Ceramide-based therapeutics for the treatment of cancer

Anti-Cancer Agents in Medicinal Chemistry

Volumn 11, Issue 9, 2011, Pages 911-919

  Barth, Brian M ^a   Cabot, Myles C ^b   Kester, Mark ^a  

^a PENN STATE COLLEGE OF MEDICINE   (United States)

^b JOHN WAYNE CANCER INSTITUTE   (United States)

Author keywords

Ceramide; Drug delivery; Nanotechnology; Sphingolipids

Indexed keywords

ANTINEOPLASTIC AGENT; B 13; CAMPTOTHECIN; CERAMIDE DERIVATIVE; CISPLATIN; CYCLOSPORIN A; CYTARABINE; DAUNORUBICIN; DOXORUBICIN; FENRETINIDE; FINGOLIMOD; FLUDARABINE; FLUOROURACIL; GEMCITABINE; IMMUNOMODULATING AGENT; IRINOTECAN; MACROGOL; N OLEOYLETHANOLAMINE; OXALIPLATIN; PACLITAXEL; RESVERATROL; SAFINGOL; SONEPCIZUMAB; SORAFENIB; SPHINGOSINE DERIVATIVE; TAMOXIFEN; UNCLASSIFIED DRUG; UNINDEXED DRUG; VALSPODAR; VINCRISTINE; VORINOSTAT;

ADVANCED CANCER; CANCER CELL; CELL DEATH; CELL PROLIFERATION; CELL STRESS; DRUG DELIVERY SYSTEM; DRUG EFFICACY; DRUG FORMULATION; DRUG MECHANISM; GLYCOSYLATION; HEAD AND NECK CANCER; HUMAN; LIPOSOMAL DELIVERY; METABOLIC INHIBITION; METABOLIC REGULATION; MULTIDRUG RESISTANCE; NANOTECHNOLOGY; NONHUMAN; PHOSPHORYLATION; REVIEW; SENESCENCE; SOLID TUMOR; SYNTHESIS; UNSPECIFIED SIDE EFFECT;

EID: 80054080467     PISSN: 18715206     EISSN: 18755992     Source Type: Journal    
DOI: 10.2174/187152011797655177     Document Type: Review

References (117)

1. Eyster, K. M. The membrane and lipids as integral participants in signal transduction: lipid signal transduction for the non-lipid biochemist. Adv. Physiol. Educ. 2007, 31, 5-16
2. Fox, T. E.; Finnegan, C. M.; Blumenthal, R.; Kester, M. The clinical potential of sphingolipid-based therapeutics. Cell Mol. Life Sci. 2006, 63, 1017-1023
3. Futerman, A. H.; Riezman, H. The ins and outs of sphingolipid synthesis. Trends Cell Biol. 2005, 15, 312-318
4. Hannun, Y. A.; Obeid, L. M. Principles of bioactive lipid signalling: lessons from sphingolipids. Nat. Rev. Mol. Cell Biol. 2008, 9, 139-150
5. Ponnusamy, S.; Meyers-Needham, M.; Senkal, C. E.; Saddoughi, S. A.; Sentelle, D.; Selvam, S. P.; Salas, A.; Ogretmen, B. Sphingolipids and cancer: ceramide and sphingosine-1-phosphate in the regulation of cell death and drug resistance. Future Oncol. 2010, 6, 1603-1624
6. Hannun, Y. A. Functions of ceramide in coordinating cellular responses to stress. Science 1996, 274, 1855-1859
7. Hannun, Y. A.; Luberto, C. Ceramide in the eukaryotic stress response. Trends Cell Biol. 2000, 10, 73-80
8. Senchenkov, A.; Litvak, D. A.; Cabot, M. C. Targeting ceramide metabolism--a strategy for overcoming drug resistance. J. Natl. Cancer Inst. 2001, 93, 347-357
9. Yamaji, T.; Kumagai, K.; Tomishige, N.; Hanada, K. Two sphingolipid transfer proteins, CERT and FAPP2: their roles in sphingolipid metabolism. IUBMB Life 2008, 60, 511-518
10. D'Angelo, G.; Polishchuk, E.; Di Tullio, G.; Santoro, M.; Di Campli, A.; Godi, A.; West, G.; Bielawski, J.; Chuang, C. C.; van der Spoel, A. C.; Platt, F. M.; Hannun, Y. A.; Polishchuk, R.; Mattjus, P.; De Matteis, M. A. Glycosphingolipid synthesis requires FAPP2 transfer of glucosylceramide. Nature 2007, 449, 62-67
11. Chavez, J. A.; Knotts, T. A.; Wang, L. P.; Li, G.; Dobrowsky, R. T.; Florant, G. L.; Summers, S. A. A role for ceramide, but not diacylglycerol, in the antagonism of insulin signal transduction by saturated fatty acids. J. Biol. Chem. 2003, 278, 10297-10303
