Antineoplastic and apoptotic effects of cannabinoids. N-acylethanolamines: Protectors or killers?

Experimental Oncology

Volumn 30, Issue 1, 2008, Pages 6-21

  Pushkarev, V M ^a   Kovzun, O I ^a   Tronko, M D ^a  

^a V P Komisarenko Institute of Endocrinology and Metabolism of the Ukraine Academy of Medical Sciences   (Ukraine)

Author keywords

Apoptosis; Cannabinoids; Ischemia; N acylethanolamines; Necrosis; Tumours

Indexed keywords

1 DEOXY 3 (1,1 DIMETHYLBUTYL) DELTA8 TETRAHYDROCANNABINOL; 2 METHYL 3 (1 NAPHTHOYL) 1 PROPYLINDOLE; 2 METHYLARACHIDONYL 2' FLUOROETHYLAMIDE; 2,3 DIHYDRO 5 METHYL 3 (MORPHOLINOMETHYL) 6 (1 NAPHTHOYL)PYRROLO[1,2,3 DE][1,4]BENZOXAZINE; 4 (1,1 DIMETHYLHEPTYL) 1',2',3',4',5',6' HEXAHYDRO 2,3' DIHYDROXY 6' (3 HYDROXYPROPYL)BIPHENYL; ANANDAMIDE; CANNABIDIOL; CANNABIGEROL; CANNABINOID DERIVATIVE; CANNABINOID RECEPTOR; CANNABINOL; CERAMIDE; CERAMIDE DERIVATIVE; COLCHICINE; CYCLOOXYGENASE 2; CYTOCHALASIN B; DEXANABINOL; DRONABINOL; DRUG METABOLITE; ENDOCANNABINOID; ETHANOLAMINE; ETHANOLAMINE DERIVATIVE; METHANANDAMIDE; N ACETYLSPHINGOSINE; N LINOLENOYLETHANOLAMINE; N LINOLEOYLETHANOLAMINE; N OLEOYLETHANOLAMINE; PALMITIC ACID; UNCLASSIFIED DRUG; UNINDEXED DRUG; VANILLOID RECEPTOR;

ANTIANGIOGENIC ACTIVITY; ANTINEOPLASTIC ACTIVITY; APOPTOSIS; CELL CYCLE ARREST; CELL DEATH; CELL KILLING; CELL PROTECTION; CELL STRESS; DRUG EFFECT; DRUG MECHANISM; DRUG RECEPTOR BINDING; GLIOBLASTOMA; GLIOMA; HUMAN; LIPID RAFT; METABOLISM; METASTASIS; METASTASIS INHIBITION; NEOPLASM; NONHUMAN; REVIEW; SIGNAL TRANSDUCTION; TISSUE INJURY; TUMOR CELL;

ANIMALS; ANTINEOPLASTIC AGENTS; APOPTOSIS; CANNABINOIDS; ENDOCANNABINOIDS; ETHANOLAMINES; HUMANS; NEOPLASMS; NEOVASCULARIZATION, PATHOLOGIC; RECEPTORS, CANNABINOID; TRPV CATION CHANNELS;

EID: 42049122799     PISSN: 18129269     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (203)

1. Hewlett AC, Barth F, Bonner TI, et al. International Union of Pharmacology. XXVII. Classification of Cannabinoid Receptors. Pharmacol Rev 2002; 54: 161-202.
2. Guzman M. Cannabinoids: potential anticancer agents. Nat Rev Cancer 2003; 3: 745-55.
3. Guzman M. Effects on cell viability. Handb Exp Pharmacol 2005; 168: 627-42.
4. Hansen HS, Moesgaard B, Hansen HH, Petersen G. N-Acylethanolamines and precursor phospholipids - relation to cell injury. Chem Phys Lipids 2000; 108: 135-50.
5. Hansen HS, Moesgaard B, Petersen G, Hansen HH. Putative neuroprotective actions of N-acyl-ethanolamines. Pharmacol Ther_2002b; 95: 119-26.
6. Maccarrone M, Finazzi-Agro A. The endocannabinoid system, anandamide and the regulation of mammalian cell apoptosis. Cell Death Differ 2003; 10: 946-55.
7. Bari M, Spagnuolo P, Fezza F, et al. Effect of lipid rafts on Cb2 receptor signaling and 2-arachidonoyl-glycerol metabolism in human immune cells. J Immunol 2006; 177: 4971-80.
8. Karanian DA, Bahr BA. Cannabinoid drugs and enhancement of endocannabinoid responses: strategies for a wide array of disease states. Curr Mol Med 2006; 6: 677-84.
9. Hiley CR, Hoi PM. Oleamide: a fatty acid amide signaling molecule in the cardiovascular system? Cardiovasc Drug Rev 2007; 25: 46-60.
10. Chemin J, Nargeot J, Lory P. Chemical determinants involved in anandamide-induced inhibition of T-type calcium channels. J Biol Chem 2007; 282: 2314-23.
11. Mitrirattanakul S, Lopez-Valdes HE, Liang J, et al. Bidirectional alterations of hippocampal cannabinoid 1 receptors and their endogenous ligands in a rat model of alcohol withdrawal and dependence. Alcohol Clin Exp Res 2007; 31: 855-67.
