Molecular mechanisms underlying methotrexate-induced intestinal injury and protective strategies

Abstract

Methotrexate (MTX) is a folic acid reductase inhibitor that manages various malignancies as well as immune-mediated inflammatory chronic diseases. Despite being frequently prescribed, MTX's severe multiple toxicities can occasionally limit its therapeutic potential. Intestinal toxicity is a severe adverse effect associated with the administration of MTX, and patients are significantly burdened by MTX-provoked intestinal mucositis. However, the mechanism of such intestinal toxicity is not entirely understood, mechanistic studies demonstrated oxidative stress and inflammatory reactions as key factors that lead to the development of MTX-induced intestinal injury. Besides, MTX causes intestinal cells to express pro-inflammatory cytokines like interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), which activate nuclear factor-kappa B (NF-κB). This is followed by the activation of the Janus kinase/signal transducer and activator of the transcription3 (JAK/STAT3) signaling pathway. Moreover, because of its dual anti-inflammatory and antioxidative properties, nuclear factor erythroid-2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) has been considered a critical signaling pathway that counteracts oxidative stress in MTX-induced intestinal injury. Several agents have potential protective effects in counteracting MTX-provoked intestinal injury such as omega-3 polyunsaturated fatty acids, taurine, umbelliferone, vinpocetine, perindopril, rutin, hesperidin, lycopene, quercetin, apocynin, lactobacillus, berberine, zinc, and nifuroxazide. This review aims to summarize the potential redox molecular mechanisms of MTX-induced intestinal injury and how they can be alleviated. In conclusion, studying these molecular pathways might open the way for early alleviation of the intestinal damage and the development of various agent plans to attenuate MTX-mediated intestinal injury.

Keywords: Inflammation; Intestinal toxicity; JAK/STAT3; Methotrexate; NF-κB; Nrf2/HO-1.

Fig. 1

Chemical structures of folic acid, MTX, and its main metabolites

Fig. 2

Illustration of the interplay between MTX, oxidative stress, JAK1/STAT3 pathway, and intestinal injury

Fig. 3

Detailed mechanism of signaling molecular pathways involved in MTX-induced intestinal injury. MTX-induced intestinal injury by increasing oxidative stress characterized by decreasing the activation of antioxidants GSH and SOD and increasing pro-oxidant MDA mediated by the downregulation of Nrf2/HO-1, PPAR-γ, and SIRT1. Also, MTX administration enhanced inflammation characterized by increasing pro-inflammatory cytokines TNF-α and IL-6 mediated by the upregulation of NF-κB and JAK/STAT3 phosphorylation and decreasing SOCS3. Furthermore, it increased apoptosis characterized by an elevation of cleaved caspase-3 and caspase-8. Abbreviations: GSH, glutathione; IL-6, interleukin-6; JAK/STAT3, Janus kinase/signal transducer and activator of transcription3; MDA, malondialdehyde; MTX, methotrexate; Nrf2/HO-1, nuclear factor erythroid-2-related factor 2/heme oxygenase-1; NF-κB, nuclear factor-kappa B; PPAR-γ, peroxisome proliferator-activated receptor-gamma; SOD, superoxide dismutase; SOCS3, suppressor of cytokine signaling3; SIRT1, silent information regulator-1; TNF-α, tumor necrosis factor-alpha