12. Chavez, J. A.; Summers, S. A. Characterizing the effects of saturated fatty acids on insulin signaling and ceramide and diacylglycerol accumulation in 3T3-L1 adipocytes and C2C12 myotubes. Arch. Biochem. Biophys. 2003, 419, 101-109
13. Stratford, S.; Hoehn, K. L.; Liu, F.; Summers, S. A. Regulation of insulin action by ceramide: dual mechanisms linking ceramide accumulation to the inhibition of Akt/protein kinase B. J. Biol. Chem. 2004, 279, 36608-36615
14. Ogretmen, B.; Hannun, Y. A. Biologically active sphingolipids in cancer pathogenesis and treatment. Nat. Rev. Cancer. 2004, 4, 604-616
15. Ryland, L. K.; Fox, T. E.; Liu, X.; Loughran, T. P.; Kester, M. Dysregulation of sphingolipid metabolism in cancer. Cancer. Biol. Ther. 2011, 11, 138-149
16. Karahatay, S.; Thomas, K.; Koybasi, S.; Senkal, C. E.; Elojeimy, S.; Liu, X.; Bielawski, J.; Day, T. A.; Gillespie, M. B.; Sinha, D.; Norris, J. S.; Hannun, Y. A.; Ogretmen, B. 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, 101-111
17. Kester, M.; Kolesnick, R. Sphingolipids as therapeutics. Pharmacol. Res. 2003, 47, 365-371
18. Obeid, L. M.; Linardic, C. M.; Karolak, L. A.; Hannun, Y. A. Programmed cell death induced by ceramide. Science 1993, 259, 1769-1771
19. Pyne, S.; Pyne, N. Sphingosine 1-phosphate signalling via the endothelial differentiation gene family of G-protein-coupled receptors. Pharmacol. Ther. 2000, 88, 115-131
20. Spiegel, S.; Milstien, S. Sphingosine 1-phosphate, a key cell signaling molecule. J. Biol. Chem. 2002, 277, 25851-25854
21. Fyrst, H.; Saba, J. D. An update on sphingosine-1-phosphate and other sphingolipid mediators. Nat. Chem. Biol. 2010, 6, 489-497
22. Morales, A.; Lee, H.; Goni, F. M.; Kolesnick, R.; Fernandez- Checa, J. C. Sphingolipids and cell death. Apoptosis 2007, 12, 923-939
23. Fox, T. E.; Houck, K. L.; O'Neill, S. M.; Nagarajan, M.; Stover, T. C.; Pomianowski, P. T.; Unal, O.; Yun, J. K.; Naides, S. J.; Kester, M. Ceramide recruits and activates protein kinase C zeta (PKC zeta) within structured membrane microdomains. J. Biol. Chem. 2007, 282, 12450-12457
24. Payne, S. G.; Milstien, S.; Spiegel, S. Sphingosine-1-phosphate: dual messenger functions. FEBS Lett. 2002, 531, 54-57
25. Shah, M. V.; Zhang, R.; Irby, R.; Kothapalli, R.; Liu, X.; Arrington, T.; Frank, B.; Lee, N. H.; Loughran, T. P., Jr Molecular profiling of LGL leukemia reveals role of sphingolipid signaling in survival of cytotoxic lymphocytes. Blood 2008, 112, 770-781
26. Hait, N. C.; Allegood, J.; Maceyka, M.; Strub, G. M.; Harikumar, K. B.; Singh, S. K.; Luo, C.; Marmorstein, R.; Kordula, T.; Milstien, S.; Spiegel, S. Regulation of histone acetylation in the nucleus by sphingosine-1-phosphate. Science 2009, 325, 1254-1257
27. Alvarez, S. E.; Harikumar, K. B.; Hait, N. C.; Allegood, J.; Strub, G. M.; Kim, E. Y.; Maceyka, M.; Jiang, H.; Luo, C.; Kordula, T.; Milstien, S.; Spiegel, S. Sphingosine-1-phosphate is a missing cofactor for the E3 ubiquitin ligase TRAF2. Nature 2010, 465, 1084-1088
28. 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, 95-102
29. Bonhoure, E.; Lauret, A.; Barnes, D. J.; Martin, C.; Malavaud, B.; Kohama, T.; Melo, J. V.; Cuvillier, O. Sphingosine kinase-1 is a downstream regulator of imatinib-induced apoptosis in chronic myeloid leukemia cells. Leukemia 2008, 22, 971-979