12. Childers SR, Breivogel CS. Cannabis and endogenous cannabinoid systems. Drug Alcohol Depend 1998; 51: 173-87.
13. Selley DE, Cassidy MP, Martin BR, Sim-Selley LJ. Long-term administration of Delta9-tetrahydrocannabinol desensitizes CB1-, adenosine A1-, and GABAB-mediated inhibition of adenylyl cyclase in mouse cerebellum. Mol Pharmacol 2004; 66: 1275-84.
14. Davis MI, Ronesi J, Lovinger DM. A predominant role for inhibition of the adenylate cyclase/protein kinase A pathway in ERK activation by cannabinoid receptor 1 in N1E-115 neuroblastoma cells. J Biol Chem 2003; 278: 48973-80.
15. Sade H, Muraki K, Ohya S, et al. Activation of large-conductance, Ca2+-activated K+ channels by cannabinoids. Am J Cell Physiol 2006; 290: 77-86.
16. De Fonseca FR, del Arco I, Bermudez-Silva FJ, et al. The endocannabinoid system: physiology and pharmacology. Alcohol Alcoholism 2005; 40: 2-14.
17. Lambert RC, Bessaih T, Leresche N. Modulation of neuronal T-type calcium channels. CNS Neurol Disord Drug Targets 2006; 5: 611-27.
18. s linkage to the CB1 receptor. J Neurosci 1997; 17: 5327-33.
19. Bisogno T, Hanus L, De Petrocellis L, et al. Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Br J Pharmacol 2001; 134: 845-52.
20. Malinowska B, Kwolek G, Gothert M. Anandamide and methanandamide induce both vanilloid VR1- and cannabinoid CB1 receptor-mediated changes in heart rate and blood pressure in anaesthetized rats. Naunyn Schmiedebergs Arch Pharmacol 2001; 364: 562-9.
21. Movahed P, Jonsson BA, Birnir B, et al. Endogenous unsaturated C18 N-acylethanolamines are vanilloid receptor (TRPV1) agonists. J Biol Chem 2005; 280: 38496-504.
22. Pertwee RG. The pharmacology of cannabinoid receptors and their ligands: an overview. Int J Obes (Lond) 2006; 30: S13-18.
23. Poblete IM, Orliac ML, Briones R, et al. Anandamide elicits an acute release of nitric oxide through endothelial TRPV1 receptor activation in the rat arterial mesenteric bed. J Physiol 2005; 568: 539-51.
24. De Petrocellis L, Bisogno T, Ligresti A, et al. Effect on cancer cell proliferation of palmitoylethanolamide, a fatty acid amide interacting with both the cannabinoid and vanilloid signalling systems. Fundam Clin Pharmacol 2002; 16: 297-302.
25. De Petrocellis L, Starowicz K, Moriello AS, et al. Regulation of transient receptor potential channels of melastatin type 8 (TRPM8): effect of cAMP, cannabinoid CB(1) receptors and endovanilloids. Exp Cell Res 2007; 313: 1911-20.
26. McVey DC, Schmid PC, Schmid HH, Vigna SR. Endocannabinoids induce ileitis in rats via the capsaicin receptor (VR1). J Pharmacol Exp Ther 2003; 304: 713-22.
27. Di Marzo V, Bisogno T, De Petrocellis L. Anandamide: some like it hot. Trends Pharmacol Sci 2002, 22: 346-9.
28. Schmid HHO, Schmid PC, Natarajan V. N-Acylated glycerophospholipids and their derivatives. Progr Lipid Res 1990; 29: 1-43.
29. Di Marzo V. Endocannabinoids' and other fatty acid derivatives with cannabimimetic properties: biochemistry and possible physiopathological relevance. Biochim Biophys Acta 1998; 1392: 153-75.
30. Leung D, Saghatelian A, Simon GM, Cravatt BF. Inactivation of N-acyl phosphatidylethanolamine phospholipase D reveals multiple mechanisms for the biosynthesis of endocannabinoids. Biochemistry 2006; 45: 4720-6.
31. Zolese G, Wozniak M, Mariani P, et al. Different modulation of phospholipase A2 activity by saturated and monounsaturated N-acylethanolamines. J Lipid Res 2003; 44: 742-53.
32. Simon GM, Cravatt BF. Endocannabinoid biosynthesis proceeding through glycerophospho-N-acylethanolamine and a role for alpha/beta-hydrolase 4 in this pathway. J Biol Chem 2006;281:26465-72.
33. Mulder AM, Cravatt BF. Endocannabinoid metabolism in the absence of fatty acid amide hydrolase (FAAH): discovery of phosphorylcholine derivatives of N-acyl ethanolamines. Biochemistry 2006; 45: 11267-77.
34. McKinney MK, Cravatt BF. Structure and function of fatty acid amide hydrolase. Annu Rev Biochem 2005; 74: 411-32.
35. Mechoulam R, Fride E, Di Marzo V. Endocannabinoids. Eur J Pharmacol 1998; 359: 1-18.
36. Hinz B, Ramer R, Eichele K, et al. R(+)-methanan- damide-induced cyclooxygenase-2 expression in H4 human neuroglioma cells: possible involvement of membrane lipid rafts. Biochem Biophys Res 2004; 324: 621-6.
