title: Sensitization of acute lymphoblastic leukemia cells for LCL161-induced cell death by targeting redox homeostasis.
abstract: Disturbed redox homeostasis with both elevated reactive oxygen species (ROS) levels and antioxidant defense mechanisms has been reported in acute lymphoblastic leukemia (ALL). We therefore hypothesized that inhibition of pathways responsible for ROS detoxification renders ALL cells more susceptible for cell death. Here, we report that pharmacological inhibitors of key pathways for the elimination of ROS, i.e. Erastin, buthionine sulfoximine (BSO) and Auranofin, sensitize ALL cells for cell death upon treatment with the Smac mimetic LCL161 that antagonizes Inhibitor of Apoptosis (IAP) proteins. Erastin, BSO or Auranofin significantly increase LCL161-induced cell death and also act in concert with LCL161 to profoundly suppress long-term clonogenic survival in several ALL cell lines. Erastin or BSO cooperates with LCL161 to stimulate ROS production and lipid peroxidation prior to cell death. ROS production and lipid peroxidation are required for this cotreatment-induced cell death, since ROS scavengers or pharmacological inhibition of lipid peroxidation provides significant protection against cell death. These results emphasize that inhibition of antioxidant defense mechanisms can serve as a potent approach to prime ALL cells for LCL161-induced cell death.
authors.affiliation: Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Komturstr. 3a, 60528 Frankfurt, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Haß
authors.affiliation: Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Komturstr. 3a, 60528 Frankfurt, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Belz
authors.affiliation: Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Komturstr. 3a, 60528 Frankfurt, Germany.
authors.forename: Hannah
authors.initials: H
authors.lastname: Schoeneberger
authors.affiliation: Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Komturstr. 3a, 60528 Frankfurt, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany. Electronic address: simone.fulda@kgu.de.
authors.forename: Simone
authors.initials: S
authors.lastname: Fulda
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000379:methods*; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells; D008715:Methionine / Q000008:administration & dosage / Q000031:analogs & derivatives; D010084:Oxidation-Reduction / Q000187:drug effects; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013454:Sulfoxides / Q000008:administration & dosage; D013844:Thiazoles / Q000008:administration & dosage*
chemical_list: D000970:Antineoplastic Agents; C574246:LCL161; D017382:Reactive Oxygen Species; D013454:Sulfoxides; D013844:Thiazoles; C000594507:buthionine sulfoxide; D008715:Methionine
keywords: Apoptosis; IAP proteins; Leukemia; ROS; Smac