title: The NAD biosynthesis inhibitor APO866 has potent antitumor activity against hematologic malignancies.
abstract: APO866 inhibits nicotinamide phosphoribosyltransferase (NMPRTase), a key enzyme involved in nicotinamide adenine dinucleotide (NAD) biosynthesis from the natural precursor nicotinamide. Intracellular NAD is essential for cell survival, and NAD depletion resulting from APO866 treatment elicits tumor cell death. Here, we determine the in vitro and in vivo sensitivities of hematologic cancer cells to APO866 using a panel of cell lines (n = 45) and primary cells (n = 32). Most cancer cells (acute myeloid leukemia [AML], acute lymphoblastic leukemia [ALL], mantle cell lymphoma [MCL], chronic lymphocytic leukemia [CLL], and T-cell lymphoma), but not normal hematopoietic progenitor cells, were sensitive to low concentrations of APO866 as measured in cytotoxicity and clonogenic assays. Treatment with APO866 decreased intracellular NAD and adenosine triphosphate (ATP) at 24 hours and 48 to72 hours, respectively. The NAD depletion led to cell death. At 96 hours, APO866-mediated cell death occurred in a caspase-independent mode, and was associated with mitochondrial dysfunction and autophagy. Further, in vivo administration of APO866 as a single agent prevented and abrogated tumor growth in animal models of human AML, lymphoblastic lymphoma, and leukemia without significant toxicity to the animals. The results support the potential of APO866 for treating hematologic malignancies.
authors.affiliation: Service of Hematology, University Hospital of Lausanne, Lausanne, Switzerland.
authors.forename: Aimable
authors.initials: A
authors.lastname: Nahimana
authors.forename: Antoine
authors.initials: A
authors.lastname: Attinger
authors.forename: Dominique
authors.initials: D
authors.lastname: Aubry
authors.forename: Peter
authors.initials: P
authors.lastname: Greaney
authors.forename: Christopher
authors.initials: C
authors.lastname: Ireson
authors.forename: Annemette V
authors.initials: AV
authors.lastname: Thougaard
authors.forename: Jette
authors.initials: J
authors.lastname: Tjørnelund
authors.forename: Keith M
authors.initials: KM
authors.lastname: Dawson
authors.forename: Marc
authors.initials: M
authors.lastname: Dupuis
authors.forename: Michel A
authors.initials: MA
authors.lastname: Duchosal
mesh_terms: D000178:Acrylamides / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D016923:Cell Death / Q000187:drug effects; D016207:Cytokines / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D018922:HL-60 Cells; D019337:Hematologic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D020014:K562 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009243:NAD / Q000096:biosynthesis* / Q000187:drug effects; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors*; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured; D020298:U937 Cells; D023041:Xenograft Model Antitumor Assays
chemical_list: D000178:Acrylamides; D000970:Antineoplastic Agents; D016207:Cytokines; C480543:N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide; D010880:Piperidines; D009243:NAD; D054409:Nicotinamide Phosphoribosyltransferase; C085455:nicotinamide phosphoribosyltransferase, human