37. Hinz B, Ramer R, Eichele K, et al. Up-regulation of cyclooxygenase-2 expression is involved in R(+)-methanandamide- inducedapoptotic death of human neuroglioma cells. Mol Pharmacol 2004; 66: 1643-51.
38. Bisogno T, Ligresti A, Di Marzo V. The endocannabinoid signalling system: Biochemical aspects. Pharmacol Biochem Behavior 2005; 81: 224-38.
39. Munson AE, Harris LS, Friedman A, et al. Antineoplastic activity of cannabinoids. J Natl Cancer Inst 1975; 55: 597-602.
40. Carchman RA, Harris LS, and Munson AE. The inhibition of DNA synthesis by cannabinoids. Cancer Res 1976; 36: 95-100.
41. Jia W, Hegde VL, Singh NP, et al. Δ9- Tetrahydrocannabinol-induced apoptosis in jurkat leukemia T cells is regulated by translocation of bad to mitochondria. Mol Cancer Res 2006; 4: 549-62.
42. Do Y, McKallip RJ, Nagarkatti M, et al. Activation through cannabinoid receptors 1 and 2 on dendritic cells triggers NF-kB-dependent apoptosis: novel role for endogenous and exogenous cannabinoids in immunoregulation. J Immunol 2004; 173: 2373-82.
43. Zhu W, Friedman H, Klein TW. Tetrahydrocannabinol induces apoptosis in macrophages and lymphocytes: involvement of bcl-2 and caspase-1. J Pharmacol Exp Ther 1998; 286: 1103-9.
44. Ruiz L, Miguel A, Diaz-Laviada I. Δ9-tetrahydrocannabinol induces apoptosis in human prostate PC-3 cells via a receptor-independent mechanism. FEBS Lett 1999; 458: 400-4.
45. Lombard C, Nagarkatti M, Nagarkatti SP. Targeting cannabinoid receptors to treat leukemia: role of cross-talk between extrinsic and intrinsic pathways in (9)-tetrahydrocannabinol (THC)-induced apoptosis of Jurkat cells. Leuk Res 2005; 29: 915-22.
46. McKallip RJ, Lombard C, Martin BR, et al. (9)-tetra-hydrocannabinol-induced apoptosis in the thymus and spleen as a mechanism of immunosuppression in vitro and in vivo. J Pharmacol Exp Ther 2002; 302: 451-65.
47. Carracedo A, Meritxell G, Mar L, et al. Cannabinoids induce apoptosis of pancreatic tumor cells via endoplasmic reticulum stress-related genes. Cancer Res 2006; 66: 6748-55.
48. Caffarel MM, Sarrió D, Palacios J, et al. Tetrahydrocannabinol inhibits cell cycle progression in human breast cancer cells through cdc2 regulation Cancer Res 2006; 66: 6615-21.
49. Powles T, Poele R, Shamash J, et al. Cannabis-induced cytotoxicity in leukemic cell lines: the role of the cannabinoid receptors and the MAPK pathway. Blood 2005; 105: 1214-21.
50. Galve-Roperh I, Sanchez C, Cortes ML, et al. Antitumoral action of cannabinoids: Involvement of sustained ceramide accumulation and extracellular signal-regulated kinase activation. Nat Med 2000; 6: 313-9.
51. Jacobsson SO, Rongard E, Stridh M, et al. Serum-dependent effects of tamoxifen and cannabinoids upon C6 glioma cell viability. Biochem Pharmacol 2000; 60: 1807-13.
52. Jacobsson SO, Wallin T, Fowler CJ. Inhibition of rat C6 glioma cell proliferation by endogenous and synthetic cannabinoids. Relative involvement of cannabinoid and vanilloid receptors. J Pharmacol Exp Ther 2001; 299: 951-9.
53. 9-Tetrahydrocannabinol induces apoptosis in C6 glioma cells. FEBS Lett 1998; 436: 6-10.
54. Sanchez C, de Ceballos ML, Gomez del Pulgar T, et al. Inhibition of glioma growth in vivo by selective activation of the CB2 cannabinoid receptor. Cancer Res 2001; 61: 5784-9.
55. Chan GC, Hinds TR, Impey S, et al. Hippocampal neurotoxicity of Δ9-tetrahydrocannabinol. J Neurosci 1998; 18: 5322-32.
56. Guzman M, Duarte MJ, Blazquez C, et al. A pilot clinical study of Delta9-tetrahydrocannabinol in patients with recurrent glioblastoma multiforme. Br J Cancer 2006; 95: 197-203.
57. McKallip RJ, Lombard C, Fisher M, et al. Targeting CB2 cannabinoid receptors as a novel therapy to treat malignant lymphoblastic disease. Blood 2002; 100: 627-34.
58. Downer E, Boland B, Fogarty M, Campbell V. Delta 9-tetrahydrocannabinol induces the apoptotic pathway in cultured cortical neurones via activation of the CB1 receptor. Neuroreport 2001; 12: 3973-8.
