Impairment of antioxidant defense via glutathione depletion sensitizes acute lymphoblastic leukemia cells for Smac mimetic-induced cell death.
Evasion of apoptosis in pediatric acute lymphoblastic leukemia (ALL) is linked to aberrant expression of inhibitor of apoptosis (IAP) proteins and dysregulated redox homeostasis, rendering leukemic cells vulnerable to redox-targeting therapies. Here we discover that inhibition of antioxidant defenses via glutathione (GSH) depletion by buthionine sulfoximine (BSO) primes ALL cells for apoptosis induced by the Smac mimetic BV6 that antagonizes IAP proteins. Similarly, BSO cooperates with BV6 to induce cell death in patient-derived primary leukemic samples, underscoring the clinical relevance. In contrast, BSO does not sensitize non-malignant lymphohematopoietic cells from healthy donors toward BV6, pointing to some tumor selectivity. Mechanistically, both agents cooperate to stimulate reactive oxygen species (ROS) production, which is required for BSO/BV6-induced cell death, as ROS inhibitors (that is, N-acetylcysteine, MnTBAP, Trolox) significantly rescue cell death. Further, BSO and BV6 cooperate to trigger lipid peroxidation, which is necessary for cell death, as genetic or pharmacological blockage of lipid peroxidation by GSH peroxidase 4 (GPX4) overexpression or α-tocopherol significantly inhibits BSO/BV6-mediated cell death. Consistently, GPX4 knockdown or GPX4 inhibitor RSL3 enhances lipid peroxidation and cell death by BSO/BV6 cotreatment. The discovery of redox regulation of Smac mimetic-induced cell death has important implications for developing rational Smac mimetic-based combination therapies.
Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Frankfurt, Germany.
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H
Schoeneberger
Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Frankfurt, Germany.
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K
Belz
Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Frankfurt, Germany.
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B
Schenk
Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Frankfurt, Germany.
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S
Fulda
D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D040761:Biomimetic Materials / Q000494:pharmacology*; D019328:Buthionine Sulfoximine / Q000494:pharmacology*; D002478:Cells, Cultured; D002648:Child; D004357:Drug Synergism; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000494:pharmacology*; D019169:Jurkat Cells; D015227:Lipid Peroxidation / Q000187:drug effects; D024101:Mitochondrial Proteins / Q000494:pharmacology*; D009842:Oligopeptides / Q000494:pharmacology*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism / Q000473:pathology*; D017382:Reactive Oxygen Species / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C582180:BV6 peptide; C412403:DIABLO protein, human; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D009842:Oligopeptides; D017382:Reactive Oxygen Species; D019328:Buthionine Sulfoximine; D005978:Glutathione