Indoleamine-pyrrole 2,3-dioxygenase (IDO orINDOEC1.13.11.52) is a heme-containingenzyme physiologically expressed in a number oftissues andcells, such as thesmall intestine,lungs, female genital tract orplacenta.[5] In humans is encoded by theIDO1gene.[6] IDO is involved in tryptophanmetabolism. It is one of three enzymes that catalyze the first and rate-limiting step in thekynurenine pathway, the O2-dependent oxidation ofL-tryptophan toN-formylkynurenine, the others beingindolamine-2,3-dioxygenase 2 (IDO2)[7] andtryptophan 2,3-dioxygenase (TDO).[8] IDO is an important part of theimmune system and plays a part in natural defense against variouspathogens.[9][10] It is produced by the cells in response toinflammation and has animmunosuppressive function because of its ability to limitT-cell function and engage mechanisms ofimmune tolerance.[11] Emerging evidence suggests that IDO becomes activated during tumor development, helping malignant cells escape eradication by the immune system. Expression of IDO has been described in a number of types of cancer, such asacute myeloid leukemia, ovarian cancer orcolorectal cancer. IDO is part of the malignant transformation process and plays a key role in suppressing the anti-tumor immune response in the body, so inhibiting it could increase the effect ofchemotherapy as well as other immunotherapeutic protocols.[12][13][14] Furthermore, there is data implicating a role for IDO1 in the modulation ofvascular tone in conditions of inflammation via a novel pathway involvingsinglet oxygen.[15]
IDO is an important molecule in the mechanisms of tolerance and its physiological functions include the suppression of potentially dangerousinflammatory processes in the body.[16] IDO also plays a role in natural defense againstmicroorganisms. Expression of IDO is induced byinterferon-gamma, which explains why the expression increases during inflammatory diseases or even duringtumorigenesis.[17] Since tryptophan is essential for the survival of pathogens, the activity of enzyme IDO destroys them. Microorganisms susceptible to tryptophan deficiency include bacteria of genusStreptococcus[18] or viruses such asherpes simplex[19] ormeasles.[20]
One of the organs with high IDO expression is theplacenta. In the 1990s, the immunosuppressive function of thisenzyme was first described in mice due to the study of placental tryptophan metabolism. Thus, mammalian placenta, due to intensive tryptophan catabolism has the ability to suppress T cell activity, thereby contributing to its position ofimmunologically privileged tissue.[21]
These mechanisms are crucial in the process ofcarcinogenesis. IDO allows tumor cells to escape theimmune system by two main mechanisms. The first mechanism is based on tryptophan depletion from thetumor microenvironment.[23] The second mechanism is based on the production of catabolic products calledkynurenins, that are cytotoxic forT lymphocytes andNK cells.[24] Overexpression of human IDO (hIDO) is described in a variety of human tumor cell lineages and is often associated with poorprognosis.[25][26] Tumors with increased production of IDO includeprostate,ovarian,lung orpancreatic cancer oracute myeloid leukemia.[27][28] Expression of IDO is under physiological conditions regulated by theBin1 gene, which can be damaged by tumor transformation.[29]
Emerging clinical studies suggest that combination of IDO inhibitors with classicalchemotherapy andradiotherapy could restore immune control and provide a therapeutic response to generally resistant tumors. Enzyme IDO used by tumors to escape immune surveillance is currently in focus of research anddrug discovery efforts,[30] as well as efforts to understand if it could be used as abiomarker for prognosis.[31]
COX-2 inhibitors down-regulate indoleamine 2,3-dioxygenase, leading to a reduction inkynurenine levels as well as reducing proinflammatory cytokine activity.[citation needed]
1-Methyltryptophan is aracemic compound that weakly inhibits indoleamine dioxygenase, but is also a very slow substrate. The specific racemer 1-methyl-D-tryptophan (known asindoximod) is in clinical trials for various cancers.
Epacadostat (INCB24360),navoximod (GDC-0919), andlinrodostat (BMS-986205) are potent inhibitors of the indoleamine 2,3-dioxygenase enzyme and are in clinical trials for various cancers.
^Uyttenhove C, Pilotte L, Théate I, Stroobant V, Colau D, Parmentier N, et al. (October 2003). "Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase".Nature Medicine.9 (10):1269–1274.doi:10.1038/nm934.PMID14502282.S2CID10618102.
^Okamoto A, Nikaido T, Ochiai K, Takakura S, Takao M, Saito M, et al. (November 2007). "Ido serves as a marker of poor prognosis in gene expression profiles of serous ovarian cancer cells".International Congress Series.1304:262–273.doi:10.1016/j.ics.2007.07.053.ISSN0531-5131.
^Inaba T, Ino K, Kajiyama H, Shibata K, Yamamoto E, Kondo S, et al. (June 2010). "Indoleamine 2,3-dioxygenase expression predicts impaired survival of invasive cervical cancer patients treated with radical hysterectomy".Gynecologic Oncology.117 (3):423–428.doi:10.1016/j.ygyno.2010.02.028.ISSN0090-8258.PMID20350764.
^Uyttenhove C, Pilotte L, Théate I, Stroobant V, Colau D, Parmentier N, et al. (2003-09-21). "Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase".Nature Medicine.9 (10):1269–1274.doi:10.1038/nm934.ISSN1078-8956.PMID14502282.S2CID10618102.
^Jiang T, Sun Y, Yin Z, Feng S, Sun L, Li Z (February 2015). "Research progress of indoleamine 2,3-dioxygenase inhibitors".Future Medicinal Chemistry.7 (2):185–201.doi:10.4155/fmc.14.151.ISSN1756-8919.PMID25686005.
^Muller AJ, DuHadaway JB, Donover PS, Sutanto-Ward E, Prendergast GC (2005-02-13). "Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy".Nature Medicine.11 (3):312–319.doi:10.1038/nm1196.ISSN1078-8956.PMID15711557.S2CID12338548.
^Jiang T, Sun Y, Yin Z, Feng S, Sun L, Li Z (2015). "Research progress of indoleamine 2,3-dioxygenase inhibitors".Future Medicinal Chemistry.7 (2):185–201.doi:10.4155/fmc.14.151.PMID25686005.
