SEARCH

SEARCH BY CITATION

Keywords:

  • bioactive sphingolipids;
  • leukemia;
  • drug resistance;
  • apoptosis

Abstract

  1. Top of page
  2. Abstract
  3. Types of Bioactive Sphingolipids
  4. Types and Characteristics of Blood Cancers
  5. Bioactive Sphingolipids in Hematological Malignancies
  6. Conclusion and Perspectives
  7. Acknowledgements
  8. References

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 such as acute and chronic leukemias, and it will provide some future perspectives for their usage as the leukemia therapeutics.

Types of Bioactive Sphingolipids

  1. Top of page
  2. Abstract
  3. Types of Bioactive Sphingolipids
  4. Types and Characteristics of Blood Cancers
  5. Bioactive Sphingolipids in Hematological Malignancies
  6. Conclusion and Perspectives
  7. Acknowledgements
  8. References

Ceramide

Ceramides are the central molecules of the sphingolipid metabolism, and they are involved in the regulation of numerous cellular processes including proliferation, differentiation, senescence, apoptosis and responses to stressful conditions. Structure of ceramides contains a sphingosine base and a fatty acid chain with varying number of carbons. Ceramide levels are regulated in the cells by several mechanisms.2 Generation of ceramides and their conversion to other sphingolipid derivatives are essential for this regulation. One of the mechanisms responsible for the generation of ceramides involves the activation of sphingomyelinase (SMase) enzyme, which catalyzes the hydrolysis of membrane phospholipid sphingomyelin (SM) to ceramide.5, 6 TNF-α, FAS ligand and oxidative stress are known to stimulate SMases for the production of ceramides7–9; therefore, this pathway is thought to be particularly important for the elevation of ceramide levels in the stress conditions. Ceramides can also be generated de novo from serine and palmitoyl CoA in endoplasmic reticulum.10, 11 These two compounds initially condense to form ketosphinganine in a reaction catalyzed by serine palmitoyltransferase. This intermediate is then reduced into dihydrosphingosine which would be subsequently converted to dihydroceramide (dhCer) by dihydroceramide synthase. Ceramide synthesis from dhCer is catalyzed by dihydroceramide desaturase in the last step of de novo ceramide production.12 In addition to those pathways, recycling of complex sphingolipids can result in the production of ceramides by a process called the salvage pathway. A variety of enzymes including cerebrosidases, SMases, ceramidases and ceramide synthases are involved in the salvage pathway as a result of which sphingolipids are broken down into sphingosine that would be reutilized for the ceramide production.13

Current evidence indicates the involvement of ceramides in apoptosis, growth arrest, proliferation, survival and aging.14 Ceramides interact with protein kinases and phosphatases for exerting regulative functions in the cellular processes stated previously. Protein phosphatase-1 (PP1) and protein phosphatase-2A (PP-2A) are activated by long-chain ceramides,15 and hence, they are known as ceramide-activated protein phosphatases (CAPPs). Activated CAPPs are responsible for carrying the signal further to downstream targets including retinoblastoma protein, cyclin-dependent kinases (CDKs) and Bcl-2 family members.14, 16 Dephosphorylation of retinoblastoma (Rb) protein upon elevation of the cellular ceramide level is linked to the growth inhibition in lymphoblastic leukemia cell line.17 Moreover, in another study, ceramide was shown to suppress cellular growth by negatively regulating cdk2 through the activation of phosphatases.18 Intrinsic apoptotic pathway is induced by the ceramides through the regulation of cytochrome c release and the loss of mitochondrial membrane potential.19 In addition to these downstream targets, ceramides are known to be interacting with Akt, protein kinase C (PKC), phospholipase D and cathepsin D.20, 21 Ceramides were also linked to the reduction of telomerase activity through the repression of telomerase reverse transcriptase promoter in lung carcinoma cell line.22 Findings of some studies indicated that ceramides with different lengths of fatty acid chains have different roles in the cellular physiology. In the majority of head and neck squamous cell carcinomas, low levels of C18-ceramide were detected, whereas C16-ceramide was significantly upregulated.23, 24 Further studies confirmed that C18-ceramide has apoptotic effects, whereas C16-ceramide contributes to prosurvival.25 In another study, C2-ceramide was found to be unable to induce cell death in K562 chronic myeloid leukemia (CML) cells, whereas C6-ceramide contributed apoptotic induction.26 Investigations in neuroepithelioma cells have shown that C6-ceramide is involved in the apoptotic induction, whereas long-chain ceramides that were accumulated upon the treatment with C6-ceramide are ineffective in this manner.27

Dihydroceramide, ceramide-1-phosphate and glucosyl ceramide

DhCer is an intermediate in the de novo ceramide generation pathway. It is synthesized from dihydrosphingosine (sphinganine) in a reaction catalyzed by dhCer synthase,28 and it is converted to ceramide by dhCer desaturase.12 Initially, dhCer was thought not to be important in apoptosis and cell cycle arrest.29, 30 However, increasing number of studies provided evidence attributing new roles to dhCer in the cells. Induction of autophagy upon treatment with exogenous dhCer analogs is the first clue of dhCer as a bioactive sphingolipid. This effect of dhCer was demonstrated on both prostate and gastric cancer cells.4, 31 Besides its role in autophagy, dhCer is also thought to be important in growth suppression and hypophosphorylation of Rb protein.32, 33 Levels of dhCer were elevated after photodynamic therapy in mice squamous cell carcinoma,34 and this event might indicate the importance of de novo ceramide generation pathway in the photodynamic therapy. Exogenously applied dhCer can be hydrolyzed by the enzymes ACER2/haCER235 and ACER336 to the dihydrosphingosine, which might then be responsible for the cellular effects thought be caused by the dhCer itself. This anticipation is supported by a recent study showing that dhCer and dihydrosphingosine levels are elevated in various tumor cells upon application of fenretinide, where dihydrosphingosine is likely to be the inducer of the cytotoxicity.37

C1P is produced by the phosphorylation of ceramide by the ceramide kinase (CerK), and the reverse reaction is catalyzed by C1P phosphatase.38 Current evidence indicates that C1P has prosurvival functions including induction of DNA replication and suppression of acid SMase that is responsible for the synthesis of ceramide, and therefore, it blocks apoptosis.39, 40 In addition to the cell cycle regulation, C1P is involved in the mammalian inflammatory responses and in the process of neutrophil phagocytosis.41, 42

GluCer is produced from ceramides by the catalysis of glucosylceramide synthase, and it is a precursor for the synthesis of complex glycosphingolipids.43 As shown by the experiments carried on various cells, GluCer has proliferative functions, and it is thought to be important in the chemotherapeutic drug resistance.44, 45 GluCer levels were found to be increased in the resistant cancer cells.46 Inhibition of the GluCer synthesis resulted in sensitization to drugs and cell cycle arrest providing supportive evidence to the roles of GluCer in the development of chemotherapeutic resistance and in the cellular proliferation.47–49 As ceramide exerts antagonistic roles to C1P and GluCer, maintenance of the homeostasis depends on the balance of those lipid species (Fig. 1). Deregulation of these pathways might possibly contribute to the progression of diseases such as cancer.

thumbnail image

Figure 1. Bioactive sphingolipids and their effects on the cell growth and suppression. The balance of the levels of those sphingolipids is essential for the determination of cell fate either as death or survival. dhCer was placed to the middle because of the lack of definitive information showing its roles in cell growth and apoptosis.