59. Campbell VA. Tetrahydrocannabinol-induced apoptosis of cultured cortical neurones is associated with cytochrome c release and caspase-3 activation. Neuropharmacol 2001; 40: 702-9.
60. Tomasini MC, Ferraro L, Bebe BW, et al. Delta(9)-tetrahydrocannabinol increases endogenous extracellular glutamate levels in primary cultures of rat cerebral cortex neurons: involvement of CB(1) receptors. J Neurosci Res 2002 May 15; 68: 449-53.
61. Scallet AC. Neurotoxicology of cannabis and THC: a review of chronic exposure studies in animals. Pharmacol Biochem Behav 1991; 40: 671-6.
62. Massi P, Vaccani A, Ceruti S, et al. Antitumor effects of cannabidiol, a nonpsychoactive cannabinoid, on human glioma cell lines. J Pharmacol Exp Therap 2004; 308: 838-45.
63. Wilkinson JD, Williamson EM. Cannabinoids inhibit human keratinocyte proliferation through a non-CB1/CB2 mechanism and have a potential therapeutic value in the treatment of psoriasis. J Dermatol Sci 2007; 45: 87-92.
64. McKallip RJ, JiaW, Schlomer J, et al. Cannabidiol-induced apoptosis in human leukemia cells: a novel role of cannabidiol in the regulation of p22phox and nox4 expression. MoI Pharmacol 2006; 70: 897-908.
65. Ligresti A, Moriello AS, Starowicz K, et al. Antitumor activity of plant cannabinoids with emphasis on the effect of cannabidiol on human breast carcinoma. J Pharmacol Exp Ther 2006; 318: 1375-87.
66. Sarfaraz S, Afaq F, Adhami VM, Mukhtar H. Cannabinoid receptor as a novel target for the treatment of prostate cancer. Cancer Res 2005; 65: 1635-41.
67. Sarfaraz S, Afaq F, Adhami VM, et al. Cannabinoid receptor agonist-induced apoptosis of human prostate cancer cells LNCaP proceeds through sustained activation of ERK1/2 leading to G1 cell cycle arrest. J Biol Chem 2006; 281: 39480-91.
68. Flygare J, Gustafsson K, Kimby E, et al. Cannabinoid receptor ligands mediate growth inhibition and cell death in mantle cell lymphoma FEBS Letters 2005; 579: 6885-9.
69. Gustafsson K, Christensson B, Sander B, Flygare J. Cannabinoid receptor-mediated apoptosis induced by R(+)-methanandamide and Win55,212-2 is associated with ceramide accumulation and p38 activation in mantle cell lymphoma. Mol Pharmacol 2006; 70: 1612-20.
70. Casanova M, Blazquez C, Martinez-Palacio J, et al. Inhibition of skin tumor growth and angiogenesis in vivo by activation of cannabinoid receptors. J Clin Invest 2003; 111: 43-50.
71. Blazquez C, Casanova ML, Planas A, et al. Inhibition of tumor angiogenesis by cannabinoids. FASEB J 2003; 17: 529-31.
72. Blazquez C, Gonzalez-Feria L, Alvarez L, et al. Cannabinoids inhibit the vascular endothelial growth factor pathway in gliomas. Cancer Res 2004; 64: 5617-23.
73. Bisogno T, Katayama K, Melck D, et al. Biosynthesis and degradation of bioactive fatty acid amides in human breast cancer and rat pheochromocytoma cells - implications for cell proliferation and differentiation. Eur J Biochem 1998; 254: 634-42.
74. De Petrocellis L, Melck D, Palmisano A, et al. The endogenous cannabinoid anandamide inhibits human breast cancer cell proliferation. Proc Natl Acad Sci USA 1998; 95: 8375-80.
75. Mimeault M, Pommery N, Wattez N, et al. Antiproliferative and apoptotic effects of anandamide in human prostatic cancer cell lines: implication of epidermal growth factor receptor down-regulation and ceramide production. Prostate 2003; 56: 1-12.
76. Sarker KP, Obara S, Nakata M, et al. Anandamide induces apoptosis of PC-12 cells: involvement of superoxide and caspase-3. FEBS Lett 2000; 472: 1039-44.
77. Sarker KP, Biswas KK, Yamakuchi M, et al. ASK1-p38 MAPK/JNK signaling cascade mediates anandamide-induced PC12 cell death. J Neurochem 2003; 85: 50-61.
78. Wang Y, Liu Y, Sarker KP, et al. Polymyxin B binds to anandamide and inhibits its cytotoxic effect. FEBS Lett 2000; 470: 151-5.
79. Giuliano M, Calvaruso G, Pellerito O, et al. Anandamide-induced apoptosis in Chang liver cells involves ceramide and JNK/AP-1 pathway. Int J Mol Med 2006; 17: 811-9.
80. Movsesyan VA, Stoica BA, Yakovlev AG, et al. Anandamide-induced cell death in primary neuronal cultures: role of calpain and caspase pathway. Cell Death Diff 2004; 11: 1121-32.
81. Yamaji K, Sarker KP, Kawahara K, et al. Anandamide induces apoptosis in human endothelial cells: its regulation system and clinical implications. Thromb Haemost 2003; 89: 875-84.
