Suppression of Kynurenine 3-Monooxygenase as a Treatment for Triple-negative Breast Carcinoma

Abstract

Kynurenine 3-monooxygenase (KMO), a key enzyme within the kynurenine (KYN) pathway of tryptophan (TRY) metabolism, enables the excess production of toxic metabolites (such as 3-hydroxykynurenine, xanthurenic acid, 3-hydroxyanthranilic acid and quinolinic acid), and modulates the balance between these toxic molecules and the protective metabolite, kynurenic acid (KYNA). Despite its importance, KMO suppression as a treatment for cancer has not been fully explored. Instead, researchers have focused on prevention of KYN pathway activity by inhibition of enzymes indoleamine 2,3-dioxygenase (IDO1 and IDO2) or tryptophan 2,3-dioxygenase (TDO, also known as TDO2). However, studies using IDO/TDO inhibitors against cancer have not yet shown that this type of treatment can be successful. We argue that KMO suppression can be an effective strategy for treatment of cancer by 1) decreasing toxic metabolites within the KYN pathway and 2) increasing levels of KYNA, which has important protective and anticancer properties. This strategy may be beneficial in the treatment of aggressive breast cancer, particularly in patients with triple-negative breast cancer. A major challenge to this strategy, when searching for an effective treatment for tumors, especially tumors like breast carcinoma that often metastasize to the brain, is finding KMO inhibitors that adequately cross the blood-brain barrier.

Keywords: IDO/TDO; KMO inhibitors; Kynurenines; breast cancer; cytokines; kynurenic acid; review; tryptophan.