Download figure to PowerPoint

Sphingosine and sphingosine-1-phosphate

Ceramide is converted to sphingosine by the ceramidases, which are classified as acid, neutral and alkaline ceramidases according to their optimal pH and cellular locations for enzymatic reaction50–52 (for more information, see the related reviews2, 53). The reverse reaction in which ceramide is synthesized from sphingosine is catalyzed by ceramide synthase. However, under certain circumstances, some ceramidases were also shown to catalyze the reverse reaction to produce ceramides by using sphingosine and a fatty acid as substrates.54, 55 Sphingosine has a strong potential to induce apoptosis in leukemia cells and in a variety of other cell types. Degradation of the genomic DNA as a hallmark of apoptosis was documented in high proportions of the leukemic cells of different origins after exposure to sphingosine.56–59 Similar observations were made for the effects of sphingosine on the cell death in multidrug-resistant cancer cell lines, suggesting that multidrug resistance mechanisms are ineffective for protection against the sphingosine-induced cell death.60, 61 Sphingosine is also effective for apoptotic induction in various cancer cells including epidermoid carcinomas, colonic carcinomas, melanomas and soft tissue sarcomas as shown by numerous other studies.56, 62, 63 Sphingosine might be exerting its functions by interacting with several cellular components. PKC is a known target of sphingosine,64 and because it can be considered as a survival protein, sphingosine-mediated inhibition of PKC is reflected as the apoptotic induction.65 Moreover, sphingosine interacts with other antiapoptotic factors such as ERK and Akt/Protein kinase B.58 Sphingosine-driven apoptotic induction is not only mediated by suppressing the antiapoptotic proteins. Sphingosine was also known to be responsible for cytochrome c release from mitochondria and activation of downstream caspases.66–68 Beta subunits of integrin molecules are among the targets of sphingosine, and their maturation is inhibited by the sphingosine generated specifically by alkaline ceramidase 2.69 In another study, this inhibition was shown to be followed by fragmentation of the Golgi complex and anoikis, which is a form of apoptosis occurring because of the insufficient adhesion.70 This study is one of the emerging studies attributing roles to sphingosine in the cellular processes in which ceramides were thought to be responsible. Similarly, sphingosine and its phosphorylated derivative S1P, both of which are synthesized from ceramides, were shown to be responsible for the regulation of cell death and survival of HeLa cells in another study.35 In accordance with those findings, neurons and oligodendrocytes were documented to have an active sphingolipid metabolism by which exogenous C2- and C6-ceramides are immediately converted into sphingosine and S1P, which in turn determines the cellular fate.71 Apoptosis of the Jurkat cells is induced by sphingosine converted from the ceramide by the acid ceramidase by a process involving cytochrome c release and activation of the executioner caspases.66

Sphingosine is phosphorylated by sphingosine kinase to produce S1P,72, 73 and S1P phosphatase simply cleaves the phosphate group of S1P liberating sphingosine in the reverse reaction.74 S1P also acts antagonistically to the ceramide and enhances cell survival. Angiogenesis, migration, adhesion and inflammation are other cellular processes in which S1P has a role.41, 75 S1P has importance in the translocation of T and B cells from lymphoid organs to the bloodstream.76 Level of S1P is elevated upon activation of sphingosine kinases by the growth factors and cytokines including VEGF and PDGF. S1P was also found to be important in the inflammatory responses by activating COX2 in the presence of TNF-α.77 Unexpectedly, S1P induces growth arrest in keratinocytes, but this observation is not mechanistically related to cytotoxicity or apoptosis; in fact, S1P acts protective for the programed cell death in these cells.78 S1P acts as a ligand to the cell surface receptors of lysophospholipid receptor family, which has five members identified up to date. Some of those receptors demonstrate expressional tissue specificity and provide different tissue-specific responses to S1P.

Types and Characteristics of Blood Cancers

  1. Top of page
  2. Abstract
  3. Types of Bioactive Sphingolipids
  4. Types and Characteristics of Blood Cancers
  5. Bioactive Sphingolipids in Hematological Malignancies
  6. Conclusion and Perspectives
  7. Acknowledgements
  8. References

Uncontrolled malignant growth of blood cells is known as leukemia. Blood cancers can be examined under two main classes as acute and chronic forms. Acute leukemia progresses when the regulation of hematopoiesis is lost at the very initial steps. In this case, malignant cells rapidly accumulate in the bone marrow and bloodstream and prevent the production and functioning of healthy cells. Acute leukemias comprise the form of blood cancer commonly seen in the children. In chronic leukemia, malignant cells are relatively differentiated, yet they are only partially functional. Their progression is slow and may require years to progress and become a life-threatening condition. In addition to these classifications, leukemias are subdivided into further types according to the affected cell lineage. Cancers of the cells having lymphoid origin that would normally differentiate into white blood cells are called as lymphoblastic/lymphocytic leukemias. Myeloid originated cells differentiate into erythrocytes, platelets and other white blood cells under normal physiological conditions; cancers of such cells are known as myeloid/myelogenous leukemia. The following sentences will briefly summarize the current knowledge about various leukemias, but the ones seeking for detailed information about the pathogenesis and progression pathways of those cancers are advised to consult the related review articles.

CML is the first leukemia whose progression is directly linked to a chromosomal aberration. The main driving force of the CML is the translocation between 9th and 22nd chromosomes resulting in the synthesis of BCR/ABL fusion protein showing constitutive tyrosine kinase activity.79 Constitutive tyrosine kinase activity induces cell proliferation and prevention of apoptosis and results in the accumulation of malignant cells in the bone marrow and bloodstream. After its pathobiology is delineated, targeted chemotherapies were developed80 for CML and survival times of the patients are greatly prolonged. Chronic lymphoblastic leukemia (CLL) is the most common form of the leukemia, and it is manifested by the accumulation of CD5-positive B cells in the circulation. Studies attempting to shed light on the molecular biology of CLL have revealed deregulation of Tcl1-Akt pathway, TNF-NFκB pathways and antiapoptotic pathways mediated by Bcl-2 in malignant cells.81 CLL cells are found to be quiescent in the G0 stage of the cell cycle; therefore, their accumulation is linked to the defective apoptotic mechanism.82 Acute myeloid leukemia (AML) is one type of myeloid lineage-originated leukemia. Chemotherapy and radiation was shown to create predisposition for the progression of this leukemia.83, 84 In addition to those, some myelodysplastic disorders are known to turn into AML.85 Acute lymphoblastic leukemia (ALL) is manifested by excess numbers of undifferentiated white blood cell progenitors in the bloodstream. Exact causes of ALL are not known, but some genetic aberrations were observed in the immature leukemic cells. Those aberrations include chromosomal translocations residing the genes encoding for transcription factors responsible for the hematopoiesis.86 Besides those major structural changes, some single nucleotide polymorphisms were shown to be related to ALL.87

Bioactive Sphingolipids in Hematological Malignancies

  1. Top of page
  2. Abstract
  3. Types of Bioactive Sphingolipids
  4. Types and Characteristics of Blood Cancers
  5. Bioactive Sphingolipids in Hematological Malignancies
  6. Conclusion and Perspectives
  7. Acknowledgements
  8. References