82. Hsu SS, Huang CJ, Cheng HH, et al. Anandamide-induced Ca(2+) elevation leading to p38 MAPK phosphorylation and subsequent cell death via apoptosis in human osteosarcoma cells. Toxicology 2007; 231: 21-9.
83. Siegmund SV, Uchinami H, Osawa Y, et al. Anandamide induces necrosis in primary hepatic stellate cells. Hepatology 2005; 41: 1085-95.
84. Siegmund SV, Seki E, Osawa Y, et al. Fatty acid amide hydrolase determines anandamide induced cell death in the liver. J Biol Chem 2006; 281: 10431-8.
85. Biswas KK, Sarker KP, Abeyama K, et al. Membrane cholesterol but not putative receptors mediates anandamide-induced hepatocyte apoptosis. Hepatology 2003; 38: 1167-77.
86. Muthian S, Rademacher DJ, Roelke CT, et al. Anandamide content is increased and CB1 cannabinoid receptor blockade is protective during transient, focal cerebral ischemia. Neuroscience 2004; 129: 743-50.
87. Eichele K. Weinzierl U, Ramer R, et al. R(+)-Methanandamide elicits a cyclooxygenase-2-dependent mitochondrial apoptosis signaling pathway in human neuroglioma cells. Pharm Res 2006; 23: 90-4.
88. Bifulco M, Laezza C, Portella G, et al. Control by the endogenous cannabinoid system of ras oncogene-dependent tumor growth. FASEB J 2001; 15: 2745-7.
89. Ligresti A, Bisogno T, Matias I, et al. Possible endocannabinoid control of colorectal cancer cell growth. Gastroenterology 2003; 125: 677-87.
90. Melck D, De Petrocellis L, Orlando P, et al. Suppression of nerve growth factor Trk receptors and prolactin receptors by endocannabinoids leads to inhibition of human breast and prostate cancer cell proliferation. Endocrinology 2000; 141: 118-26.
91. Nithipatikom K, Endsley MP, Isbell MA, et al. 2-Arachidonoylglycerol a novel inhibitor of androgen-independent prostate cancer cell invasion. Cancer Res 2004; 64: 8826-30.
92. Maccarrone M, Pauselli R, Di Rienzo M, Finazzi-Agro A. Binding, degradation and apoptotic activity of stearoylethanolamide in rat C6 glioma cells. Biochem J 2002; 366: 137-44.
93. Coroneos E, Martinez M, McKenna S, Kester M. Differential regulation of sphingomyelinase and ceramidase activities by growth factors and cytokines. J Biol Chem 1995; 270: 23305-9.
94. Huwiler A, Pfeilschifter J, Van den Bosch H. Nitric oxide donors induce stress signaling via ceramide formation in rat renal mesangial cells. J Biol Chem 1999; 274: 7190-5.
95. Wiesner DA, Dawson G. Staurosporine induces programmed cell death in embryonic neurons and activation of the ceramide pathway. J Neurochem 1996; 66: 1418-25.
96. Wiesner DA, Dawson G. Programmed cell death in neurotumour cells involves the generation of ceramide. Glycoconjugate J 1996; 13: 327-33.
97. L. J Biol Chem 1997; 272: 9868-76.
98. Sugita M, Williams M, Dulaney J, Moser H. Ceramidase and ceramide synthesis in human kidney and cerebellum. Description of a new alkaline ceramidase. Biochim Biophys Acta 1975; 398: 125-31.
99. Kostyuchenko N, Pushkarev V, Kashevarov G, et al. Effects of N-acylethanolamines and various antimitotic agents on apoptotic DNA fragmentation in conventionally normal and tumor tissue of human adrenals. Exp Oncol 2005; 27: 215-9.
100. Levchuk NI, Kovzun OI, Tron'ko MD, Pushkarev VM. Effect of N-stearoylethanolamine on the apoptosis intensity in tumor tissues of human adrenals. Endokrynologia 2007; 12: 121-5.
101. Zhukov OD, Artamonov MV, Klimashevs'kyii VM, et al. N-acylethanolamine - a new class of natural adrenotropic modulators. Ukr Biochem J 2000; 72 (2): 24-7.
102. Gula NM, Khmel TO, Klimashevsky VM, et al. N-stearoylethanolamine inhibits growth and metastasis of the Lewis carcinoma and modulates lipid composition of the lung under tumorogenesis in mice. Ukr Biochem J 2006; 78: 135-42.
103. Schmid PC, Wold LE, Krebsbach RJ, et al. Anandamide and other N-acylethanolamines in human tumors. Lipids 2002; 37: 907-12.
104. Franklin A, Parmentier-Batteur S, Walter L, et al. Palmitoylethanolamide increases after focal cerebral ischemia and potentiates microglial cell motility. J Neurosci 2003; 23: 7767-75.
105. Di Marzo V, Melck D, Orlando P, et al. Palmitoylethanolamide inhibits the expression of fatty acid amide hydrolase and enhances the anti-proliferative effect of anandamide in human breast cancer cells. Biochem J 2001; 358: 249-55.
