Inflammation-induced activation of the indoleamine 2,3-dioxygenase pathway: Relevance to cancer-related fatigue

Abstract

This review examines the increasing data that implicate the indoleamine 2,3-dioxygenase pathway in the etiology of cancer-related fatigue, and it explores potential translational implications for novel treatments for cancer-related fatigue. Cancer-related fatigue (CRF) is a common complication of cancer and its treatment that can significantly impair quality of life. Although the specific mechanisms remain poorly understood, inflammation is now considered to be a distinct component of CRF in addition to effects of depression, anxiety, insomnia, and other factors. One key biological pathway that may link inflammation and CRF is indoleamine 2,3-dioxygenase (IDO). Induced by inflammatory stimuli, IDO catabolizes tryptophan to kynurenine (KYN), which is subsequently converted into neuroactive metabolites. Here we summarize current knowledge concerning the relevance of the IDO pathway to CRF, including activation of the IDO pathway in cancer patients and, as a consequence, accumulation of neurotoxic KYN metabolites and depletion of serotonin in the brain. Because IDO inhibitors are already being evaluated as therapeutic agents in cancer, the elucidation of the relationship between IDO activation and CRF in cancer patients may lead to novel diagnostic and clinical approaches to managing CRF and its debilitating consequences. Cancer 2015;121:2129-2136.