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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 (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 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 Related Articles in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted August 11, 2008 Accepted January 21, 2009 The NAD biosynthesis inhibitor APO866 has potent antitumor activity against hematological malignancies Aimable Nahimana, Antoine Attinger, Dominique Aubry, Peter Greaney, Christopher Ireson, Annemette V. Thougaard, Jette Tjornelund, Keith M. Dawson, Marc Dupuis, and Michel A. Duchosal* Service of Hematology, University Hospital of Lausanne, Lausanne, Switzerland TopoTarget Switzerland, S.A., Lausanne, Switzerland TopoTarget Denmark, S.A., Copenhagen, Denmark * Corresponding author; email: michel.duchosal{at}chuv.ch. APO866 inhibits nicotinamide phosphoribosyltransferase (NMPRTase), a key enzyme involved in 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 hematological cancer cells to APO866 using a panel of cell lines (n=45) and primary cells (n=32). Most cancer cells (AML, ALL, MCL, 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 ATP at 24 h and 48-72 h respectively. The NAD depletion led to cell death. At 96 h, 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 acute myeloid leukemia, lymphoblastic lymphoma and leukemia without significant toxicity to the animals. The results support the potential of APO866 for treating hematological 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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