, Volume 20, Issue 5, pp 689–711 | Cite as

Tumor suppressive functions of ceramide: evidence and mechanisms

  • Sehamuddin GaladariEmail author
  • Anees Rahman
  • Siraj Pallichankandy
  • Faisal Thayyullathil


Studies over the past two decades have identified ceramide as a multifunctional central molecule in the sphingolipid biosynthetic pathway. Given its diverse tumor suppressive activities, molecular understanding of ceramide action will produce fundamental insights into processes that limit tumorigenesis and may identify key molecular targets for therapeutic intervention. Ceramide can be activated by a diverse array of stresses such as heat shock, genotoxic damage, oxidative stress and anticancer drugs. Ceramide triggers a variety of tumor suppressive and anti-proliferative cellular programs such as apoptosis, autophagy, senescence, and necroptosis by activating or repressing key effector molecules. Defects in ceramide generation and metabolism in cancer contribute to tumor cell survival and resistance to chemotherapy. The potent and versatile anticancer activity profile of ceramide has motivated drug development efforts to (re-)activate ceramide in established tumors. This review focuses on our current understanding of the tumor suppressive functions of ceramide and highlights the potential downstream targets of ceramide which are involved in its tumor suppressive action.


Ceramide Apoptosis Autophagy Senescence Tumor suppression Molecular targets 



This work was financially supported by grants from the UAE University-National Research Foundation (31M097), Terry Fox Foundation for Cancer Research (21M093), The Sheikh Hamdan Award for Medical Sciences (MRG-60/2011-2012). SG is supported by the Al Jalila Foundation for Medical Education and Research.


  1. 1.
    Hannun YA, Obeid LM (2008) Principles of bioactive lipid signalling: lessons from sphingolipids. Nat Rev Mol Cell Biol 9:139–150PubMedGoogle Scholar
  2. 2.
    Albi E, Cataldi S, Bartoccini E et al (2006) Nuclear sphingomyelin pathway in serum deprivation-induced apoptosis of embryonic hippocampal cells. J Cell Physiol 206:189–195PubMedGoogle Scholar
  3. 3.
    Yabu T, Imamura S, Yamashita M, Okazaki T (2008) Identification of Mg2+-dependent neutral sphingomyelinase 1 as a mediator of heat stress-induced ceramide generation and apoptosis. J Biol Chem 283:29971–29982PubMedCentralPubMedGoogle Scholar
  4. 4.
    Kimura K, Markowski M, Edsall LC, Spiegel S, Gelmann EP (2003) Role of ceramide in mediating apoptosis of irradiated LNCaP prostate cancer cells. Cell Death Differ 10:240–248PubMedGoogle Scholar
  5. 5.
    Obeid LM, Linardic CM, Karolak LA, Hannun YA (1993) Programmed cell death induced by ceramide. Science (New York, NY) 259:1769–1771Google Scholar
  6. 6.
    Yabu T, Shiba H, Shibasaki Y et al (2014) Stress-induced ceramide generation and apoptosis via the phosphorylation and activation of nSMase1 by JNK signaling. Cell Death Differ 22:258–273PubMedCentralPubMedGoogle Scholar
  7. 7.
    Pfeilschifter J, Huwiler A (1998) Identification of ceramide targets in interleukin-1 and tumor necrosis factor-alpha signaling in mesangial cells. Kidney Int Suppl 67:S34–S39PubMedGoogle Scholar
  8. 8.
    MacKichan ML, DeFranco AL (1999) Role of ceramide in lipopolysaccharide (LPS)-induced signaling. LPS increases ceramide rather than acting as a structural homolog. J Biol Chem 274:1767–1775PubMedGoogle Scholar
  9. 9.
    Hannun YA, Luberto C (2000) Ceramide in the eukaryotic stress response. Trends Cell Biol 10:73–80PubMedGoogle Scholar
  10. 10.
    Kolesnick R, Fuks Z (2003) Radiation and ceramide-induced apoptosis. Oncogene 22:5897–5906PubMedGoogle Scholar
  11. 11.
    Kizhakkayil J, Thayyullathil F, Chathoth S, Hago A, Patel M, Galadari S (2012) Glutathione regulates caspase-dependent ceramide production and curcumin-induced apoptosis in human leukemic cells. Free Radic Biol Med 52:1854–1864PubMedGoogle Scholar
  12. 12.
    Thayyullathil F, Chathoth S, Kizhakkayil J et al (2011) Glutathione selectively inhibits Doxorubicin induced phosphorylation of p53 Ser(15), caspase dependent ceramide production and apoptosis in human leukemic cells. Biochem Biophys Res Commun 411:1–6PubMedGoogle Scholar
  13. 13.
    Thayyullathil F, Rahman A, Pallichankandy S, Patel M, Galadari S (2014) ROS-dependent prostate apoptosis response-4 (Par-4) up-regulation and ceramide generation are the prime signaling events associated with curcumin-induced autophagic cell death in human malignant glioma. FEBS Open Bio 4:763–776PubMedCentralPubMedGoogle Scholar
  14. 14.
    Young MM, Kester M, Wang HG (2013) Sphingolipids: regulators of crosstalk between apoptosis and autophagy. J Lipid Res 54:5–19PubMedCentralPubMedGoogle Scholar
  15. 15.
    Saddoughi SA, Ogretmen B (2013) Diverse functions of ceramide in cancer cell death and proliferation. Adv Cancer Res 117:37–58PubMedGoogle Scholar
  16. 16.
    Galadari S, Rahman A, Pallichankandy S, Galadari A, Thayyullathil F (2013) Role of ceramide in diabetes mellitus: evidence and mechanisms. Lipids Health Dis 12:98PubMedCentralPubMedGoogle Scholar
  17. 17.
    Senkal CE, Ponnusamy S, Rossi MJ et al (2007) Role of human longevity assurance gene 1 and C18-ceramide in chemotherapy-induced cell death in human head and neck squamous cell carcinomas. Mol Cancer Ther 6:712–722Google Scholar
  18. 18.
    Koybasi S, Senkal CE, Sundararaj K et al (2004) 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 279:44311–44319PubMedGoogle Scholar
  19. 19.
    Min J, Mesika A, Sivaguru M et al (2007) (Dihydro)ceramide synthase 1 regulated sensitivity to cisplatin is associated with the activation of p38 mitogen-activated protein kinase and is abrogated by sphingosine kinase 1. Mol Cancer Res 5:801–812PubMedGoogle Scholar
  20. 20.
    White-Gilbertson S, Mullen T, Senkal C et al (2009) Ceramide synthase 6 modulates TRAIL sensitivity and nuclear translocation of active caspase-3 in colon cancer cells. Oncogene 28:1132–1141PubMedCentralPubMedGoogle Scholar
  21. 21.
    Schiffmann S, Ziebell S, Sandner J et al (2010) Activation of ceramide synthase 6 by celecoxib leads to a selective induction of C16:0-ceramide. Biochem Pharmacol 80:1632–1640PubMedGoogle Scholar
  22. 22.
    Mesicek J, Lee H, Feldman T et al (2010) Ceramide synthases 2, 5, and 6 confer distinct roles in radiation-induced apoptosis in HeLa cells. Cell Signal 22:1300–1307PubMedCentralPubMedGoogle Scholar
  23. 23.
    Mullen TD, Jenkins RW, Clarke CJ, Bielawski J, Hannun YA, Obeid LM (2011) Ceramide synthase-dependent ceramide generation and programmed cell death: involvement of salvage pathway in regulating postmitochondrial events. J Biol Chem 286:15929–15942PubMedCentralPubMedGoogle Scholar
  24. 24.
    Ali M, Fritsch J, Zigdon H, Pewzner-Jung Y, Schutze S, Futerman AH (2013) Altering the sphingolipid acyl chain composition prevents LPS/GLN-mediated hepatic failure in mice by disrupting TNFR1 internalization. Cell Death Dis 4:e929PubMedCentralPubMedGoogle Scholar
  25. 25.
    Senkal CE, Ponnusamy S, Bielawski J, Hannun YA, Ogretmen B (2010) Antiapoptotic roles of ceramide-synthase-6-generated C16-ceramide via selective regulation of the ATF6/CHOP arm of ER-stress-response pathways. FASEB J 24:296–308PubMedCentralPubMedGoogle Scholar
  26. 26.
    Senkal CE, Ponnusamy S, Manevich Y et al (2011) Alteration of ceramide synthase 6/C16-ceramide induces activating transcription factor 6-mediated endoplasmic reticulum (ER) stress and apoptosis via perturbation of cellular Ca2 + and ER/Golgi membrane network. J Biol Chem 286:42446–42458PubMedCentralPubMedGoogle Scholar
  27. 27.
    Schiffmann S, Sandner J, Birod K et al (2009) Ceramide synthases and ceramide levels are increased in breast cancer tissue. Carcinogenesis 30:745–752PubMedGoogle Scholar
  28. 28.
    Marchesini N, Osta W, Bielawski J, Luberto C, Obeid LM, Hannun YA (2004) Role for mammalian neutral sphingomyelinase 2 in confluence-induced growth arrest of MCF7 cells. J Biol Chem 279:25101–25111PubMedGoogle Scholar
  29. 29.
    Zhu XF, Liu ZC, Xie BF, Feng GK, Zeng YX (2003) Ceramide induces cell cycle arrest and upregulates p27kip in nasopharyngeal carcinoma cells. Cancer Lett 193:149–154PubMedGoogle Scholar
  30. 30.
    Venable ME, Lee JY, Smyth MJ, Bielawska A, Obeid LM (1995) Role of ceramide in cellular senescence. J Biol Chem 270:30701–30708PubMedGoogle Scholar
  31. 31.