30. Baran, Y.; Salas, A.; Senkal, C. E.; Gunduz, U.; Bielawski, J.; Obeid, L. M.; 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, 10922-10934
31. Schiffmann, S.; Sandner, J.; Birod, K.; Wobst, I.; Angioni, C.; Ruckhaberle, E.; Kaufmann, M.; Ackermann, H.; Lotsch, J.; Schmidt, H.; Geisslinger, G.; Grosch, S. Ceramide synthases and ceramide levels are increased in breast cancer tissue. Carcinogenesis 2009, 30, 745-752
32. Koybasi, S.; Senkal, C. E.; Sundararaj, K.; Spassieva, S.; Bielawski, J.; Osta, W.; Day, T. A.; Jiang, J. C.; Jazwinski, S. M.; Hannun, Y. A.; Obeid, L. M.; 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, 44311-44319
33. Saddoughi, S. A.; Song, P.; Ogretmen, B. Roles of bioactive sphingolipids in cancer biology and therapeutics. Subcell. Biochem. 2008, 49, 413-440
34. Morjani, H.; Madoulet, C. Immunosuppressors as multidrug resistance reversal agents. Methods Mol. Biol. 2010, 596, 433-446
35. Sabbadini, R. A. Sphingosine-1-phosphate antibodies as potential agents in the treatment of cancer and age-related macular degeneration. Br. J. Pharmacol. 2011, 162, 1225-1238
36. Dumitru, C. A.; Weller, M.; Gulbins, E. Ceramide metabolism determines glioma cell resistance to chemotherapy. J. Cell. Physiol. 2009, 221, 688-695
37. Dumitru, C. A.; Sandalcioglu, I. E.; Wagner, M.; Weller, M.; Gulbins, E. Lysosomal ceramide mediates gemcitabine-induced death of glioma cells. J. Mol. Med. 2009, 87, 1123-1132
38. Modrak, D. E.; Leon, E.; Goldenberg, D. M.; Gold, D. V. Ceramide regulates gemcitabine-induced senescence and apoptosis in human pancreatic cancer cell lines. Mol. Cancer. Res. 2009, 7, 890-896
39. Wu, B. X.; Zeidan, Y. H.; Hannun, Y. A. Downregulation of neutral ceramidase by gemcitabine: Implications for cell cycle regulation. Biochim. Biophys. Acta 2009, 1791, 730-739
40. Nemoto, S.; Nakamura, M.; Osawa, Y.; Kono, S.; Itoh, Y.; Okano, Y.; Murate, T.; Hara, A.; Ueda, H.; Nozawa, Y.; Banno, Y. Sphingosine kinase isoforms regulate oxaliplatin sensitivity of human colon cancer cells through ceramide accumulation and Akt activation. J. Biol. Chem. 2009, 284, 10422-10432
41. Zeidan, Y. H.; Jenkins, R. W.; Hannun, Y. A. Remodeling of cellular cytoskeleton by the acid sphingomyelinase/ceramide pathway. J. Cell Biol. 2008, 181, 335-350
42. Saad, A. F.; Meacham, W. D.; Bai, A.; Anelli, V.; Elojeimy, S.; Mahdy, A. E.; Turner, L. S.; Cheng, J.; Bielawska, A.; Bielawski, J.; Keane, T. E.; Obeid, L. M.; Hannun, Y. A.; Norris, J. S.; Liu, X. The functional effects of acid ceramidase overexpression in prostate cancer progression and resistance to chemotherapy. Cancer Biol. Ther. 2007, 6, 1455-1460
43. Rebillard, A.; Tekpli, X.; Meurette, O.; Sergent, O.; LeMoigne- Muller, G.; Vernhet, L.; Gorria, M.; Chevanne, M.; Christmann, M.; Kaina, B.; Counillon, L.; Gulbins, E.; Lagadic-Gossmann, D.; Dimanche-Boitrel, M. T. Cisplatin-induced apoptosis involves membrane fluidification via inhibition of NHE1 in human colon cancer cells. Cancer Res. 2007, 67, 7865-7874
44. Sridevi, P.; Alexander, H.; Laviad, E. L.; Min, J.; Mesika, A.; Hannink, M.; Futerman, A. H.; Alexander, S. Stress-induced ER to Golgi translocation of ceramide synthase 1 is dependent on proteasomal processing. Exp. Cell Res. 2010, 316, 78-91
45. Chauvier, D.; Morjani, H.; Manfait, M. Ceramide involvement in homocamptothecin- and camptothecin-induced cytotoxicity and apoptosis in colon HT29 cells. Int. J. Oncol. 2002, 20, 855-863
