The NAD biosynthesis inhibitor APO866 has potent antitumor activity against hematologic malignancies.

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Serval ID
serval:BIB_160C5D8712FE
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
The NAD biosynthesis inhibitor APO866 has potent antitumor activity against hematologic malignancies.
Journal
Blood
Author(s)
Nahimana A., Attinger A., Aubry D., Greaney P., Ireson C., Thougaard A.V., Tjørnelund J., Dawson K.M., Dupuis M., Duchosal M.A.
ISSN
1528-0020[electronic]
Publication state
Published
Issued date
2009
Volume
113
Number
14
Pages
3276-3286
Language
english
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.
Keywords
Acrylamides, Animals, Antineoplastic Agents, Cell Death, Cytokines, Dose-Response Relationship, Drug, HL-60 Cells, Hematologic Neoplasms, Humans, Jurkat Cells, K562 Cells, Mice, Mice, Inbred BALB C, Mice, Nude, NAD, Nicotinamide Phosphoribosyltransferase, Piperidines, Tumor Cells, Cultured, U937 Cells, Xenograft Model Antitumor Assays
Pubmed
Web of science
Open Access
Yes
Create date
29/05/2009 13:31
Last modification date
20/08/2019 12:45
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