• 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.