46. Gouaze-Andersson, V.; Flowers, M.; Karimi, R.; Fabrias, G.; Delgado, A.; Casas, J.; Cabot, M. C. Inhibition of acid ceramidase by a 2-substituted aminoethanol amide synergistically sensitizes prostate cancer cells to N-(4-hydroxyphenyl) retinamide. Prostate 2011, 71(10), 1064-73
47. Park, M. A.; Mitchell, C.; Zhang, G.; Yacoub, A.; Allegood, J.; Haussinger, D.; Reinehr, R.; Larner, A.; Spiegel, S.; Fisher, P. B.; Voelkel-Johnson, C.; Ogretmen, B.; Grant, S.; Dent, P. 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. 2010, 70, 6313-6324
48. Senkal, C. E.; Ponnusamy, S.; Rossi, M. J.; Bialewski, J.; Sinha, D.; Jiang, J. C.; Jazwinski, S. M.; Hannun, Y. A.; Ogretmen, B. 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. 2007, 6, 712-722
49. Separovic, D.; Bielawski, J.; Pierce, J. S.; Merchant, S.; Tarca, A. L.; Bhatti, G.; Ogretmen, B.; Korbelik, M. 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. 2011, 38, 521-527
50. Kolesnick, R.; Fuks, Z. Radiation and ceramide-induced apoptosis. Oncogene 2003, 22, 5897-5906
51. Signorelli, P.; Munoz-Olaya, J. M.; 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, 238-243
52. Gatouillat, G.; Balasse, E.; Joseph-Pietras, D.; Morjani, H.; Madoulet, C. Resveratrol induces cell-cycle disruption and apoptosis in chemoresistant B16 melanoma. J. Cell. Biochem. 2010, 110, 893-902
53. Chapman, J. V.; Gouaze-Andersson, V.; Messner, M. C.; Flowers, M.; Karimi, R.; Kester, M.; Barth, B. M.; Liu, X.; Liu, Y. Y.; Giuliano, A. E.; Cabot, M. C. Metabolism of short-chain ceramide by human cancer cells--implications for therapeutic approaches. Biochem. Pharmacol. 2010, 80, 308-315
54. Barth, B. M.; Gustafson, S. J.; Young, M. M.; Fox, T. E.; Shanmugavelandy, S. S.; Kaiser, J. M.; Cabot, M. C.; Kester, M.; Kuhn, T. B. Inhibition of NADPH oxidase by glucosylceramide confers chemoresistance. Cancer Biol. Ther. 2010, 10, 1126-1136
55. Ratner, M. Novartis eyes oral MS drug as potential blockbuster. Nat. Biotechnol. 2010, 28, 1135-1136
56. Brinkmann, V.; Billich, A.; Baumruker, T.; Heining, P.; Schmouder, R.; Francis, G.; Aradhye, S.; Burtin, P. Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis. Nat. Rev. Drug Discov. 2010, 9, 883-897
57. Jeffery, D. R.; Markowitz, C. E.; Reder, A. T.; Weinstock- Guttman, B.; Tobias, K. Fingolimod for the treatment of relapsing multiple sclerosis. Expert Rev. Neurother. 2011, 11, 165-183
58. Wong, L.; Tan, S. S.; Lam, Y.; Melendez, A. J. Synthesis and evaluation of sphingosine analogues as inhibitors of sphingosine kinases. J. Med. Chem. 2009, 52, 3618-3626
59. Leroux, M. E.; Auzenne, E.; Evans, R.; Hail, N., Jr; Spohn, W.; Ghosh, S. C.; Farquhar, D.; McDonnell, T.; Klostergaard, J. Sphingolipids and the sphingosine kinase inhibitor, SKI II, induce BCL-2-independent apoptosis in human prostatic adenocarcinoma cells. Prostate 2007, 67, 1699-1717
60. Khodadadian, M.; Leroux, M. E.; Auzenne, E.; Ghosh, S. C.; Farquhar, D.; Evans, R.; Spohn, W.; Zou, Y.; Klostergaard, J. MRP- and BCL-2-mediated drug resistance in human SCLC: effects of apoptotic sphingolipids in vitro. Lung Cancer 2009, 66, 48-57
61. Ghosh, S. C.; Auzenne, E.; Farquhar, D.; Klostergaard, J. N,Ndimethylsphingosine- coumarin: synthesis, chemical characterization, and biological evaluation. Bioconjug. Chem. 2007, 18, 731-735
