1-L-MT, an IDO inhibitor, prevented colitis-associated cancer by inducing CDC20 inhibition-mediated mitotic death of colon cancer cells.

Abstract

Indoleamine 2,3-dioxygenase 1 (IDO1), known as IDO, catabolizes tryptophan through kynurenine pathway, whose activity is correlated with impaired clinical outcome of colorectal cancer. Here we showed that 1-L-MT, a canonical IDO inhibitor, suppressed proliferation of human colorectal cancer cells through inducing mitotic death. Our results showed that inhibition of IDO decreased the transcription of CDC20, which resulted in G2/M cycle arrest of HCT-116 and HT-29. Furthermore, 1-L-MT induced mitochondria injuries and caused apoptotic cancer cells. Importantly, 1-L-MT protected mice from azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colon carcinogenesis, with reduced mortality, tumor number and size. What is more, IDO1-/- mice exhibited fewer tumor burdens and reduced proliferation in the neoplastic epithelium, while, 1-L-MT did not exhibit any further protective effects on IDO-/- mice, confirming the critical role of IDO and the protective effect of 1-L-MT-mediated IDO inhibition in CRC. Furthermore, 1-L-MT also alleviated CRC in Rag1-/- mice, demonstrating the modulatory effects of IDO independent of its role in modulating adaptive immunity. Taken together, our findings validated that the anti-proliferation effect of 1-L-MT in vitro and the prevention of CRC in vivo were through IDO-induced cell cycle disaster of colon cancer cells. Our results identified 1-L-MT as a promising candidate for the chemoprevention of CRC.

• Authors: Xiuting Liu, Wei Zhou, Xin Zhang, Yang Ding, Qianming Du, Rong Hu
• Journal: International journal of cancer (Int J Cancer) Vol. 143 Issue 6 Pg. 1516-1529 (09 15 2018) ISSN: 1097-0215 [Electronic] United States
• PMID: 29607498 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 UICC.

Chemical References

• 1-methyl-L-tryptophan
• Carcinogens
• Cdc20 Proteins
• Cdc20 protein, mouse
• Enzyme Inhibitors
• Homeodomain Proteins
• IDO1 protein, mouse
• Indoleamine-Pyrrole 2,3,-Dioxygenase
• RAG-1 protein
• Tryptophan
• Azoxymethane

Topics

• Animals
• Apoptosis
• Azoxymethane (toxicity)
• Carcinogens (toxicity)
• Cdc20 Proteins (antagonists & inhibitors, genetics, metabolism)
• Cell Cycle
• Cell Proliferation
• Colitis (chemically induced, complications)
• Colonic Neoplasms (enzymology, etiology, prevention & control)
• Enzyme Inhibitors (chemistry, pharmacology, therapeutic use)
• Homeodomain Proteins (physiology)
• Humans
• Indoleamine-Pyrrole 2,3,-Dioxygenase (antagonists & inhibitors, genetics, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mitosis
• Tryptophan (chemistry, pharmacology, therapeutic use)
• Tumor Cells, Cultured