Despite the advancements of the therapeutic options and the prolonged survival times in recent years, thanks to them; hematological malignancies are still far away from being eradicated because of the recurrence after the treatment in most cases. Because sphingolipids have important functions in cell cycle regulation and differentiation, considerable effort is being made to reveal the roles of bioactive sphingolipids in the progression or prevention of the blood cancers. Ceramide as the central component of the sphingolipid metabolism is one of the most widely studied sphingolipid species for that purpose. It is involved in a variety of cellular processes such as differentiation and programmed cell death, which are altered in the malignant transformation. Induction of ceramide synthesis and accumulation were documented in the leukemic cells undergoing apoptosis upon treatment with several chemotherapeutic agents. In a study with acute promyelocytic leukemia (APL) and adult T-cell leukemia/lymphoma (ATL) cells, it was shown that cytotoxic levels of ceramides accumulate upon treatment with arsenic trioxide, suggesting that ceramides might be the mediator of the arsenic trioxide-dependent cell death.88 Chemotherapeutic agent etaposide was shown to induce de novo ceramide generation pathway as a result of which cellular ceramide levels are increased and apoptosis is triggered in ALL cell line.89 One study with sodium nitroprusside, which is an NO-donating apoptotic inducer, showed that ceramide generation takes place in NO-induced apoptosis of promyelocytic leukemia cells. This study also provided a link between the enzymes of apoptotic pathway and the enzymes responsible for the production of ceramides from SM, which might be interesting for future research to reveal the roles of sphingolipid species in NO signaling.90 Cannabinoids are compounds having proapoptotic properties for the tumor cells. These compounds induce intrinsic apoptotic pathway, which was shown to be stimulated by the increased levels of ceramides in the Jurkat cell line.91 Retinoids are also known with their apoptotic properties especially through p53-dependent cytotoxicity and increased level of ceramides in solid tumor samples. One study showed that retinoids induce apoptosis through increasing the cellular ceramide levels in ALL cells, whereas no cytotoxicity is observed in the nonmalignant cells.92 Some other chemotherapeutic agents including fludarabine and histone deacetylase inhibitors were also found to induce leukemic cell death through a mechanism involving enhanced ceramide generation.93–95 Cytotoxicity of resveratrol, a novel potent antineoplastic agent, also involves the accumulation of ceramides as documented by various studies.96, 97 By several other studies, direct incorporation of ceramides or ceramide analogs to the cell media was shown to suppress growth of various cancer cell lines.26, 98–102 In addition to their roles in chemotherapeutic cell death, ceramides were also shown to be associated with the photodynamic therapy-induced and gamma radiation-induced apoptosis in different leukemia cell lines.103, 104 As supportive to those observations, suppression of sphingomyelin synthase converting ceramide into SM was shown to potentiate the effects of photodynamic therapy.105 However, according to the cell type used in the experiment, observations for roles of ceramides may differ. For instance, unlike the process in the Jurkat cells,104 ceramides were found to be nonessential for the radiation-induced apoptosis in MOLT-4 cells.106 Some experiments with ALL and AML cells have revealed that ceramides are also functional in cell cycle arrest besides inducing apoptosis.107, 108 Ceramides were also shown to be important second messengers in FAS-induced apoptosis.109, 110

In addition to its roles in suppression of cell growth, ceramide metabolism was also implicated to be altered in the differentiation and chemotherapeutic resistance. In differentiation of AML blasts to macrophage-like and granulocyte-like cells, CerK that produces C1P from ceramide was shown to be differentially regulated, suggesting that CerK may have important functions in differentiation of leukemic cells.111 Involvement of ceramides in differentiation was also addressed by several other studies some of which provide promising data for the usage of ceramides as a therapeutic option for the enhanced responses to the conventional chemotherapy.112–114 Defective ceramide signaling and the loss of the balance between apoptotic and proliferative sphingolipids contribute to the chemotherapeutic resistance in the leukemic cells. Decrease of the ceramide level by its conversion into antiapoptotic GluCer and S1P was shown to be important for conferring chemotherapeutic resistance to leukemic cells in various studies.115, 116 P-glycoprotein (P-gp), an ATP-binding cassette transporter found in the cell membrane, increases cell survival through modulating sphingomyelin–ceramide pathway in addition to its known role in effusing the drug from the cell.117 By further studies, evidence was provided linking P-gp and GluCer synthesis for chemotherapeutic resistance.118, 119 Moreover, defective ceramide metabolism was also shown to contribute to the resistance to radiation-induced cell death, suggesting an important role of ceramides in the apoptosis induced by radiation.120, 121

There are few studies about dhCer as a bioactive sphingolipid in hematological malignancies compared to the ceramide. In one study, dhCer was shown to be unable to induce apoptosis in leukemic cells unlike the ceramides, which might indicate the importance of the double bond in the structure for growth suppressive actions.122 Supporting to the findings of this study, incorporation of the synthetic dhCer to the B-CLL and ALL cells did not result in the increased amount of apoptosis in other studies.101, 123 Suppression of the enzyme sphingomyelin synthase, which is responsible for the conversion of ceramide into SM, caused the accumulation of dhCer and ceramide and eventually sensitized Jurkat T lymphoma/leukemia cells to photodynamic therapy, but dhCer might possibly be an intermediate compound for the subsequent synthesis of ceramides; therefore, apoptotic induction cannot be attributable to the dhCer directly in this scenario.105 However, in another study, cytotoxicity caused by the anticancer agent 4-HPR was shown to be related with the increased amounts of dhCer in HL-60 cells.37

Sphingosine and S1P are other important bioactive sphingolipids in leukemic cells having proapoptotic and antiapoptotic properties, respectively. In various leukemic cell lines, it was shown that sphingosine and its methylated derivative induce apoptosis independent of the involvement of ceramide synthase.56 In another study, sphingosine was shown to induce c-jun expression and apoptosis by a distinct mechanism than ceramide analogs.124 S1P produced by the phosphorylation of sphingosine exerts antiapoptotic functions and thus possibly involved in chemotherapeutic resistance. In fact, apoptosis induced by the application of various chemotherapeutic drugs including imatinib and daunorubicin was suppressed by the S1P as shown in the various leukemia cell lines.125, 126 Because of its tumor-promoting properties, inhibition of S1P synthesis was shown to be potent for obtaining more effective therapeutic responses to conventional drugs in various leukemia types and for overcoming multiple drug resistance.126–131 Studies aiming to shed light on the importance of S1P have revealed that sphingosine kinase is activated by BCR/ABL, Il6 and vitamin D in the CML, multiple myeloma and AML cells, respectively.132–134 Antagonistic function of S1P to apoptosis was found to be mediated by inhibition of the cytochrome c and Smac/DIABLO release from mitochondria in acute leukemia cells.135 Possible chemotactic roles were also attributed to S1P for attracting the nearby phagocytic cells such as macrophages and primary monocytes for the engulfment of the apoptotic cell.136

Conclusion and Perspectives

  1. Top of page
  2. Abstract
  3. Types of Bioactive Sphingolipids
  4. Types and Characteristics of Blood Cancers
  5. Bioactive Sphingolipids in Hematological Malignancies
  6. Conclusion and Perspectives
  7. Acknowledgements
  8. References

Sphingolipids are important constituents of the cells with emerging roles in the regulation of numerous cellular processes. Loss of regulation of the sphingolipid metabolism is involved in the progression of malignancy and drug resistance. As different sphingolipids exert differential functions on the cell growth, one promising approach for eradication of the hematological malignancies is increasing the proapoptotic sphingolipids such as ceramides while suppressing the synthesis of the antiapoptotic ones such as glucosyl ceramide and sphingosine-1-phospate. A variety of studies have shown that this approach is feasible for obtaining better responses to the chemotherapy.35, 40, 43 Usage of bioactive sphingolipids as a therapeutic option as independently or in combination with other drugs gained importance especially for the hematological malignancies in recent years, because leukemic cells are not eradicated completely in the patients despite highly specific drugs, causing relapse of the disease with the resistance to chemotherapy. In this manner, manipulation of sphingolipid metabolism might be a good opportunity to tackle the drug resistance commonly seen in many forms of hematological malignancies. However, because apoptotic sphingolipids such as ceramides may cause cytotoxicity in healthy cells too, future endeavor might be concentrated on delivering those species specifically to the malignant cells. For this reason, studies conducted in the cell lines should be carried further, and more in vivo experiments are needed to be done to reveal the actual potentials of bioactive sphingolipids as cancer therapeutics in leukemias. In the light of the extensive literature being accumulated in this area, responses to leukemia therapies would possibly be advanced in the near future by the involvement of bioactive sphingolipids.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Types of Bioactive Sphingolipids
  4. Types and Characteristics of Blood Cancers
  5. Bioactive Sphingolipids in Hematological Malignancies
  6. Conclusion and Perspectives
  7. Acknowledgements
  8. References

The authors do not have any kind of conflict of interest affecting the compilation of the current knowledge in this area for writing this review. They apologize to the ones whose elegant studies are not included here because of space limitations.

