Abstract
We recently demonstrated that Nicotinamide phosphoribosyltransferase (Nampt) inhibition depletes intracellular NAD⁺ content leading, to autophagic multiple myeloma (MM) cell death. Bortezomib has remarkably improved MM patient outcome, but dose-limiting toxicities and development of resistance limit its long-term utility. Here we observed higher Nampt messenger RNA levels in bortezomib-resistant patient MM cells, which correlated with decreased overall survival. We demonstrated that combining the NAD⁺ depleting agent FK866 with bortezomib induces synergistic anti-MM cell death and overcomes bortezomib resistance. This effect is associated with (1) activation of caspase-8, caspase-9, caspase-3, poly (ADP-ribose) polymerase, and downregulation of Mcl-1; (2) enhanced intracellular NAD⁺ depletion; (3) inhibition of chymotrypsin-like, caspase-like, and trypsin-like proteasome activities; (4) inhibition of nuclear factor κB signaling; and (5) inhibition of angiogenesis. Furthermore, Nampt knockdown significantly enhances the anti-MM effect of bortezomib, which can be rescued by ectopically overexpressing Nampt. In a murine xenograft MM model, low-dose combination FK866 and Bortezomib is well tolerated, significantly inhibits tumor growth, and prolongs host survival. Taken together, these findings indicate that intracellular NAD⁺ level represents a major determinant in the ability of bortezomib to induce apoptosis in MM cells and provide proof of concept for the combination with FK866 as a new strategy to enhance sensitivity or overcome resistance to bortezomib.
Publication types
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Comparative Study
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Acrylamides / pharmacology
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Animals
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Antineoplastic Agents / pharmacology*
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Antineoplastic Combined Chemotherapy Protocols
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Apoptosis / drug effects
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Autophagy / drug effects
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Biomarkers, Tumor / genetics
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Biomarkers, Tumor / metabolism
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Blotting, Western
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Boronic Acids / pharmacology*
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Bortezomib
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Case-Control Studies
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Caspases / genetics
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Caspases / metabolism
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Cell Proliferation / drug effects
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Drug Synergism
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Female
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Fluorescent Antibody Technique
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Gene Expression Profiling
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Humans
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Male
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Mice
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Mice, SCID
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Multiple Myeloma / drug therapy*
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Multiple Myeloma / metabolism
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Multiple Myeloma / mortality
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NAD / metabolism*
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NF-kappa B / genetics
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NF-kappa B / metabolism
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Neoplasm Recurrence, Local / drug therapy*
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Neoplasm Recurrence, Local / metabolism
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Neoplasm Recurrence, Local / mortality
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Nicotinamide Phosphoribosyltransferase / antagonists & inhibitors
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Nicotinamide Phosphoribosyltransferase / genetics
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Nicotinamide Phosphoribosyltransferase / metabolism*
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Oligonucleotide Array Sequence Analysis
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Piperidines / pharmacology
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Poly(ADP-ribose) Polymerases / genetics
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Poly(ADP-ribose) Polymerases / metabolism
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Prognosis
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Pyrazines / pharmacology*
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RNA, Messenger / genetics
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Real-Time Polymerase Chain Reaction
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Reverse Transcriptase Polymerase Chain Reaction
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Survival Rate
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Tumor Cells, Cultured
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Xenograft Model Antitumor Assays
Substances
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Acrylamides
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Antineoplastic Agents
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Biomarkers, Tumor
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Boronic Acids
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N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide
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NF-kappa B
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Piperidines
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Pyrazines
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RNA, Messenger
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NAD
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Bortezomib
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Nicotinamide Phosphoribosyltransferase
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Poly(ADP-ribose) Polymerases
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Caspases