    Dbaibo GS, Pushkareva MY, Jayadev S et al (1995) Retinoblastoma gene product as a downstream target for a ceramide-dependent pathway of growth arrest. Proc Natl Acad Sci USA 92:1347–1351PubMedCentralPubMedGoogle Scholar
  32. 32.
    Clarke CJ, Mediwala K, Jenkins RW, Sutton CA, Tholanikunnel BG, Hannun YA (2011) Neutral sphingomyelinase-2 mediates growth arrest by retinoic acid through modulation of ribosomal S6 kinase. J Biol Chem 286:21565–21576PubMedCentralPubMedGoogle Scholar
  33. 33.
    Chen L, Luo LF, Lu J et al (2014) FTY720 induces apoptosis of M2 subtype acute myeloid leukemia cells by targeting sphingolipid metabolism and increasing endogenous ceramide levels. PLoS ONE 9:e103033PubMedCentralPubMedGoogle Scholar
  34. 34.
    Lee JY, Bielawska AE, Obeid LM (2000) Regulation of cyclin-dependent kinase 2 activity by ceramide. Exp Cell Res 261:303–311PubMedGoogle Scholar
  35. 35.
    Pruschy M, Resch H, Shi YQ, Aalame N, Glanzmann C, Bodis S (1999) Ceramide triggers p53-dependent apoptosis in genetically defined fibrosarcoma tumour cells. Br J Cancer 80:693–698PubMedCentralGoogle Scholar
  36. 36.
    Kim WH, Kang KH, Kim MY, Choi KH (2000) Induction of p53-independent p21 during ceramide-induced G1 arrest in human hepatocarcinoma cells. Biochem Cell Biol 78:127–135PubMedGoogle Scholar
  37. 37.
    Kim SW, Kim HJ, Chun YJ, Kim MY (2010) Ceramide produces apoptosis through induction of p27(kip1) by protein phosphatase 2A-dependent Akt dephosphorylation in PC-3 prostate cancer cells. J Toxicol Environ Health A 73:1465–1476PubMedGoogle Scholar
  38. 38.
    Rani CS, Abe A, Chang Y et al (1995) Cell cycle arrest induced by an inhibitor of glucosylceramide synthase. Correlation with cyclin-dependent kinases. J Biol Chem 270:2859–2867PubMedGoogle Scholar
  39. 39.
    Phillips DC, Hunt JT, Moneypenny CG et al (2007) Ceramide-induced G2 arrest in rhabdomyosarcoma (RMS) cells requires p21Cip1/Waf1 induction and is prevented by MDM2 overexpression. Cell Death Differ 14:1780–1791PubMedGoogle Scholar
  40. 40.
    Rayess H, Wang MB, Srivatsan ES (2012) Cellular senescence and tumor suppressor gene p16. Int J Cancer 130:1715–1725PubMedCentralPubMedGoogle Scholar
  41. 41.
    Modrak DE, Leon E, Goldenberg DM, Gold DV (2009) Ceramide regulates gemcitabine-induced senescence and apoptosis in human pancreatic cancer cell lines. Mol Cancer Res 7:890–896PubMedGoogle Scholar
  42. 42.
    De Simone C, Ferranti P, Picariello G et al (2011) Peptides from water buffalo cheese whey induced senescence cell death via ceramide secretion in human colon adenocarcinoma cell line. Mol Nutr Food Res 55:229–238PubMedGoogle Scholar
  43. 43.
    Chen JY, Hwang CC, Chen WY et al (2010) Additive effects of C(2)-ceramide on paclitaxel-induced premature senescence of human lung cancer cells. Life Sci 87:350–357PubMedGoogle Scholar
  44. 44.
    Harley CB (2008) Telomerase and cancer therapeutics. Nat Rev Cancer 8:167–179PubMedGoogle Scholar
  45. 45.
    Ogretmen B, Schady D, Usta J et al (2001) Role of ceramide in mediating the inhibition of telomerase activity in A549 human lung adenocarcinoma cells. J Biol Chem 276:24901–24910PubMedGoogle Scholar
  46. 46.
    Ogretmen B, Kraveka JM, Schady D, Usta J, Hannun YA, Obeid LM (2001) Molecular mechanisms of ceramide-mediated telomerase inhibition in the A549 human lung adenocarcinoma cell line. J Biol Chem 276:32506–32514PubMedGoogle Scholar
  47. 47.
    Sundararaj KP, Wood RE, Ponnusamy S et al (2004) Rapid shortening of telomere length in response to ceramide involves the inhibition of telomere binding activity of nuclear glyceraldehyde-3-phosphate dehydrogenase. J Biol Chem 279:6152–6162PubMedGoogle Scholar
  48. 48.
    Ashkenazi A, Dixit VM (1998) Death receptors: signaling and modulation. Science 281:1305–1308PubMedGoogle Scholar
  49. 49.
    Pettus BJ, Chalfant CE, Hannun YA (2002) Ceramide in apoptosis: an overview and current perspectives. Biochim Biophys Acta 1585:114–125PubMedGoogle Scholar
  50. 50.
    Morad SA, Cabot MC (2013) Ceramide-orchestrated signalling in cancer cells. Nat Rev Cancer 13:51–65PubMedGoogle Scholar
  51. 51.
    Dumitru CA, Gulbins E (2006) TRAIL activates acid sphingomyelinase via a redox mechanism and releases ceramide to trigger apoptosis. Oncogene 25:5612–5625PubMedGoogle Scholar
  52. 52.
    Park MA, Mitchell C, Zhang G et al (2010) Vorinostat and sorafenib increase CD95 activation in gastrointestinal tumor cells through a Ca(2 +)-de novo ceramide-PP2A-reactive oxygen species-dependent signaling pathway. Cancer Res 70:6313–6324PubMedCentralPubMedGoogle Scholar
  53. 53.
    Park MA, Zhang G, Martin AP, Hamed H, Mitchell C, Hylemon PB, Graf M, Rahmani M, Ryan K, Liu X, Spiegel S, Norris J, Fisher PB, Grant S, Dent P (2008) Vorinostat and sorafenib increase ER stress, autophagy and apoptosis via ceramide-dependent CD95 and PERK activation. Cancer Biol Ther 7:1648–1662PubMedCentralPubMedGoogle Scholar
  54. 54.
    Schaefer JT, Barthlen W, Schweizer P (2000) Ceramide induces apoptosis in neuroblastoma cell cultures resistant to CD95 (Fas/APO-1)-mediated apoptosis. J Pediatr Surg 35:473–479PubMedGoogle Scholar
  55. 55.
    Voelkel-Johnson C, Hannun YA, El-Zawahry A (2005) Resistance to TRAIL is associated with defects in ceramide signaling that can be overcome by exogenous C6-ceramide without requiring down-regulation of cellular FLICE inhibitory protein. Mol Cancer Ther 4:1320–1327PubMedGoogle Scholar
  56. 56.
    Asakuma J, Sumitomo M, Asano T, Asano T, Hayakawa M (2003) Selective Akt inactivation and tumor necrosis actor-related apoptosis-inducing ligand sensitization of renal cancer cells by low concentrations of paclitaxel. Cancer Res 63:1365–1370PubMedGoogle Scholar
  57. 57.
    Yoon G, Kim KO, Lee J, Kwon D, Shin JS, Kim SJ, Choi IH (2002) Ceramide increases Fas-mediated apoptosis in glioblastoma cells through FLIP down-regulation. J Neurooncol 60:135–1341PubMedGoogle Scholar
  58. 58.
    Novgorodov SA, Szulc ZM, Luberto C et al (2005) Positively charged ceramide is a potent inducer of mitochondrial permeabilization. J Biol Chem 280:16096–16105PubMedGoogle Scholar
  59. 59.
    Birbes H, El Bawab S, Hannun YA, Obeid LM (2001) Selective hydrolysis of a mitochondrial pool of sphingomyelin induces apoptosis. FASEB J 15:2669–2679PubMedGoogle Scholar
  60. 60.
    Birbes H, Luberto C, Hsu YT, El Bawab S, Hannun YA, Obeid LM (2005) A mitochondrial pool of sphingomyelin is involved in TNFalpha-induced Bax translocation to mitochondria. Biochem J 386:445–451PubMedCentralPubMedGoogle Scholar
  61. 61.
    Kashkar H, Wiegmann K, Yazdanpanah B, Haubert D, Kronke M (2005) Acid sphingomyelinase is indispensable for UV light-induced Bax conformational change at the mitochondrial membrane. J Biol Chem 280:20804–20813PubMedGoogle Scholar
  62. 62.
    Birbes H, El Bawab S, Obeid LM, Hannun YA (2002) Mitochondria and ceramide: intertwined roles in regulation of apoptosis. Adv Enzyme Regul 42:113–129PubMedGoogle Scholar
  63. 63.
    von Haefen C, Wieder T, Gillissen B et al (2002) Ceramide induces mitochondrial activation and apoptosis via a Bax-dependent pathway in human carcinoma cells. Oncogene 21:4009–4019Google Scholar
  64. 64.
    Siskind LJ, Kolesnick RN, Colombini M (2006) Ceramide forms channels in mitochondrial outer membranes at physiologically relevant concentrations. Mitochondrion 6:118–125PubMedCentralPubMedGoogle Scholar
  65. 65.
    Sumitomo P, Valverde AM, Rohn JL, Benito M, Lorenzo M (2000) Akt mediates insulin rescue from apoptosis in brown adipocytes: effect of ceramide. Growth Horm IGF Res 10:256–266Google Scholar
  66. 66.