References

  1. Top of page
  2. Abstract
  3. Types of Bioactive Sphingolipids
  4. Types and Characteristics of Blood Cancers
  5. Bioactive Sphingolipids in Hematological Malignancies
  6. Conclusion and Perspectives
  7. Acknowledgements
  8. References
  • 1
    Hannun YA, Obeid LM. Principles of bioactive lipid signalling: lessons from sphingolipids. Nat Rev Mol Cell Biol 2008; 9: 13950.
  • 2
    Bartke N, Hannun YA. Bioactive sphingolipids: metabolism and function. J Lipid Res 2009; 50( Suppl): S91S96.
  • 3
    Radin NS, Shayman JA, Inokuchi J. Metabolic effects of inhibiting glucosylceramide synthesis with PDMP and other substances. Adv Lipid Res 1993; 26: 183213.
  • 4
    Zheng W, Kollmeyer J, Symolon H, Momin A, Munter E, Wang E, Kelly S, Allegood JC, Liu Y, Peng Q, Ramaraju H, Sullards MC, et al. Ceramides and other bioactive sphingolipid backbones in health and disease: lipidomic analysis, metabolism and roles in membrane structure, dynamics, signaling and autophagy. Biochim Biophys Acta 2006; 1758: 186484.
  • 5
    Schneider PB, Kennedy EP. Sphingomyelinase in normal human spleens and in spleens from subjects with Niemann-Pick disease. J Lipid Res 1967; 8: 2029.
  • 6
    Clarke CJ, Snook CF, Tani M, Matmati N, Marchesini N, Hannun YA. The extended family of neutral sphingomyelinases. Biochemistry 2006; 45: 1124756.
  • 7
    Schwandner R, Wiegmann K, Bernardo K, Kreder D, Kronke M. TNF receptor death domain-associated proteins TRADD and FADD signal activation of acid sphingomyelinase. J Biol Chem 1998; 273: 591622.
  • 8
    Lin T, Genestier L, Pinkoski MJ, Castro A, Nicholas S, Mogil R, Paris F, Fuks Z, Schuchman EH, Kolesnick RN, Green DR. Role of acidic sphingomyelinase in Fas/CD95-mediated cell death. J Biol Chem 2000; 275: 865763.
  • 9
    Goldkorn T, Balaban N, Shannon M, Chea V, Matsukuma K, Gilchrist D, Wang H, Chan C. H2O2 acts on cellular membranes to generate ceramide signaling and initiate apoptosis in tracheobronchial epithelial cells. J Cell Sci 1998; 111( Part 21): 320920.
  • 10
    Merrill AH, Jr, Wang E, Mullins RE. Kinetics of long-chain (sphingoid) base biosynthesis in intact LM cells: effects of varying the extracellular concentrations of serine and fatty acid precursors of this pathway. Biochemistry 1988; 27: 3405.
  • 11
    Nagiec MM, Lester RL, Dickson RC. Sphingolipid synthesis: identification and characterization of mammalian cDNAs encoding the Lcb2 subunit of serine palmitoyltransferase. Gene 1996; 177: 23741.
  • 12
    Michel C, van Echten-Deckert G, Rother J, Sandhoff K, Wang E, Merrill AH, Jr. Characterization of ceramide synthesis. A dihydroceramide desaturase introduces the 4,5-trans-double bond of sphingosine at the level of dihydroceramide. J Biol Chem 1997; 272: 224327.
  • 13
    Kitatani K, Idkowiak-Baldys J, Hannun YA. The sphingolipid salvage pathway in ceramide metabolism and signaling. Cell Signal 2008; 20: 101018.
  • 14
    Ogretmen B, Hannun YA. Biologically active sphingolipids in cancer pathogenesis and treatment. Nat Rev Cancer 2004; 4: 60416.
  • 15
    Chalfant CE, Kishikawa K, Mumby MC, Kamibayashi C, Bielawska A, Hannun YA. Long chain ceramides activate protein phosphatase-1 and protein phosphatase-2A. Activation is stereospecific and regulated by phosphatidic acid. J Biol Chem 1999; 274: 2031317.
  • 16
    Wolff RA, Dobrowsky RT, Bielawska A, Obeid LM, Hannun YA. Role of ceramide-activated protein phosphatase in ceramide-mediated signal transduction. J Biol Chem 1994; 269: 196059.
  • 17
    Dbaibo GS, Pushkareva MY, Jayadev S, Schwarz JK, Horowitz JM, Obeid LM, Hannun YA. Retinoblastoma gene product as a downstream target for a ceramide-dependent pathway of growth arrest. Proc Natl Acad Sci USA 1995; 92: 134751.
  • 18
    Lee JY, Bielawska AE, Obeid LM. Regulation of cyclin-dependent kinase 2 activity by ceramide. Exp Cell Res 2000; 261: 30311.
  • 19
    Smyth MJ, Perry DK, Zhang J, Poirier GG, Hannun YA, Obeid LM. prICE: a downstream target for ceramide-induced apoptosis and for the inhibitory action of Bcl-2. Biochem J 1996; 316( Part 1): 258.
  • 20
    Hannun YA, Obeid LM. The ceramide-centric universe of lipid-mediated cell regulation: stress encounters of the lipid kind. J Biol Chem 2002; 277: 2584750.
  • 21
    Heinrich M, Neumeyer J, Jakob M, Hallas C, Tchikov V, Winoto-Morbach S, Wickel M, Schneider-Brachert W, Trauzold A, Hethke A, Schutze S. Cathepsin D links TNF-induced acid sphingomyelinase to Bid-mediated caspase-9 and -3 activation. Cell Death Differ 2004; 11: 55063.
  • 22
    Ogretmen B, Kraveka JM, Schady D, Usta J, Hannun YA, Obeid LM. Molecular mechanisms of ceramide-mediated telomerase inhibition in the A549 human lung adenocarcinoma cell line. J Biol Chem 2001; 276: 3250614.
  • 23
    Koybasi S, Senkal CE, Sundararaj K, Spassieva S, Bielawski J, Osta W, Day TA, Jiang JC, Jazwinski SM, Hannun YA, Obeid LM, Ogretmen B. Defects in cell growth regulation by C18:0-ceramide and longevity assurance gene 1 in human head and neck squamous cell carcinomas. J Biol Chem 2004; 279: 4431119.
  • 24
    Karahatay S, Thomas K, Koybasi S, Senkal CE, Elojeimy S, Liu X, Bielawski J, Day TA, Gillespie MB, Sinha D, Norris JS, Hannun YA, et al. Clinical relevance of ceramide metabolism in the pathogenesis of human head and neck squamous cell carcinoma (HNSCC): attenuation of C(18)-ceramide in HNSCC tumors correlates with lymphovascular invasion and nodal metastasis. Cancer Lett 2007; 256: 10111.
  • 25
    Senkal CE, Ponnusamy S, Bielawski J, Hannun YA, Ogretmen B. Antiapoptotic roles of ceramide-synthase-6-generated C16-ceramide via selective regulation of the ATF6/CHOP arm of ER-stress-response pathways. FASEB J 2010; 24: 296308.
  • 26
    Nica AF, Tsao CC, Watt JC, Jiffar T, Kurinna S, Jurasz P, Konopleva M, Andreeff M, Radomski MW, Ruvolo PP. Ceramide promotes apoptosis in chronic myelogenous leukemia-derived K562 cells by a mechanism involving caspase-8 and JNK. Cell Cycle 2008; 7: 336270.
  • 27
