The NAD biosynthesis inhibitor APO866 has potent antitumor activity against hematologic malignancies.
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.
Nahimana
Aimable
A
Service of Hematology, University Hospital of Lausanne, Lausanne, Switzerland.
Attinger
Antoine
A
Aubry
Dominique
D
Greaney
Peter
P
Ireson
Christopher
C
Thougaard
Annemette V
AV
Tjørnelund
Jette
J
Dawson
Keith M
KM
Dupuis
Marc
M
Duchosal
Michel A
MA
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
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