Targeting Sphingolipids for Cancer Therapy (original) (raw)
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Novel Agents Targeting Bioactive Sphingolipids for the Treatment of Cancer
Current Medicinal Chemistry, 2012
Sphingolipids are a class of lipids that have important functions in a variety of cellular processes such as, differentiation, proliferation, senescence, apoptosis and chemotherapeutic resistance. The most widely studied bioactive shingolipids include ceramides, dihydroceramide (dhCer), ceramide-1-phosphate (C1P), glucosyl-ceramide (GluCer), sphingosine and sphingosine-1-phosphate (S1P). Although the length of fatty acid chain affects the physiological role, ceramides and sphingosine are known to induce apoptosis whereas C1P, S1P and GluCer induce proliferation of cells, which causes the development of chemoresistance. Previous studies have implicated the significance of bioactive shingolipids in oncogenesis, cancer progression and drug-and radiation-resistance. Therefore, targeting the elements of sphingolipid metabolism appears important for the development of novel therapeutics or to increase the effectiveness of the current treatment strategies. Some approaches involve the development of synthetic ceramide analogs, small molecule inhibitors of enzymes such as sphingosine kinase, acid ceramidase or ceramide synthase that catalyze ceramide catabolism or its conversion to various molecular species and S1P receptor antagonists. These approaches mainly aim to up-regulate the levels of apoptotic shingolipids while the proliferative ones are down-regulated, or to directly deliver cytotoxic sphingolipids like short-chain ceramide analogs to tumor cells. It is suggested that a combination therapy with conventional cytotoxic approaches while preventing the conversion of ceramide to S1P and consequently increasing the ceramide levels would be more beneficial. This review compiles the current knowledge about sphingolipids, and mainly focuses on novel agents modulating sphingolipid pathways that represent recent therapeutic strategies for the treatment of cancer.
Sphingolipids: Key Regulators of Apoptosis and Pivotal Players in Cancer Drug Resistance
International Journal of Molecular Sciences, 2014
Drug resistance elicited by cancer cells still constitutes a huge problem that frequently impairs the efficacy of both conventional and novel molecular therapies. Chemotherapy usually acts to induce apoptosis in cancer cells; therefore, the investigation of apoptosis control and of the mechanisms used by cancer cells to evade apoptosis could be translated in an improvement of therapies. Among many tools acquired by cancer cells to this end, the de-regulated synthesis and metabolism of sphingolipids have been well documented. Sphingolipids are known to play many structural and signalling roles in cells, as they are involved in the control of growth, survival, adhesion, and motility. In particular, in order to increase survival, cancer cells: (a) counteract the accumulation of ceramide that is endowed with pro-apoptotic potential and is induced by many drugs; (b) increase the synthesis of sphingosine-1-phosphate and glucosylceramide that are pro-survivals signals; (c) modify the synthesis and the metabolism of complex glycosphingolipids, particularly increasing the levels of modified species of gangliosides such as 9-O acetylated GD3 (αNeu5Ac(2-8)αNeu5Ac(2-3)βGal(1-4)βGlc(1-1)Cer) or N-glycolyl GM3 (αNeu5Ac (2-3)βGal(1-4)βGlc(1-1)Cer) and de-N-acetyl GM3 (NeuNH(2)βGal(1-4)βGlc(1-1)Cer) endowed with anti-apoptotic roles and of globoside Gb3 related to a higher expression of the multidrug resistance gene MDR1. In light of this evidence, the employment of chemical or genetic approaches specifically targeting sphingolipid dysregulations appears a promising tool for the improvement of current chemotherapy efficacy.
Cancer and sphingolipid storage disease therapy using novel synthetic analogs of sphingolipids
Chemistry and Physics of Lipids, 2012
Sphingolipid metabolites have become recognized for their participation in cell functions and signaling events that control a wide array of cellular activities. Two main sphingolipids, ceramide and sphingosine-1-phosphate, are involved in signaling pathways that regulate cell proliferation, apoptosis, motility, differentiation, angiogenesis, stress responses, protein synthesis, carbohydrate metabolism, and intracellular trafficking. Ceramide and S1P often exert opposing effects on cell survival, ceramide being pro-apoptotic and S1P generally promoting cell survival. Therefore, the conversion of one of these metabolites to the other by sphingolipid enzymes provides a vast network of regulation and provides a useful therapeutic target. Here we provide a survey of the current knowledge of the roles of sphingolipid metabolites in cancer and in lipid storage disease. We review our attempts to interfere with this network of regulation and so provide new treatments for a range of diseases. We synthesized novel analogs of sphingolipids which inhibit the hydrolysis of ceramide or its conversion to more complex sphingolipids. These analogs caused elevation of ceramide levels, leading to apoptosis of a variety of cancer cells. Administration of a synthetic analog to tumor-bearing mice resulted in reduction and even disappearance of the tumors. Therapies for sphingolipid storage diseases, such as Niemann-Pick and Gaucher diseases were achieved by two different strategies: inhibition of the biosynthesis of the substrate (substrate reduction therapy) and protection of the mutated enzyme (chaperone therapy). Sphingolipid metabolism was monitored by the use of novel fluorescent sphingolipid analogs. The results described in this review indicate that our synthetic analogs could be developed both as anticancer drugs and for the treatment of sphingolipid storage diseases.
