory Medicine, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, SAR, P.R. China.
authors.forename: Sze-Kwan
authors.initials: SK
authors.lastname: Lam
authors.affiliation: Division of Respiratory Medicine, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, SAR, P.R. China.
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Li
authors.affiliation: Division of Respiratory Medicine, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, SAR, P.R. China.
authors.forename: James Chung-Man
authors.initials: JC
authors.lastname: Ho
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D002083:Butylated Hydroxyanisole / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D010084:Oxidation-Reduction; D010087:Oxides / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013879:Thioredoxins / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D001152:Arsenicals; D010087:Oxides; D017382:Reactive Oxygen Species; D002083:Butylated Hydroxyanisole; D013879:Thioredoxins; D005978:Glutathione; D000077237:Arsenic Trioxide