5-Fluorouracil Induced Intestinal Mucositis via Nuclear Factor-κB Activation by Transcriptomic Analysis and In Vivo Bioluminescence Imaging

Abstract

5-Fluorouracil (5-FU) is a commonly used drug for the treatment of malignant cancers. However, approximately 80% of patients undergoing 5-FU treatment suffer from gastrointestinal mucositis. The aim of this report was to identify the drug target for the 5-FU-induced intestinal mucositis. 5-FU-induced intestinal mucositis was established by intraperitoneally administering mice with 100 mg/kg 5-FU. Network analysis of gene expression profile and bioluminescent imaging were applied to identify the critical molecule associated with 5-FU-induced mucositis. Our data showed that 5-FU induced inflammation in the small intestine, characterized by the increased intestinal wall thickness and crypt length, the decreased villus height, and the increased myeloperoxidase activity in tissues and proinflammatory cytokine production in sera. Network analysis of 5-FU-affected genes by transcriptomic tool showed that the expression of genes was regulated by nuclear factor-κB (NF-κB), and NF-κB was the central molecule in the 5-FU-regulated biological network. NF-κB activity was activated by 5-FU in the intestine, which was judged by in vivo bioluminescence imaging and immunohistochemical staining. However, 5-aminosalicylic acid (5-ASA) inhibited 5-FU-induced NF-κB activation and proinflammatory cytokine production. Moreover, 5-FU-induced histological changes were improved by 5-ASA. In conclusion, our findings suggested that NF-κB was the critical molecule associated with the pathogenesis of 5-FU-induced mucositis, and inhibition of NF-κB activity ameliorated the mucosal damage caused by 5-FU.

Histological and immunohistochemical study of the potential healing effects of glucosamine and platelets rich plasma on experimentally induced oral mucositis in adult male rats

“…Caspase-3 is the major downstream effector in apoptosis. Some researchers reported that 5 -Flurouracil induces DNA damage and the production of reactive oxygen species, deteriorates the metabolism in progenitor cells and causes inhibition of mitosis and rises of apoptosis [2,3,6,27]. Other scientists [5,23,24] found that the toxicity of chemotherapeutic agents as 5-FU decreases proliferation of cells of mucosa, also impairment of their cellular renewal or regeneration and thus lead to significant decrease of PCNA immunostaining expression of the mucosal cells.…”

Pien Tze Huang alleviates 5-fluorouracil-induced intestinal mucositis in CT-26 tumor-bearing mice

“…5-FU is one of the anti-cancer drugs widely utilized in the treatment of CRC in clinical practice (6). However, continuous use of 5-FU usually has severe toxic effects, particularly intestinal mucositis (12), resulting in discontinuation of cancer chemotherapy and impairment of the quality of life of patients.…”

“…However, normal cells, tissues and their functions are inevitably injured by 5-FU, which disrupts the balance of the body's self-regulatory system (4,5). The major side effects of 5-FU include intestinal mucositis, myelosuppression and immunosuppression (6). It has been reported that ~80% of cancer patients who have received 5-FU treatment displayed clinical manifestations of intestinal mucositis, such as severe diarrhea, mal-absorption, vomiting and bleeding (7,8).…”

A review of complementary therapies for chemotherapy induced gastrointestinal mucositis

“…At the same time, reactive oxygen species (ROS) are formed, starting downstream biological events. Nuclear factor kappa B (NFκB), cyclooxygenase-2 (COX-2) as well as pro-inflammatory cytokines like interleukin-6 (IL-6), interleukin-1β (IL-1β) and tumour-necrosis factor (TNF) have been suggested to play a key role in the development of GIM (17)(18)(19)(20). These overlapping steps are thought to be largely driven by the activation of NFκB, subsequently promoting key pro-inflammatory cytokines.…”