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Blood, 2 April 2009, Vol. 113, No. 14, pp. 3276-3286. Prepublished online as a Blood First Edition Paper on February 5, 2009; DOI 10.1182/blood-2008-08-173369. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2008-08-173369v1 113/14/3276    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Nahimana, A. Articles by Duchosal, M. A. Search for Related Content PubMed PubMed Citation Articles by Nahimana, A. Articles by Duchosal, M. A. Related Collections Myeloid Neoplasia Lymphoid Neoplasia Related Articles in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  LYMPHOID NEOPLASIA The NAD biosynthesis inhibitor APO866 has potent antitumor activity against hematologic malignancies Aimable Nahimana1, Antoine Attinger2, Dominique Aubry1, Peter Greaney2, Christopher Ireson2, Annemette V. Thougaard3, Jette Tjørnelund3, Keith M. Dawson2, Marc Dupuis2, and Michel A. Duchosal1 1 Service of Hematology, University Hospital of Lausanne, Lausanne, Switzerland; 2 TopoTarget Switzerland, Lausanne, Switzerland; and 3 TopoTarget Denmark, Copenhagen, Denmark 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Articles in Blood Online: APO866 activity in hematologic malignancies: a preclinical in vitro study Michele Cea, Gabriele Zoppoli, Santina Bruzzone, Floriana Fruscione, Eva Moran, Anna Garuti, Ilaria Rocco, Gabriella Cirmena, Salvatore Casciaro, Francesca Olcese, Ivana Pierri, Antonia Cagnetta, Fabio Ferrando, Riccardo Ghio, Marco Gobbi, Alberto Ballestrero, Franco Patrone, and Alessio Nencioni Blood 2009 113: 6035-6037. [Full Text] [PDF] Response: NAD targeting efficiently kills hematologic cancer cells Aimable Nahimana, Dominique Aubry, Steven Butcher, and Michel A. Duchosal Blood 2009 113: 6037-6038. [Full Text] [PDF] This article has been cited by other articles: M. Cea, G. Zoppoli, S. Bruzzone, F. Fruscione, E. Moran, A. Garuti, I. Rocco, G. Cirmena, S. Casciaro, F. Olcese, et al. APO866 activity in hematologic malignancies: a preclinical in vitro study Blood, June 4, 2009; 113(23): 6035 - 6037. [Full Text] [PDF] A. Nahimana, D. Aubry, S. Butcher, and M. A. Duchosal Response: NAD targeting efficiently kills hematologic cancer cells Blood, June 4, 2009; 113(23): 6037 - 6038. [Full Text] [PDF]

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