Anakinra and dexamethasone treatment of idarubicin‐induced mucositis and diarrhoea in rats

Abstract

Chemotherapy-induced mucositis, characterized by diarrhoea and villous atrophy, is a severe side effect contributing to reduced quality of life and premature death in cancer patients treated with cytostatics. Despite its high incidence, there is no effective supportive therapy available. The main objective of this study was to determine if the anti-inflammatory drugs anakinra and/or dexamethasone-which have different mechanisms-of-action-might be used to effectively treat idarubicin-induced mucositis in rats. Mucositis was induced through a single injection with 2 mg/kg idarubicin (with saline as control), followed by daily treatments of anakinra (100 mg/kg/day), dexamethasone (10 mg/kg/day) or both for 3 days. After 72 h, jejunal tissue was collected for morphological, apoptotic and proliferative analyses, and colonic faecal water content and body weight change were determined. The diarrhoea that was induced by idarubicin (from 63.5% to 78.6% water content in faeces) was completely reversed by anakinra alone, and the jejunal villus height reduction by 36% was prevented by a combination of anakinra and dexamethasone. Dexamethasone reduced apoptosis in the jejunal crypts, both alone and in combination with anakinra. These positive effects encouraged further investigations into the use of anakinra and dexamethasone as supportive therapies for chemotherapy-induced intestinal mucositis and diarrhoea.Global cancer incidence is estimated at 19 million cases in 2020, 1 which should increase as mortality rates from stroke and cardiovascular disease decrease. 2 Cancer patients are often treated with chemotherapeutics, which also affect rapidly proliferating non-tumour tissues. 3 The intestinal mucosa is especially susceptible, and gastrointestinal (GI) toxicity, such as chemotherapy-induced mucositis (CIM) 4,5 and diarrhoea, 6,7 affects more than 80% of patients in certain chemotherapy regimens. The occurrence of severe GI complications depends on several

Endoplasmic reticulum stress in the pathogenesis of chemotherapy‐induced mucositis: Physiological mechanisms and therapeutic implications

“…Understanding the underlying mechanisms that contribute to CIM and the accompanying diarrhea are crucial for developing effective preventive strategies and supportive care that could improve quality of life for cancer patients. 3…”

“…Understanding the underlying mechanisms of chemotherapy-induced intestinal mucositis (CIM) is crucial for developing effective preventive strategies and supportive care. 3 In recent years, research has suggested an interplay between endoplasmic reticulum (ER) stress and the development of mucositis, revealing promising avenues for new therapeutic interventions to relieve chemotherapy-induced side effects.…”

“…12 Chemotherapeutics can directly and indirectly disrupt ER homeostasis, leading to ER-stress and activation of the UPR in different cell types, including intestinal epithelial cells. 3,13,14,15 The UPR can then induce signaling pathways that exacerbate tissue inflammation and damage, but also influence the differentiation and fate of intestinal epithelial cells, compromising the integrity of this mucosal barrier. All of these factors contribute significantly to mucositis's development and progression.…”

The Role of the Innate Immune Response in Oral Mucositis Pathogenesis

“…Given the inherent similarities in pathophysiology, investigating the efficacy of drugs that have shown promise in the treatment of intestinal mucositis in the context of OM represents an important avenue for future research. Anakinra is a recombinant human IL-1 receptor antagonist, which has been shown to alleviate intestinal mucositis in various preclinical models [96][97][98]. Clinical Phase IIA trials of anakinra have also established safety in HSCT recipients, with Phase IIB trials currently establishing efficacy in the management of intestinal mucositis [98,99].…”

Mucositis and Infection in Hematology Patients

“…Treatment with anakinra did not affect the degree and duration of neutropenia. Anakinra alone prevented diarrhea and in combination with dexamethasone protected rats from villous atrophy and reduced idarubicin-induced jejunal apoptosis [112]. IL-1 inhibition with the IL-1 receptor antagonist anakinra has shown to be safe in other human diseases, and much clinical experience with anakinra is available, including some experience in hematology and HCT settings [107].…”