    Sumitomo M, Ohba M, Asakuma J et al (2002) Protein kinase Cdelta amplifies ceramide formation via mitochondrial signaling in prostate cancer cells. J Clin Invest 109:827–836PubMedCentralPubMedGoogle Scholar
  67. 67.
    He C, Klionsky DJ (2009) Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet 43:67–93PubMedCentralPubMedGoogle Scholar
  68. 68.
    Scarlatti F, Bauvy C, Ventruti A et al (2004) Ceramide-mediated macroautophagy involves inhibition of protein kinase B and up-regulation of beclin 1. J Biol Chem 279:18384–18391PubMedGoogle Scholar
  69. 69.
    Pattingre S, Bauvy C, Carpentier S, Levade T, Levine B, Codogno P (2009) Role of JNK1-dependent Bcl-2 phosphorylation in ceramide-induced macroautophagy. J Biol Chem 284:2719–2728PubMedCentralPubMedGoogle Scholar
  70. 70.
    Taniguchi M, Kitatani K, Kondo T et al (2012) Regulation of autophagy and its associated cell death by “sphingolipid rheostat”: reciprocal role of ceramide and sphingosine-1-phosphate in the mammalian target of rapamycin pathway. J Biol Chem 287:39898–39910PubMedCentralPubMedGoogle Scholar
  71. 71.
    Li DD, Wang LL, Deng R et al (2009) The pivotal role of c-Jun NH2-terminal kinase-mediated Beclin 1 expression during anticancer agents-induced autophagy in cancer cells. Oncogene 28:886–898PubMedGoogle Scholar
  72. 72.
    Daido S, Kanzawa T, Yamamoto A, Takeuchi H, Kondo Y, Kondo S (2004) Pivotal role of the cell death factor BNIP3 in ceramide-induced autophagic cell death in malignant glioma cells. Cancer Res 64:4286–4293PubMedGoogle Scholar
  73. 73.
    Sentelle RD, Senkal CE, Jiang W et al (2012) Ceramide targets autophagosomes to mitochondria and induces lethal mitophagy. Nat Chem Biol 8:831–838PubMedCentralPubMedGoogle Scholar
  74. 74.
    Salazar M, Carracedo A, Salanueva IJ et al (2009) Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells. J Clin Invest 119:1359–1372PubMedCentralPubMedGoogle Scholar
  75. 75.
    Deroyer C, Renert AF, Merville MP, Fillet M (2014) New role for EMD (emerin), a key inner nuclear membrane protein, as an enhancer of autophagosome formation in the C16-ceramide autophagy pathway. Autophagy 10:1229–1240PubMedGoogle Scholar
  76. 76.
    Yang YL, Ji C, Bi ZG et al (2013) Deguelin induces both apoptosis and autophagy in cultured head and neck squamous cell carcinoma cells. PLoS ONE 8:e54736PubMedCentralPubMedGoogle Scholar
  77. 77.
    Bhutia SK, Das SK, Azab B et al (2011) Autophagy switches to apoptosis in prostate cancer cells infected with melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24). Autophagy 7:1076–1077PubMedCentralPubMedGoogle Scholar
  78. 78.
    Zhu W, Wang X, Zhou Y, Wang H (2014) C2-ceramide induces cell death and protective autophagy in head and neck squamous cell carcinoma cells. Int J Mol Sci 15:3336–3355PubMedCentralPubMedGoogle Scholar
  79. 79.
    Young MM, Takahashi Y, Khan O et al (2012) Autophagosomal membrane serves as platform for intracellular death-inducing signaling complex (iDISC)-mediated caspase-8 activation and apoptosis. J Biol Chem 287:12455–12468PubMedCentralPubMedGoogle Scholar
  80. 80.
    Vandenabeele P, Galluzzi L, Vanden Berghe T, Kroemer G (2010) Molecular mechanisms of necroptosis: an ordered cellular explosion. Nat Rev Mol Cell Biol 11:700–714PubMedGoogle Scholar
  81. 81.
    Thon L, Mohlig H, Mathieu S et al (2005) Ceramide mediates caspase-independent programmed cell death. FASEB J 19:1945–1956PubMedGoogle Scholar
  82. 82.
    Jones BE, Lo CR, Srinivasan A, Valentino KL, Czaja MJ (1999) Ceramide induces caspase-independent apoptosis in rat hepatocytes sensitized by inhibition of RNA synthesis. Hepatology 30:215–222PubMedGoogle Scholar
  83. 83.
    Mengubas K, Fahey AA, Lewin J, Mehta AB, Hoffbrand AV, Wickremasinghe RG (1999) Killing of T lymphocytes by synthetic ceramide is by a nonapoptotic mechanism and is abrogated following mitogenic activation. Exp Cell Res 249:116–122PubMedGoogle Scholar
  84. 84.
    Ardestani S, Deskins DL, Young PP (2013) Membrane TNF-alpha-activated programmed necrosis is mediated by Ceramide-induced reactive oxygen species. J Mol Signal 8:12PubMedCentralPubMedGoogle Scholar
  85. 85.
    Voigt S, Philipp S, Davarnia P et al (2014) TRAIL-induced programmed necrosis as a novel approach to eliminate tumor cells. BMC Cancer 14:74PubMedCentralPubMedGoogle Scholar
  86. 86.
    Colell A, Ricci JE, Tait S et al (2007) GAPDH and autophagy preserve survival after apoptotic cytochrome c release in the absence of caspase activation. Cell 129:983–997PubMedGoogle Scholar
  87. 87.
    Krasnov GS, Dmitriev AA, Snezhkina AV, Kudryavtseva AV (2013) Deregulation of glycolysis in cancer: glyceraldehyde-3-phosphate dehydrogenase as a therapeutic target. Expert Opin Ther Targets 17:681–693PubMedGoogle Scholar
  88. 88.
    Ryland LK, Doshi UA, Shanmugavelandy SS et al (2013) C6-ceramide nanoliposomes target the Warburg effect in chronic lymphocytic leukemia. PLoS ONE 8:e84648PubMedCentralPubMedGoogle Scholar
  89. 89.
    Simpson CD, Anyiwe K, Schimmer AD (2008) Anoikis resistance and tumor metastasis. Cancer Lett 272:177–185PubMedGoogle Scholar
  90. 90.
    Widau RC, Jin Y, Dixon SA, Wadzinski BE, Gallagher PJ (2010) Protein phosphatase 2A (PP2A) holoenzymes regulate death-associated protein kinase (DAPK) in ceramide-induced anoikis. J Biol Chem 285:13827–13838PubMedCentralPubMedGoogle Scholar
  91. 91.
    Erdreich-Epstein A, Tran LB, Cox OT et al (2005) Endothelial apoptosis induced by inhibition of integrins alphavbeta3 and alphavbeta5 involves ceramide metabolic pathways. Blood 105:4353–4361PubMedCentralPubMedGoogle Scholar
  92. 92.
    Hu W, Xu R, Zhang G et al (2005) Golgi fragmentation is associated with ceramide-induced cellular effects. Mol Biol Cell 16:1555–1567PubMedCentralPubMedGoogle Scholar
  93. 93.
    Goto F, Goto K, Weindel K, Folkman J (1993) Synergistic effects of vascular endothelial growth factor and basic fibroblast growth factor on the proliferation and cord formation of bovine capillary endothelial cells within collagen gels. Lab Invest 69:508–517PubMedGoogle Scholar
  94. 94.
    Yabu T, Tomimoto H, Taguchi Y, Yamaoka S, Igarashi Y, Okazaki T (2005) Thalidomide-induced antiangiogenic action is mediated by ceramide through depletion of VEGF receptors, and is antagonized by sphingosine-1-phosphate. Blood 106:125–134PubMedGoogle Scholar
  95. 95.
    Bansode RR, Ahmedna M, Svoboda KR, Losso JN (2011) Coupling in vitro and in vivo paradigm reveals a dose dependent inhibition of angiogenesis followed by initiation of autophagy by C6-ceramide. Int J Biol Sci 7:629–644PubMedCentralPubMedGoogle Scholar
  96. 96.
    Blazquez C, Gonzalez-Feria L, Alvarez L, Haro A, Casanova ML, Guzman M (2004) Cannabinoids inhibit the vascular endothelial growth factor pathway in gliomas. Cancer Res 64:5617–5623PubMedGoogle Scholar
  97. 97.
    Blazquez C, Salazar M, Carracedo A et al (2008) Cannabinoids inhibit glioma cell invasion by down-regulating matrix metalloproteinase-2 expression. Cancer Res 68:1945–1952PubMedGoogle Scholar
  98. 98.
    Yazama H, Kitatani K, Fujiwara K et al (2014) Dietary glucosylceramides suppress tumor growth in a mouse xenograft model of head and neck squamous cell carcinoma by the inhibition of angiogenesis through an increase in ceramide. Int J Clin Oncol. PMID:25080062Google Scholar
  99. 99.
    Egeblad M, Werb Z (2002) New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2:161–174PubMedGoogle Scholar
  100. 100.
    Debret R, Brassart-Pasco S, Lorin J et al (2008) Ceramide inhibition of MMP-2 expression and human cancer bronchial cell invasiveness involve decreased histone acetylation. Biochim Biophys Acta 1783:1718–1727PubMedGoogle Scholar
  101. 101.
    Zhang S, Zhou J, Zhang C et al (2012) Arsenic trioxide inhibits HCCLM3 cells invasion through de novo ceramide synthesis and sphingomyelinase-induced ceramide production. Med Oncol 29:2251–2260PubMedGoogle Scholar
  102. 102.
    Zhang Y, Yao B, Delikat S et al (1997) Kinase suppressor of Ras is ceramide-activated protein kinase. Cell 89:63–72PubMedGoogle Scholar
  103. 103.
