Inhibitors of Ceramide- and Sphingosine-Metabolizing Enzymes as Sensitizers in Radiotherapy and Chemotherapy for Head and Neck Squamous Cell Carcinoma

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.

Gut mucus layer degradation is associated with aggressive cervical cancer phenotype

“…The tumor promoting effects of glycan degradation and utilization of major degradation products, such as galactose and other pentoses [19], may help drive this aggressive tumor growth. Glycan degradation leads to production of metabolites with known tumor growth promoting effects and with resistance to radio-and chemotherapy, such as ornithine [52] and ceramides [53,54]. The metabolites are produced as by-products of glycan degradation (Fig.…”

“…1e) and can be further metabolized either by bacteria or by host and give oncogenic effect after their metabolization. Ceramide itself, for example, is a powerful tumor suppressor, but products of its metabolism are potent tumor survival factors associated with resistance to cancer therapies [53]. Ornithine can be used by the consortium or by the host to synthesize the polyamines putrescine and spermidine (Additional File 1: Figure S8), which cause tumorigenic transformation and tumor progression [55].…”

Targeting Chronic Inflammation of the Digestive System in Cancer Prevention: Modulators of the Bioactive Sphingolipid Sphingosine-1-Phosphate Pathway

“…Elevated SphK1 leads to an S1PR1/ERK-and IL-6 /gp130-mediated increase in proliferation, migration, and inflammatory and a more aggressive HNSCC phenotype [101]. Indirect targeting of the sphingolipid pathway was demonstrated to sensitise chemo-and radiotherapy-resistant HNSCC, supporting their clinical usefulness in hard-to-treat tumours [102]. Indirect inhibition of SphK1 using a targeted microRNA, miR-124, was shown to suppress HNSCC [103].…”

“…Direct clinical evidence to support sphingolipid-based therapies for HNSCC, including salivary gland cancers, however, is still very limited and is mainly based on inference from other S1P-therapy-based cancer studies and clinical trials in solid cancers [102].…”

The Role of Sphingolipid Signaling in Oxidative Lung Injury and Pathogenesis of Bronchopulmonary Dysplasia

“…BPD [29,30] Pulmonaryfibrosis [79,100] Cancer [101] SK2 modulators ABC294640 (Opaganib) Cancer [102] CERS inhibitors CERS 2, 4, and 6 Cancer [103] Cerk inhibitors NVP-231 Cancer [104] Recently the role of deoxysphingolipids came to light in various pathological disorders [105]. As explained earlier, SPT, physiologically conjugates l-serine and palmitoyl-CoA to form 3-keto-phinganine, which is converted to sphinganine [54,106].…”