Antineoplastic Agents Targeting Sphingolipid Pathways

Abstract

Emerging studies in the enigmatic area of bioactive lipids have made many exciting new discoveries in recent years. Once thought to play a strictly structural role in cellular function, it has since been determined that sphingolipids and their metabolites perform a vast variety of cellular functions beyond what was previously believed. Of utmost importance is their role in cellular signaling, for it is now well understood that select sphingolipids serve as bioactive molecules that play critical roles in both cancer cell death and survival, as well as other cellular responses such as chronic inflammation, protection from intestinal pathogens, and intrinsic protection from intestinal contents, each of which are associated with oncogenesis. Importantly, it has been demonstrated time and time again that many different tumors display dysregulation of sphingolipid metabolism, and the exact profile of said dysregulation has been proven to be useful in determining not only the presence of a tumor, but also the susceptibility to various chemotherapeutic drugs, as well as the metastasizing characteristics of the malignancies. Since these discoveries surfaced it has become apparent that the understanding of sphingolipid metabolism and profile will likely become of great importance in the clinic for both chemotherapy and diagnostics of cancer. The goal of this paper is to provide a comprehensive review of the current state of chemotherapeutic agents that target sphingolipid metabolism that are undergoing clinical trials. Additionally, we will formulate questions involving the use of sphingolipid metabolism as chemotherapeutic targets in need of further research.

Keywords: ceramides; lipid biomarkers; sphingolipids; sphingomyelin; sphingosine-1-phosphate.

Figure 1

Potential targets in ceramide synthesis (sphingolipid) pathways. De novo ceramide synthesis begins at the endoplasmic reticulum (ER) with the condensation of serine and palmitoyl-CoA via serine palmitoyltransferase (SPT) forming 3-ketosphingosine, which is subsequently reduced by 3-ketoshinganine reductase (KSA reductase) to dihydrosphingosine. An acyl group is then linked via an amide bond by ceramide synthase (CerS 1-6) to form dihydroceramide, which is quickly dehydrated between carbons 4 and 5 by dihydroceramide desaturase (DES) to form ceramide (3). Once synthesized, ceramide may be translocated to the trans-golgi via ceramide transferase (CERT), at which it may be degraded, or reformed via salvage pathways (4). Alternatively, ceramide may diffuse to the cis-golgi at which it is converted into glucosylceramide (GluCer), a precursor for important fatty acids such as glycosphingolipids (GSL) and gangliosides (5). The action of sphingomyelin synthase 1 (SMS1) on ceramide at the trans-golgi results in the production of sphingomyelin (SM), composed of a long-chain sphingoid base, an amide-linked acyl chain and a phosphorylcholine headgroup (6). The isoenzymes differ in cellular location, SMS1 localized at the golgi whereas sphingomyelin synthase 2 (SMS2) may be found on the golgi or the plasma membrane (7). Acid sphingomyelinase (SMase) is an enzyme that converts sphingomyelin into ceramide, thus it is an important component of the rheostat. In response to apoptotic stimuli it is has been shown that phospholipid scrambling moves sequestered sphingomyelin from the outer leaflet to the cytosolic side of the plasma membrane such that sphingomyelinase may act on it, producing the apoptotic ceramide (8). The reverse of this process occurs via sphingomyelin synthase, thus to alter the rheostat to favor cell death, chemotherapeutic agents aim to induce sphingomyelinase and inhibit sphingomyelin synthase. Figure 1 has enzymes colored green and red to represent druggable targets that if inhibited, alter the rheostat to promote a pro-survival or pro-apoptotic cellular state respectively. C1P, ceramide-1-phosphate; C1PP, ceramide-1-phosphate phosphatase; CDase, ceramidase; CerK, ceramide kinase; GCase, glucocerebrosidase; GCS, glucosylceramide synthase; nCDase, neutral ceramidase; nSMase, neutral sphingomyelinase; S1P, Sphingosine-1-phosphate; Sph, sphingosine; SphK, sphingosine kinase.

Figure 2

Metabolic pathways of sphingolipids and chemical structures of inhibitors of the pathways. (A) Major synthetic and metabolic pathways of sphingolipids. Increased ceramide leading to cytotoxicty comes from de novo synthesis resulted from stimulation of serine palmitoyltransferase and/or dihydroceramide synthase, or by degradation of sphingomyelins via spingomyelinases. The formation of ceramide-1-phosphate or glucosylceramide is considered shunting pathways to less toxic forms of sphingolipids. (B) The structures of small molecules that are currently under clinical investigation in cancer patients are shown.

Figure 3

Rheostat of sphinglipid. The balance between cell survival and death (apoptosis) in sphingolipids is controlled by four enzymes: sphingosine kinase (SphK), sphingosine-1-phosphate phosphatase (S1PP), ceramidase, and ceramide synthase. The increase in ceramide turns up the rheostat toward apoptosis, and the increase in apoptotic precursors [e.g., sphingosine-1-phosphate (S1P)] toward cell survival.