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The Nampt (nicotinamide phosphoribosyltransferase) inhibitor APO866 depletes intracellular NAD(+) and shows promising anticancer activity in preclinical studies. TNF-Related Apoptosis Inducing Ligand (TRAIL) binds to plasma membrane receptors DR4 and DR5 and induces apoptosis via caspase-8 and -10. Here, we have explored the interaction between APO866 and TRAIL in leukemia cell lines and in primary B-CLL cells.
Cells were treated with APO866, TRAIL, or their combination. Viability and mitochondrial transmembrane potential (DeltaPsi(m)) were determined by cell staining with propidium iodide and TMRE, respectively, and flow cytometry. Nampt and gamma-tubulin levels, as well as caspase-3 cleavage were detected by immunoblotting. DR4 and DR5 expression were assessed by immunostaining and flow cytometry. Caspases were inhibited with zVAD-fmk and zDEVD-fmk; autophagy with 3-MA, LY294002, and wortmannin. Intracellular NAD(+) and ATP were measured by cycling assays and HPLC, respectively.
APO866 induced NAD(+) depletion, DeltaPsi(m) dissipation, and ATP shortage in leukemia cells, thereby leading to autophagic cell death. TRAIL induced caspase-dependent apoptosis. TRAIL addition to APO866 synergistically increased its activity in leukemia cells by enhancing NAD(+) depletion, DeltaPsi(m) dissipation, and ATP shortage. No DR5 upregulation at the cell surface in response to APO866 was observed. Remarkably, in healthy leukocytes APO866 and TRAIL were poorly active and failed to show any cooperation.
Activation of the extrinsic apoptotic cascade with TRAIL selectively amplifies the sequelae of Nampt inhibition in leukemia cells, and appears as a promising strategy to enhance APO866 activity in hematological malignancies.
Department of Internal Medicine (DIMI), University of Genoa, 16132 Genoa, Italy; Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
This article was published in the following journal.
Name: Experimental hematology
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An inhibitor of apoptosis protein that is translated by a rare cap-independent mechanism. It blocks caspase-mediated cellular destruction by inhibiting CASPASE 3; CASPASE 7; and CASPASE 9.
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An inhibitor of apoptosis protein that was initially identified during analysis of CHROMOSOME DELETIONS associated with SPINAL MUSCULAR ATROPHY. Naip contains a nucleotide binding oligomerization domain and a carboxy-terminal LEUCINE rich repeat.
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