Effects of a novel toll-like receptor 4 antagonist IAXO-102 in a murine model of chemotherapy-induced gastrointestinal toxicity

Abstract

Introduction Gastrointestinal mucositis (GIM) is a side effect of high-dose irinotecan (CPT-11), causing debilitating symptoms that are often poorly managed. The role of TLR4 in the development of GIM has been clearly demonstrated. We, therefore, aimed to investigate the potential of the TLR4 antagonist, IAXO-102, to attenuate gastrointestinal inflammation as well as supress tumour activity in a colorectal-tumour-bearing mouse model of GIM induced by CPT-11. Methods 24 C57BL/6 mice received a vehicle, daily i.p. IAXO-102 (3 mg/kg), i.p. CPT-11 (270 mg/kg) or a combination of CPT-11 and IAXO-102. GIM was assessed using validated toxicity markers. At 72 h, colon and tumour tissue were collected and examined for histopathological changes and RT-PCR for genes of interest; TLR4, MD-2, CD-14, MyD88, IL-6, IL-6R, CXCL2, CXCR1, and CXCR2. Results IAXO-102 prevented diarrhoea in mice treated with CPT-11. Tumour volume in IAXO-102-treated mice was lower compared to vehicle at 48 h (P < 0.05). There were no differences observed in colon and tumour weights between the treatment groups. Mice who received the combination treatment had improved tissue injury score (P < 0.05) in the colon but did not show any improvements in cell proliferation or apoptotic rate. Expression of all genes was similar across all treatment groups in the tumour (P > 0.05). In the colon, there was a difference in transcript expression in vehicle vs. IAXO-102 (P < 0.05) and CPT-11 vs. combination (P < 0.01) in MD-2 and IL-6R, respectively. Conclusion IAXO-102 was able to attenuate symptomatic parameters of GIM induced by CPT-11 as well as reduce tissue injury in the colon. However, there was no effect on cell proliferation and apoptosis. As such, TLR4 activation plays a partial role in GIM development but further research is required to understand the specific inflammatory signals underpinning tissue-level changes.

Gastrointestinal mucositis: a sign of a (systemic) inflammatory response

“…In 5-FU-injected mice, high molecular weight hyaluronic acid supplementation significantly reduced serum levels of IL-6 and the chemokine CXCL1/KC, while the serum antioxidant activity of superoxide dismutase was elevated [49 ▪▪ ]. More directed at the role of microbiota or microbial–host metabolites, research on the novel TLR4 antagonist, IAXO-102, indicated that it attenuated gastrointestinal inflammation [50 ▪ ], and offered options for interfering with metabolite crosstalk [51 ▪ ] and use of probiotics. Lactobacillus rhamnosus -treated mice had significantly attenuated proinflammatory cytokine levels (IL-1beta, IL-6, and TNFα), mitigated damaged tight junction integrity via upregulation of the levels of claudin, occludin, ZO-1, and mucin-2 protein (MUC-2) and enhanced growth of beneficial bacteria that is Firmicutes and Lachnospiraceae , while the relative abundance of the opportunistic bacteria Bacteroides and Proteobacteria was decreased.…”