106. Maccarrone M, Melino G, Finazzi-Agro A. Lipoxygenases and their involvement in programmed cell death. Cell Death Differ 2001; 8: 776-84.
107. Van der Stelt M, Minke A. Noordermeer, et al. Formation of a new class of oxylipins from N-acyl(ethanol)amines by the lipoxygenase pathway. Eur J Biochem 2000; 267: 2000-7.
108. De Pablo MA, Susin SA, Jacotot E, et al. Palmitate induces apoptosis via a direct effect on mitochondria. Apoptosis 1999; 4: 81-7.
109. Srivastava S, Chan C. Hydrogen peroxide and hydroxyl radicals mediate palmitate-induced cytotoxicity to hepatoma cells: Relation to mitochondrial permeability transition. Free Radical Res 2007; 41: 38-49.
110. Hickson-Bick DLM, Sparagna GC, Buja ML, McMillin JB. Palmitate induced apoptosis in neonatal cardiomyocytes is not dependent on the generation of ROS. Am J Physiol Heart Circ Physiol 2002; 282: H656-64.
111. Blazquez C, Galve-Roperh I, Guzman M. Denovo-synthesized ceramide signals apoptosis in astrocytes via extracellular signal-regulated kinase. FASEB J 2000; 14: 2315-22.
112. Lu Z-H, Mu Y-M, Wang B-A, et al. Saturated free fatty acids, palmitic acid and stearic acid, induce apoptosis by stimulation of ceramide generation in rat testicular Leydig cell. Biochem Biophys Res Commun 2003; 303: 1002-7.
113. Listenberger LL, Ory DS, Schaffer JE. Palmitate-induced apoptosis can occur through a ceramide-independent pathway. J Biol Chem 2001; 276: 14890-5.
114. Wei Y, Wang D, Topczewski F, Pagliassotti MJ. Saturated fatty acids induce endoplasmic reticulum stress and apoptosis independently of ceramide in liver cells. Am J Physiol Endocrinol Metab 2006; 291: E275-81.
115. Feldstein AE, Werneburg NW, Canbay A, et al. Free fatty acids promote hepatic lipotoxicity by stimulating TNF-alpha expression via a lysosomal pathway. Hepatology 2004; 40: 185-94.
116. Maccarrone M, Attina M, Bari M, et al. Anandamide degradation and N-acylethanolamines level in wild-type and CB1 cannabinoid receptor knockout mice of different ages. J Neurochem 2001; 78: 339-48.
117. Portella G, Laezza C, Laccetti P, et al. Inhibitory effects of cannabinoid CB1 receptor stimulation on tumor growth and metastatic spreading: actions on signals involved in angiogenesis and metastasis. FASEB J 2003; 17: 1771-3.
118. Pisanti S, Borselli C, Oliviero O, et al. Antiangiogenic activity of the endocannabinoid anandamide: Correlation to its tumor-suppressor efficacy. J Cell Physiol 2007; 211: 495-503.
119. Grimaldi C, Pisanti S, Laezza C, et al. Anandamide inhibits adhesion and migration of breast cancer cells. Exp Cell Res 2006; 312: 363-73.
120. Joseph J, Niggemann B, Zaenker KS, Entschladen F. Anandamide is an endogenous inhibitor for the migration of tumor cells and T lymphocytes. Cancer Immunol Immunother 2004; 53: 723-8.
121. Kogan NM, Blazquez C, Alvarez L, et al. A cannabinoid quinone inhibits angiogenesis by targeting vascular endothelial cells. Mol Pharmacol 2006; 70: 51-9.
122. Velasco G, Galve-Roperh I, Sanchez C, et al. Hypothesis: cannabinoid therapy for the treatment of gliomas. Neuropharmacology 2004; 47: 315-23.
123. Nieri P, Romiti N, Adinolfi B, et al. Modulation of P-glycoprotein activity by cannabinoid molecules in HK-2 renal cells. Br J Pharmacol 2006; 148: 682-7.
124. Blazquez C, Carracedo A, Barrado L, et al. Cannabinoid receptors as novel targets for the treatment of melanoma. FASEB J 2006; 20: 2633-5.
125. Hansen HH, Azcoitia I, Pons S, et al. Blockade of cannabinoid CB(1) receptor function protects against in vivo disseminating brain damage following NMDA-induced excitotoxicity. J Neurochem 2002; 82: 154-8.
126. Herrera B, Carracedo A, Diez-Zaera M, et al. The CB2 cannabinoid receptor signals apoptosis via ceramide-dependent activation of the mitochondrial intrinsic pathway. Exp Cell Res 2006; 312: 2121-31.
127. Maccarrone M, Lorenzon T, Bari M, et al. Anandamide induces apoptosis in human cells via vanilloid receptors. Evidence for a protective role of cannabinoid receptors. J Biol Chem 2000; 275: 31938-45.
128. Sarker KP, Maruyama I. Anandamide induces cell death independently of cannabinoid receptors or vanilloid receptor 1: possible involvement of lipid rafts. Cell Mol Life Sci 2003; 60: 1200-8.
