Kynurenines as a Novel Target for the Treatment of Malignancies

Abstract

Malignancies are unquestionably a significant public health problem. Their effective treatment is still a big challenge for modern medicine. Tumors have developed a wide range of mechanisms to evade an immune and therapeutic response. As a result, there is an unmet clinical need for research on solutions aimed at overcoming this problem. An accumulation of tryptophan metabolites belonging to the kynurenine pathway can enhance neoplastic progression because it causes the suppression of immune system response against cancer cells. They are also involved in the development of the mechanisms responsible for the resistance to antitumor therapy. Kynurenine belongs to the most potent immunosuppressive metabolites of this pathway and has a significant impact on the development of malignancies. This fact prompted researchers to assess whether targeting the enzymes responsible for its synthesis could be an effective therapeutic strategy for various cancers. To date, numerous studies, both preclinical and clinical, have been conducted on this topic, especially regarding the inhibition of indoleamine 2,3-dioxygenase activity and their results can be considered noteworthy. This review gathers and systematizes the knowledge about the role of the kynurenine pathway in neoplastic progression and the findings regarding the usefulness of modulating its activity in anticancer therapy.

Keywords: cancer; cancer treatment; enzyme inhibitors; immune escape; indoleamine 2,3-dioxygenase; kynurenine; kynurenine pathway; tryptophan; tryptophan 2,3-dioxygenase.

Figure 1

The course of the kynurenine pathway in neoplastic cells. The kynurenine pathway enzymes are in italics, while those involved in carcinogenesis are marked in red. AMO: aminocarboxymuconatesemialdehyde decarboxylase, IDO: indoleamine 2,3-dioxygenase, KAT: kynurenine aminotransferase, KMO: kynurenine 3-monooxygenase, KYN: kynurenine, KYNU: kynureninase, TDO: tryptophan 2,3-dioxygenase.

Figure 2

Upstream regulators of 2,3-dioxygenases activity and downstream effectors of kynurenine involved in neoplastic progression. IL-1, IL-6, TNF-α and IFN-γ stimulates IDO leading to enhanced synthesis of kynurenine. Its main effectors are presented in the circles. AhR: aryl hydrocarbon receptor, IDO: indoleamine 2,3-dioxygenase, IFN-γ: interferon-γ, IL-1: interleukin 1, IL-6: interleukin 6, KYN: kynurenine, STAT3: signal transducer and activator of transcription 3, TDO: tryptophan 2,3-dioxygenase, TNF-α: tumor necrosis factor-α, TRP: tryptophan.

Figure 3

Effects of inhibition of 2,3-dioxygenases activity in selected types of cancers. APC: antigen presenting cells, CD8+ T cells: cytotoxic T cells IDO: indoleamine 2,3-dioxygenase, KYN: kynurenine, MDSCs: myeloid-derived suppressor cells, NK: natural killer cells, PBMCs: peripheral blood mononuclear cells, PD-L1: programmed cell death protein-1 ligand, ROS: reactive oxygen species, TDO: tryptophan 2,3-dioxygenase, Th: Helper T cells, TRP: tryptophan, Tregs: T regulatory cell.