Interactions of IDO and the Kynurenine Pathway with Cell Transduction Systems and Metabolism at the Inflammation–Cancer Interface

SIMPLE SUMMARY: There is clear evidence that inflammation can contribute to the development of cancers, but the underlying mechanisms are not fully understood. This review focuses on metabolites of the amino acid tryptophan, especially kynurenine and related compounds, which are produced in response to inflammation and which have been implicated in cancer progression. Unfortunately, one drug that inhibits the generation of these compounds, epacadostat, has not been very successful. The review explains the actions of each of the relevant tryptophan metabolites and discusses how they interact with other compounds and biochemical pathways known to affect cancer formation. The objective is to demonstrate that the kynurenine pathway could be targeted to affect those interacting pathways indirectly and that those alternative routes could represent a means of modifying tryptophan metabolism indirectly. In either case, the range of possible targets for drugs that inhibit the link between inflammation and cancer would be expanded. ABSTRACT: The mechanisms underlying a relationship between inflammation and cancer are unclear, but much emphasis has been placed on the role of tryptophan metabolism to kynurenine and downstream metabolites, as these make a substantial contribution to the regulation of immune tolerance and susceptibility to cancer. The proposed link is supported by the induction of tryptophan metabolism by indoleamine-2,3-dioxygenase (IDO) or tryptophan-2,3-dioxygenase (TDO), in response to injury, infection or stress. This review will summarize the kynurenine pathway and will then focus on the bi-directional interactions with other transduction pathways and cancer-related factors. The kynurenine pathway can interact with and modify activity in many other transduction systems, potentially generating an extended web of effects other than the direct effects of kynurenine and its metabolites. Conversely, the pharmacological targeting of those other systems could greatly enhance the efficacy of changes in the kynurenine pathway. Indeed, manipulating those interacting pathways could affect inflammatory status and tumor development indirectly via the kynurenine pathway, while pharmacological modulation of the kynurenine pathway could indirectly influence anti-cancer protection. While current efforts are progressing to account for the failure of selective IDO1 inhibitors to inhibit tumor growth and to devise means of circumventing the issue, it is clear that there are wider factors involving the relationship between kynurenines and cancer that merit detailed consideration as alternative drug targets.