    Mancinetti A, Di Bartolomeo S, Spinedi A. Long-chain ceramide produced in response to N-hexanoylsphingosine does not induce apoptosis in CHP-100 cells. Lipids 2009; 44: 103946.
  • 28
    Koyanagi S, Kuga M, Soeda S, Hosoda Y, Yokomatsu T, Takechi H, Akiyama T, Shibuya S, Shimeno H. Elevation of de novo ceramide synthesis in tumor masses and the role of microsomal dihydroceramide synthase. Int J Cancer 2003; 105: 16.
  • 29
    Bielawska A, Crane HM, Liotta D, Obeid LM, Hannun YA. Selectivity of ceramide-mediated biology. Lack of activity of erythro-dihydroceramide. J Biol Chem 1993; 268: 2622632.
  • 30
    Ahn EH, Schroeder JJ. Sphingoid bases and ceramide induce apoptosis in HT-29 and HCT-116 human colon cancer cells. Exp Biol Med (Maywood) 2002; 227: 34553.
  • 31
    Signorelli P, Munoz-Olaya JM, Gagliostro V, Casas J, Ghidoni R, Fabrias G. Dihydroceramide intracellular increase in response to resveratrol treatment mediates autophagy in gastric cancer cells. Cancer Lett 2009; 282: 23843.
  • 32
    Jiang Q, Wong J, Fyrst H, Saba JD, Ames BN. gamma-Tocopherol or combinations of vitamin E forms induce cell death in human prostate cancer cells by interrupting sphingolipid synthesis. Proc Natl Acad Sci USA 2004; 101: 1782530.
  • 33
    Kraveka JM, Li L, Szulc ZM, Bielawski J, Ogretmen B, Hannun YA, Obeid LM, Bielawska A. Involvement of dihydroceramide desaturase in cell cycle progression in human neuroblastoma cells. J Biol Chem 2007; 282: 1671828.
  • 34
    Separovic D, Bielawski J, Pierce JS, Merchant S, Tarca AL, Ogretmen B, Korbelik M. Increased tumour dihydroceramide production after Photofrin-PDT alone and improved tumour response after the combination with the ceramide analogue LCL29. Evidence from mouse squamous cell carcinomas. Br J Cancer 2009; 100: 62632.
  • 35
    Xu R, Jin J, Hu W, Sun W, Bielawski J, Szulc Z, Taha T, Obeid LM, Mao C. Golgi alkaline ceramidase regulates cell proliferation and survival by controlling levels of sphingosine and S1P. FASEB J 2006; 20: 181325.
  • 36
    Hu W, Xu R, Sun W, Szulc ZM, Bielawski J, Obeid LM, Mao C. Alkaline ceramidase 3 (ACER3) hydrolyzes unsaturated long-chain ceramides, and its down-regulation inhibits both cell proliferation and apoptosis. J Biol Chem 2010; 285: 796476.
  • 37
    Wang H, Maurer BJ, Liu YY, Wang E, Allegood JC, Kelly S, Symolon H, Liu Y, Merrill AH, Jr, Gouaze-Andersson V, Yu JY, Giuliano AE, et al. N-(4-Hydroxyphenyl)retinamide increases dihydroceramide and synergizes with dimethylsphingosine to enhance cancer cell killing. Mol Cancer Ther 2008; 7: 296776.
  • 38
    Sugiura M, Kono K, Liu H, Shimizugawa T, Minekura H, Spiegel S, Kohama T. Ceramide kinase, a novel lipid kinase. Molecular cloning and functional characterization. J Biol Chem 2002; 277: 23294300.
  • 39
    Gomez-Munoz A, Duffy PA, Martin A, O'Brien L, Byun HS, Bittman R, Brindley DN. Short-chain ceramide-1-phosphates are novel stimulators of DNA synthesis and cell division: antagonism by cell-permeable ceramides. Mol Pharmacol 1995; 47: 8339.
  • 40
    Gomez-Munoz A, Kong JY, Salh B, Steinbrecher UP. Ceramide-1-phosphate blocks apoptosis through inhibition of acid sphingomyelinase in macrophages. J Lipid Res 2004; 45: 99105.
  • 41
    Chalfant CE, Spiegel S. Sphingosine 1-phosphate and ceramide 1-phosphate: expanding roles in cell signaling. J Cell Sci 2005; 118: 460512.
  • 42
    Hinkovska-Galcheva VT, Boxer LA, Mansfield PJ, Harsh D, Blackwood A, Shayman JA. The formation of ceramide-1-phosphate during neutrophil phagocytosis and its role in liposome fusion. J Biol Chem 1998; 273: 332039.
  • 43
    Neskovic NM, Rebel G, Harth S, Mandel P. Biosynthesis of galactocerebrosides and glucocerebrosides in glial cell lines. J Neurochem 1981; 37: 136370.
  • 44
    Li R, Manela J, Kong Y, Ladisch S. Cellular gangliosides promote growth factor-induced proliferation of fibroblasts. J Biol Chem 2000; 275: 3421323.
  • 45
    Lucci A, Cho WI, Han TY, Giuliano AE, Morton DL, Cabot MC. Glucosylceramide: a marker for multiple-drug resistant cancers. Anticancer Res 1998; 18: 47580.
  • 46
    Lavie Y, Cao H, Bursten SL, Giuliano AE, Cabot MC. Accumulation of glucosylceramides in multidrug-resistant cancer cells. J Biol Chem 1996; 271: 195306.
  • 47
    Liu YY, Han TY, Giuliano AE, Hansen N, Cabot MC. Uncoupling ceramide glycosylation by transfection of glucosylceramide synthase antisense reverses adriamycin resistance. J Biol Chem 2000; 275: 713843.
  • 48
    Liu YY, Han TY, Giuliano AE, Cabot MC. Expression of glucosylceramide synthase, converting ceramide to glucosylceramide, confers adriamycin resistance in human breast cancer cells. J Biol Chem 1999; 274: 11406.
  • 49
    Rani CS, Abe A, Chang Y, Rosenzweig N, Saltiel AR, Radin NS, Shayman JA. Cell cycle arrest induced by an inhibitor of glucosylceramide synthase. Correlation with cyclin-dependent kinases. J Biol Chem 1995; 270: 285967.
  • 50
    Bernardo K, Hurwitz R, Zenk T, Desnick RJ, Ferlinz K, Schuchman EH, Sandhoff K. Purification, characterization, and biosynthesis of human acid ceramidase. J Biol Chem 1995; 270: 11098102.
  • 51
    Ohlsson L, Palmberg C, Duan RD, Olsson M, Bergman T, Nilsson A. Purification and characterization of human intestinal neutral ceramidase. Biochimie 2007; 89: 95060.
  • 52
    Sugita M, Willians M, Dulaney JT, Moser HW. Ceramidase and ceramide synthesis in human kidney and cerebellum. Description of a new alkaline ceramidase. Biochim Biophys Acta 1975; 398: 12531.
  • 53
    el Bawab S, Mao C, Obeid LM, Hannun YA. Ceramidases in the regulation of ceramide levels and function. Subcell Biochem 2002; 36: 187205.
  • 54
    Okino N, He X, Gatt S, Sandhoff K, Ito M, Schuchman EH. The reverse activity of human acid ceramidase. J Biol Chem 2003; 278: 2994853.
  • 55
    El Bawab S, Birbes H, Roddy P, Szulc ZM, Bielawska A, Hannun YA. Biochemical characterization of the reverse activity of rat brain ceramidase. A CoA-independent and fumonisin B1-insensitive ceramide synthase. J Biol Chem 2001; 276: 1675866.
  • 56
