Oral administration of cystine and theanine attenuates 5-fluorouracil-induced intestinal mucositis and diarrhea by suppressing both glutathione level decrease and ROS production in the small intestine of mucositis mouse model

Abstract

Background Chemotherapy is frequently used in cancer treatment; however, it may cause adverse events, which must be managed. Reactive oxygen species (ROS) have been reported to be involved in the induction of intestinal mucositis and diarrhea, which are common side effects of treatment with fluoropyrimidine 5-fluorouracil (5-FU). Our previous studies have shown that oral administration of cystine and theanine (CT) increases glutathione (GSH) production in vivo. In the present study, we hypothesized that CT might inhibit oxidative stress, including the overproduction of ROS, and attenuate 5-FU-induced mucositis and diarrhea. Methods We investigated the inhibitory effect of CT administration on mucositis and diarrhea, as well as its mechanism, using a mouse model of 5-FU-induced intestinal mucositis. Results CT administration suppressed 5-FU-induced diarrhea and weight loss in the studied mice. After 5-FU administration, the GSH level and the GSH/GSSG ratio in the small intestine mucosal tissue decreased compared to normal control group; but CT administration improved the GSH/GSSG ratio to normal control levels. 5-FU induced ROS production in the basal region of the crypt of the small intestine mucosal tissue, which was inhibited by CT. CT did not affect the antitumor effect of 5-FU. Conclusions CT administration suppressed intestinal mucositis and diarrhea in a mouse model. This finding might be associated with the antioxidant characteristics of CT, including the improved rate of GSH redox and the reduced rate of ROS production in the small intestine mucosal tissue. CT might be a suitable candidate for the treatment of gastrointestinal mucositis associated with chemotherapy.

Network pharmacology and experimental verification-based strategy to explore the underlying mechanism of Liu Jun An Wei formula in the treatment of gastrointestinal reactions caused by chemotherapy for colorectal cancer

“…These pathways have been proved to be closely related to the occurrence and development of intestinal injury caused by chemotherapy. Chemotherapy agents such as 5-FU may damage intestinal mucosa by increasing intestinal permeability, promoting the release of inflammatory cytokines, strengthening the oxidative stress response, and accelerating the intestinal epithelial cell apoptosis, thus causing GR ( de Barros et al, 2018 ; Zhang et al, 2018 ; Yoneda et al, 2021 ). Li et al ( Zeng et al, 2020 ) reported that 5-FU might significantly increase the expression levels of apoptosis-related genes such as PUMA and Bax.…”

Therapeutic effects and mechanisms of plant-derived natural compounds against intestinal mucositis

“…Frontiers in Pharmacology frontiersin.org (Boeing et al, 2020). The content of antioxidases decreases or cannot remove superfluous ROS, resulting in elevated oxidative stress and cell injury (Yoneda et al, 2021). Moreover, convincing evidence have demonstrated that elevated expressions of inflammatory factors were strongly related to the destruction of enteric mucosa barrier (Tappenden, 2008).…”

“…Excessive production of ROS and uncontrolled inflammatory symptoms could disturb enteric homeostasis, change the normal microflora and stimulate a sequence of acute reactions to injure cells and tissues, resulting in mucosa damage and mucositis ( Boeing et al, 2020 ). The content of antioxidases decreases or cannot remove superfluous ROS, resulting in elevated oxidative stress and cell injury ( Yoneda et al, 2021 ). Moreover, convincing evidence have demonstrated that elevated expressions of inflammatory factors were strongly related to the destruction of enteric mucosa barrier ( Tappenden, 2008 ).…”

Intestinal Mucositis Induced by 5- Fluorouracil and the Possible Protective Effect of Probiotics Containing Lactobacillus in Adult Male Albino Rats: Histological and Immunohistochemical Study

“…Mucositis is initiated by 5-FU by decreasing antioxidant glutathione (GSH) and increasing extracellular release of MPO which produces reactive oxygen species (ROS) that cause intestinal oxidative damage [31] . Another study on the effect of 5-FU on jejunum of rats concluded that it increased level of malondialdehyde (MDA) and up regulated of NF-κB signaling pathway within the jejunum, this caused disturbance of gut epithelial barrier [1,32,33] .…”