erastin and Fibrosarcoma

Ferroptosis is a form of regulated cell death induced by lipid peroxidation that is dependent on iron. This pathway is being considered as an alternative anticancer therapeutic strategy, and the chemoreagent erastin induces ferroptosis by blocking system Xc

Topics: Animals; Carcinoma, Hepatocellular; Cell Line, Tumor; Down-Regulation; Ferroptosis; Fibrosarcoma; Gene Knockdown Techniques; Humans; Isocitrate Dehydrogenase; Mice; Piperazines

Ferroptosis is a new mode of regulated cell death, which is completely distinct from other cell death modes based on morphological, biochemical, and genetic criteria. This study evaluated the therapeutic role of ferroptosis in classic chemotherapy drugs, including the underlying mechanism.. Cell viabilitywas detected by using the methylthiazoltetrazlium dye uptake method. RNAiwas used to knockout iron-responsive element binding protein 2, and polymerase chain reaction, western blot was used to evaluate the efficiency. Intracellular reduced glutathione level and glutathione peroxidases activitywere determined by related assay kit. Intracellularreactive oxygen species levelswere determined by flowcytometry. Electron microscopywas used to observe ultrastructure changes in cell.. Among five chemotherapeutic drugs screened in this study, cisplatin was found to be an inducer for both ferroptosis and apoptosis in A549 and HCT116 cells. The depletion of reduced glutathione caused by cisplatin and the inactivation of glutathione peroxidase played the vital role in the underlying mechanism. Besides, combination therapy of cisplatin and erastin showed significant synergistic effect on their anti-tumor activity.. Ferroptosis had great potential to become a new approach in anti-tumor therapies and make up for some classic drugs, which open up a new way for their utility in clinic.

Topics: A549 Cells; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Death; Cisplatin; Colorectal Neoplasms; Fibrosarcoma; Glutathione Peroxidase; HCT116 Cells; Humans; Lung Neoplasms; Neoplasms; Piperazines

In cancer cells the small compounds erastin and RSL3 promote a novel type of cell death called ferroptosis, which requires iron-dependent accumulation of lipid reactive oxygen species. Here we assessed the contribution of lipid peroxidation activity of lipoxygenases (LOX) to ferroptosis in oncogenic Ras-expressing cancer cells. Several 12/15-LOX inhibitors prevented cell death induced by erastin and RSL3. Furthermore, siRNA-mediated silencing of ALOX15 significantly decreased both erastin-induced and RSL3-induced ferroptotic cell death, whereas exogenous overexpression of ALOX15 enhanced the effect of these compounds. Immunofluorescence analyses revealed that the ALOX15 protein consistently localizes to cell membrane during the course of ferroptosis. Importantly, treatments of cells with ALOX15-activating compounds accelerated cell death at low, but not high doses of erastin and RSL3. These observations suggest that tumor ferroptosis is promoted by LOX-catalyzed lipid hydroperoxide generation in cellular membranes.

Topics: Arachidonate 15-Lipoxygenase; Carbolines; Cell Death; Cell Line, Tumor; Fibrosarcoma; Gene Expression Regulation, Neoplastic; Humans; Lipid Peroxidation; Pancreatic Neoplasms; Piperazines; RNA, Small Interfering