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

Nahimana, Aimable; Attinger, Antoine; Aubry, Dominique; Greaney, Peter; Ireson, Christopher; Thougaard, Annemette V.; Tjørnelund, Jette; Dawson, Keith M.; Dupuis, Marc; Duchosal, Michel A.

doi:10.1182/blood-2008-08-173369

Cited by 196Sirtuins and Resveratrol in MedicineBiochemical and Molecular ResearchPARP inhibition in cancer therapy

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

Nahimana, Aimable, Attinger, Antoine, Aubry, Dominique, Greaney, Peter, Ireson, Christopher, Thougaard, Annemette V., Tjørnelund, Jette, Dawson, Keith M. +2 more·2009·Blood

DOI 10.1182/blood-2008-08-173369

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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.

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“Small-molecules targeting NAMPT can be effective anti-tumor agents in vitro and in xenograft cancer models (Nahimana et al., 2009; Tan et al., 2015b; Watson et al., 2009).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Nahimana et al., 2009

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Response: NAD targeting efficiently kills hematologic cancer cells
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Antitumor efficacy of APO866 against Myla-2059, a model of cutaneous t-cell lymphoma
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Self-citation

Authors: Nahimana, A., Attinger, A., Aubry, D., Greaney, P., Ireson, C., Thougaard, A. V., Tjørnelund, J., Dawson, K. M., Dupuis, M., & Duchosal, M. A.
Affiliations: Centre Hospitalier Universitaire Vaudois (CH)
TopoTarget Switzerland, Lausanne, Switzerland; and
TopoTarget Denmark, Copenhagen, Denmark
ORCID: Nahimana, Aimable
Thougaard, Annemette V.
Dawson, Keith M.
Dupuis, Marc
Duchosal, Michel A.
Venue: Blood
Publisher: American Society of Hematology
Published: 2009-04-02
Volume: 113
Issue: 14
Pages: 3276-3286
ISSN: 0006-4971 (ISSN-L)
1528-0020
DOI: 10.1182/blood-2008-08-173369
OpenAlex: W2072944938
Cited by: 190
References: 31
Citations by year: 2026: 6 · 2025: 4 · 2024: 10 · 2023: 10 · 2022: 5 · 2021: 8 · 2020: 10 · 2019: 14 · 2018: 13 · 2017: 9 · 2016: 15 · 2015: 21 · 2014: 11 · 2013: 18 · 2012: 9
FWCI: 8.30
Type: journal article
Language: en
Open access: closed
Locations: Blood (publishedVersion)
PubMed (publishedVersion)
IRIS (submittedVersion)
SERVAL (Université de Lausanne) (submittedVersion)
Topics: Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
Keywords: NAD biosynthesis, hematologic malignancies, acute myeloid leukemia, acute lymphoblastic leukemia, mantle cell lymphoma, chronic lymphocytic leukemia, T-cell lymphoma, NAD+ depletion, caspase-independent cell death, mitochondrial dysfunction, autophagy, anticancer activity
MeSH terms: Acrylamides, Animals, Antineoplastic Agents, Dose-Response Relationship, Drug, Humans, Mice, Inbred BALB C, Mice, Nude, NAD, Piperidines, Tumor Cells, Cultured, Cytokines, Cell Death, HL-60 Cells, Jurkat Cells, Hematologic Neoplasms, K562 Cells, U937 Cells, Xenograft Model Antitumor Assays, Mice, Nicotinamide Phosphoribosyltransferase

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

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