2021
Ceramide metabolism is a potential target for anti-cancer therapy. Studies show that chemotherapeutic agents can induce apoptosis and it is mediated by ceramide. Synthesized sphingolipid analogs can induce cell death in human lymphocytes and leukemia cells. By screening a group of synthetic sphingolipid analogs, we found that low concentrations of AD2750 and AD2646 induced cell death in human cancer cells by preventing ceramide from converting to sphingomyelin, individually or in combination with commercial cancer drugs. The combination of low concentrations of Taxol and AD2750 or AD2646 significantly increased cell death on human colon cancer cells (HT29). Co-administering low concentrations of Doxorubicin with AD2750 or AD2646 elevated cellular toxicity on human pancreatic cancer cells (CRL1687). This synergistic effect is related to the elevated cellular ceramide. Combining AD2750 or AD2646 with chemotherapy drugs can be used to manipulate ceramide and sphingomyelin metabolism, p...
The Role of Sphingolipids Metabolism in Cancer Drug Resistance
Frontiers in Oncology, 2021
Drug resistance continues to be one of the major challenges to cure cancer. As research in this field evolves, it has been proposed that numerous bioactive molecules might be involved in the resistance of cancer cells to certain chemotherapeutics. One well-known group of lipids that play a major role in drug resistance are the sphingolipids. Sphingolipids are essential components of the lipid raft domains of the plasma membrane and this structural function is important for apoptosis and/or cell proliferation. Dysregulation of sphingolipids, including ceramide, sphingomyelin or sphingosine 1-phosphate, has been linked to drug resistance in different types of cancer, including breast, melanoma or colon cancer. Sphingolipid metabolism is complex, involving several lipid catabolism with the participation of key enzymes such as glucosylceramide synthase (GCS) and sphingosine kinase 1 (SPHK1). With an overview of the latest available data on this topic and its implications in cancer thera...
Sphingolipid-Based Synergistic Interactions to Enhance Chemosensitivity in Lung Cancer Cells
Cells
Tumor heterogeneity leads to drug resistance in cancer treatment with the crucial role of sphingolipids in cell fate and stress signaling. We analyzed sphingolipid metabolism and autophagic flux to study chemotherapeutic interactions on the A549 lung cancer model. Loaded cells with fluorescent sphingomyelin analog (BODIPY) and mCherry-EGFP-LC3B were used to track autophagic flux and assess cytotoxicity when cells are exposed to chemotherapy (epirubicin, cisplatin, and paclitaxel) together with sphingolipid pathway inhibitors and autophagy modulators. Our cell model approach employed fluorescent sphingolipid biosensors and a Gaussian Mixture Model of cell heterogeneity profiles to map the influence of chemotherapy on the sphingolipid pathway and infer potential synergistic interactions. Results showed significant synergy, especially when combining epirubicin with autophagy inducers (rapamycin and Torin), reducing cell viability. Cisplatin also synergized with a ceramidase inhibitor. ...
Sphingolipids: regulators of crosstalk between apoptosis and autophagy
The Journal of Lipid Research, 2013
decades ago, pioneering work by Hannun et al. and Kolesnick et al. established the foundation for the bioactive nature of sphingolipids by demonstrating the inhibition of protein kinase C (PKC) by sphingosine and the stimulation of a ceramide-activated protein kinase in response to tumor necrosis factor (TNF)-␣ , respectively ( 1, 2 ). Sphingolipids have since been recognized as critical activators or inhibitors of various protein kinases and phosphatases, receptors, and ion transporters ( 3 ). Moreover, sphingolipids have been identifi ed as key regulators of a vast number of cellular processes, including cell growth, adhesion, migration, senescence, apoptosis, and most recently, autophagy ( 3, 4 ).
A Review of the Role of Sphingolipids in Apoptosis Phenomenon
Journal of Babol University of Medical Sciences, 2018
BACKGROUND AND OBJECTIVE: Cancer is one of the major health problems in the world and chemotherapy is still the most common solution for its treatment. A great deal of studies in this area have been devoted to evaluating the occurrence of apoptosis as a key factor in preventing cell's escape from cell cycle regulation mechanisms. The aim of this study is to summarize the studies on metabolism, messenger pathways and effective pharmaceutical factors on sphingolipids involved in apoptosis. METHODS: In this review article, the national and international databases of PubMed, Scopus, Google Scholar, Web of Science, ISC and Magiran were searched for the keywords "apoptosis", "sphingolipids", "ceramide", "sphingosine" and "cancer" without time limit and the related material was collected. FINDINGS: Among the apoptotic messenger molecules, the key role of the sphingosine and ceramide has been considered as the cornerstone of sphingolipids in many of its controlling processes. It has been shown that ceramide is a key regulator in apoptosis, and increase in its cytoplasmic levels increase the proliferation of cascades resulting in programmed cell death. The bio-production and bio-destruction of ceramide is accomplished by the activity of several enzymes, and much evidence suggests the effect of external factors on enzyme systems. In contrast, the phosphorylated form of sphingosine is an important index for guiding cells toward proliferation and differentiation. It has been found that several commonly used chemotherapy drugs and compounds that are being studied in the treatment of cancer affect at least one of the enzymes of sphingolipids metabolism. CONCLUSION: Sphingolipids and the enzymes involved in their metabolism are introduced as new pharmacological targets for the induction of apoptosis, and it is obvious that analyzing the effective therapeutic factors and the ways of controlling them would be helpful in finding anticancer drugs.