Therapeutic applications of bioactive sphingolipids in hematological malignancies

Abstract

Sphingolipids are sphingosine-based lipid molecules that have important functions in cellular signal transduction and in a variety of cellular processes including proliferation, differentiation, programmed cell death (apoptosis) and responses to stressful conditions. Ceramides, dihydroceramide, sphingosine and sphingosine-1-phosphate are examples of those bioactive sphingolipids. They have a major impact on determination of the cell fate by contributing to the cell survival or cell death through apoptosis. Despite the number of carbon atoms in the fatty acid chain changes the physiological role; ceramides generally exert suppressive roles on the cell proliferation. There have been several enzymes identified in this pathway that are responsible for the conversion of ceramide into other sphingolipid derivatives. Those derivatives also have differential roles on those cellular processes. Sphingosine-1-phosphate is an example of such sphingolipid derivatives which has antiapoptotic effects. As they have significant impacts particularly on the cell death and survival, bioactive sphingolipids have a great potential to be targets in cancer therapy. Increasing number of studies indicates that sphingolipid derivatives are important in the progression of hematological malignancies, and they are also involved in the resistance to current chemotherapeutic options. This review compiles the current knowledge in this area for enlightening the therapeutic potentials of bioactive sphingolipids in various leukemias.Sphingolipids are one type of lipids that are formed by the combination of a fatty acid and amino alcohol sphingosine with a changeable side chain. Different groups linked to the sphingosine backbone determine the type of the sphingolipid. Ceramide is the fundamental unit for the synthesis of other sphingolipids. They are important constituents of the eukaryotic plasma membranes with the exception of few bacterial species. Since their identification in 1876, sphingolipids have been considered to have mainly structural roles in the cells. However, arising evidence showed that sphingolipids are versatile macromolecules having important roles in a variety of processes including signal transduction, differentiation, proliferation and programed cell death. 1,2 Most widely studied bioactive sphingolipids include ceramide, ceramide-1-phosphate (C1P), dihydroceramide (dhCer), sphingosine and sphingosine-1-phosphate (S1P). 2 Glucosyl ceramide (GluCer) is an another intermediate of sphingolipid metabolism, which was implicated in the drug resistance and cellular trafficking. 3 As sphingolipids are involved in the regulation of essential pathways ensuring the homeostasis, deregulated or defective sphingolipid metabolism might be reflected as pathologic conditions. Indeed, there are numerous studies indicating the importance of sphingolipids in health and disease. 4 This review will present general information about bioactive sphingolipids with an emphasis on the involvement of bioactive sphingolipids in hematological malignancies...

Therapeutic potential of targeting ceramide/glucosylceramide pathway in cancer

“…These membrane lipids do not only function as structural components of the cell membrane, but they also possess important roles in signal transduction as second messengers and in vital cellular processes such as differentiation, migration, apoptosis, cell proliferation, cell cycle arrest, senescence, and inflammation [5][6][7][8]. The basic structure of all sphingolipids consists of up to three components: a sphingoid backbone (such as sphingosine, 1,3-dihydroxy-2-aminoalkane and its derivatives), an amide-linked long-chain fatty acid tail, and several distinct modifications of the head group [9,10].…”

“…Bioactive sphingolipids including ceramide, ceramide-1-phosphate (C1P), dihydroceramide (dhCer), sphingosine, and sphingosine-1-phosphate (S1P) play important roles in malignant growth [6,19]. Ceramide is the central molecule in sphingolipid and glycosphingolipid biosynthesis, and there are three metabolic pathways leading to ceramide: the sphingomyelinase pathway, the de novo pathway, and the exogenous ceramide-recycling pathway [11,18].…”

“…Glucosylceramide (GlcCer) is an important glycosphingolipid metabolic intermediate [6,30,31] which serves as the starting point in the biosynthesis of a wide variety of GSLs [32]. The synthesis and organization of lipids take place at the endoplasmic reticulum (ER) and the Golgi complex and are precisely regulated.…”

“…It either undergoes vesicular trafficking to the cis-Golgi, where it is converted to GlcCer, or gets transported to the trans-Golgi for conversion to sphingomyelin (SM) [33]. GlcCer is the product of the transfer of glucose by glucosylceramide synthase (GCS) from UDP-glucose to ceramide [6,34]. Studies have shown that GluCer has proliferative functions on various cells.…”

“…Studies have shown that GluCer has proliferative functions on various cells. Therefore, it is important in the chemotherapeutic drug resistance [6].…”