Abstract
Oral mucositis (OM) is a common complication in cancer patients undergoing anticancer treatment. Despite the clinical and economic consequences of OM, there are no drugs available for its fundamental control. Here we show that high-mobility group box 1 (HMGB1), a “danger signal” that acts as a potent innate immune mediator, plays a critical role in the pathogenesis of OM. In addition, we investigated treatment of OM through HMGB1 blockade using NecroX-7 (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholin-4-yl)methyl-1Hindole-7-yl]amine). NecroX-7 ameliorated basal layer epithelial cell death and ulcer size in OM induced by chemotherapy or radiotherapy. This protective effect of NecroX-7 was mediated by inhibition of HMGB1 release and downregulation of mitochondrial oxidative stress. Additionally, NecroX-7 inhibited the HMGB1-induced release of tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, and macrophage inflammatory protein (MIP)-1β, as well as the expression of p53-upregulated modulator of apoptosis (PUMA) and the excessive inflammatory microenvironment, including nuclear factor-kB (NF-kB) pathways. In conclusion, our findings suggest that HMGB1 plays a key role in the pathogenesis of OM; therefore, blockade of HMGB1 by NecroX-7 may be a novel therapeutic strategy for OM.
Highlights
Oral mucositis (OM) is a devastating side effect in hematopoietic stem cell transplant (HSCT) settings, and in patients undergoing chemotherapy or radiotherapy for cancer treatment.[1,2] Despite the clinical and economic consequences of OM, oral irrigation to prevent secondary bacterial infections or pain relief by narcotic analgesics is currently the only treatment option in clinical practice
The cytoplasmic High-mobility group box 1 (HMGB1) levels were significantly increased in the presence of chemotherapy-induced oral mucosa, but NecroX7 application led to retention of HMGB1 staining in the nucleus (Fig. 3c). These results suggest that HMGB1 is involved in the NecroX-7 decreases HMGB1 and p53-upregulated modulator of apoptosis release To determine whether HMGB1 release is associated with cell death during chemotherapy, we evaluated the levels of apoptosisrelated proteins and genes. p53/p53upregulated modulator of apoptosis (PUMA) is the major mediator of chemotherapy-induced mucosal injury.[27,28]
We clearly demonstrated that HMGB1 overexpression exacerbates chemotherapy-induced mucosal injury and inflammatory responses including the nuclear factor κB (NF-κB) pathway (Fig. 8)
Summary
Oral mucositis (OM) is a devastating side effect in hematopoietic stem cell transplant (HSCT) settings, and in patients undergoing chemotherapy or radiotherapy for cancer treatment.[1,2] Despite the clinical and economic consequences of OM, oral irrigation to prevent secondary bacterial infections or pain relief by narcotic analgesics is currently the only treatment option in clinical practice. Activation of WNT/β-catenin pathways, including Rspondin[1,5,6,7] growth factors,[8] and LGR5 receptor agonists[9,10] has been proposed as the treatment strategy to regenerate progenitor and stromal cells in mucosal injury, and radioprotective agents including mTOR inhibitors[8] and amifostine[11] have been proposed to prevent OM. Han et al reported that smad[7] blocks transforming growth factor-induced apoptosis and growth arrest, and plays a key role in inhibiting the inflammatory response due to nuclear factor κB (NF-κB) activation.[12] few drugs for control of OM are available
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