    Yin X, Zafrullah M, Lee H, Haimovitz-Friedman A, Fuks Z, Kolesnick R (2009) A ceramide-binding C1 domain mediates kinase suppressor of ras membrane translocation. Cell Physiol Biochem 24:219–230PubMedCentralPubMedGoogle Scholar
  104. 104.
    Huwiler A, Brunner J, Hummel R et al (1996) Ceramide-binding and activation defines protein kinase c-Raf as a ceramide-activated protein kinase. Proc Natl Acad Sci USA 93:6959–6963PubMedCentralPubMedGoogle Scholar
  105. 105.
    Bourbon NA, Sandirasegarane L, Kester M (2002) Ceramide-induced inhibition of Akt is mediated through protein kinase Czeta: implications for growth arrest. J Biol Chem 277:3286–3292PubMedGoogle Scholar
  106. 106.
    Bourbon NA, Yun J, Kester M (2000) Ceramide directly activates protein kinase C zeta to regulate a stress-activated protein kinase signaling complex. J Biol Chem 275:35617–35623PubMedGoogle Scholar
  107. 107.
    Rana A, Rana B, Mishra R et al (2013) Mixed lineage kinase-c-Jun N-terminal kinase axis: a potential therapeutic target in cancer. Genes Cancer 4:334–341PubMedCentralPubMedGoogle Scholar
  108. 108.
    Sathyanarayana P, Barthwal MK, Kundu CN et al (2002) Activation of the Drosophila MLK by ceramide reveals TNF-alpha and ceramide as agonists of mammalian MLK3. Mol Cell 10:1527–1533PubMedGoogle Scholar
  109. 109.
    Galadari S, Kishikawa K, Kamibayashi C, Mumby MC, Hannun YA (1998) Purification and characterization of ceramide-activated protein phosphatases. Biochemistry 37:11232–11238PubMedGoogle Scholar
  110. 110.
    Wolff RA, Dobrowsky RT, Bielawska A, Obeid LM, Hannun YA (1994) Role of ceramide-activated protein phosphatase in ceramide-mediated signal transduction. J Biol Chem 269:19605–19609PubMedGoogle Scholar
  111. 111.
    Perry DM, Kitatani K, Roddy P, El-Osta M, Hannun YA (2012) Identification and characterization of protein phosphatase 2C activation by ceramide. J Lipid Res 53:1513–1521PubMedCentralPubMedGoogle Scholar
  112. 112.
    Manning BD, Cantley LC (2007) AKT/PKB signaling: navigating downstream. Cell 129:1261–1274PubMedCentralPubMedGoogle Scholar
  113. 113.
    Thayyullathil F, Chathoth S, Shahin A et al (2011) Protein phosphatase 1-dependent dephosphorylation of Akt is the prime signaling event in sphingosine-induced apoptosis in Jurkat cells. J Cell Biochem 112:1138–1153PubMedGoogle Scholar
  114. 114.
    Salinas M, Lopez-Valdaliso R, Martin D, Alvarez A, Cuadrado A (2000) Inhibition of PKB/Akt1 by C2-ceramide involves activation of ceramide-activated protein phosphatase in PC12 cells. Mol Cell Neurosci 15:156–169Google Scholar
  115. 115.
    Schubert KM, Scheid MP, Duronio V (2000) Ceramide inhibits protein kinase B/Akt by promoting dephosphorylation of serine 473. J Biol Chem 275:13330–13335PubMedGoogle Scholar
  116. 116.
    Zhu QY, Wang Z, Ji C et al (2011) C6-ceramide synergistically potentiates the anti-tumor effects of histone deacetylase inhibitors via AKT dephosphorylation and alpha-tubulin hyperacetylation both in vitro and in vivo. Cell Death Dis 2:e117PubMedCentralPubMedGoogle Scholar
  117. 117.
    Mandil R, Ashkenazi E, Blass M et al (2001) Protein kinase Calpha and protein kinase Cdelta play opposite roles in the proliferation and apoptosis of glioma cells. Cancer Res 61:4612–4619PubMedGoogle Scholar
  118. 118.
    Lee JY, Hannun YA, Obeid LM (1996) Ceramide inactivates cellular protein kinase Calpha. J Biol Chem 271:13169–13174Google Scholar
  119. 119.
    Yip KW, Reed JC (2008) Bcl-2 family proteins and cancer. Oncogene 27:6398–6406PubMedGoogle Scholar
  120. 120.
    Ruvolo PP, Deng X, May WS (2001) Phosphorylation of Bcl2 and regulation of apoptosis. Leukemia 15:515–522PubMedGoogle Scholar
  121. 121.
    Ruvolo PP, Deng X, Ito T, Carr BK, May WS (1999) Ceramide induces Bcl2 dephosphorylation via a mechanism involving mitochondrial PP2A. J Biol Chem 274:20296–20300PubMedGoogle Scholar
  122. 122.
    Xin M, Deng X (2006) Protein phosphatase 2A enhances the proapoptotic function of Bax through dephosphorylation. J Biol Chem 281:18859–18867PubMedGoogle Scholar
  123. 123.
    Long JC, Caceres JF (2009) The SR protein family of splicing factors: master regulators of gene expression. Biochem J 417:15–27PubMedGoogle Scholar
  124. 124.
    Chalfant CE, Ogretmen B, Galadari S, Kroesen BJ, Pettus BJ, Hannun YA (2001) FAS activation induces dephosphorylation of SR proteins; dependence on the de novo generation of ceramide and activation of protein phosphatase 1. J Biol Chem 276:44848–44855PubMedGoogle Scholar
  125. 125.
    Patwardhan GA, Hosain SB, Liu DX et al (2014) Ceramide modulates pre-mRNA splicing to restore the expression of wild-type tumor suppressor p53 in deletion-mutant cancer cells. Biochim Biophys Acta 1841:1571–1580PubMedGoogle Scholar
  126. 126.
    Dick FA, Rubin SM (2013) Molecular mechanisms underlying RB protein function. Nat Rev Mol Cell Biol 14:297–306PubMedGoogle Scholar
  127. 127.
    Kishikawa K, Chalfant CE, Perry DK, Bielawska A, Hannun YA (1999) Phosphatidic acid is a potent and selective inhibitor of protein phosphatase 1 and an inhibitor of ceramide-mediated responses. J Biol Chem 274:21335–21341PubMedGoogle Scholar
  128. 128.
    Laplante M, Sabatini DM (2009) mTOR signaling at a glance. J Cell Sci 122:3589–3594PubMedCentralPubMedGoogle Scholar
  129. 129.
    Reyes JG, Robayna IG, Delgado PS et al (1996) c-Jun is a downstream target for ceramide-activated protein phosphatase in A431 cells. J Biol Chem 271:21375–21380PubMedGoogle Scholar
  130. 130.
    Jin Y, Blue EK, Gallagher PJ (2006) Control of death-associated protein kinase (DAPK) activity by phosphorylation and proteasomal degradation. J Biol Chem 281:39033–39040PubMedCentralPubMedGoogle Scholar
  131. 131.
    Shohat G, Spivak-Kroizman T, Cohen O et al (2001) The pro-apoptotic function of death-associated protein kinase is controlled by a unique inhibitory autophosphorylation-based mechanism. J Biol Chem 276:47460–47467PubMedGoogle Scholar
  132. 132.
    Pelled D, Raveh T, Riebeling C et al (2002) Death-associated protein (DAP) kinase plays a central role in ceramide-induced apoptosis in cultured hippocampal neurons. J Biol Chem 277:1957–1961PubMedGoogle Scholar
  133. 133.
    Elliott BE, Meens JA, SenGupta SK, Louvard D, Arpin M (2005) The membrane cytoskeletal crosslinker ezrin is required for metastasis of breast carcinoma cells. Breast Cancer Res 7:R365–R373PubMedCentralPubMedGoogle Scholar
  134. 134.
    Canals D, Roddy P, Hannun YA (2012) Protein phosphatase 1alpha mediates ceramide-induced ERM protein dephosphorylation: a novel mechanism independent of phosphatidylinositol 4, 5-biphosphate (PIP2) and myosin/ERM phosphatase. J Biol Chem 287:10145–10155PubMedCentralPubMedGoogle Scholar
  135. 135.
    Canals D, Jenkins RW, Roddy P et al (2010) Differential effects of ceramide and sphingosine 1-phosphate on ERM phosphorylation: probing sphingolipid signaling at the outer plasma membrane. J Biol Chem 285:32476–32485PubMedCentralPubMedGoogle Scholar
  136. 136.
    Wada T, Penninger JM (2004) Mitogen-activated protein kinases in apoptosis regulation. Oncogene 23:2838–2849PubMedGoogle Scholar
  137. 137.
    Nica AF, Tsao CC, Watt JC et al (2008) Ceramide promotes apoptosis in chronic myelogenous leukemia-derived K562 cells by a mechanism involving caspase-8 and JNK. Cell Cycle 7:3362–3370PubMedCentralPubMedGoogle Scholar
  138. 138.
    Mondal S, Mandal C, Sangwan R, Chandra S, Mandal C (2010) Withanolide D induces apoptosis in leukemia by targeting the activation of neutral sphingomyelinase-ceramide cascade mediated by synergistic activation of c-Jun N-terminal kinase and p38 mitogen-activated protein kinase. Mol Cancer 9:239PubMedCentralPubMedGoogle Scholar
  139. 139.
    Lu Z, Xu S (2006) ERK1/2 MAP kinases in cell survival and apoptosis. IUBMB Life 58(621):631Google Scholar
  140. 140.
