The DOI matches its Crossref record; 28 of the 31 references it cites were found in a registry or an index.
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.
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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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Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression
Le, A., Cooper, C. R., Gouw, A. M., Dinavahi, R., Maitra, A., Deck, L. M., Royer, R. E., Jagt, D. L. V., Semenza, G. L., & Dang, C. V. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0914433107 · Cited by 1,528
Targeting Metabolism for Cancer Therapy
Luengo, A., Gui, D. Y., & Vander Heiden, M. G. (2017) · Cell Chemical Biology · doi:10.1016/j.chembiol.2017.08.028 · Cited by 971
Camacho-Pereira, J., Tarragó, M. G., Chini, C. C. S., Nin, V., Escande, C., Warner, G. M., Puranik, A. S., Schoon, R. A., Reid, J. M., Galina, A., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.05.006 · Cited by 901
Physiological and pathophysiological roles of NAMPT and NAD metabolism.
Garten, A., Schuster, S., Penke, M., Gorski, T., de Giorgis, T., & Kiess, W. (2015) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2015.117 · Cited by 708
The emerging link between cancer, metabolism, and circadian rhythms
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Metadata
- 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
- 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
- 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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