title: Intracellular ROS Generation Mediates Maleimide-induced Cytotoxicity in Leukemia Cells.
abstract: Maleimides consist of an important class of compounds easily synthesized with multiple functional group modification that provides expressive pharmacological properties including, antitumoral activity, mediated mainly by oxidative stress. For this reason, the present study was designed to evaluate the cytotoxicity and the role of reactive oxygen species (ROS) in maleimide-induced cell death. Cell viability assays were performed to determine the cell death type in leukemia cell line induced by the compounds. The oxidative stress in maleimidetreated cells was characterized by antioxidant enzymes activities, intracellular ROS generation, and lipid peroxidation. In addition, we evaluated mitochondrial membrane potential and ATP level. Maleimide derivatives exhibited cytotoxic effects in leukemia cells with significantly increased ROS generation. However, cell viability was partly restored by catalase-treated cells. Caspases activities and caspase-independent key genes related to apoptosis were not altered by maleimides, suggesting necrosis as the main cell death process. Maleimide-induced necrosis was associated with oxidative stress, as an imbalance between ROS levels and glutathione reductase (GR) activity. This damage was also demonstrated by loss of mitochondrial membrane potential (MMP) and ATP depletion in cells treated with maleimide derivatives. These findings strongly confirmed that maleimide derivatives promoted cell death in leukemia cells triggered by oxidative stress, indicating that these compounds might be promising antitumor agents or lead molecules.
authors.forename: Daiane
authors.initials: D
authors.lastname: Rosolen
authors.forename: Vania F
authors.initials: VF
authors.lastname: Noldin
authors.forename: Evelyn
authors.initials: E
authors.lastname: Winter
authors.forename: Fabiola B
authors.initials: FB
authors.lastname: Filippin-Monteiro
authors.forename: Fatima
authors.initials: F
authors.lastname: Campos-Buzzi
authors.forename: Valdir
authors.initials: V
authors.lastname: Cechinel-Filho
authors.affiliation: Departamento de Ciencias Farmaceuticas, Centro de Ciencias da Saude, Universidade Federal de Santa Catarina, 88040-900, CP 476 Florianopolis, SC, Brazil. tania.pasa@ufsc.br.
authors.forename: Tania B
authors.initials: TB
authors.lastname: Creczynski-Pasa
mesh_terms: D000818:Animals; D002374:Catalase / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D015870:Gene Expression / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007938:Leukemia / Q000473:pathology*; D015227:Lipid Peroxidation / Q000187:drug effects; D008301:Maleimides / Q000494:pharmacology*; D051379:Mice; D011419:Propidium / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D008301:Maleimides; D017382:Reactive Oxygen Species; C043592:maleimide; D011419:Propidium; D002374:Catalase