    Galve-Roperh I, Sanchez C, Cortes ML, Gomez del Pulgar T, Izquierdo M, Guzman M (2000) Anti-tumoral action of cannabinoids: involvement of sustained ceramide accumulation and extracellular signal-regulated kinase activation. Nat Med 6:313–319PubMedGoogle Scholar
  141. 141.
    Czubowicz K, Strosznajder R (2014) Ceramide in the molecular mechanisms of neuronal cell death. The role of sphingosine-1-phosphate. Mol Neurobiol 50:26–37PubMedCentralPubMedGoogle Scholar
  142. 142.
    Kim HJ, Oh JE, Kim SW, Chun YJ, Kim MY (2008) Ceramide induces p38 MAPK-dependent apoptosis and Bax translocation via inhibition of Akt in HL-60 cells. Cancer Lett 260:88–95PubMedGoogle Scholar
  143. 143.
    Chen CL, Lin CF, Chang WT, Huang WC, Teng CF, Lin YS (2008) Ceramide induces p38 MAPK and JNK activation through a mechanism involving a thioredoxin-interacting protein-mediated pathway. Blood 111:4365–4374PubMedGoogle Scholar
  144. 144.
    Ito A, Uehara T, Tokumitsu A, Okuma Y, Nomura Y (1999) Possible involvement of cytochrome c release and sequential activation of caspases in ceramide-induced apoptosis in SK-N-MC cells. Biochim Biophys Acta 1452:263–274PubMedGoogle Scholar
  145. 145.
    Hearps AC, Burrows J, Connor CE, Woods GM, Lowenthal RM, Ragg SJ (2002) Mitochondrial cytochrome c release precedes transmembrane depolarisation and caspase-3 activation during ceramide-induced apoptosis of Jurkat T cells. Apoptosis 7:387–394PubMedGoogle Scholar
  146. 146.
    Cande C, Vahsen N, Garrido C, Kroemer G (2004) Apoptosis-inducing factor (AIF): caspase-independent after all. Cell Death Differ 11:591–595PubMedGoogle Scholar
  147. 147.
    Daugas E, Susin SA, Zamzami N et al (2000) Mitochondrio-nuclear translocation of AIF in apoptosis and necrosis. FASEB J 14:729–739PubMedGoogle Scholar
  148. 148.
    Kim NH, Kim K, Park WS, Son HS, Bae Y (2007) PKB/Akt inhibits ceramide-induced apoptosis in neuroblastoma cells by blocking apoptosis-inducing factor (AIF) translocation. J Cell Biochem 102:1160–1170PubMedGoogle Scholar
  149. 149.
    Park JY, Kim MJ, Kim YK, Woo JS (2011) Ceramide induces apoptosis via caspase-dependent and caspase-independent pathways in mesenchymal stem cells derived from human adipose tissue. Arch Toxicol 85:1057–1065PubMedGoogle Scholar
  150. 150.
    Li LY, Luo X, Wang X (2001) Endonuclease G is an apoptotic DNase when released from mitochondria. Nature 412:95–99PubMedGoogle Scholar
  151. 151.
    Basnakian AG, Ueda N, Hong X, Galitovsky VE, Yin X, Shah SV (2005) Ceramide synthase is essential for endonuclease-mediated death of renal tubular epithelial cells induced by hypoxia-reoxygenation. Am J Physiol Renal Physiol 288:F308–F314PubMedGoogle Scholar
  152. 152.
    Cuvillier O, Levade T (2001) Sphingosine 1-phosphate antagonizes apoptosis of human leukemia cells by inhibiting release of cytochrome c and Smac/DIABLO from mitochondria. Blood 98:2828–2836PubMedGoogle Scholar
  153. 153.
    Gong T, Wang Q, Lin Z, Chen ML, Sun GZ (2012) Endoplasmic reticulum (ER) stress inhibitor salubrinal protects against ceramide-induced SH-SY5Y cell death. Biochem Biophys Res Commun 427:461–465PubMedGoogle Scholar
  154. 154.
    Yao J, Bi HE, Sheng Y et al (2013) Ultraviolet (UV) and hydrogen peroxide activate ceramide-ER stress-AMPK signaling axis to promote retinal pigment epithelium (RPE) cell apoptosis. Int J Mol Sci 14:10355–10368PubMedCentralPubMedGoogle Scholar
  155. 155.
    Lin CF, Chen CL, Chiang CW, Jan MS, Huang WC, Lin YS (2007) GSK-3beta acts downstream of PP2A and the PI 3-kinase-Akt pathway, and upstream of caspase-2 in ceramide-induced mitochondrial apoptosis. J Cell Sci 120:2935–2943PubMedGoogle Scholar
  156. 156.
    Zhu Q, Lin L, Cheng Q et al (2012) The role of acid sphingomyelinase and caspase 5 in hypoxia-induced HuR cleavage and subsequent apoptosis in hepatocytes. Biochim Biophys Acta 1821:1453–1461PubMedGoogle Scholar
  157. 157.
    Cuvillier O, Rosenthal DS, Smulson ME, Spiegel S (1998) Sphingosine 1-phosphate inhibits activation of caspases that cleave poly(ADP-ribose) polymerase and lamins during Fas- and ceramide-mediated apoptosis in Jurkat T lymphocytes. J Biol Chem 273:2910–2916PubMedGoogle Scholar
  158. 158.
    Jiang YJ, Kim P, Uchida Y et al (2013) Ceramides stimulate caspase-14 expression in human keratinocytes. Exp Dermatol 22:113–118PubMedCentralPubMedGoogle Scholar
  159. 159.
    Heinrich M, Neumeyer J, Jakob M et al (2004) Cathepsin D links TNF-induced acid sphingomyelinase to Bid-mediated caspase-9 and -3 activation. Cell Death Differ 11:550–563PubMedGoogle Scholar
  160. 160.
    Heinrich M, Wickel M, Schneider-Brachert W et al (1999) Cathepsin D targeted by acid sphingomyelinase-derived ceramide. EMBO J 18:5252–5263PubMedCentralPubMedGoogle Scholar
  161. 161.
    Khoo KH, Verma CS, Lane DP (2014) Drugging the p53 pathway: understanding the route to clinical efficacy. Nat Rev Drug Discov 13:217–236PubMedGoogle Scholar
  162. 162.
    Kim SS, Chae HS, Bach JH et al (2002) P53 mediates ceramide-induced apoptosis in SKN-SH cells. Oncogene 21:2020–2028PubMedGoogle Scholar
  163. 163.
    Liu YY, Patwardhan GA, Bhinge K, Gupta V, Gu X, Jazwinski SM (2011) Suppression of glucosylceramide synthase restores p53-dependent apoptosis in mutant p53 cancer cells. Cancer Res 71:2276–2285PubMedCentralPubMedGoogle Scholar
  164. 164.
    Kim HJ, Mun JY, Chun YJ, Choi KH, Kim MY (2001) Bax-dependent apoptosis induced by ceramide in HL-60 cells. FEBS Lett 505:264–268PubMedGoogle Scholar
  165. 165.
    Jin J, Mullen TD, Hou Q et al (2009) AMPK inhibitor Compound C stimulates ceramide production and promotes Bax redistribution and apoptosis in MCF7 breast carcinoma cells. J Lipid Res 50:2389–2397PubMedCentralPubMedGoogle Scholar
  166. 166.
    Sawada M, Nakashima S, Banno Y et al (2000) Ordering of ceramide formation, caspase activation, and Bax/Bcl-2 expression during etoposide-induced apoptosis in C6 glioma cells. Cell Death Differ 7:761–772PubMedGoogle Scholar
  167. 167.
    Kurinna SM, Tsao CC, Nica AF, Jiffar T, Ruvolo PP (2004) Ceramide promotes apoptosis in lung cancer-derived A549 cells by a mechanism involving c-Jun NH2-terminal kinase. Cancer Res 64:7852–7856PubMedGoogle Scholar
  168. 168.
    Basu S, Bayoumy S, Zhang Y, Lozano J, Kolesnick R (1998) BAD enables ceramide to signal apoptosis via Ras and Raf-1. J Biol Chem 273:30419–30426PubMedGoogle Scholar
  169. 169.
    Fulda S, Vucic D (2012) Targeting IAP proteins for therapeutic intervention in cancer. Nat Rev Drug Discov 11:109–124PubMedGoogle Scholar
  170. 170.
    Paschall AV, Zimmerman MA, Torres CM et al (2014) Ceramide targets xIAP and cIAP1 to sensitize metastatic colon and breast cancer cells to apoptosis induction to suppress tumor progression. BMC Cancer 14:24PubMedCentralPubMedGoogle Scholar
  171. 171.
    Liu X, Ryland L, Yang J et al (2010) Targeting of survivin by nanoliposomal ceramide induces complete remission in a rat model of NK-LGL leukemia. Blood 116:4192–4201PubMedCentralPubMedGoogle Scholar
  172. 172.
    Lin IL, Chou HL, Lee JC et al (2014) The antiproliferative effect of C2-ceramide on lung cancer cells through apoptosis by inhibiting Akt and NFkappaB. Cancer Cell Int 14:1PubMedCentralPubMedGoogle Scholar
  173. 173.
    Struckhoff AP, Patel B, Beckman BS (2010) Inhibition of p53 sensitizes MCF-7 cells to ceramide treatment. Int J Oncol 37:21–30PubMedGoogle Scholar
  174. 174.
    Alesse E, Zazzeroni F, Angelucci A, Giannini G, Di Marcotullio L, Gulino A (1998) The growth arrest and downregulation of c-myc transcription induced by ceramide are related events dependent on p21 induction, Rb underphosphorylation and E2F sequestering. Cell Death Differ 5:381–389PubMedGoogle Scholar
  175. 175.
