Reactive Oxygen Species-Mediated Apoptosis and Cytotoxicity of Newly Synthesized Pyridazin-3-Ones In P815 (Murin Mastocytoma) Cell Line

摘要: Background In cancer cells, the intracellular antioxidant capacity and redox homeostasis are mainly maintained by glutathione- thioredoxin-dependent systems which considered as promising targets for anticancer drugs. Pyridazinones constitute an interesting source of heterocyclic compounds drug discovery. The present investigation focused on studying in-vitro antitumor activity newly synthesized Pyridazin-3(2h)-ones derivatives against P815 (Murin mastocytoma) cell line. Methods cytotoxic activities were investigated toward line using tetrazolium-based MTT assay. Lipid peroxidation specific enzymes also determined. Results had a selective dose-dependent effect without affecting normal cells (PBMCs). Apoptosis was further confirmed through characteristic apoptotic morphological changes DNA fragmentation. Two (6f 7h) highly submitted to extend biological testing determine likely mechanisms their cytotoxicity. showed that these molecules may induce cytotoxicity via disturbing homeostasis. Importantly, 6f 7h could be due reactive oxygen species hypergeneration significant loss glutathione reductase thioredoxin activities. This eventually leads oxidative stress-mediated apoptosis. Furthermore, co-administration or with Methotrexate exhibited synergistic effect. Conclusions considering chemosensitivity, improve therapeutic efficacy current treatment cancer.