title: PX-12 inhibits the growth of A549 lung cancer cells via G2/M phase arrest and ROS-dependent apoptosis.
abstract: PX-12 (1-methylpropyl 2-imidazolyl disulfide) is an inhibitor of thioredoxin (Trx-1), which has antitumor effects. However, little is known about the toxicological effect of PX-12 on cancer cells. We investigated the anti-growth effects of PX-12 on A549 lung cancer cells in relation to reactive oxygen species (ROS) and glutathione (GSH) levels. Based on MTT assays, PX-12 inhibited the growth of A549 cells with an IC50 of approximately 20 µM at 72 h. DNA flow cytometric analysis indicated that PX-12 significantly induced the G2/M phase arrest of the cell cycle in A549 cells. This agent also induced apoptotic cell death, as demonstrated by Annexin V-FITC staining cells and the loss of mitochondrial membrane potential MMP (∆ψm). In addition, the administration of Bax siRNA attenuated PX-12-induced A549 cell death. All the tested caspase inhibitors, especially Z-VAD significantly prevented apoptosis induced by PX-12. With respect to ROS and GSH levels, PX-12 increased ROS levels including O2(•)- in A549 cells and induced GSH depletion. N-acetyl cysteine (NAC) markedly reduced ROS levels in PX-12-treated A549 cells. NAC also prevented apoptotic cell death and GSH depletion induced by PX-12. This is the first report to show that PX-12 inhibits the growth of A549 cells via G2/M phase arrest, and Bax-mediated and ROS-dependent apoptosis.
authors.affiliation: Department of Physiology, Medical School, Research Institute for Endocrine Sciences, Chonbuk National University, Jeonju 561-180, Republic of Korea.
authors.forename: Bo Ra
authors.initials: BR
authors.lastname: You
authors.forename: Hye Rim
authors.initials: HR
authors.lastname: Shin
authors.forename: Woo Hyun
authors.initials: WH
authors.lastname: Park
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004220:Disulfides / Q000008:administration & dosage*; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D004220:Disulfides; D007093:Imidazoles; D017382:Reactive Oxygen Species; C412893:1-methylpropyl-2-imidazolyl disulfide; D005978:Glutathione