Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 11, Issue 9, 2011

Although sphingolipids were originally discovered in brain extracts more than one and a quarter centuries ago, our understanding of their roles in physiological and pathophysiological processes only began in the last three decades. Sphingolipids are a diverse group of lipids in which fatty acids are linked via amide bonds to a long-chain base or sphingoid (e.g., sphingosine). The term “sphingo-” was coined by the German bioche Read More

Sphingosine-1-phosphate (S1P) is a bioactive lipid with diverse functions including the promotion of cell survival, proliferation and migration, as well as the regulation of angiogenesis, inflammation, immunity, vascular permeability and nuclear mechanisms that control gene transcription. S1P is derived from metabolism of ceramide, which itself has diverse and generally growth-inhibitory effects through its impact on downstrea Read More

Sphingosine-1-phosphate (S1P) is a pleiotropic bioactive lipid mediator that regulates several processes important for hematologic cancer progression. S1P is generated by two sphingosine kinases, SphK1 and SphK2, and is exported outside the cell, where it activates specific cell surface S1P G-protein coupled receptors in autocrine/paracrine manner, coined “inside-out signaling”. In this review, we highlight the im Read More

The sphingolipids ceramide, sphingosine and sphingosine 1-phosphate have emerged as important signaling molecules that regulate a number of important cellular processes. Sphingosine 1-phosphate enhances cell survival and proliferation, and also regulates angiogenesis, cell invasion, and differentiation via both its cell surface G protein-coupled receptors and recently identified intracellular effectors. In contrast, ceramide a Read More

Sphingosine 1-phosphate (S1P) is a bioactive lipid with diverse biological functions, including cell proliferation, differentiation, angiogenesis, chemotaxis, and migration. Many of the activities of S1P are mediated through five closely related G-protein-coupled receptors of the sphingosine-1-phosphate receptor family (S1PR) which play a crucial role in sphingolipid metabolism. Each of these receptors appears to be tissue sp Read More

The sphingolipid sphingosine-1-phosphate (S1P) is an important regulator of immune cell functions in vivo. Besides recruiting lymphocytes to blood and lymph, it may promote immune cell survival and proliferation, but also interferes with their activation. Hereby, S1P may act as an intracellular second messenger or cofactor or, upon being secreted from cells, may bind to and activate a family of specific G-protein-coupled recep Read More

Ceramidases are ubiquitous amidohydrolases that catalyze the cleavage of ceramides into sphingosine and fatty acids. This reaction exerts a cytoprotective role in physiological conditions, while altered ceramidase activities favour a number of human diseases. Among these diseases, several reports point to important roles of ceramidases, mainly the acid ceramidase, in the initiation and progression of cancer, and the Read More

Autophagy is an evolutionary conserved process by which cells recycle intracellular materials to maintain homeostasis in different cellular contexts. Under basal conditions it prevents accumulation of damaged proteins and organelles; during starvation, autophagy provides cells with sufficient nutrients to survive. Sphingolipids are a family of bioactive molecules modulating vital cellular functions such as apoptosis, cell cycle arr Read More

Hypoxia, defined as reduced tissue oxygen concentration, is a characteristic of solid tumors and is an indicator of unfavorable diagnosis in patients. At the cellular level, the adaptation to hypoxia is under the control of two related transcription factors, HIF-1α and HIF-2α (Hypoxia-Inducible Factor), which activate expression of genes promoting angiogenesis, metastasis, increased tumor growth and resistance to treatments. Read More

Since the discovery and initial characterizations of sphingolipids (SLs) in 1884, extensive research has established that these molecules not only are structural components of eukaryotic membranes but they are also critical bioactive lipids involved in fundamental cellular processes such as proliferation, differentiation, apoptosis, inflammation, migration, and autophagy. Altered SL metabolism has been observed in many pat Read More

Almost all classes of bioactive lipids such as cholesterol and cholesterol derivatives, phospholipids and lysophospholipids, eicosanoids, and sphingolipids are critically involved in tumorigenesis. However, a systematic analysis of the distinct tumorigenic functions of lipids is rare. As a general principle, lipids either act directly by binding to receptors and other cell signaling proteins in growth control, or indirectly by regu Read More

Drug resistance represents a serious barrier to the successful treatment of hematological malignancies. In leukemias, resistance mechanisms that involve membrane-resident proteins belonging to the ABC (ATP-binding cassette) transporter protein family are of particular interest, wherein enhanced expression is often associated with poor prognosis and frequent in relapsed or refractory disease. These proteins reduce the i Read More

Sphingolipids are important structural components of membranes, and play an equally important role in basic cellular processes as second messengers. Recently, sphingolipids are receiving increasing attention in cancer research. Ceramide is the central molecule that regulates sphingolipid metabolism forming the basic structural backbone of sphingolipids and the precursor of all complex sphingolipids. It is been Read More

The bioactive sphingolipid, ceramide, has garnered major interest as a principle regulator of cellular stress, proliferation, senescence, and death. Of particular interest to cancer biologists and clinical oncologist, dysregulated ceramide metabolism has been documented in both solid and non-solid malignancies. Moreover, most anticancer chemotherapeutics stimulate ceramide accumulation through increased ceramide synth Read More