Protective Effects of Cannabidiol on Chemotherapy-Induced Oral Mucositis via the Nrf2/Keap1/ARE Signaling Pathways

Abstract

Oral mucositis (OM) is a common complication during chemotherapy characterized by ulceration, mucosa atrophy, and necrosis, which seriously interferes with nutritional intake and oncotherapy procedures among patients. However, the efficacy of current treatments for OM remains limited. Cannabidiol (CBD) is a natural cannabinoid with multiple biological activities, including antioxidant and anti-inflammatory potential. In this study, we aimed to investigate the chemopreventive effects and mechanisms of CBD in protecting C57BL/6N mice and human oral keratinocytes (HOK) from 5-fluorouracil- (5-FU-) induced OM. Here, we found that CBD alleviated the severity of 5-FU-induced OM in mice, including improved survival, decreased body weight loss, reduced ulcer sizes, and improved clinical scores. Histologically, CBD restored epithelial thickness and normal structure in tongue tissues. Meanwhile, CBD attenuated reactive oxygen species (ROS) overproduction and improved the antioxidant response, suppressed the inflammatory response, promoted the proliferation of epithelial cells, and inhibited 5-FU-induced apoptosis. In vitro, consistent outcomes showed that CBD suppressed cellular ROS levels, enhanced antioxidant ability, reduced inflammatory response, promoted proliferation, and inhibited apoptosis in 5-FU-treated HOK cells. In particular, CBD upregulated the expression levels of antioxidant enzymes, heme oxygenase-1 (HO-1) and NAD(P)H quinine oxidoreductase 1 (NQO1), by increasing the expression and nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and decreasing Kelch-like ECH-associated protein 1 (Keap1). Notably, the Nrf2 inhibitor ML385 reversed the protective effect of CBD. Nrf2-siRNA transfection also significantly blunted the antioxidant effect of CBD in in vitro OM model. Collectively, our findings suggested that CBD protected against 5-FU-induced OM injury at least partially via the Nrf2/Keap1/ARE signaling pathways, highlighting the therapeutic prospects of CBD as a novel strategy for chemotherapy-induced OM.

Cannabidiol modulates expression of type I IFN response genes and HIV infection in macrophages

“…p62 links autophagy and Nrf2/Keap1/ARE signaling, which is a redox sensitive signaling axis that functions to protect cells against oxidative stress and environmental toxicants ( 57 ). Recent reports suggest that CBD can activate the Nrf2/Keap1/ARE pathway and attenuate production of ROS ( 58 , 59 ). P62 is also a target gene for Nrf2 transcription factor, which binds to the ARE (Antioxidant response element) in p62 promoter.…”

The molecular activity of cannabidiol in the regulation of Nrf2 system interacting with NF-κB pathway under oxidative stress

“…It was also shown that UV-irradiated keratinocytes treated with CBD (1 μM) have stimulated the Nrf2 pathway and at the same time downregulation of the NF-κB pathway along with increased expression of phosphorylated IκBβ [ 15 ]. Moreover, a similar effect of CBD (30 μM) on the Nrf2 pathway (including Keap1 downregulation and Nrf2 activation) correlated with blanking the NF-κB pathway by lowering the TNF-α was also observed in animals with oral mucositis [ 122 ]. On the other hand, CBD (2.5 μM) did not affect the level of NF-κB family member p50 in response to TNF - α in C2C12 muscle cells [ 123 ].…”

Cannabinoid Therapeutic Effects in Inflammatory Bowel Diseases: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

“…To our knowledge, this is the only secondary study that analyzes cannabinoid effectiveness as supplementation therapy in IBD and gives an estimation of CDAI reduction. The only other meta-analysis on the topic was performed by Doeve et al, [ 24 ] who included in their work both experimental and observational trials, but could not give an estimation of disease activity index variation. The present one is the first work that gives a separate estimation of overall RR of successful cannabinoid supplementation in both CD and UC.…”

“…Some pharmaceutical agents have already been investigated, and have shown some potential in pre-clinical studies [ 23 ]. In particular, Cannabidiol has been proven effective as a therapeutic option for oral wound healing in vivo mouse models, both in Chemotherapy-Induced Oral Mucositis (via the Nrf2/Keap1/ARE Signaling Pathways) and on wound-induced ulcers [ 24 , 25 ]. Some patients also use cannabinoids in order to alleviate their symptoms, and while effective, a higher usage has been associated with a higher risk of surgery in patients with Crohn’s disease [ 26 ].…”