    Bocci G, Fioravanti A, Orlandi P et al (2012) Metronomic ceramide analogs inhibit angiogenesis in pancreatic cancer through up-regulation of caveolin-1 and thrombospondin-1 and down-regulation of cyclin D1. Neoplasia 14:833–845PubMedCentralPubMedGoogle Scholar
  176. 176.
    Dhule SS, Penfornis P, He J et al (2014) The combined effect of encapsulating curcumin and C6 ceramide in liposomal nanoparticles against osteosarcoma. Mol Pharm 11:417–427PubMedGoogle Scholar
  177. 177.
    Venable ME, Bielawska A, Obeid LM (1996) Ceramide inhibits phospholipase D in a cell-free system. J Biol Chem 271:24800–24805PubMedGoogle Scholar
  178. 178.
    Abousalham A, Liossis C, O’Brien L, Brindley DN (1997) Cell-permeable ceramides prevent the activation of phospholipase D by ADP-ribosylation factor and RhoA. J Biol Chem 272:1069–1075PubMedGoogle Scholar
  179. 179.
    Singh IN, Stromberg LM, Bourgoin SG, Sciorra VA, Morris AJ, Brindley DN (2001) Ceramide inhibition of mammalian phospholipase D1 and D2 activities is antagonized by phosphatidylinositol 4,5-bisphosphate. Biochemistry 40:11227–11233PubMedGoogle Scholar
  180. 180.
    Ji C, Yang B, Yang YL et al (2010) Exogenous cell-permeable C6 ceramide sensitizes multiple cancer cell lines to Doxorubicin-induced apoptosis by promoting AMPK activation and mTORC1 inhibition. Oncogene 29:6557–6568PubMedGoogle Scholar
  181. 181.
    Chen MB, Zhang Y, Wei MX et al (2013) Activation of AMP-activated protein kinase (AMPK) mediates plumbagin-induced apoptosis and growth inhibition in cultured human colon cancer cells. Cell Signal 25:1993–2002PubMedGoogle Scholar
  182. 182.
    Koomoa DL, Yco LP, Borsics T, Wallick CJ, Bachmann AS (2008) Ornithine decarboxylase inhibition by alpha-difluoromethylornithine activates opposing signaling pathways via phosphorylation of both Akt/protein kinase B and p27Kip1 in neuroblastoma. Cancer Res 68:9825–9831PubMedCentralPubMedGoogle Scholar
  183. 183.
    Flamigni F, Faenza I, Marmiroli S et al (1997) Inhibition of the expression of ornithine decarboxylase and c-Myc by cell-permeant ceramide in difluoromethylornithine-resistant leukaemia cells. Biochem J 324(Pt 3):783–789PubMedCentralPubMedGoogle Scholar
  184. 184.
    Ulrich S, Huwiler A, Loitsch S, Schmidt H, Stein JM (2007) De novo ceramide biosynthesis is associated with resveratrol-induced inhibition of ornithine decarboxylase activity. Biochem Pharmacol 74:281–289PubMedGoogle Scholar
  185. 185.
    Siskind LJ, Mullen TD, Romero Rosales K et al (2010) The BCL-2 protein BAK is required for long-chain ceramide generation during apoptosis. J Biol Chem 285:11818–11826PubMedCentralPubMedGoogle Scholar
  186. 186.
    Zeidan YH, Wu BX, Jenkins RW, Obeid LM, Hannun YA (2008) A novel role for protein kinase Cdelta-mediated phosphorylation of acid sphingomyelinase in UV light-induced mitochondrial injury. FASEB J 22:183–193PubMedGoogle Scholar
  187. 187.
    Alphonse G, Aloy MT, Broquet P et al (2002) Ceramide induces activation of the mitochondrial/caspases pathway in Jurkat and SCC61 cells sensitive to gamma-radiation but activation of this sequence is defective in radioresistant SQ20B cells. Int J Radiat Biol 78:821–835PubMedGoogle Scholar
  188. 188.
    Alphonse G, Bionda C, Aloy MT, Ardail D, Rousson R, Rodriguez-Lafrasse C (2004) Overcoming resistance to gamma-rays in squamous carcinoma cells by poly-drug elevation of ceramide levels. Oncogene 23:2703–2715PubMedGoogle Scholar
  189. 189.
    Kimura K, Bowen C, Spiegel S, Gelmann EP (1999) Tumor necrosis factor-alpha sensitizes prostate cancer cells to gamma-irradiation-induced apoptosis. Cancer Res 59:1606–1614PubMedGoogle Scholar
  190. 190.
    Verheij M, Bose R, Lin XH et al (1996) Requirement for ceramide-initiated SAPK/JNK signalling in stress-induced apoptosis. Nature 380:75–79PubMedGoogle Scholar
  191. 191.
    Kondo T, Matsuda T, Kitano T et al (2000) Role of c-jun expression increased by heat shock- and ceramide-activated caspase-3 in HL-60 cell apoptosis. Possible involvement of ceramide in heat shock-induced apoptosis. J Biol Chem 275:7668–7676PubMedGoogle Scholar
  192. 192.
    Martin D, Salinas M, Fujita N, Tsuruo T, Cuadrado A (2002) Ceramide and reactive oxygen species generated by H2O2 induce caspase-3-independent degradation of Akt/protein kinase B. J Biol Chem 277:42943–42952PubMedGoogle Scholar
  193. 193.
    Won JS, Singh I (2006) Sphingolipid signaling and redox regulation. Free Radic Biol Med 40:1875–1888PubMedGoogle Scholar
  194. 194.
    Salh B, Assi K, Huang S, O’Brien L, Steinbrecher U, Gomez-Muñoz A (2002) Dissociated ROS production and ceramide generation in sulfasalazine-induced cell death in Raw 264.7 cells. J Leukoc Biol 72:790–799PubMedGoogle Scholar
  195. 195.
    Dbaibo GS, Obeid LM, Hannun YA (1993) Tumor necrosis factor-alpha (TNF-alpha) signal transduction through ceramide. Dissociation of growth inhibitory effects of TNF-alpha from activation of nuclear factor-kappa B. J Biol Chem 268:17762–17766PubMedGoogle Scholar
  196. 196.
    Smyth MJ, Perry DK, Zhang J, Poirier GG, Hannun YA, Obeid LM (1996) prICE: a downstream target for ceramide-induced apoptosis and for the inhibitory action of Bcl-2. Biochem J 316:25–28PubMedCentralPubMedGoogle Scholar
  197. 197.
    Bezombes C, Maestre N, Laurent G, Levade T, Bettaïeb A, Jaffrézou JP (1998) Restoration of TNF-alpha-induced ceramide generation and apoptosis in resistant human leukemia KG1a cells by the P-glycoprotein blocker PSC833. FASEB J 12:101–109PubMedGoogle Scholar
  198. 198.
    Hetz CA, Hunn M, Rojas P, Torres V, Leyton L, Quest AF (2002) Caspase-dependent initiation of apoptosis and necrosis by the Fas receptor in lymphoid cells: onset of necrosis is associated with delayed ceramide increase. J Cell Sci 115:4671–4683PubMedGoogle Scholar
  199. 199.
    Dobrowsky RT, Werner MH, Castellino AM, Chao MV, Hannun YA (1994) Activation of the sphingomyelin cycle through the low-affinity neurotrophin receptor. Science 265:1596–1599PubMedGoogle Scholar
  200. 200.
    Edsall LC, Pirianov GG, Spiegel S (1997) Involvement of sphingosine-1-phosphate in nerve growth factor-mediated neuronal survival and differentiation. J Neurosci 17:6952–6960PubMedGoogle Scholar
  201. 201.
    Kawase M, Watanabe M, Kondo T et al (2002) Increase of ceramide in adriamycin-induced HL-60 cell apoptosis: detection by a novel anti-ceramide antibody. Biochim Biophys Acta 1584:104–114PubMedGoogle Scholar
  202. 202.
    Bose R, Verheij M, Haimovitz-Friedman A, Scotto K, Fuks Z, Kolesnick R (1995) Ceramide synthase mediates daunorubicin-induced apoptosis: an alternative mechanism for generating death signals. Cell 82:405–414PubMedGoogle Scholar
  203. 203.
    Jaffrézou JP, Levade T, Bettaïeb A et al (1996) Daunorubicin-induced apoptosis: triggering of ceramide generation through sphingomyelin hydrolysis. EMBO J 15:2417–2424PubMedCentralPubMedGoogle Scholar
  204. 204.
    Turnbull KJ, Brown BL, Dobson PR (1999) Caspase-3-like activity is necessary but not sufficient for daunorubicin-induced apoptosis in Jurkat human lymphoblastic leukemia cells. Leukemia 13:1056–1061PubMedGoogle Scholar
  205. 205.
    Perry DK, Carton J, Shah AK, Meredith F, Uhlinger DJ, Hannun YA (2000) Serine palmitoyltransferase regulates de novo ceramide generation during etoposide-induced apoptosis. J Biol Chem 275:9078–9084PubMedGoogle Scholar
  206. 206.
    Jiang L, Pan X, Chen Y, Wang K, Du Y, Zhang J (2011) Preferential involvement of both ROS and ceramide in fenretinide-induced apoptosis of HL60 rather than NB4 and U937 cells. Biochem Biophys Res Commun 405:314–318PubMedGoogle Scholar
  207. 207.
    O’Donnell PH, Guo WX, Reynolds CP, Maurer BJ (2002) N-(4-hydroxyphenyl)retinamide increases ceramide and is cytotoxic to acute lymphoblastic leukemia cell lines, but not to non-malignant lymphocytes. Leukemia 16:902–910PubMedGoogle Scholar
  208. 208.
