1. Intracellular NAD+ depletion enhances bortezomib-induced anti-myeloma activity.
- Author
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Cagnetta, Antonia, Cea, Michele, Calimeri, Teresa, Acharya, Chirag, Fulciniti, Mariateresa, Yu-Tzu Tai, Hideshima, Teru, Chauhan, Dharminder, Zhong, Mike Y., Patrone, Franco, Nencioni, Alessio, Gobbi, Marco, Richardson, Paul, Munshi, Nikhil, and Anderson, Kenneth C.
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NICOTINAMIDE , *MYELOMA proteins , *TUMOR proteins , *MULTIPLE myeloma , *CELL death , *XENOGRAFTS , *APOPTOSIS - 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. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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