129. Berdyshev EV, Schmid PC, Krebsbach RJ, et al. Cannabinoid-receptor-independent cell signalling by N-acylethanolamines. Biochem J 2001; 360: 67-75.
130. Schmid HH, Berdyshev EV. Cannabinoid receptor-inactive N-acylethanolamines and other fatty acid amides: metabolism and function. Prostaglandins Leukot Essent Fatty Acids 2002; 66: 363-76.
131. Bari M, Battista N, Fezza F, et al. Lipid rafts control signaling of type-1 cannabinoid receptors in neuronal cells implications for anandamide-induced apoptosis. J Biol Chem 2005; 280: 12212-20.
132. McFarland MJ, Barker EL. Lipid rafts: a nexus for endocannabinoid signaling? Life Sci 2005; 77: 1640-50.
133. McFarland MJ, Terebova EA, Barker EL. Detergent-resistant membrane microdomains in the disposition of the lipid signaling molecule anandamide. AAPS J 2006; 8: E95-100.
134. Herrera B, Carracedo A, Diez-Zaera M, et al. p38 MAPK is involved in CB2 receptor-induced apoptosis of human leukaemia cells. FEBS Lett 2005; 579: 5084-8.
135. Ramer R, Weinzierl U, Schwind B, et al. Ceramide is involved in R(+)-methanandamide-induced cyclooxygenase-2 expression in human neuroglioma cells. Mol Pharmacol 2003; 64: 1189-98.
136. Sancho R, Calzado MA, Di Marzo V, et al. Anandamide inhibits nuclear factor-kB activation through a cannabinoid receptor-independent pathway. Mol Pharmacol 2003; 63: 429-38.
137. Perkins ND. Integrating cell-signalling pathways with NF-κB and IKK function Nat Rev Mol Cell Biol 2007; 8: 49-62.
138. Downer EJ, Fogarty MP, Campbell VA. Tetrahydrocannabinol-induced neurotoxicity depends on CB1 receptor-mediated c-Jun N-terminal kinase activation in cultured cortical neurons. British Journal of Pharmacology 2003; 140: 547-57.
139. Downer EJ, Gowran A, Murphy AC, Campbell VA. The tumour suppressor protein, p53, is involved in the activation of the apoptotic cascade by Delta9-tetrahydrocannabinol in cultured cortical neurons. Eur J Pharmacol 2007; 564: 57-65.
140. Laezza C, Pisanti S, Crescenzi E, Bifulco M. Anandamide inhibits Cdk2 and activates Chk1 leading to cell cycle arrest in human breast cancer cells. FEBS Lett 2006; 580: 6076-82.
141. Howlett AC, Mukhopadhyay S. Cellular signal transduction by anandamide and 2-arachidonoylglycerol. Chem Phys Lipids 2000; 108: 53-70.
142. Yeh JH, Cheng HH, Huang CJ, et al. Effect of anandamide on cytosolic Ca(2+) levels and proliferation in canine renal tubular cells. Basic Clin Pharmacol Toxicol 2006; 98: 416-22.
143. Lauckner JE, Hille B, Mackie K. The cannabinoid agonist WIN55,212-2 increases intracellular calcium via CB1 receptor coupling to Gq/11 G proteins. Proc Natl Acad Sci USA 2005; 102: 19144-9.
144. Guzman M, Galve-Roperh I, Sanchez C. Ceramide: a new second messenger of cannabinoid action. Trends Pharmacol Sci 2001; 22: 19-22.
145. Schmid HH. Pathways and mechanisms of N-acylethanolamine biosynthesis: can anandamide be generated selectively? Chem Phys Lipids 2000; 108: 71-87.
146. Venkataraman K, Futerman AH. Ceramide as a second messenger: sticky solutions to sticky problems. Trends Cell Biol 2000; 10: 408-12.
147. Gomez del Pulgar T, Velasco G, Sanchez C, et al. De novo-synthesized ceramide is involved in cannabinoid-induced apoptosis. Biochem J 2002; 363: 183-8.
148. Spinedi A, Di Bartolomeo S, Piacentini M. N-oleoylethanolamine inhibits glucosylation of natural ceramides in CHP-100 neuroepithelioma cells: Possible implications for apoptosis. Biochem Biophys Res Commun 1999; 255: 456-9.
149. Ping SE, Barrett GL. Ceramide can induce cell death in sensory neurons, whereas ceramide analogues and sphingosine promote survival. J Neurosci Res 1999; 54: 206-13.
150. Gulbins E, Li PL. Physiological and pathophysiological aspects of ceramide Am J Physiol Regul Integr Comp Physiol 2006; 290: 11-26.
151. Velasco G, Galve-Roperh I, Sanchez C, et al. Cannabinoids and ceramide: two lipids acting hand-by-hand. Life Seci 2005; 77: 1723-31.
152. Ramer R, Brune K, Pahl A, Hinz B. R-(+)-Methanandamide induces cyclooxygenase-2 expression in human neuroglioma cells via a non-cannabinoid receptor-mediated mechanism. Biochem Biophys Res Commun 2001; 286: 1144-52.
153. Patsos HA, Hicks DJ, Dobson RR, et al. The endogenous cannabinoid, anandamide, induces cell death in colorectal carcinoma cells: a possible role for cyclooxygenase 2. Gut 2005; 54: 1741-50.
