IL-17/Notch1/STAT3 Pathway Contributes to 5-Fluorouracil-Induced Intestinal Mucositis in Rats: Amelioration by Thymol Treatment

Abstract

5-Fluorouracil (5-FU) is an anticancer drug with intestinal mucositis (IM) as a deleterious side effect. Thymol is a monoterpene phenol which has been reported to possess an antioxidant and anti-inflammatory activity versus 5-FU-induced IM. The Notch pathway affects multiple cellular activities, such as cellular proliferation, in addition to inflammatory responses modulation. Accordingly, this work was carried out in order to elucidate the role of the Notch pathway in 5-FU-induced IM and to further elucidate the immunomodulatory protective mechanisms of thymol. Experimental rats were divided randomly into four groups: Control, 5-FU, 5-FU+thymol (60 mg/kg/day), and 5-FU+thymol (120 mg/kg/day). 5-FU was injected intraperitoneally at a dose of 150 mg/kg on days 6 and 7, while thymol was orally administered daily for 11 days. By the end of the study, intestinal tissues were collected for the determination of IL-17, CD4, CD8, Notch1, Hes-1, pSTAT3, and STAT-3 protein expressions. The effect of thymol on 5-FU cytotoxicity was also examined using WST1 assay. 5-FU induced a marked increase in IL-17 levels, along with a marked downregulation of CD4 and the upregulation of CD8, Notch1, Hes-1 protein expressions, and activation of STAT3 in the intestinal tissue when compared with the control group. Thymol ameliorated the changes that occurred in these parameters. Additionally, cytotoxicity testing revealed that thymol augmented the antiproliferative action of 5-FU against breast and colorectal human cancer cell lines. This study was the first to show that the IL-17/Notch1/STAT3 pathway is involved in the molecular mechanism of 5-FU-induced IM, as well as the immunomodulatory activity of thymol.

LTβR-RelB signaling in intestinal epithelial cells protects from chemotherapy-induced mucosal damage

“…5-FU is another commonly used chemotherapeutic agent employed in the therapy of various cancers, which can cause damage to intestinal epithelial cells and result in intestinal mucositis ( 15 , 65 , 66 ). To test the role of LTβR signaling in a 5-FU model of chemotherapy-induced intestinal injury, we treated WT and LTβR -/- mice with 50 mg/kg 5-FU daily for 4 days ( Supplementary Figure S1 ).…”

Radioprotective Effects of Carvacrol and/or Thymol against Gamma Irradiation-Induced Acute Nephropathy: In Silico and In Vivo Evidence of the Involvement of Insulin-like Growth Factor-1 (IGF-1) and Calcitonin Gene-Related Peptide

“…In addition, radioprotective effects of thymol and carvacrol have been documented in different ionizing radiation-induced injuries [ 32 , 33 , 34 , 35 , 36 ]. Studies showed that carvacrol and thymol have some promising effects against chemotherapy-induced nephrotoxicity through antioxidative, antiapoptotic, anti-inflammatory, and cytoprotective mechanisms [ 37 , 38 , 39 , 40 ]. Carvacrol has been reported to be a ligand for the transient receptor potential channel ankyrin 1 (TRPA1), which mediates the expression and release of CGRP [ 41 , 42 ].…”