Targeting Glutamate in Prostate Cancer-Induced Depression

Abstract

Affecting one in every eight Canadian men, prostate cancer is the most common type of cancer among males. As with other forms of cancer, men with prostate cancer are much more likely to develop comorbid depression than the general population without cancer diagnoses. Depression negatively affects these men’s quality of life and increases mortality rates among cancer patients. Therefore, effective therapies to manage depression in this unique subpopulation are needed. This project sets out to assess the efficacy of glutamate-targeting drugs as antidepressants. The major excitatory neurotransmitter in the central nervous system, glutamate is released in excessive quantities by cancer cells. It is thought that this abundance of glutamate leads to excitotoxicity and neurodegeneration, affecting neurons in important regions of the brain relating to mood and mood regulation. A validated mouse model of depression was established using RM1 murine prostate cancer cells. This model was then used to test the properties of three drugs: sulfasalazine (SSZ), (S)-4-carboxyphenylglycine ((S)-4-CPG), and 2,3-dioxo-6-nitro-1,2,3,4-tetrahydro-benzo[f]quinoxaline-7-sulfonamide (NBQX). Results show that these drugs were able to improve depressive-like behaviours and symptoms to varying degrees, at least partially reversing the negative effects of tumours. This project showed that disrupting glutamate release and/or signaling could be an effective approach for an antidepressant therapy or adjuvant in prostate cancer patients.