Dietary nitrate supplementation prevents radiotherapy-induced xerostomia.

ABSTRACT

Management of salivary gland hypofunction caused by irradiation (IR) therapy for head and neck cancer remains lack of effective treatments. Salivary glands, especially the parotid gland, actively uptake dietary nitrate and secrete it into saliva. Here, we investigated the effect of dietary nitrate on the prevention and treatment of IR-induced parotid gland hypofunction in miniature pigs, and elucidated the underlying mechanism in human parotid gland cells. We found that nitrate administration prevented IR-induced parotid gland damage in a dose-dependent manner, by maintaining the function of irradiated parotid gland tissue. Nitrate could increase sialin expression, a nitrate transporter expressed in the parotid gland, making the nitrate-sialin feedback loop that facilitates nitrate influx into cells for maintaining cell proliferation and inhibiting apoptosis. Furthermore, nitrate enhanced cell proliferation via the epidermal growth factor receptor (EGFR)-protein kinase B (AKT)-mitogen-activated protein kinase (MAPK) signaling pathway in irradiated parotid gland tissue. Collectively, nitrate effectively prevented IR-induced xerostomia via the EGFR-AKT-MAPK signaling pathway. Dietary nitrate supplementation may provide a novel, safe, and effective way to resolve IR-induced xerostomia.

Head and neck cancers are commonly treated using radiotherapy, where a beam of high-energy radiation is targeted at the tumour. This often severely damages the surrounding salivary glands, leading to chronic dry mouth and impairing a patient's sense of taste, nutrient intake, speech and immune system. Despite this significant impact on quality of life, there is no effective treatment yet for this side effect. In the body, salivary glands are one of the primary users of a compound known as nitrate, which is commonly found in the diet. In the glands, it is ushered into cells thanks to a protein known as sialin. The nutrient supports the activity and maintenance of the glands, before it is released in the saliva. Feng, Wu et al. therefore decided to test whether nitrate could offer protection during neck and head radiotherapy. The experiments used miniature pigs, which have similar salivary glands to humans. The animals that received sodium nitrate before and after exposure to radiation preserved up to 85% of their saliva production. By comparison, without any additional nitrate, saliva production fell to 20% of pre-radiation levels. To understand how this protective effect emerged, Feng, Wu et al. added nitrate to cells from a human salivary gland known as the parotid. This led to the cells producing more sialin, creating a feedback loop which increases the amount of nitrate in the salivary glands. Further examination then showed that the compound promotes growth of cells and reduce their death. These findings therefore suggest that clinical studies may be worthwhile to test if nitrate could be used to prevent dry mouth in head and neck cancer patients who undergo radiotherapy.