Behavioural Effects of Using Sulfasalazine to Inhibit Glutamate Released by Cancer Cells: A Novel target for Cancer-Induced Depression

Abstract

Despite the lack of robust evidence of effectiveness, current treatment options for cancer-induced depression (CID) are limited to those developed for non-cancer related depression. Here, anhedonia-like and coping behaviours were assessed in female BALB/c mice inoculated with 4T1 mammary carcinoma cells. The behavioural effects of orally administered sulfasalazine (SSZ), a system xc− inhibitor, were compared with fluoxetine (FLX). FLX and SSZ prevented the development of anhedonia-like behaviour on the sucrose preference test (SPT) and passive coping behaviour on the forced swim test (FST). The SSZ metabolites 5-aminosalicylic acid (5-ASA) and sulfapyridine (SP) exerted an effect on the SPT but not on the FST. Although 5-ASA is a known anti-inflammatory agent, neither treatment with SSZ nor 5-ASA/SP prevented tumour-induced increases in serum levels of interleukin-1β (IL-1β) and IL-6, which are indicated in depressive disorders. Thus, the observed antidepressant-like effect of SSZ may primarily be attributable to the intact form of the drug, which inhibits system xc−. This study represents the first attempt at targeting cancer cells as a therapeutic strategy for CID, rather than targeting downstream effects of tumour burden on the central nervous system. In doing so, we have also begun to characterize the molecular pathways of CID.

Genetic deletion of xCT attenuates peripheral and central inflammation and mitigates LPS‐induced sickness and depressive‐like behavior in mice

“…Moreover, we showed attenuated LPSinduced increase in microglial cell number and morphological activation in xCT 2/2 mice 1 week p.i. In line with our results, pharmacological inhibition of system x 2 c with sulfasalazine, an anti-inflammatory drug, has been recently proposed as novel strategy against cancerinduced depression (Nashed et al, 2017). In contrast, we recently reported that system x 2 c deficiency does not affect depressionassociated behavior in the corticosterone mouse model (Demuyser et al, 2017).…”

“…In line with our results, pharmacological inhibition of system x 2 c with sulfasalazine, an anti-inflammatory drug, has been recently proposed as novel strategy against cancerinduced depression (Nashed et al, 2017). After establishing that the acute response to LPS is different between xCT 1/1 and xCT 2/2 mice, we investigated the effect of absence of system x 2 c on LPS-induced inflammation and depressivelike behavior 1 week p.i., when both xCT 1/1 and xCT 2/2 mice were recovered from LPS-induced hypothermia and did not show any motor impairment in the open field test.…”

Cystine/Glutamate Antiporter (xCT) Is Required for Chief Cell Plasticity After Gastric Injury

“…To validate further that our observations were owing to specific xCT blockade by sulfasalazine and not the anti-inflammatory properties of sulfasalazine metabolites, we treated mice with sulfapyridine or mesalazine 2 days before and throughout 3 days of L635 treatment (Figure 14 A ) 36 . Immunostaining for CD44v9, mucus granule marker GSII lectin, and zymogenic granule marker GIF showed similar high numbers of triple-positive cells in both sulfapyridine + L635–treated mice and mesalazine + L635–treated mice (Figure 14 B and C ).…”

Metabolite Transporters as Regulators of Immunity

“…Sulfasalazine blocks the cystine–glutamate exchange transporter XCT that has also been found to be overexpressed in tumor cells [ 137 ]. Sulfasalazine is currently being tested in various tumor models, showing promising results in enhancing tumor clearance in prostate cancer [ 138 , 139 ]. Combined blockage of metabolite transporters in tumor cells may thus offer a new strategy for cancer therapy.…”