fk-866 and Colonic-Neoplasms

Nicotinamide phosphoribosyltransferase (NAMPT, also referred to as pre-B cell colony-enhancing factor or visfatin) is critically required for the maintenance of cellular nicotinamide adenine dinucleotide (NAD) supply catalysing the rate-limiting step of the NAD. We investigated the impact of NAMPT inhibition by the small-molecule inhibitor FK866 in the dextran sulfate sodium (DSS) model of colitis and the azoxymethane/DSS model of colitis-associated cancer. The impact of NAD depletion on differentiation of mouse and human primary monocytes/macrophages was studied in vitro. Finally, we tested the efficacy of FK866 compared with dexamethasone and infliximab in lamina propria mononuclear cells (LPMNC) isolated from patients with IBD.. Our data emphasise the importance of NAD immunometabolism for mucosal immunity and highlight FK866-mediated NAMPT blockade as a promising therapeutic approach in acute intestinal inflammation.

Topics: Acrylamides; Animals; Cell Differentiation; Colitis, Ulcerative; Colonic Neoplasms; Dexamethasone; Energy Metabolism; Gastrointestinal Agents; Humans; Infliximab; Intestinal Mucosa; Macrophages; Mice; Monocytes; NAD; Nicotinamide Phosphoribosyltransferase; Piperidines

Many types of malignant cells have a higher nicotinamide adenine dinucleotide (NAD) turnover rate than normal cells, as well as the ability to escape immune responses. Indoleamine 2,3-dioxygenase (IDO) is reported to be a negative immune regulator. Overexpression of IDO in dendritic cells is observed in tumor-draining lymph nodes. IDO-expressing dendritic cells suppress T-cell activation and promote immune tolerance. The nicotinamide phosphoribosyl transferase (NAMPT) inhibitor APO866 (also called FK866 or WK175) selectively inhibits tumor growth through intracellular NAD depletion. The IDO-specific inhibitor L-1-methyl-tryptophan (L-1MT) activates immune responses and reduces tumor volume in murine tumor models. We combined L-1MT and APO866 treatments and tested their antitumor effects in the murine gastric and bladder tumor models. In immune-competent mice, a combination of APO866 and L-1MT had a better therapeutic effect than did either L-1MT or APO866 alone. The intracellular level of NAD was suppressed by APO866 but not L-1MT. However, an additive inhibitory effect on tumor growth was not observed in tumor-bearing immune-deficient mice. The new strategy of combining a metabolic inhibitor and an immune adjuvant induced a potent therapeutic effect.

Topics: Acrylamides; Animals; Antineoplastic Agents; Cell Line, Tumor; Colonic Neoplasms; Drug Synergism; Drug Therapy, Combination; Female; Indoleamine-Pyrrole 2,3,-Dioxygenase; Liver Neoplasms, Experimental; Mice; Mice, Inbred C3H; Mice, Inbred ICR; Mice, Inbred NOD; Neoplasms, Experimental; Nicotinamide Phosphoribosyltransferase; Piperidines; Tryptophan; Urinary Bladder Neoplasms