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Review
. 2021 Oct 22;10(11):1666.
doi: 10.3390/antiox10111666.

Mechanism, Prevention, and Treatment of Radiation-Induced Salivary Gland Injury Related to Oxidative Stress

Zijing Liu  1   2   3 , Lihua Dong  1   2   3 , Zhuangzhuang Zheng  1   2   3 , Shiyu Liu  1   2   3 , Shouliang Gong  1   2   3 , Lingbin Meng  4 , Ying Xin  5 , Xin Jiang  1   2   3
Affiliations
Review

Mechanism, Prevention, and Treatment of Radiation-Induced Salivary Gland Injury Related to Oxidative Stress

Zijing Liu et al. Antioxidants (Basel). .

Abstract

Radiation therapy is a common treatment for head and neck cancers. However, because of the presence of nerve structures (brain stem, spinal cord, and brachial plexus), salivary glands (SGs), mucous membranes, and swallowing muscles in the head and neck regions, radiotherapy inevitably causes damage to these normal tissues. Among them, SG injury is a serious adverse event, and its clinical manifestations include changes in taste, difficulty chewing and swallowing, oral infections, and dental caries. These clinical symptoms seriously reduce a patient's quality of life. Therefore, it is important to clarify the mechanism of SG injury caused by radiotherapy. Although the mechanism of radiation-induced SG injury has not yet been determined, recent studies have shown that the mechanisms of calcium signaling, microvascular injury, cellular senescence, and apoptosis are closely related to oxidative stress. In this article, we review the mechanism by which radiotherapy causes oxidative stress and damages the SGs. In addition, we discuss effective methods to prevent and treat radiation-induced SG damage.

Keywords: head and neck cancer; injury; oxidative stress; radiotherapy; salivary glands.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Calcium signal mechanism of radiation-induced salivary gland injury. Acetylcholine acts on G-protein-coupled receptors and activates the G-protein effector PLC by activating the G protein so that PIP2 is decomposed into IP3 and DAG. IP3 acts on the IP3 receptor on the endoplasmic reticulum, and then intracellular Ca2+ is released and the intracytoplasmic Ca2+ concentration increases. As the second messenger, Ca2+ increases [Ca2+i] through Ca2+ sensor protein STIM1, which regulates the SOCE. This process is controlled by the channels TRPC1 and Orai1. When exposed to a muscarinic acetylcholine receptor agonist, the irradiated salivary gland cells isolated from the body are impaired in their ability to mobilize [Ca2+i] after irradiation. NAD+ and ROS accumulate during inflammation and tissue damage. External NAD+ may be converted to ADPR, cADPR, and nicotinic acid adenine dinucleotide phosphate by the ectoenzymes CD38 and CD157. Extracellular ADPR may then bind to plasma membrane receptors, increase [Ca2+i] through the release of Ca2+ from stores via G-proteins, and activate PLC with subsequent IP3 production. H2O2 may also cross the plasma membrane and mobilize ADPR from mitochondria (both H2O2 and cADPR can synergize with ADPR to activate TRPM2). Free cytosolic ADPR will act on the plasma membrane TRPM2 channels, enabling Ca2+ influx across the plasma membrane and/or the release of lysosomal Ca2+.
Figure 2
Figure 2
The mechanism of cell apoptosis in radiotherapy-induced salivary gland injury. When H2O2 is produced by the oxidative stress of radiation, phosphorylation at PKCδ-Y64 and Y155 opens the PKCδ conformation. The exposure of NLS allows both Hsp90 and importin-α to bind to the binding sites of PKCδ. Under the binding of importin-α, PKCδ accumulates in the nucleus. When phosphorylated PKCδ enters the nucleus, PKCδ can control the expression of p53 in a transcription-dependent manner in the nucleus and activate p53 via the phosphorylation of different serine and threonine residues in an indirect manner. After radiation causes DNA damage, PKCδ activates Bcl-2-related transcription factor (Btf) and binds with it to the CPE region of p53, thereby inducing p53 transcription. At the same time, activated p53 can in turn promote PKCδ transcription in response to DNA damage. PKCδ entering the nucleus can also be cleaved by nuclear capsase-3 to produce pro-apoptotic δCF. Acid sphingomyelinase hydrolyzes sphingomyelin in the plasma membrane of endothelial cells to produce ceramide. Ceramide, acting as a second messenger in receptor-mediated signal transduction, activates BAX. The elevation of BAX regulates vascular endothelial cell apoptosis by releasing mitochondrial cytochrome c.
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