Targeting Ceramide Metabolism in Hepatocellular Carcinoma: New Points for Therapeutic Intervention

Background: Hepatocellular Carcinoma (HCC) is one of the greatest global health burdens because of its uncontrolled cell growth and proliferation, aggressive nature as well as inherited chemoresistance. In spite of different treatment options currently available for HCC, the 5-year relative survival rates for HCC patients with regional and distant stages of the disease are still low, which highlights the urgent need for novel therapeutic strategies for HCC. Recent findings strongly suggest that specific lipid species, such as sphingolipids, play a prominent role in tumorigenesis. Objective: We will give an overview of recent literature findings on the role of ceramide metabolism in the pathogenesis and treatment of HCC. Results: HCC is characterised by dysregulation of ceramide metabolism, which could be ascribed to altered activity and expression of ceramide synthases 2, 4 and 6, and acid and alkaline ceramidases 2 and 3, as well as to deregulation of Sphingosine kinases (SphK) 1 and 2 and sphingosine-1- phosphate receptors, in particular, S1PR1. Among them, SphK2 has emerged as a clinically relevant drug target in HCC whose inhibition by ABC294640 is currently being investigated in a clinical trial in patients with advanced HCC. Another promising strategy includes restoration of ceramide levels in HCC tissues, whereby nanoliposomal ceramides, in particular C6-ceramide, has emerged as an effective therapeutic agent against HCC whose safety and recommended dosing is currently being clinically investigated. Conclusion: Development of novel drugs specifically targeting ceramide metabolism could provide an enhanced therapeutic response and improved survival outcome in HCC patients.