Journal
BLOOD
Volume 120, Issue 17, Pages 3519-3529Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2012-03-416776
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Funding
- National Institutes of Health [RO-1 50947, RO-1 73878]
- DF/HCC SPORE in Multiple Myeloma [P-50100707]
- American Italian Cancer Foundation
- International Multiple Myeloma Foundation
- Associazione Cristina Bassi
- Associazione Italiana per la Ricerca sul Cancro [START-UP P-6108]
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Malignant cells have a higher nicotinamide adenine dinucleotide (NAD(+)) turnover rate than normal cells, making this biosynthetic pathway an attractive target for cancer treatment. Here we investigated the biologic role of a rate-limiting enzyme involved in NAD(+) synthesis, Nampt, in multiple myeloma (MM). Nampt-specific chemical inhibitor FK866 triggered cytotoxicity in MM cell lines and patient MM cells, but not normal donor as well as MM patients PBMCs. Importantly, FK866 in a dose-dependent fashion triggered cytotoxicity in MM cells resistant to conventional and novel anti-MM therapies and overcomes the protective effects of cytokines (IL-6, IGF-1) and bone marrow stromal cells. Nampt knockdown by RNAi confirmed its pivotal role in maintenance of both MM cell viability and intracellular NAD(+) stores. Interestingly, cytotoxicity of FK866 triggered autophagy, but not apoptosis. A transcriptional-dependent (TFEB) and independent (PI3K/mTORC1) activation of autophagy mediated FK866 MM cytotoxicity. Finally, FK866 demonstrated significant anti-MM activity in a xenograft-murine MM model, associated with down-regulation of ERK1/2 phosphorylation and proteolytic cleavage of LC3 in tumor cells. Our data therefore define a key role of Nampt in MM biology, providing the basis for a novel targeted therapeutic approach. (Blood. 2012;120(17):3519-3529)
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