    Morales MC, Pérez-Yarza G, Rementería NN et al (2007) 4-HPR-mediated leukemia cell cytotoxicity is triggered by ceramide-induced mitochondrial oxidative stress and is regulated downstream by Bcl-2. Free Radic Res 41:591–601PubMedGoogle Scholar
  209. 209.
    Erdreich-Epstein A, Tran LB, Bowman NN et al (2002) Ceramide signaling in fenretinide-induced endothelial cell apoptosis. J Biol Chem 277:49531–49537PubMedGoogle Scholar
  210. 210.
    Dbaibo GS, Pushkareva MY, Rachid RA et al (1998) p53-dependent ceramide response to genotoxic stress. J Clin Invest 102:329–339PubMedCentralPubMedGoogle Scholar
  211. 211.
    Noda S, Yoshimura S, Sawada M et al (2001) Role of ceramide during cisplatin-induced apoptosis in C6 glioma cells. J Neurooncol 52:11–21PubMedGoogle Scholar
  212. 212.
    Lacour S, Hammann A, Grazide S et al (2004) Cisplatin-induced CD95 redistribution into membrane lipid rafts of HT29 human colon cancer cells. Cancer Res 64:3593–3598PubMedGoogle Scholar
  213. 213.
    Garzotto M, White-Jones M, Jiang Y et al (1998) 12-O-tetradecanoylphorbol-13-acetate-induced apoptosis in LNCaP cells is mediated through ceramide synthase. Cancer Res 58:2260–2264PubMedGoogle Scholar
  214. 214.
    Whitman SP, Civoli F, Daniel LW (1997) Protein kinase CbetaII activation by 1-beta-D-arabinofuranosylcytosine is antagonistic to stimulation of apoptosis and Bcl-2alpha down-regulation. J Biol Chem 272:23481–23484PubMedGoogle Scholar
  215. 215.
    Bradshaw CD, Ella KM, Thomas AL, Qi C, Meier KE (1996) Effects of Ara-C on neutral sphingomyelinase and mitogen- and stress-activated protein kinases in T-lymphocyte cell lines. Biochem Mol Biol Int 40:709–719PubMedGoogle Scholar
  216. 216.
    Charles AG, Han TY, Liu YY, Hansen N, Giuliano AE, Cabot MC (2001) Taxol-induced ceramide generation and apoptosis in human breast cancer cells. Cancer Chemother Pharmacol 47:444–450PubMedGoogle Scholar
  217. 217.
    Zhang J, Alter N, Reed JC, Borner C, Obeid LM, Hannun YA (1996) Bcl-2 interrupts the ceramide-mediated pathway of cell death. Proc Natl Acad Sci USA 93:5325–5328PubMedCentralPubMedGoogle Scholar
  218. 218.
    Cabot MC, Giuliano AE, Han TY, Liu YY (1999) SDZ PSC 833, the cyclosporine A analogue and multidrug resistance modulator, activates ceramide synthesis and increases vinblastine sensitivity in drug-sensitive and drug-resistant cancer cells. Cancer Res 59:880–885PubMedGoogle Scholar
  219. 219.
    Giussani P, Bassi R, Anelli V et al (2012) Glucosylceramide synthase protects glioblastoma cells against autophagic and apoptotic death induced by temozolomide and Paclitaxel. Cancer Invest 30:27–37PubMedGoogle Scholar
  220. 220.
    Dbaibo GS, Kfoury Y, Darwiche N et al (2007) 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 92:753–762PubMedGoogle Scholar
  221. 221.
    Cifone MG, Migliorati G, Parroni R et al (1999) Dexamethasone-induced thymocyte apoptosis: apoptotic signal involves the sequential activation of phosphoinositide-specific phospholipase C, acidic sphingomyelinase, and caspases. Blood 93:2282–2296PubMedGoogle Scholar
  222. 222.
    Gill JS, Windebank AJ (1997) Role of ceramide in suramin-induced cancer cell death. Cancer Lett 119:169–176PubMedGoogle Scholar
  223. 223.
    Rubio S, Quintana J, Eiroa JL, Triana J, Estevez F (2010) Betuletol 3-methyl ether induces G(2)-M phase arrest and activates the sphingomyelin and MAPK pathways in human leukemia cells. Mol Carcinog 49:32–43PubMedGoogle Scholar
  224. 224.
    Wiesner DA, Dawson G (1996) Staurosporine induces programmed cell death in embryonic neurons and activation of the ceramide pathway. J Neurochem 66:1418–1425PubMedGoogle Scholar
  225. 225.
    Kurita-Ochiai T, Amano S, Fukushima K, Ochiai K (2003) Cellular events involved in butyric acid-induced T cell apoptosis. J Immunol 171:3576–3584PubMedGoogle Scholar
  226. 226.
    Yun SH, Park ES, Shin SW et al (2012) Stichoposide C induces apoptosis through the generation of ceramide in leukemia and colorectal cancer cells and shows in vivo antitumor activity. Clin Cancer Res 18:5934–5948PubMedGoogle Scholar
  227. 227.
    Dumitru CA, Sandalcioglu IE, Wagner M, Weller M, Gulbins E (2009) Lysosomal ceramide mediates gemcitabine-induced death of glioma cells. Lysosomal ceramide mediates gemcitabine-induced death of glioma cells. J Mol Med (Berl). 87:1123–1132PubMedGoogle Scholar
  228. 228.
    Baran Y, Salas A, Senkal CE et al (2007) 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 282:10922–10934PubMedGoogle Scholar
  229. 229.
    Gencer EB, Ural AU, Avcu F, Baran Y (2011) A novel mechanism of dasatinib-induced apoptosis in chronic myeloid leukemia; ceramide synthase and ceramide clearance genes. Ann Hematol 90:1265–1275PubMedGoogle Scholar
  230. 230.
    Wang H, Giuliano AE, Cabot MC (2002) Enhanced de novo ceramide generation through activation of serine palmitoyltransferase by the P-glycoprotein antagonist SDZ PSC 833 in breast cancer cells. Mol Cancer Ther 1:719–726PubMedGoogle Scholar
  231. 231.
    Litvak DA, Bilchik AJ, Cabot MC (2003) Modulators of ceramide metabolism sensitize colorectal cancer cells to chemotherapy: a novel treatment strategy. J Gastrointest Surg 7:140–148PubMedGoogle Scholar
  232. 232.
    Laethem RM, Hannun YA, Jayadev S et al (1998) Increases in neutral, Mg2+-dependent and acidic, Mg2+-independent sphingomyelinase activities precede commitment to apoptosis and are not a consequence of caspase 3-like activity in Molt-4 cells in response to thymidylate synthase inhibition by GW1843. Blood 91:4350–4360PubMedGoogle Scholar
  233. 233.
    Cianchi F, Vinci MC, Supuran CT et al (2010) Selective inhibition of carbonic anhydrase IX decreases cell proliferation and induces ceramide-mediated apoptosis in human cancer cells. J Pharmacol Exp Ther 334:710–719PubMedGoogle Scholar
  234. 234.
    Wang M, Yu T, Zhu C et al (2014) Resveratrol triggers protective autophagy through the ceramide/Akt/mTOR pathway in melanoma B16 cells. Nutr Cancer 66:435–440PubMedGoogle Scholar
  235. 235.
    Scarlatti F, Sala G, Somenzi G, Signorelli P, Sacchi N, Ghidoni R (2003) Resveratrol induces growth inhibition and apoptosis in metastatic breast cancer cells via de novo ceramide signaling. FASEB J 17:2339–2341PubMedGoogle Scholar
  236. 236.
    Chow SE, Kao CH, Liu YT et al (2014) Resveratrol induced ER expansion and ER caspase-mediated apoptosis in human nasopharyngeal carcinoma cells. Apoptosis 19:527–541PubMedGoogle Scholar
  237. 237.
    Moussavi M, Assi K, Gomez-Munoz A, Salh B (2006) Curcumin mediates ceramide generation via the de novo pathway in colon cancer cells. Carcinogenesis 27:1636–1644PubMedGoogle Scholar
  238. 238.
    Li J, Yu W, Tiwary R et al (2010) α-TEA-induced death receptor dependent apoptosis involves activation of acid sphingomyelinase and elevated ceramide-enriched cell surface membranes. Cancer Cell Int 10:40PubMedCentralPubMedGoogle Scholar
  239. 239.
    Sánchez AM, Malagarie-Cazenave S, Olea N, Vara D, Chiloeches A, Díaz-Laviada I (2007) Apoptosis induced by capsaicin in prostate PC-3 cells involves ceramide accumulation, neutral sphingomyelinase, and JNK activation. Apoptosis 12:2013–2024PubMedGoogle Scholar
  240. 240.
    Zheng QY, Jin FS, Yao C, Zhang T, Zhang GH, Ai X (2012) Ursolic acid-induced AMP-activated protein kinase (AMPK) activation contributes to growth inhibition and apoptosis in human bladder cancer T24 cells. Biochem Biophys Res Commun 419:741–747PubMedGoogle Scholar
  241. 241.
    Gopalan A, Yu W, Jiang Q, Jang Y, Sanders BG, Kline K (2012) Involvement of de novo ceramide synthesis in gamma-tocopherol and gamma-tocotrienol-induced apoptosis in human breast cancer cells. Mol Nutr Food Res 56:1803–1811PubMedGoogle Scholar
  242. 242.
    Tan X, Zhang Y, Jiang B, Zhou D (2002) Changes in ceramide levels upon catechins-induced apoptosis in LoVo cells. Life Sci 70:2023–2029PubMedGoogle Scholar
  243. 243.
