title: The anti-lymphoma activity of APO866, an inhibitor of nicotinamide adenine dinucleotide biosynthesis, is potentialized when used in combination with anti-CD20 antibody.
abstract: APO866 is an inhibitor of nicotinamide adenine dinucleotide (NAD) biosynthesis that exhibits potent anti-lymphoma activity. Rituximab (RTX), an anti-CD20 antibody, kills lymphoma cells by direct apoptosis and antibody- and complement-dependent cell-mediated cytotoxicities, and has clinical efficacy in non-Hodgkin cell lymphomas. In the present study, we evaluated whether RTX could potentiate APO866-induced human B-lymphoma cell death and shed light on death-mediated mechanisms associated with this drug combination. We found that RTX significantly increases APO866-induced death in lymphoma cells from patients and lines. Mechanisms include enhancement of autophagy-mediated cell death, activation of caspase 3 and exacerbation of mitochondrial depolarization, but not increase of reactive oxygen species (ROS) production, when compared with those induced by each drug alone. In vivo, combined administration of APO866 with RTX in a laboratory model of human aggressive lymphoma significantly decreased tumor burden and prolonged survival over single-agent treatment. Our study demonstrates that the combination of RTX and APO866 optimizes B-cell lymphoma apoptosis and therapeutic efficacy over both compounds administered separately.
authors.affiliation: Service and Central Laboratory of Hematology, University Hospital of Lausanne , Lausanne , Switzerland.
authors.forename: Aimable
authors.initials: A
authors.lastname: Nahimana
authors.forename: Dominique
authors.initials: D
authors.lastname: Aubry
authors.forename: Caroline S
authors.initials: CS
authors.lastname: Breton
authors.forename: Somi R
authors.initials: SR
authors.lastname: Majjigapu
authors.forename: Bernard
authors.initials: B
authors.lastname: Sordat
authors.forename: Pierre
authors.initials: P
authors.lastname: Vogel
authors.forename: Michel A
authors.initials: MA
authors.lastname: Duchosal
mesh_terms: D000178:Acrylamides / Q000494:pharmacology*; D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053898:Biosynthetic Pathways / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004357:Drug Synergism; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy / Q000401:mortality / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D016513:Mice, SCID; D009243:NAD / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D000069283:Rituximab; D023041:Xenograft Model Antitumor Assays
chemical_list: D000178:Acrylamides; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; C480543:N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide; D010880:Piperidines; D017382:Reactive Oxygen Species; D009243:NAD; D000069283:Rituximab; D053148:Caspase 3
keywords: APO866; FK866; RTX; leukemia; lymphoma; therapy