62. Dickson, M. A.; Carvajal, R. D.; Merrill, A. H.; Gonen, M.; Cane, L. M.; Schwartz, G. K. A Phase I Clinical Trial of Safingol in Combination with Cisplatin in Advanced Solid Tumors. Clin. Cancer Res. 2011, 17(8), 2484-92
63. Paugh, S. W.; Paugh, B. S.; Rahmani, M.; Kapitonov, D.; Almenara, J. A.; Kordula, T.; Milstien, S.; Adams, J. K.; Zipkin, R. E.; Grant, S.; Spiegel, S. A selective sphingosine kinase 1 inhibitor integrates multiple molecular therapeutic targets in human leukemia. Blood 2008, 112, 1382-1391
64. French, K. J.; Schrecengost, R. S.; Lee, B. D.; Zhuang, Y.; Smith, S. N.; Eberly, J. L.; Yun, J. K.; Smith, C. D. Discovery and evaluation of inhibitors of human sphingosine kinase. Cancer Res. 2003, 63, 5962-5969
65. French, K. J.; Upson, J. J.; Keller, S. N.; Zhuang, Y.; Yun, J. K.; Smith, C. D. Antitumor activity of sphingosine kinase inhibitors. J. Pharmacol. Exp. Ther. 2006, 318, 596-603
66. French, K. J.; Zhuang, Y.; Maines, L. W.; Gao, P.; Wang, W.; Beljanski, V.; Upson, J. J.; Green, C. L.; Keller, S. N.; Smith, C. D. Pharmacology and antitumor activity of ABC294640, a selective inhibitor of sphingosine kinase-2. J. Pharmacol. Exp. Ther. 2010, 333, 129-139
67. Hengst, J. A.; Wang, X.; Sk, U. H.; Sharma, A. K.; Amin, S.; Yun, J. K. Development of a sphingosine kinase 1 specific smallmolecule inhibitor. Bioorg. Med. Chem. Lett. 2010, 20, 7498-7502
68. Bai, A.; Szulc, Z. M.; Bielawski, J.; Mayroo, N.; Liu, X.; Norris, J.; Hannun, Y. A.; Bielawska, A. Synthesis and bioevaluation of omega-N-amino analogs of B13. Bioorg. Med. Chem. 2009, 17, 1840-1848
69. Selzner, M.; Bielawska, A.; Morse, M. A.; Rudiger, H. A.; Sindram, D.; Hannun, Y. A.; Clavien, P. A. Induction of apoptotic cell death and prevention of tumor growth by ceramide analogues in metastatic human colon cancer. Cancer Res. 2001, 61, 1233-1240
70. Mahdy, A. E.; Cheng, J. C.; Li, J.; Elojeimy, S.; Meacham, W. D.; Turner, L. S.; Bai, A.; Gault, C. R.; McPherson, A. S.; Garcia, N.; Beckham, T. H.; Saad, A.; Bielawska, A.; Bielawski, J.; Hannun, Y. A.; Keane, T. E.; Taha, M. I.; Hammouda, H. M.; Norris, J. S.; Liu, X. Acid ceramidase upregulation in prostate cancer cells confers resistance to radiation: AC inhibition, a potential radiosensitizer. Mol. Ther. 2009, 17, 430-438
71. Natoli, T. A.; Smith, L. A.; Rogers, K. A.; Wang, B.; Komarnitsky, S.; Budman, Y.; Belenky, A.; Bukanov, N. O.; Dackowski, W. R.; Husson, H.; Russo, R. J.; Shayman, J. A.; Ledbetter, S. R.; Leonard, J. P.; Ibraghimov-Beskrovnaya, O. Inhibition of glucosylceramide accumulation results in effective blockade of polycystic kidney disease in mouse models. Nat. Med. 2010, 16, 788-792
72. Shayman, J. A. The riddle of the sphinx redux. Kidney Int. 2010, 77, 843-845
73. Shayman, J. A.; Abe, A.; Hiraoka, M. A turn in the road: How studies on the pharmacology of glucosylceramide synthase inhibitors led to the identification of a lysosomal phospholipase A2 with ceramide transacylase activity. Glycoconjug. J. 2004, 20, 25-32
74. Zhao, H.; Przybylska, M.; Wu, I. H.; Zhang, J.; Maniatis, P.; Pacheco, J.; Piepenhagen, P.; Copeland, D.; Arbeeny, C.; Shayman, J. A.; Aerts, J. M.; Jiang, C.; Cheng, S. H.; Yew, N. S. Inhibiting glycosphingolipid synthesis ameliorates hepatic steatosis in obese mice. Hepatology 2009, 50, 85-93