    Sweeney EA, Sakakura C, Shirahama T, Masamune A, Ohta H, Hakomori S, Igarashi Y. Sphingosine and its methylated derivative N,N-dimethylsphingosine (DMS) induce apoptosis in a variety of human cancer cell lines. Int J Cancer 1996; 66: 35866.
  • 57
    Jarvis WD, Fornari FA, Traylor RS, Martin HA, Kramer LB, Erukulla RK, Bittman R, Grant S. Induction of apoptosis and potentiation of ceramide-mediated cytotoxicity by sphingoid bases in human myeloid leukemia cells. J Biol Chem 1996; 271: 827584.
  • 58
    Jarvis WD, Fornari FA, Jr, Auer KL, Freemerman AJ, Szabo E, Birrer MJ, Johnson CR, Barbour SE, Dent P, Grant S. Coordinate regulation of stress- and mitogen-activated protein kinases in the apoptotic actions of ceramide and sphingosine. Mol Pharmacol 1997; 52: 93547.
  • 59
    Ohta H, Sweeney EA, Masamune A, Yatomi Y, Hakomori S, Igarashi Y. Induction of apoptosis by sphingosine in human leukemic HL-60 cells: a possible endogenous modulator of apoptotic DNA fragmentation occurring during phorbol ester-induced differentiation. Cancer Res 1995; 55: 6917.
  • 60
    Klostergaard J, Auzenne E, Leroux E. Characterization of cytotoxicity induced by sphingolipids in multidrug-resistant leukemia cells. Leuk Res 1998; 22: 104956.
  • 61
    Shirahama T, Sweeney EA, Sakakura C, Singhal AK, Nishiyama K, Akiyama S, Hakomori S, Igarashi Y. In vitro and in vivo induction of apoptosis by sphingosine and N, N-dimethylsphingosine in human epidermoid carcinoma KB-3-1 and its multidrug-resistant cells. Clin Cancer Res 1997; 3: 25764.
  • 62
    Nitzsche H, Rosenkranz G. [Examinations foe optimization of exposure voltage in lymphangiography (author's transl)]. Radiol Diagn (Berl) 1976; 17: 191200.
  • 63
    Auzenne E, Leroux ME, Hu M, Pollock RE, Feig B, Klostergaard J. Cytotoxic effects of sphingolipids as single or multi-modality agents on human melanoma and soft tissue sarcoma in vitro. Melanoma Res 1998; 8: 22739.
  • 64
    Hannun YA, Loomis CR, Merrill AH, Jr, Bell RM. Sphingosine inhibition of protein kinase C activity and of phorbol dibutyrate binding in vitro and in human platelets. J Biol Chem 1986; 261: 126049.
  • 65
    Taha TA, Mullen TD, Obeid LM. A house divided: ceramide, sphingosine, and sphingosine-1-phosphate in programmed cell death. Biochim Biophys Acta 2006; 1758: 202736.
  • 66
    Cuvillier O, Edsall L, Spiegel S. Involvement of sphingosine in mitochondria-dependent Fas-induced apoptosis of type II Jurkat T cells. J Biol Chem 2000; 275: 15691700.
  • 67
    Cuvillier O, Nava VE, Murthy SK, Edsall LC, Levade T, Milstien S, Spiegel S. Sphingosine generation, cytochrome c release, and activation of caspase-7 in doxorubicin-induced apoptosis of MCF7 breast adenocarcinoma cells. Cell Death Differ 2001; 8: 16271.
  • 68
    Hung WC, Chang HC, Chuang LY. Activation of caspase-3-like proteases in apoptosis induced by sphingosine and other long-chain bases in Hep3B hepatoma cells. Biochem J 1999; 338( Part 1): 1616.
  • 69
    Sun W, Hu W, Xu R, Jin J, Szulc ZM, Zhang G, Galadari SH, Obeid LM, Mao C. Alkaline ceramidase 2 regulates beta1 integrin maturation and cell adhesion. FASEB J 2009; 23: 65666.
  • 70
    Hu W, Xu R, Zhang G, Jin J, Szulc ZM, Bielawski J, Hannun YA, Obeid LM, Mao C. Golgi fragmentation is associated with ceramide-induced cellular effects. Mol Biol Cell 2005; 16: 155567.
  • 71
    Qin J, Berdyshev E, Goya J, Natarajan V, Dawson G. Neurons and oligodendrocytes recycle sphingosine-1-phosphate to ceramide; significance for apoptosis and multiple sclerosis. J Biol Chem 2010; 285: 1413443.
  • 72
    Liu H, Sugiura M, Nava VE, Edsall LC, Kono K, Poulton S, Milstien S, Kohama T, Spiegel S. Molecular cloning and functional characterization of a novel mammalian sphingosine kinase type 2 isoform. J Biol Chem 2000; 275: 1951320.
  • 73
    Kohama T, Olivera A, Edsall L, Nagiec MM, Dickson R, Spiegel S. Molecular cloning and functional characterization of murine sphingosine kinase. J Biol Chem 1998; 273: 237228.
  • 74
    Mandala SM. Sphingosine-1-phosphate phosphatases. Prostaglandins 2001; 64: 14356.
  • 75
    Spiegel S, Milstien S. Sphingosine-1-phosphate: an enigmatic signalling lipid. Nat Rev Mol Cell Biol 2003; 4: 397407.
  • 76
    Baumruker T, Billich A, Brinkmann V. FTY720, an immunomodulatory sphingolipid mimetic: translation of a novel mechanism into clinical benefit in multiple sclerosis. Expert Opin Investig Drugs 2007; 16: 2839.
  • 77
    Pettus BJ, Bielawski J, Porcelli AM, Reames DL, Johnson KR, Morrow J, Chalfant CE, Obeid LM, Hannun YA. The sphingosine kinase 1/sphingosine-1-phosphate pathway mediates COX-2 induction and PGE2 production in response to TNF-alpha. FASEB J 2003; 17: 141121.
  • 78
    Vogler R, Sauer B, Kim DS, Schafer-Korting M, Kleuser B. Sphingosine-1-phosphate and its potentially paradoxical effects on critical parameters of cutaneous wound healing. J Invest Dermatol 2003; 120: 693700.
  • 79
    Tough IM, Court Brown WM, Baikie AG, Buckton KE, Harnden DG, Jacobs PA, King MJ, Mc BJ. Cytogenetic studies in chronic myeloid leukaemia and acute leukaemia associated with monogolism. Lancet 1961; 1: 41117.
  • 80
    Sawyers CL, Hochhaus A, Feldman E, Goldman JM, Miller CB, Ottmann OG, Schiffer CA, Talpaz M, Guilhot F, Deininger MW, Fischer T, O'Brien SG, et al. Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood 2002; 99: 35309.
  • 81
    Pekarsky Y, Zanesi N, Aqeilan RI, Croce CM. Animal models for chronic lymphocytic leukemia. J Cell Biochem 2007; 100: 110918.
  • 82
    Reed JC. Molecular biology of chronic lymphocytic leukemia. Semin Oncol 1998; 25: 1118.
  • 83
    Bizzozero OJ, Jr, Johnson KG, Ciocco A. Radiation-related leukemia in Hiroshima and Nagasaki, 1946-1964. I. Distribution, incidence and appearance time. N Engl J Med 1966; 274: 1095101.
  • 84
    Le Beau MM, Albain KS, Larson RA, Vardiman JW, Davis EM, Blough RR, Golomb HM, Rowley JD. Clinical and cytogenetic correlations in 63 patients with therapy-related myelodysplastic syndromes and acute nonlymphocytic leukemia: further evidence for characteristic abnormalities of chromosomes no. 5 and 7. J Clin Oncol 1986; 4: 32545.
