Preventive Mechanism of Lycopene on Intestinal Toxicity Caused by Cyclophosphamide Chemotherapy in Mice by Regulating TLR4-MyD88/TRIF-TRAF6 Signaling Pathway and Gut-Liver Axis

Abstract

Cyclophosphamide (CYC) is the first-line chemotherapy drug for cancer in clinical practice, and its intestinal toxicity seriously affects the treatment effect and prognosis of patients. Lycopene (LP) is the main pigment of ripe tomatoes and has strong antioxidant activity. However, the mechanism by which LP prevents CYC-induced intestinal injury remains unclear. The aim of this study was to investigate the mechanism of LP in preventing intestinal toxicity caused by CYC chemotherapy in mice. The results showed that LP significantly prevented spleen and thymus atrophy induced by CYC. In terms of intestinal injury, LP significantly increased the levels of superoxide dismutase (SOD), secretory immunoglobulin A (sIgA), interleukin (IL)-4, IL-12, and interferon (IFN)-γ, decreased the content of lipid oxidation (MDA), upregulated the protein expressions of toll-like receptors 4 (TLR4), myeloid differentiation factor 88 (MyD88), tumor necrosis factor receptor-associated factor 6 (TRAF6), toll/IL-1receptor domain containing adaptor protein inducing IFN-β (TRIF), p-P38 MAPK (P38), and p- nuclear factor kappa-B (NF-κB) p65, and improved the small intestine tissue injury induced by CYC. In terms of liver injury, LP significantly increased the content of glutathione (GSH), decreased the contents of MDA, nitric oxide (NO), IL-1β, IL-6, and tumor necrosis factor (TNF)-α, and repaired the liver tissue injury induced by CYC. Importantly, 10 mg/kg LP significantly prevented intestinal microbiota dysregulation in CYC mice. These results suggested that LP significantly prevented intestinal injury induced by CYC in mice by regulating the TLR4-MyD88/TRIF-TRAF6 signaling pathway and gut-liver axis.

A phase I study of docetaxel plus synthetic lycopene in metastatic prostate cancer patients

“…Lycopene has been reported to prevent toxicities from several cytotoxic drugs, including methotrexate and cyclophosphamide. 42,43 Docetaxel is well known for producing diarrhea. Possibly lycopene antagonises this agent's mucosal toxicity as well.…”

“…Clearly, the colon epithelium was continually exposed to lycopene since almost all subjects reported ongoing red‐ or orange‐coloured stool during treatment. Lycopene has been reported to prevent toxicities from several cytotoxic drugs, including methotrexate and cyclophosphamide 42,43 . Docetaxel is well known for producing diarrhea.…”

Oral exosome-like nanovesicles from Phellinus linteus suppress metastatic hepatocellular carcinoma by reactive oxygen species generation and microbiota rebalancing

“…46 In the context of Enterorhabdus, it is closely associated with immune factors that combat tumors. 47 Therefore, the increased abundance of these beneficial bacteria is conducive to enhancing the anti-tumor effect. In addition, compared with the PBS control group that harbored many harmful bacteria, including Alloprevotella, Muribaculaceae, and Butyricimonas, 48,49 the P-ELN (H) treatment observably reduced their abundance.…”

Current insights into the interplay between gut microbiota-derived metabolites and metabolic-associated fatty liver disease

“…Then, the LPS/LBP complex activates TLR4. Activated TLR4 delivers the LPS signal to its downstream signal molecules, promoting the production of pro-inflammatory cytokines by Kupffer cells (TNF-α, ILs, and IF-γ) and further hepatic inflammation [ 54 ]. More importantly, TLR4 expression is overexpressed in MAFLD patients [ 55 ].…”