Abstract
In the treatment of advanced head and neck squamous cell carcinoma (HNSCC), including oral SCC, radiotherapy is a commonly performed therapeutic modality. The combined use of radiotherapy with chemotherapy improves therapeutic effects, but it also increases adverse events. Ceramide, a central molecule in sphingolipid metabolism and signaling pathways, mediates antiproliferative responses, and its level increases in response to radiotherapy and chemotherapy. However, when ceramide is metabolized, prosurvival factors, such as sphingosine-1-phosphate (S1P), ceramide-1-phosphate (C1P), and glucosylceramide, are produced, reducing the antitumor effects of ceramide. The activities of ceramide- and sphingosine-metabolizing enzymes are also associated with radio- and chemo-resistance. Ceramide analogs and low molecular-weight compounds targeting these enzymes exert anticancer effects. Synthetic ceramides and a therapeutic approach using ultrasound have also been developed. Inhibitors of ceramide- and sphingosine-metabolizing enzymes and synthetic ceramides can function as sensitizers of radiotherapy and chemotherapy for HNSCC.
Highlights
Head and neck cancers are malignant tumors of the oral cavity, pharynx, and larynx, with the sixth highest incidence worldwide, accounting for 5% of all cancers [1,2,3]
Ceramide is metabolized by the action of ceramidase (CDase) and sphingosine, which is phosphorylated by sphingosine kinase 1 (SphK1) and SphK2 to become converted into sphingosine, which is phosphorylated by sphingosine kinase 1 (SphK1) and SphK2 to sphingosine-1-phosphate (S1P)
The antitumor effects of FTY720 were suggested to be due to its ability to stimulate reactive oxygen species (ROS) production, which culminated in PKCδ activation and subsequent caspase-3-dependent apoptosis in hepatocellular carcinoma cells [170] (Figure 3B)
Summary
Head and neck cancers are malignant tumors of the oral cavity, pharynx, and larynx, with the sixth highest incidence worldwide, accounting for 5% of all cancers [1,2,3]. A characteristic of head and neck SCC (HNSCC), including oral SCC, is the availability of radiotherapy. The Cancer Genome Atlas (TCGA) program reported the results of whole-genome sequencing on tumor tissues from 279 patients with HNSCC [8]. In HPV-negative HNSCC, activating mutations in classic oncogenes are relatively rare, and most genetic alterations are in tumor suppressor genes such as p53 and cyclin-dependent kinase inhibitor 2A (CDKN2A). This finding is important to develop therapeutic agents because the discovering of new compounds to restore the activity of altered tumor suppressor genes is highly challenging [10]. We review the metabolic pathways of ceramide, its function, the inhibitors of ceramide- and sphingosine-metabolizing enzymes, and their mechanisms of action
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