Lipoxygenase inhibitors protect acute lymphoblastic leukemia cells from ferroptotic cell death

• Published in: Biochemical pharmacology Vol. 140; pp. 41 - 52
• Main Authors: Probst, Lukas, Dächert, Jasmin, Schenk, Barbara, Fulda, Simone
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 15.09.2017
• Subjects: Acute leukemia; alpha-Tocopherol - pharmacology; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antioxidants - pharmacology; Arachidonate 12-Lipoxygenase - chemistry; Arachidonate 12-Lipoxygenase - genetics; Arachidonate 12-Lipoxygenase - metabolism; Arachidonate 15-Lipoxygenase - chemistry; Arachidonate 15-Lipoxygenase - genetics; Arachidonate 15-Lipoxygenase - metabolism; Carbolines - antagonists & inhibitors; Carbolines - pharmacology; Cell death; Cell Death - drug effects; Cell Line, Tumor; Cyclohexylamines - pharmacology; Fas-Associated Death Domain Protein - genetics; Fas-Associated Death Domain Protein - metabolism; Ferroptosis; Flavanones - pharmacology; Gene Expression Regulation, Neoplastic - drug effects; Glutathione Peroxidase - antagonists & inhibitors; Glutathione Peroxidase - genetics; Glutathione Peroxidase - metabolism; Humans; Kinetics; Lipid Peroxidation - drug effects; Lipoxygenase Inhibitors - pharmacology; Masoprocol - pharmacology; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Oxidative Stress - drug effects; Phenylenediamines - pharmacology; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor Cell Lymphoblastic Leukemia-Lymphoma - enzymology; Precursor Cell Lymphoblastic Leukemia-Lymphoma - metabolism; Reactive Oxygen Species - antagonists & inhibitors; Reactive Oxygen Species - metabolism; Redox; ROS; Acute leukemia; Redox; Ferroptosis; Cell death; ROS
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2017.06.112

[Display omitted] 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.