    Li T, Ying L, Wang H et al (2012) Microcystin-LR induces ceramide to regulate PP2A and destabilize cytoskeleton in HEK293 cells. Toxicol Sci 128:147–157PubMedGoogle Scholar
  244. 244.
    Gong L, Yang B, Xu M et al (2014) Bortezomib-induced apoptosis in cultured pancreatic cancer cells is associated with ceramide production. Cancer Chemother Pharmacol 73:69–77PubMedGoogle Scholar
  245. 245.
    Chauvier D, Morjani H, Manfait M (2002) Ceramide involvement in homocamptothecin- and camptothecin-induced cytotoxicity and apoptosis in colon HT29 cells. Int J Oncol 20:855–863PubMedGoogle Scholar
  246. 246.
    Meyers-Needham M, Lewis JA, Gencer S et al (2012) Off-target function of the Sonic hedgehog inhibitor cyclopamine in mediating apoptosis via nitric oxide-dependent neutral sphingomyelinase 2/ceramide induction. Mol Cancer Ther 11:1092–1102PubMedCentralPubMedGoogle Scholar
  247. 247.
    Huang H, Zhang Y, Liu X et al (2011) Acid sphingomyelinase contributes to evodiamine-induced apoptosis in human gastric cancer SGC-7901 cells. DNA Cell Biol 30:407–412PubMedGoogle Scholar
  248. 248.
    Biswal SS, Datta K, Acquaah-Mensah GK, Kehrer JP (2000) Changes in ceramide and sphingomyelin following fludarabine treatment of human chronic B-cell leukemia cells. Toxicology 154:45–53PubMedGoogle Scholar
  249. 249.
    Maggio SC, Rosato RR, Kramer LB et al (2004) The histone deacetylase inhibitor MS-275 interacts synergistically with fludarabine to induce apoptosis in human leukemia cells. Cancer Res 64:2590–2600PubMedGoogle Scholar
  250. 250.
    Bareford MD, Hamed HA, Allegood J et al (2012) Sorafenib and pemetrexed toxicity in cancer cells is mediated via SRC-ERK signaling. Cancer Biol Ther 13:793–803PubMedCentralPubMedGoogle Scholar
  251. 251.
    Ji C, Yang YL, He L et al (2012) Increasing ceramides sensitizes genistein-induced melanoma cell apoptosis and growth inhibition. Biochem Biophys Res Commun 421:462–467PubMedGoogle Scholar
  252. 252.
    Guillermet-Guibert J, Davenne L, Pchejetski D et al (2009) Targeting the sphingolipid metabolism to defeat pancreatic cancer cell resistance to the chemotherapeutic gemcitabine drug. Mol Cancer Ther 8:809–820PubMedGoogle Scholar
  253. 253.
    Zhu X, Du X, Deng X et al (2014) C6 ceramide sensitizes pemetrexed-induced apoptosis and cytotoxicity in osteosarcoma cells. Biochem Biophys Res Commun 452:72–78PubMedGoogle Scholar
  254. 254.
    Morad SA, Madigan JP, Levin JC et al (2013) Tamoxifen magnifies therapeutic impact of ceramide in human colorectal cancer cells independent of p53. Biochem Pharmacol 85:1057–1065PubMedCentralPubMedGoogle Scholar
  255. 255.
    Mehta S, Blackinton D, Omar I et al (2000) Combined cytotoxic action of paclitaxel and ceramide against the human Tu138 head and neck squamous carcinoma cell line. Cancer Chemother Pharmacol 46:85–92PubMedGoogle Scholar
  256. 256.
    Flowers M, Fabriás G, Delgado A, Casas J, Abad JL, Cabot MC (2012) C6-ceramide and targeted inhibition of acid ceramidase induce synergistic decreases in breast cancer cell growth. Breast Cancer Res Treat 133:447–458PubMedGoogle Scholar
  257. 257.
    Qin LS, Yu ZQ, Zhang SM et al (2013) The short chain cell-permeable ceramide (C6) restores cell apoptosis and perifosine sensitivity in cultured glioblastoma cells. Mol Biol Rep 40:5645–5655PubMedGoogle Scholar
  258. 258.
    Yu T, Li J, Sun H (2010) C6 ceramide potentiates curcumin-induced cell death and apoptosis in melanoma cell lines in vitro. Cancer chemother and pharmacol 66:999–1003Google Scholar
  259. 259.
    Tran MA, Smith CD, Kester M, Robertson GP (2008) Combining nanoliposomal ceramide with sorafenib synergistically inhibits melanoma and breast cancer cell survival to decrease tumor development. Clin Cancer Res 14:3571–3581PubMedGoogle Scholar
  260. 260.
    Jiang Y, DiVittore NA, Kaiser JM et al (2011) Combinatorial therapies improve the therapeutic efficacy of nanoliposomal ceramide for pancreatic cancer. Cancer Biol Ther 12:574–585PubMedCentralPubMedGoogle Scholar
  261. 261.
    Yang L, Zheng LY, Tian Y et al (2015) C6 ceramide dramatically enhances docetaxel-induced growth inhibition and apoptosis in cultured breast cancer cells: a mechanism study. Exp Cell Res. S0014-4827(14)00558-8. doi: 10.1016/j.yexcr.2014.12.017
  262. 262.
    Separovic D, Saad ZH, Edwin EA et al (2011) C16-ceramide analog combined with Pc 4 photodynamic therapy evokes enhanced total ceramide accumulation, promotion of DEVDase activation in the absence of apoptosis, and augmented overall cell killing. J Lipids 2011:713867PubMedCentralPubMedGoogle Scholar
  263. 263.
    Separovic D, Bielawski J, Pierce JS et al (2011) Enhanced tumor cures after Foscan photodynamic therapy combined with the ceramide analog LCL29. Evidence from mouse squamous cell carcinomas for sphingolipids as biomarkers of treatment response. Int J Oncol 38:521–527PubMedCentralPubMedGoogle Scholar
  264. 264.
    Separovic D, Bielawski J, Pierce JS et al (2009) 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 100:626–632PubMedCentralPubMedGoogle Scholar
  265. 265.
    Giovannetti E, Leon LG, Bertini S et al (2010) Study of apoptosis induction and deoxycytidine kinase/cytidine deaminase modulation in the synergistic interaction of a novel ceramide analog and gemcitabine in pancreatic cancer cells. Nucleosides Nucleotides Nucleic Acids 29:419–426PubMedGoogle Scholar
  266. 266.
    Chiu WH, Chen HH, Chang JY et al (2014) Inhibiting glucosylceramide synthase facilitates the radiosensitizing effects of vinorelbine in lung adenocarcinoma cells. Cancer Lett 349:144–151PubMedGoogle Scholar
  267. 267.
    Gouazé V, Liu YY, Prickett CS, Yu JY, Giuliano AE, Cabot MC (2005) Glucosylceramide synthase blockade down-regulates P-glycoprotein and resensitizes multidrug-resistant breast cancer cells to anticancer drugs. Cancer Res 65:3861–3867PubMedGoogle Scholar
  268. 268.
    Huang WC, Tsai CC, Chen CL et al (2011) Glucosylceramide synthase inhibitor PDMP sensitizes chronic myeloid leukemia T315I mutant to Bcr-Abl inhibitor and cooperatively induces glycogen synthase kinase-3-regulated apoptosis. FASEB J 25:3661–3673PubMedGoogle Scholar
  269. 269.
    Chen B, Yin L, Cheng J et al (2011) Effect of D, L-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol and tetrandrine on the reversion of multidrug resistance in K562/A02 cells. Hematology 16:24–30PubMedGoogle Scholar
  270. 270.
    Casson L, Howell L, Mathews LA et al (2013) Inhibition of ceramide metabolism sensitizes human leukemia cells to inhibition of BCL2-like proteins. PLoS ONE 8:e54525PubMedCentralPubMedGoogle Scholar
  271. 271.
    Gouaze-Andersson V, Flowers M, Karimi R et al (2011) Inhibition of acid ceramidase by a 2-substituted aminoethanol amide synergistically sensitizes prostate cancer cells to N-(4-hydroxyphenyl) retinamide. Prostate 71:1064–1073PubMedGoogle Scholar
  272. 272.
    Elojeimy S, Liu X, McKillop JC et al (2007) Role of acid ceramidase in resistance to FasL: therapeutic approaches based on acid ceramidase inhibitors and FasL gene therapy. Mol Ther 15:1259–1263PubMedGoogle Scholar
  273. 273.
    Mahdy AE, Cheng JC, Li J et al (2009) Acid ceramidase upregulation in prostate cancer cells confers resistance to radiation: AC inhibition, a potential radiosensitizer. Mol Ther 17:430–438PubMedCentralPubMedGoogle Scholar
  274. 274.
    Realini N, Solorzano C, Pagliuca C et al (2013) Discovery of highly potent acid ceramidase inhibitors with in vitro tumor chemosensitizing activity. Sci Rep 3:1035PubMedCentralPubMedGoogle Scholar
  275. 275.
    Morales A, Paris R, Villanueva A, Llacuna L, Garcia-Ruiz C, Fernandez-Checa JC (2007) Pharmacological inhibition or small interfering RNA targeting acid ceramidase sensitizes hepatoma cells to chemotherapy and reduces tumor growth in vivo. Oncogene 26:905–916PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Sehamuddin Galadari
    • 1
    • 2
    Email author
  • Anees Rahman
    • 1
  • Siraj Pallichankandy
    • 1
  • Faisal Thayyullathil
    • 1
  1. 1.Cell Signaling Laboratory, Department of Biochemistry, College of Medicine and Health SciencesUAE UniversityAbu DhabiUnited Arab Emirates
  2. 2.Al Jalila Foundation Research CentreDubaiUnited Arab Emirates

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