title: Antibody-induced nonapoptotic cell death in human lymphoma and leukemia cells is mediated through a novel reactive oxygen species-dependent pathway.
abstract: Monoclonal antibodies (mAbs) have revolutionized the treatment of B-cell malignancies. Although Fc-dependent mechanisms of mAb-mediated tumor clearance have been extensively studied, the ability of mAbs to directly evoke programmed cell death (PCD) in the target cell and the underlying mechanisms involved remain under-investigated. We recently demonstrated that certain mAbs (type II anti-CD20 and anti-HLA DR mAbs) potently evoked PCD through an actin-dependent, lysosome-mediated process. Here, we reveal that the induction of PCD by these mAbs, including the type II anti-CD20 mAb GA101 (obinutuzumab), directly correlates with their ability to produce reactive oxygen species (ROS) in human B-lymphoma cell lines and primary B-cell chronic lymphocytic leukemia cells. ROS scavengers abrogated mAb-induced PCD indicating that ROS are required for the execution of cell death. ROS were generated downstream of mAb-induced actin cytoskeletal reorganization and lysosome membrane permeabilization. ROS production was independent of mitochondria and unaffected by BCL-2 overexpression. Instead, ROS generation was mediated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. These findings provide further insights into a previously unrecognized role for NADPH oxidase-derived ROS in mediating nonapoptotic PCD evoked by mAbs in B-cell malignancies. This newly characterized cell death pathway may potentially be exploited to eliminate malignant cells, which are refractory to conventional chemotherapy and immunotherapy.
authors.affiliation: Targeted Therapy Group, Paterson Institute for Cancer Research, School of Cancer and Enabling Sciences, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK.
authors.forename: Jamie
authors.initials: J
authors.lastname: Honeychurch
authors.forename: Waleed
authors.initials: W
authors.lastname: Alduaij
authors.forename: Mahsa
authors.initials: M
authors.lastname: Azizyan
authors.forename: Eleanor J
authors.initials: EJ
authors.lastname: Cheadle
authors.forename: Helene
authors.initials: H
authors.lastname: Pelicano
authors.forename: Andrei
authors.initials: A
authors.lastname: Ivanov
authors.forename: Peng
authors.initials: P
authors.lastname: Huang
authors.forename: Mark S
authors.initials: MS
authors.lastname: Cragg
authors.forename: Tim M
authors.initials: TM
authors.lastname: Illidge
mesh_terms: D000199:Actins / Q000378:metabolism; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D018951:Antigens, CD20 / Q000276:immunology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007938:Leukemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008223:Lymphoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D000199:Actins; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018951:Antigens, CD20; D008562:Membrane Glycoproteins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C543332:obinutuzumab