Lipoxygenase inhibitors protect acute lymphoblastic leukemia cells from ferroptotic cell death
| Autor: | Barbara Schenk, Lukas Probst, Jasmin Dächert, Simone Fulda |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Programmed cell death Fas-Associated Death Domain Protein alpha-Tocopherol Antineoplastic Agents Phenylenediamines GPX4 Arachidonate 12-Lipoxygenase Biochemistry Antioxidants Lipid peroxidation 03 medical and health sciences chemistry.chemical_compound Cell Line Tumor Arachidonate 15-Lipoxygenase Humans Masoprocol FADD Lipoxygenase Inhibitors Death domain Pharmacology chemistry.chemical_classification Reactive oxygen species Cyclohexylamines Glutathione Peroxidase biology Cell Death Precursor Cell Lymphoblastic Leukemia-Lymphoma Phospholipid Hydroperoxide Glutathione Peroxidase Neoplasm Proteins Nordihydroguaiaretic acid Gene Expression Regulation Neoplastic Kinetics Oxidative Stress 030104 developmental biology chemistry Apoptosis Flavanones biology.protein Cancer research Lipid Peroxidation Reactive Oxygen Species Carbolines |
| Zdroj: | Biochemical pharmacology. 140 |
| ISSN: | 1873-2968 |
| Popis: | Ferroptosis has recently been identified as a mode of programmed cell death. However, little is yet known about the signaling mechanism. Here, we report that lipoxygenases (LOX) contribute to the regulation of RSL3-induced ferroptosis in acute lymphoblastic leukemia (ALL) cells. We show that the glutathione (GSH) peroxidase 4 (GPX4) inhibitor RSL3 triggers lipid peroxidation, production of reactive oxygen species (ROS) and cell death in ALL cells. All these events are impeded in the presence of Ferrostatin-1 (Fer-1), a small-molecule inhibitor of lipid peroxidation. Also, lipid peroxidation and ROS production precede the induction of cell death, underscoring their contribution to cell death upon exposure to RSL3. Importantly, LOX inhibitors, including the selective 12/15-LOX inhibitor Baicalein and the pan-LOX inhibitor nordihydroguaiaretic acid (NDGA), protect ALL cells from RSL3-stimulated lipid peroxidation, ROS generation and cell death, indicating that LOX contribute to ferroptosis. RSL3 triggers lipid peroxidation and cell death also in FAS-associated Death Domain (FADD)-deficient cells which are resistant to death receptor-induced apoptosis indicating that the induction of ferroptosis may bypass apoptosis resistance. By providing new insights into the molecular regulation of ferroptosis, our study contributes to the development of novel treatment strategies to reactivate programmed cell death in ALL. |
| Databáze: | OpenAIRE |
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