Intracellular ROS Generation Mediates Maleimide-induced Cytotoxicity in Leukemia Cells
Vania F. Noldin,
Fabiola B. Filippin-Monteiro,
Tania B. Creczynski-Pasa.
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.
Keywords: Cytotocixity, leukemia, maleimides, mitochondrial membrane potential, necrosis, ROS generation.
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