Intracellular NAD+ depletion enhances bortezomib-induced anti-myeloma activity.

Antonia Cagnetta, Michele Cea, Teresa Calimeri, Chirag Acharya, Mariateresa Fulciniti, Yu Tzu Tai, Teru Hideshima, Dharminder Chauhan, Mike Y. Zhong, Franco Patrone, Alessio Nencioni, Marco Gobbi, Paul Richardson, Nikhil Munshi, Kenneth C. Anderson

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1243-1255
Number of pages13
JournalBlood
Volume122
Issue number7
DOIs
Publication statusPublished - Aug 15 2013

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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    Cagnetta, A., Cea, M., Calimeri, T., Acharya, C., Fulciniti, M., Tai, Y. T., Hideshima, T., Chauhan, D., Zhong, M. Y., Patrone, F., Nencioni, A., Gobbi, M., Richardson, P., Munshi, N., & Anderson, K. C. (2013). Intracellular NAD+ depletion enhances bortezomib-induced anti-myeloma activity. Blood, 122(7), 1243-1255. https://doi.org/10.1182/blood-2013-02-483511