  • 85
    Sanz GF, Sanz MA, Vallespi T, Canizo MC, Torrabadella M, Garcia S, Irriguible D, San Miguel JF. Two regression models and a scoring system for predicting survival and planning treatment in myelodysplastic syndromes: a multivariate analysis of prognostic factors in 370 patients. Blood 1989; 74: 395408.
  • 86
    Teitell MA, Mikkola HK. Transcriptional activators, repressors, and epigenetic modifiers controlling hematopoietic stem cell development. Pediatr Res 2006; 59: 33R39R.
  • 87
    Papaemmanuil E, Hosking FJ, Vijayakrishnan J, Price A, Olver B, Sheridan E, Kinsey SE, Lightfoot T, Roman E, Irving JA, Allan JM, Tomlinson IP, et al. Loci on 7p12.2, 10q21.2 and 14q11.2 are associated with risk of childhood acute lymphoblastic leukemia. Nat Genet 2009; 41: 100610.
  • 88
    Dbaibo GS, Kfoury Y, Darwiche N, Panjarian S, Kozhaya L, Nasr R, Abdallah M, Hermine O, El-Sabban M, de The H, Bazarbachi A. Arsenic trioxide induces accumulation of cytotoxic levels of ceramide in acute promyelocytic leukemia and adult T-cell leukemia/lymphoma cells through de novo ceramide synthesis and inhibition of glucosylceramide synthase activity. Haematologica 2007; 92: 75362.
  • 89
    Perry DK, Carton J, Shah AK, Meredith F, Uhlinger DJ, Hannun YA. Serine palmitoyltransferase regulates de novo ceramide generation during etoposide-induced apoptosis. J Biol Chem 2000; 275: 907884.
  • 90
    Takeda Y, Tashima M, Takahashi A, Uchiyama T, Okazaki T. Ceramide generation in nitric oxide-induced apoptosis. Activation of magnesium-dependent neutral sphingomyelinase via caspase-3. J Biol Chem 1999; 274: 1065460.
  • 91
    Herrera B, Carracedo A, Diez-Zaera M, Gomez del Pulgar T, Guzman M, Velasco G. The CB2 cannabinoid receptor signals apoptosis via ceramide-dependent activation of the mitochondrial intrinsic pathway. Exp Cell Res 2006; 312: 212131.
  • 92
    O'Donnell PH, Guo WX, Reynolds CP, Maurer BJ. N-(4-hydroxyphenyl)retinamide increases ceramide and is cytotoxic to acute lymphoblastic leukemia cell lines, but not to non-malignant lymphocytes. Leukemia 2002; 16: 90210.
  • 93
    Rosato RR, Maggio SC, Almenara JA, Payne SG, Atadja P, Spiegel S, Dent P, Grant S. The histone deacetylase inhibitor LAQ824 induces human leukemia cell death through a process involving XIAP down-regulation, oxidative injury, and the acid sphingomyelinase-dependent generation of ceramide. Mol Pharmacol 2006; 69: 21625.
  • 94
    Biswal SS, Datta K, Acquaah-Mensah GK, Kehrer JP. Changes in ceramide and sphingomyelin following fludarabine treatment of human chronic B-cell leukemia cells. Toxicology 2000; 154: 4553.
  • 95
    Meng A, Luberto C, Meier P, Bai A, Yang X, Hannun YA, Zhou D. Sphingomyelin synthase as a potential target for D609-induced apoptosis in U937 human monocytic leukemia cells. Exp Cell Res 2004; 292: 38592.
  • 96
    Dolfini E, Roncoroni L, Dogliotti E, Sala G, Erba E, Sacchi N, Ghidoni R. Resveratrol impairs the formation of MDA-MB-231 multicellular tumor spheroids concomitant with ceramide accumulation. Cancer Lett 2007; 249: 1437.
  • 97
    Scarlatti F, Sala G, Somenzi G, Signorelli P, Sacchi N, Ghidoni R. Resveratrol induces growth inhibition and apoptosis in metastatic breast cancer cells via de novo ceramide signaling. FASEB J 2003; 17: 233941.
  • 98
    Maguer-Satta V. CML and apoptosis: the ceramide pathway. Hematol Cell Ther 1998; 40: 2336.
  • 99
    Bielawska A, Linardic CM, Hannun YA. Modulation of cell growth and differentiation by ceramide. FEBS Lett 1992; 307: 21114.
  • 100
    Granot T, Milhas D, Carpentier S, Dagan A, Segui B, Gatt S, Levade T. Caspase-dependent and -independent cell death of Jurkat human leukemia cells induced by novel synthetic ceramide analogs. Leukemia 2006; 20: 3929.
  • 101
    Mengubas K, Riordan FA, Bravery CA, Lewin J, Owens DL, Mehta AB, Hoffbrand AV, Wickremasinghe RG. Ceramide-induced killing of normal and malignant human lymphocytes is by a non-apoptotic mechanism. Oncogene 1999; 18: 2499506.
  • 102
    Dagan A, Wang C, Fibach E, Gatt S. Synthetic, non-natural sphingolipid analogs inhibit the biosynthesis of cellular sphingolipids, elevate ceramide and induce apoptotic cell death. Biochim Biophys Acta 2003; 1633: 1619.
  • 103
    Separovic D, Mann KJ, Oleinick NL. Association of ceramide accumulation with photodynamic treatment-induced cell death. Photochem Photobiol 1998; 68: 1019.
  • 104
    Ardail D, Maalouf M, Boivin A, Chapet O, Bodennec J, Rousson R, Rodriguez-Lafrasse C. Diversity and complexity of ceramide generation after exposure of jurkat leukemia cells to irradiation. Int J Radiat Oncol Biol Phys 2009; 73: 121118.
  • 105
    Separovic D, Semaan L, Tarca AL, Awad Maitah MY, Hanada K, Bielawski J, Villani M, Luberto C. Suppression of sphingomyelin synthase 1 by small interference RNA is associated with enhanced ceramide production and apoptosis after photodamage. Exp Cell Res 2008; 314: 18608.
  • 106
    Takahashi E, Inanami O, Asanuma T, Kuwabara M. Effects of ceramide inhibition on radiation-induced apoptosis in human leukemia MOLT-4 cells. J Radiat Res (Tokyo) 2006; 47: 1925.
  • 107
    Jayadev S, Liu B, Bielawska AE, Lee JY, Nazaire F, Pushkareva M, Obeid LM, Hannun YA. Role for ceramide in cell cycle arrest. J Biol Chem 1995; 270: 204752.
  • 108
    Ben Rejeb A, Boubaker S, Turki I, Massaoudi L, Chibani M, Khouja H. [Placental aspergillosis: myth or reality? Apropos of a case with fetal death in utero]. J Gynecol Obstet Biol Reprod (Paris) 1993; 22: 859.
  • 109
    Herr I, Wilhelm D, Bohler T, Angel P, Debatin KM. Activation of CD95 (APO-1/Fas) signaling by ceramide mediates cancer therapy-induced apoptosis. EMBO J 1997; 16: 62008.
  • 110
    Gulbins E, Bissonnette R, Mahboubi A, Martin S, Nishioka W, Brunner T, Baier G, Baier-Bitterlich G, Byrd C, Lang F, Kolesnick R, Altman A, et al. FAS-induced apoptosis is mediated via a ceramide-initiated RAS signaling pathway. Immunity 1995; 2: 34151.
  • 111
