Natural Products and Small Molecules Targeting Cellular Ceramide Metabolism to Enhance Apoptosis in Cancer Cells

Abstract

Molecular targeting strategies have been used for years in order to control cancer progression and are often based on targeting various enzymes involved in metabolic pathways. Keeping this in mind, it is essential to determine the role of each enzyme in a particular metabolic pathway. In this review, we provide in-depth information on various enzymes such as ceramidase, sphingosine kinase, sphingomyelin synthase, dihydroceramide desaturase, and ceramide synthase which are associated with various types of cancers. We also discuss the physicochemical properties of well-studied inhibitors with natural product origins and their related structures in terms of these enzymes. Targeting ceramide metabolism exhibited promising mono- and combination therapies at preclinical stages in preventing cancer progression and cemented the significance of sphingolipid metabolism in cancer treatments. Targeting ceramide-metabolizing enzymes will help medicinal chemists design potent and selective small molecules for treating cancer progression at various levels.

Keywords: anticancer therapies; ceramide; ceramide synthase; natural products and related small molecules; sphingolipids.

Figure 1

Ceramide biosynthesis and metabolism pathway.

Figure 2

3D crystal structure of human acid ceramidase (ASAH1, aCDase). PDB ID: 5U7Z. Chain A is red, chain B is teal, and dashed lines indicate hydrogen bonding. The active site is located near Cys143 and a binding pocket near the active site was generated using ezPocket with fconv at 89.4, −3.53, and 203.26 (x, y, z), respectively.

Figure 3

Examples of AC inhibitors.

Figure 4

Crystal structure of Sphingosine Kinase 1. PDB ID: 3VZB. Protein is shown in rainbow color scheme, the ligand D-erythro sphingosine is shown in element color scheme with gray, red, and blue for carbon, oxygen, and nitrogen, respectively, and sulfur ion is also shown in crystal structure with element color scheme yellow for sulfur. Active site is located near α8 and 9 helix and β10 sheet.

Figure 5

Sphingosine Kinase 2 inhibitors.

Figure 6

Other Sphingosine Kinase inhibitors.

Figure 7

Sphingomyelin Synthase inhibitors.

Figure 8

Natural products and small molecules of non-Sphingolipid analogs reported as dihydroceramide desaturase inhibitors.

Figure 9

Chemical structure of sphingolipid analogs reported as dihydroceramide desaturase inhibitors.