A combination of the metabolic enzyme inhibitor APO866 and the immune adjuvant L-1-methyl tryptophan induces additive antitumor activity

Huei Jiun Yang, Meng Chi Yen, Chi Chen Lin, Chiu Mei Lin, Yi Ling Chen, Tzu Yang Weng, Tzu Ting Huang, Chao-Liang Wu, Ming-Derg Lai

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)869-876
Number of pages8
JournalExperimental Biology and Medicine
Volume235
Issue number7
DOIs
Publication statusPublished - 2010 Jul 1

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Indoleamine-Pyrrole 2,3,-Dioxygenase
Enzyme Inhibitors
Tumors
NAD
Therapeutic Uses
Neoplasms
Dendritic Cells
Immune Tolerance
Niacinamide
Bearings (structural)
Growth
Transferases
Tumor Burden
Urinary Bladder Neoplasms
T-cells
Stomach
Lymph Nodes
N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide
tryptophan methyl ester
T-Lymphocytes

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Yang, Huei Jiun ; Yen, Meng Chi ; Lin, Chi Chen ; Lin, Chiu Mei ; Chen, Yi Ling ; Weng, Tzu Yang ; Huang, Tzu Ting ; Wu, Chao-Liang ; Lai, Ming-Derg. / A combination of the metabolic enzyme inhibitor APO866 and the immune adjuvant L-1-methyl tryptophan induces additive antitumor activity. In: Experimental Biology and Medicine. 2010 ; Vol. 235, No. 7. pp. 869-876.
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A combination of the metabolic enzyme inhibitor APO866 and the immune adjuvant L-1-methyl tryptophan induces additive antitumor activity. / Yang, Huei Jiun; Yen, Meng Chi; Lin, Chi Chen; Lin, Chiu Mei; Chen, Yi Ling; Weng, Tzu Yang; Huang, Tzu Ting; Wu, Chao-Liang; Lai, Ming-Derg.

In: Experimental Biology and Medicine, Vol. 235, No. 7, 01.07.2010, p. 869-876.

Research output: Contribution to journalArticle

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