    Date T, Mitsutake S, Igarashi Y. Ceramide kinase expression is altered during macrophage-like cell differentiation of the leukemia cell line HL-60. In Vitro Cell Dev Biol Anim 2007; 43: 3213.
  • 112
    Kim DS, Kim SH, Song JH, Chang YT, Hwang SY, Kim TS. Enhancing effects of ceramide derivatives on 1,25-dihydroxyvitamin D(3)-induced differentiation of human HL-60 leukemia cells. Life Sci 2007; 81: 163844.
  • 113
    Pillai S, Mahajan M, Carlomusto M. Ceramide potentiates, but sphingomyelin inhibits, vitamin D-induced keratinocyte differentiation: comparison between keratinocytes and HL-60 cells. Arch Dermatol Res 1999; 291: 2849.
  • 114
    Murate T, Suzuki M, Hattori M, Takagi A, Kojima T, Tanizawa T, Asano H, Hotta T, Saito H, Yoshida S, Tamiya-Koizumi K. Up-regulation of acid sphingomyelinase during retinoic acid-induced myeloid differentiation of NB4, a human acute promyelocytic leukemia cell line. J Biol Chem 2002; 277: 993643.
  • 115
    Baran Y, Salas A, Senkal CE, Gunduz U, Bielawski J, Obeid LM, Ogretmen B. Alterations of ceramide/sphingosine 1-phosphate rheostat involved in the regulation of resistance to imatinib-induced apoptosis in K562 human chronic myeloid leukemia cells. J Biol Chem 2007; 282: 1092234.
  • 116
    Itoh M, Kitano T, Watanabe M, Kondo T, Yabu T, Taguchi Y, Iwai K, Tashima M, Uchiyama T, Okazaki T. Possible role of ceramide as an indicator of chemoresistance: decrease of the ceramide content via activation of glucosylceramide synthase and sphingomyelin synthase in chemoresistant leukemia. Clin Cancer Res 2003; 9: 41523.
  • 117
    Pallis M, Russell N. P-glycoprotein plays a drug-efflux-independent role in augmenting cell survival in acute myeloblastic leukemia and is associated with modulation of a sphingomyelin-ceramide apoptotic pathway. Blood 2000; 95: 2897904.
  • 118
    Gouaze V, Yu JY, Bleicher RJ, Han TY, Liu YY, Wang H, Gottesman MM, Bitterman A, Giuliano AE, Cabot MC. Overexpression of glucosylceramide synthase and P-glycoprotein in cancer cells selected for resistance to natural product chemotherapy. Mol Cancer Ther 2004; 3: 6339.
  • 119
    Turzanski J, Grundy M, Shang S, Russell N, Pallis M. P-glycoprotein is implicated in the inhibition of ceramide-induced apoptosis in TF-1 acute myeloid leukemia cells by modulation of the glucosylceramide synthase pathway. Exp Hematol 2005; 33: 6272.
  • 120
    Bruno AP, Laurent G, Averbeck D, Demur C, Bonnet J, Bettaieb A, Levade T, Jaffrezou JP. Lack of ceramide generation in TF-1 human myeloid leukemic cells resistant to ionizing radiation. Cell Death Differ 1998; 5: 17282.
  • 121
    Michael JM, Lavin MF, Watters DJ. Resistance to radiation-induced apoptosis in Burkitt's lymphoma cells is associated with defective ceramide signaling. Cancer Res 1997; 57: 36005.
  • 122
    Obeid LM, Linardic CM, Karolak LA, Hannun YA. Programmed cell death induced by ceramide. Science 1993; 259: 176971.
  • 123
    Geley S, Hartmann BL, Kofler R. Ceramides induce a form of apoptosis in human acute lymphoblastic leukemia cells that is inhibited by Bcl-2, but not by CrmA. FEBS Lett 1997; 400: 1518.
  • 124
    Sawai H, Okazaki T, Domae N. Sphingosine-induced c-jun expression: differences between sphingosine- and C2-ceramide-mediated signaling pathways. FEBS Lett 2002; 524: 1036.
  • 125
    Bonhoure E, Lauret A, Barnes DJ, Martin C, Malavaud B, Kohama T, Melo JV, Cuvillier O. Sphingosine kinase-1 is a downstream regulator of imatinib-induced apoptosis in chronic myeloid leukemia cells. Leukemia 2008; 22: 9719.
  • 126
    Sobue S, Nemoto S, Murakami M, Ito H, Kimura A, Gao S, Furuhata A, Takagi A, Kojima T, Nakamura M, Ito Y, Suzuki M, et al. Implications of sphingosine kinase 1 expression level for the cellular sphingolipid rheostat: relevance as a marker for daunorubicin sensitivity of leukemia cells. Int J Hematol 2008; 87: 26675.
  • 127
    Park SR, Cho HJ, Moon KJ, Chun KH, Kong SY, Yoon SS, Lee JS, Park S. Cytotoxic effects of novel phytosphingosine derivatives, including N,N-dimethylphytosphingosine and N-monomethylphytosphingosine, in human leukemia cell line HL60. Leuk Lymphoma 2010; 51: 13245.
  • 128
    Paugh SW, Paugh BS, Rahmani M, Kapitonov D, Almenara JA, Kordula T, Milstien S, Adams JK, Zipkin RE, Grant S, Spiegel S. A selective sphingosine kinase 1 inhibitor integrates multiple molecular therapeutic targets in human leukemia. Blood 2008; 112: 138291.
  • 129
    Kim BM, Choi YJ, Han Y, Yun YS, Hong SH. N,N-dimethyl phytosphingosine induces caspase-8-dependent cytochrome c release and apoptosis through ROS generation in human leukemia cells. Toxicol Appl Pharmacol 2009; 239: 8797.
  • 130
    Bonhoure E, Pchejetski D, Aouali N, Morjani H, Levade T, Kohama T, Cuvillier O. Overcoming MDR-associated chemoresistance in HL-60 acute myeloid leukemia cells by targeting sphingosine kinase-1. Leukemia 2006; 20: 95102.
  • 131
    Ricci C, Onida F, Servida F, Radaelli F, Saporiti G, Todoerti K, Deliliers GL, Ghidoni R. In vitro anti-leukaemia activity of sphingosine kinase inhibitor. Br J Haematol 2009; 144: 3507.
  • 132
    Li QF, Huang WR, Duan HF, Wang H, Wu CT, Wang LS. Sphingosine kinase-1 mediates BCR/ABL-induced upregulation of Mcl-1 in chronic myeloid leukemia cells. Oncogene 2007; 26: 79048.
  • 133
    Li QF, Wu CT, Duan HF, Sun HY, Wang H, Lu ZZ, Zhang QW, Liu HJ, Wang LS. Activation of sphingosine kinase mediates suppressive effect of interleukin-6 on human multiple myeloma cell apoptosis. Br J Haematol 2007; 138: 6329.
  • 134
    Kleuser B, Cuvillier O, Spiegel S. 1Alpha,25-dihydroxyvitamin D3 inhibits programmed cell death in HL-60 cells by activation of sphingosine kinase. Cancer Res 1998; 58: 181724.
  • 135
    Cuvillier O, Levade T. Sphingosine 1-phosphate antagonizes apoptosis of human leukemia cells by inhibiting release of cytochrome c and Smac/DIABLO from mitochondria. Blood 2001; 98: 282836.
  • 136
    Gude DR, Alvarez SE, Paugh SW, Mitra P, Yu J, Griffiths R, Barbour SE, Milstien S, Spiegel S. Apoptosis induces expression of sphingosine kinase 1 to release sphingosine-1-phosphate as a “come-and-get-me” signal. FASEB J 2008; 22: 262938.