Acid ceramidase-1 (ASAH1/aCDase) an important for anticancer drug discovery: a review

Background

Dysregulated sphingolipid metabolism has emerged as a major pathway in multiple human cancers. Sphingolipids are major structural components of cell membranes, playing key roles in maintaining structural integrity, fluidity, and barrier function. Sphingolipids are diverse and involved in regulating growth, the cell cycle, cell motility, adhesion, migration, and more by influencing cell signaling functions. The major sphingolipids include ceramides, sphingomyelins, cerebrosides, and gangliosides. De novo sphingolipid synthesis generates ceramide, a central hub for this pathway with several possible fates. Ceramide can be phosphorylated to ceramide-1-phosphate by ceramide kinase or converted to sphingomyelin by sphingomyelin synthase. Furthermore, ceramide may be degraded by ceramidase to form sphingosine, which can then be further phosphorylated by sphingosine kinase 1/2 to create sphingosine-1-phosphate (S1P). S1P has a multifaced role in the pro-survival progression of cancer and is crucial for immunomodulation.

Main body of the abstract

Ceramidase is a group of essential enzymes required to regulate bioactive lipids, particularly ceramide. These enzymes regulate several biological processes, including autophagy, apoptosis, differentiation, and cell proliferation. Based on the literature, acid ceramidase-1 (AC) is an important enzyme that converts ceramide to sphingosine, which is further processed to S1P by sphingosine kinase 1/2. Intriguingly, several human cancers exhibit overexpression of AC activity, but systematic research on its involvement in cancer progression is lacking, indicating the need for further research on this emerging target.

Short conclusion

The present review article provides a comprehensive summary of all known AC inhibitors. Through an analysis of reported IC50 values, we have aimed to increase our understanding of these inhibitors structure–activity relationship. Additionally, using molecular modeling techniques, we have refined the structural prerequisites for developing future AC inhibitors.