A combination of the metabolic enzyme inhibitor APO866 and the immune adjuvant L-1-methyl tryptophan induces additive antitumor activity.
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.
Yang
Huei-Jiun
HJ
Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, No. 1 University Rd., Tainan City, Tainan, Taiwan, R.O.C.
Yen
Meng-Chi
MC
Lin
Chi-Chen
CC
Lin
Chiu-Mei
CM
Chen
Yi-Ling
YL
Weng
Tzu-Yang
TY
Huang
Tzu-Ting
TT
Wu
Chao-Liang
CL
Lai
Ming-Derg
MD
D000178:Acrylamides / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy; D051379:Mice; D008809:Mice, Inbred C3H; D008813:Mice, Inbred ICR; D016688:Mice, Inbred NOD; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000201:enzymology; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D014364:Tryptophan / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy
D000178:Acrylamides; D000970:Antineoplastic Agents; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; C480543:N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide; D010880:Piperidines; D014364:Tryptophan; D054409:Nicotinamide Phosphoribosyltransferase; C525396:1-methyltryptophan