75. Gaver, R. C.; Sweeley, C. C. Chemistry and metabolism of sphingolipids. 3-Oxo derivatives of N-acetylsphingosine and Nacetyldihydrosphingosine. J. Am. Chem. Soc. 1966, 88, 3643-3647
76. Dobrowsky, R. T.; Hannun, Y. A. Ceramide stimulates a cytosolic protein phosphatase. J. Biol. Chem. 1992, 267, 5048-5051
77. Stover, T.; Kester, M. Liposomal delivery enhances short-chain ceramide-induced apoptosis of breast cancer cells. J. Pharmacol. Exp. Ther. 2003, 307, 468-475
78. Novgorodov, S. A.; Szulc, Z. M.; Luberto, C.; Jones, J. A.; Bielawski, J.; Bielawska, A.; Hannun, Y. A.; Obeid, L. M. Positively charged ceramide is a potent inducer of mitochondrial permeabilization. J. Biol. Chem. 2005, 280, 16096-16105
79. Senkal, C. E.; Ponnusamy, S.; Rossi, M. J.; Sundararaj, K.; Szulc, Z.; Bielawski, J.; Bielawska, A.; Meyer, M.; Cobanoglu, B.; Koybasi, S.; Sinha, D.; Day, T. A.; Obeid, L. M.; Hannun, Y. A.; Ogretmen, B. Potent antitumor activity of a novel cationic pyridinium- ceramide alone or in combination with gemcitabine against human head and neck squamous cell carcinomas in vitro and in vivo. J. Pharmacol. Exp. Ther. 2006, 317, 1188-1199
80. Macchia, M.; Barontini, S.; Bertini, S.; Di Bussolo, V.; Fogli, S.; Giovannetti, E.; Grossi, E.; Minutolo, F.; Danesi, R. Design, synthesis, and characterization of the antitumor activity of novel ceramide analogues. J. Med. Chem. 2001, 44, 3994-4000
81. 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, 161-169
82. 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, 392-399
83. Qin, J. D.; Weiss, L.; Slavin, S.; Gatt, S.; Dagan, A. Synthetic, nonnatural analogs of ceramide elevate cellular ceramide, inducing apoptotic death to prostate cancer cells and eradicating tumors in mice. Cancer Invest. 2010, 28, 535-543
84. Bieberich, E.; Hu, B.; Silva, J.; MacKinnon, S.; Yu, R. K.; Fillmore, H.; Broaddus, W. C.; Ottenbrite, R. M. Synthesis and characterization of novel ceramide analogs for induction of apoptosis in human cancer cells. Cancer Lett. 2002, 181, 55-64
85. Bieberich, E.; Kawaguchi, T.; Yu, R. K. N-acylated serinol is a novel ceramide mimic inducing apoptosis in neuroblastoma cells. J. Biol. Chem. 2000, 275, 177-181
86. Bieberich, E.; Silva, J.; Wang, G.; Krishnamurthy, K.; Condie, B. G. Selective apoptosis of pluripotent mouse and human stem cells by novel ceramide analogues prevents teratoma formation and enriches for neural precursors in ES cell-derived neural transplants. J. Cell Biol. 2004, 167, 723-734
87. Karasavvas, N.; Erukulla, R. K.; Bittman, R.; Lockshin, R.; Zakeri, Z. Stereospecific induction of apoptosis in U937 cells by Noctanoyl- sphingosine stereoisomers and N-octyl-sphingosine. The ceramide amide group is not required for apoptosis. Eur. J. Biochem. 1996, 236, 729-737
88. Antoon, J. W.; Liu, J.; Ponnapakkam, A. P.; Gestaut, M. M.; Foroozesh, M.; Beckman, B. S. Novel D: -erythro N-octanoyl sphingosine analogs as chemo- and endocrine-resistant breast cancer therapeutics. Cancer Chemother. Pharmacol. 2010, 65, 1191-1195
89. Liu, J.; Antoon, J. W.; Ponnapakkam, A.; Beckman, B. S.; Foroozesh, M. Novel anti-viability ceramide analogs: design, synthesis, and structure-activity relationship studies of substituted (S)- 2-(benzylideneamino)-3-hydroxy-N-tetradecylpropanamides. Bioorg. Med. Chem. 2010, 18, 5316-5322
