Pharmacological Inhibition of Nicotinamide Phosphoribosyltransferase/Visfatin Enzymatic Activity Identifies a New Inflammatory Pathway Linked to NAD

Abstract

Nicotinamide phosphoribosyltransferase (NAMPT), also known as visfatin, is the rate-limiting enzyme in the salvage pathway of NAD biosynthesis from nicotinamide. Since its expression is upregulated during inflammation, NAMPT represents a novel clinical biomarker in acute lung injury, rheumatoid arthritis, and Crohn's disease. However, its role in disease progression remains unknown. We report here that NAMPT is a key player in inflammatory arthritis. Increased expression of NAMPT was confirmed in mice with collagen-induced arthritis, both in serum and in the arthritic paw. Importantly, a specific competitive inhibitor of NAMPT effectively reduced arthritis severity with comparable activity to etanercept, and decreased pro-inflammatory cytokine secretion in affected joints. Moreover, NAMPT inhibition reduced intracellular NAD concentration in inflammatory cells and circulating TNFα levels during endotoxemia in mice. In vitro pharmacological inhibition of NAMPT reduced the intracellular concentration of NAD and pro-inflammatory cytokine secretion by inflammatory cells. Thus, NAMPT links NAD metabolism to inflammatory cytokine secretion by leukocytes, and its inhibition might therefore have therapeutic efficacy in immune-mediated inflammatory disorders.

Suppression of leukocyte infiltration and cartilage degradation by selective inhibition of pre-B cell colony-enhancing factor/visfatin/nicotinamide phosphoribosyltransferase: Apo866-mediated therapy in human fibroblasts and murine collagen-induced arthrit

“…The results of the present study support previous findings (18), but, importantly, our findings also demonstrate the efficacy of APO866 in ameliorating disease severity by providing protection against further cartilage and bone destruction, as shown in an animal model of CIA in which the clinical score of arthritis was Ն5. Furthermore, as far as we are aware, this is the first report to describe the delivery of APO866 by continuous subcutaneous minipump in mice, and to identify the appropriate dosage of APO866 for achieving clinical efficacy in this model.…”

“…The regulation of inflammation by PBEF is further illustrated in experimental models of arthritis, in which disease induction leads to an increase in the synovial levels of PBEF (1,18). In this respect, PBEF is abundantly expressed by inflammatory leukocytes and synovial fibroblasts (6,18,31,42,43).…”

“…In this respect, PBEF is abundantly expressed by inflammatory leukocytes and synovial fibroblasts (6,18,31,42,43). Consequently, PBEF may contribute to the regulation of inflammation in joint disease.…”

“…The recently developed small molecule inhibitor APO866 has been shown to act as a competitive inhibitor of PBEF/NAMPT activity by inhibiting binding of its natural substrate, nicotinamide (14,15). Moreover, in vivo, APO866 displays antiinflammatory effects, and favorable results have been obtained with APO866 treatment in murine tumor models and models of inflammation (16)(17)(18)(19)(20)(21).…”

NAMPT overexpression in prostate cancer and its contribution to tumor cell survival and stress response

“…Chronic inflammation in the prostate gland, which produces reactive oxygen species, is an important etiological factor for prostate carcinogenesis (Nelson et al, 2003;De Marzo et al, 2007). Intriguingly, NAMPT is an inflammation-response gene, and its expression increases in multiple inflammatory tissues (Ognjanovic et al, 2001;Ye et al, 2005;Busso et al, 2008). That NAMPT expression is elevated early in prostate neoplasia suggests NAMPT may have a role in the etiology of prostate cancer.…”