Radiotherapy has become increasingly important for treatment of head and neck squamous cell carcinoma. Oral mucositis, associated with both radiation and chemotherapy, is a very common, painful, and dose-limiting toxicity, with an incidence that can be as high as 90%. Exposure of normal tissue to radiation can cause both acute and chronic toxicities including dermatitis, xerostomia or mucositis, and this can result in not only a cessation of the intended therapy, but also a decrease in quality of life for the patient. There has been a lot of effort to reduce the radiation toxicities, mainly by focusing on technological improvements in radiation delivery. Also, many radioprotective agents have been attempted to prevent radiation-induced mucositis. Despite this, no intervention has yet been completely successful in preventing radiation-induced mucositis. Green tea consumed in a balanced and controlled diet improves anti-oxidative status and can protect against oxidative damage. Beneficial activities attributed to green tea extracts and/or constituents include antibacterial, antiviral, antioxidative, antitumor, and antimutagenic activities. Furthermore, green tea extract can scavenge nitric oxide (NO) and superoxide anions (O2 −) very effectively. Epicatechin (EC), a component of green tea, prevents cisplatin and radiation-induced, ROS-mediated ototoxicity and prevents changes in mitochondrial membrane potential. EC is among the important constituents responsible for the protective and antioxidant effects exhibited by green tea and is also active in lessening ionizing radiation-induced damage to DNA. However, the effect of EC as a radioprotective agent has not been investigated.
In this study, the therapeutic effects and protective mechanism of epicatechin on radiation-induced oral mucositis were investigated in HaCaT human keratinocyte line, primary cultured human fibroblasts, and in vivo in rat and zebrafish model. EC significantly inhibited radiation-induced apoptosis, change of MMP, and intracellular ROS generation in HaCaT cells and fibroblasts. EC treatment markedly attenuated the expression of p-JNK, p-38, and cleaved caspase-3 after irradiation in the HaCaT cells and fibroblasts. EC represents an effective means of reducing cellular damage and facilitating wound healing after radiation exposure. Rats with radiation-induced oral mucositis showed decreased oral intake, weight and survival rate, but oral administration of EC significantly restored all three parameters. Histopathologic changes were significantly decreased in the EC-treated irradiated rats. TUNEL staining of rat oral mucosa revealed that EC treatment significantly decreased radiation-induced apoptotic cells. Also EC attenuated the radiation-induced embryotoxicity in a zebrafish model. Although larger numbers of animals and clinically relevant fractionation schemes are necessary to confirm the effect of EC, these results suggest the possibility of EC to inhibit radiation-induced oral mucositis, a common complication in radiotherapy of head and neck cancers. EC may be a safe and effective candidate treatment for the prevention of radiation-induced mucositis.