90. Struckhoff, A. P.; Bittman, R.; Burow, M. E.; Clejan, S.; Elliott, S.; Hammond, T.; Tang, Y.; Beckman, B. S. Novel ceramide analogs as potential chemotherapeutic agents in breast cancer. J. Pharmacol. Exp. Ther. 2004, 309, 523-532
91. Fyrst, H.; Oskouian, B.; Bandhuvula, P.; Gong, Y.; Byun, H. S.; Bittman, R.; Lee, A. R.; Saba, J. D. Natural sphingadienes inhibit Akt-dependent signaling and prevent intestinal tumorigenesis. Cancer Res. 2009, 69, 9457-9464
92. Sugawara, T.; Zaima, N.; Yamamoto, A.; Sakai, S.; Noguchi, R.; Hirata, T. Isolation of sphingoid bases of sea cucumber cerebrosides and their cytotoxicity against human colon cancer cells. Biosci. Biotechnol. Biochem. 2006, 70, 2906-2912
93. Chintalapati, M.; Truax, R.; Stout, R.; Portier, R.; Losso, J. N. In vitro and in vivo anti-angiogenic activities and inhibition of hormone- dependent and -independent breast cancer cells by ceramide methylaminoethylphosphonate. J. Agric. Food Chem. 2009, 57, 5201-5210
94. Berra, B.; Colombo, I.; Sottocornola, E.; Giacosa, A. Dietary sphingolipids in colorectal cancer prevention. Eur. J. Cancer Prev. 2002, 11, 193-197
95. Vesper, H.; Schmelz, E. M.; Nikolova-Karakashian, M. N.; Dillehay, D. L.; Lynch, D. V.; Merrill, A. H., Jr Sphingolipids in food and the emerging importance of sphingolipids to nutrition. J. Nutr. 1999, 129, 1239-1250
96. Shabbits, J. A.; Mayer, L. D. High ceramide content liposomes with in vivo antitumor activity. Anticancer Res. 2003, 23, 3663-3669
97. Shabbits, J. A.; Mayer, L. D. Intracellular delivery of ceramide lipids via liposomes enhances apoptosis in vitro. Biochim. Biophys. Acta 2003, 1612, 98-106
98. Stover, T. C.; Sharma, A.; Robertson, G. P.; Kester, M. Systemic delivery of liposomal short-chain ceramide limits solid tumor growth in murine models of breast adenocarcinoma. Clin. Cancer Res. 2005, 11, 3465-3474
99. Tagaram, H. R.; Divittore, N. A.; Barth, B. M.; Kaiser, J. M.; Avella, D.; Kimchi, E. T.; Jiang, Y.; Isom, H. C.; Kester, M.; Staveley-O'Carroll, K. F. Nanoliposomal ceramide prevents in vivo growth of hepatocellular carcinoma. Gut 2011, 60, 695-701
100. Liu, X.; Ryland, L.; Yang, J.; Liao, A.; Aliaga, C.; Watts, R.; Tan, S. F.; Kaiser, J.; Shanmugavelandy, S. S.; Rogers, A.; Loughran, K.; Petersen, B.; Yuen, J.; Meng, F.; Baab, K. T.; Jarbadan, N. R.; Broeg, K.; Zhang, R.; Liao, J.; Sayers, T. J.; Kester, M.; Loughran, T. P.,Jr Targeting of survivin by nanoliposomal ceramide induces complete remission in a rat model of NK-LGL leukemia. Blood 2010, 116, 4192-4201
101. Tran, M. A.; Gowda, R.; Sharma, A.; Park, E. J.; Adair, J.; Kester, M.; Smith, N. B.; Robertson, G. P. Targeting V600EB-Raf and Akt3 using nanoliposomal-small interfering RNA inhibits cutaneous melanocytic lesion development. Cancer Res. 2008, 68, 7638-7649
102. Kester, M.; Heakal, Y.; Fox, T.; Sharma, A.; Robertson, G. P.; Morgan, T. T.; Altinoglu, E. I.; Tabakovic, A.; Parette, M. R.; Rouse, S. M.; Ruiz-Velasco, V.; Adair, J. H. Calcium phosphate nanocomposite particles for in vitro imaging and encapsulated chemotherapeutic drug delivery to cancer cells. Nano Lett. 2008, 8, 4116-4121
103. Morgan, T. T.; Muddana, H. S.; Altinoglu, E. I.; Rouse, S. M.; Tabakovic, A.; Tabouillot, T.; Russin, T. J.; Shanmugavelandy, S. S.; Butler, P. J.; Eklund, P. C.; Yun, J. K.; Kester, M.; Adair, J. H. Encapsulation of organic molecules in calcium phosphate nanocomposite particles for intracellular imaging and drug delivery. Nano Lett. 2008, 8, 4108-4115
104. Stover, T. C.; Kim, Y. S.; Lowe, T. L.; Kester, M. Thermoresponsive and biodegradable linear-dendritic nanoparticles for targeted and sustained release of a pro-apoptotic drug. Biomaterials 2008, 29, 359-369
105. Desai, A.; Vyas, T.; Amiji, M. Cytotoxicity and apoptosis enhancement in brain tumor cells upon coadministration of paclitaxel and ceramide in nanoemulsion formulations. J. Pharm. Sci. 2008, 97, 2745-2756
106. Devalapally, H.; Duan, Z.; Seiden, M. V.; Amiji, M. M. Modulation of drug resistance in ovarian adenocarcinoma by enhancing intracellular ceramide using tamoxifen-loaded biodegradable polymeric nanoparticles. Clin. Cancer Res. 2008, 14, 3193-3203
107. Devalapally, H.; Duan, Z.; Seiden, M. V.; Amiji, M. M. Paclitaxel and ceramide co-administration in biodegradable polymeric nanoparticulate delivery system to overcome drug resistance in ovarian cancer. Int. J. Cancer 2007, 121, 1830-1838
108. van Vlerken, L. E.; Duan, Z.; Seiden, M. V.; Amiji, M. M. Modulation of intracellular ceramide using polymeric nanoparticles to overcome multidrug resistance in cancer. Cancer Res. 2007, 67, 4843-4850
109. Zolnik, B. S.; Stern, S. T.; Kaiser, J. M.; Heakal, Y.; Clogston, J. D.; Kester, M.; McNeil, S. E. Rapid distribution of liposomal shortchain ceramide in vitro and in vivo. Drug Metab. Dispos. 2008, 36, 1709-1715
110. Barth, B. M.; Sharma, R.; Altinoglu, E. I.; Morgan, T. T.; Shanmugavelandy, S. S.; Kaiser, J. M.; McGovern, C.; Matters, G. L.; Smith, J. P.; Kester, M.; Adair, J. H. Bioconjugation of calcium phosphosilicate composite nanoparticles for selective targeting of human breast and pancreatic cancers in vivo. ACS Nano 2010, 4, 1279-1287
111. van Lummel, M.; van Blitterswijk, W. J.; Vink, S. R.; Veldman, R. J.; van der Valk, M. A.; Schipper, D.; Dicheva, B. M.; Eggermont, A. M.; ten Hagen, T. L.; Verheij, M.; Koning, G. A. Enriching lipid nanovesicles with short-chain glucosylceramide improves doxorubicin delivery and efficacy in solid tumors. FASEB J. 2011, 25, 280-289
112. Altinoglu, E. I.; Russin, T. J.; Kaiser, J. M.; Barth, B. M.; Eklund, P. C.; Kester, M.; Adair, J. H. Near-infrared emitting fluorophoredoped calcium phosphate nanoparticles for in vivo imaging of human breast cancer. ACS Nano 2008, 2, 2075-2084
113. Adair, J. H.; Parette, M. P.; Altinoglu, E. I.; Kester, M. Nanoparticulate alternatives for drug delivery. ACS Nano 2010, 4, 4967-4970
114. Kline, C. L.; Shanmugavelandy, S. S.; Kester, M.; Irby, R. B. Delivery of PAR-4 plasmid in vivo via nanoliposomes sensitizes colon tumor cells subcutaneously implanted into nude mice to 5-FU. Cancer. Biol. Ther. 2009, 8, 1831-1837
115. Matters, G. L.; Harms, J. F.; McGovern, C. O.; Jayakumar, C.; Crepin, K.; Smith, Z. P.; Nelson, M. C.; Stock, H.; Fenn, C. W.; Kaiser, J.; Kester, M.; Smith, J. P. Growth of human pancreatic cancer is inhibited by down-regulation of gastrin gene expression. Pancreas 2009, 38, e151-61
116. Jabr-Milane, L. S.; van Vlerken, L. E.; Yadav, S.; Amiji, M. M. Multi-functional nanocarriers to overcome tumor drug resistance. Cancer Treat. Rev. 2008, 34, 592-602
117. Chapman, J. V.; Gouaze-Andersson, V.; Karimi, R.; Messner, M. C.; Cabot, M. C. P-glycoprotein antagonists confer synergistic sensitivity to short-chain ceramide in human multidrug-resistant cancer cells. Exp. Cell Res. 2011.