154. Guzman M, Lo Verme J, Fu J, et al. Oleoylethanolamide stimulates lipolysis by activating the nuclear receptor peroxisome proliferator-activated receptor alpha (PPAR-alpha). J Biol Chem 2004; 279: 27849-54.
155. Gutierrez G, Mendoza C, Montano LF, Lopez-Marure R. Ceramide induces early and late apoptosis in human papilloma virus+ cervical cancer cells by inhibiting reactive oxygen species decay, diminishing the intracellular concentration of glutathione and increasing nuclear factor-kappa B translocation. Anticancer Drugs 2007; 18: 149-59.
156. Zolese G, Bacchetti T, Ambrosini A, et al. Increased plasma concentrations of palmitoylethanolamide, an endogenous fatty acid amide, affect oxidative damage of human low-density lipoproteins: An in vitro study. Atherosclerosis 2005; 182: 47-55.
157. Matas D, Juknat A, Pietr M, et al. Anandamide protects from low serum-induced apoptosis via its degradation to ethanolamine. J Biol Chem 2007; 282: 7885-92.
158. Wasilewski M, Wojtczak L. Effects of N-acylethanolamines on the respiratory chain and production of reactive oxygen species in heart mitochondria FEBS Letters 2005; 579: 4724-8.
159. Ronco AM, Llanos M, Tamayo D, Hirsch S. Anandamide inhibits endothelin-1 production by human cultured endothelial cells: a new vascular action of this endocannabinoid. Pharmacol 2007; 79: 12-6.
160. Costa B, Siniscalco D, Trovato AE, et al. AM404, an inhibitor of anandamide uptake, prevents pain behaviour and modulates cytokine and apoptotic pathways in a rat model of neuropathic pain. Br J Pharmacol 2006; 148: 1022-32.
161. Jung JY, Han CR, Jeong YJ, et al. Epigallocatechin gallate inhibits nitric oxide-induced apoptosis in rat PC 12 cells. Neurosci Lett 2007; 411: 222-7.
162. Ryter SW, Kim HP, Hoetzel A, et al. Mechanisms of cell death in oxidative stress. Antioxid Redox Signal 2007; 9: 49-89.
163. Carracedo A, Lorente M, Egia A, et al. The stress-regulated protein p8 mediates cannabinoid-induced apoptosis of tumor cells. Cancer Cell 2006; 9: 301-12.
164. Shen MX, Thayer SA. Cannabinoid receptor agonists protect cultured rat hippocampal neurons from excitotoxicity. Mol Pharmacol 1998; 54: 459-62.
165. Skaper SD, Buriani A, Dal Toso R, et al. The ALIAmide palmitoylethanolamide and cannabinoids, but not anandamide, are protective in a delayed postglutamate paradigm of excitotoxic death in cerebellar granule neurons Proc Natl Acad Sci USA 1996; 93: 3984-9.
166. Nagayama T, Sinor AD, Simon RP, et al. Cannabinoids and neuroprotection in global and focal cerebral ischemia and in neuronal cultures. J Neurosci 1999; 19: 2987-95.
167. Abood ME, Rizvi G, Sallapudi N, et al. Activation of the CB1 cannabinoid receptor protects cultured mouse spinal neurons against excitotoxicity. Neurosci Lett 2001; 309: 197-201.
168. Van der Stelt M, Veldhuis WB, Bar PR, et al. Neuroprotection by Δ9-tetrahydrocannabinol, the main active compound in marijuana, against ouabain-induced in vivo excitotoxicity. J Neurosci 2001; 21: 6475-9.
169. Hampson AJ, Grimaldi M, Lolic D, et al. Neuroprotective antioxidants from marijuana. Ann N-Y Acad Sci 2000; 899: 274-82.
170. El-Remessy AB, Khalil IE, Matragoon S, et al. Neuroprotective effect of (Δ)9-tetrahydrocannabinol and cannabidiol in N-methyl-D-aspartate-induced retinal neurotoxicity. Involvement of peroxynitrite. Am J Pathol 2003; 163: 1997-2008.
171. Fernandez-Lopez D, Martínez-Orgado J, Nuñez E, et al. Characterization of the neuroprotective effect of the cannabinoid agonist WIN-55212 in an in vitro model of hypoxic-ischemic brain damage in newborn rats. Pediatr Res 2006; 60: 169-73.
172. Di Filippo C, Rossi F, Rossi S, et al. Cannabinoid CB2 receptor activation reduces mouse myocardial ischemia-reperfusion injury: involvement of cytokine/chemokines and PMN. J Leukocyte Biol 2004; 75: 453-9.
173. Hart S, Fischer OM, Ullrich A. Cannabinoids induce cancer cell proliferation via tumor necrosis factor α-converting enzyme (TACE/ADAM17)-mediated transactivation of the epidermal growth factor receptor. Cancer Res 2004; 64: 1943-50.
174. Lastres-Becker I, Molina-Holgado F, Ramos JA, et al. Cannabinoids provide neuroprotection against 6-hydroxydopamine toxicity in vivo and in vitro: Relevance to Parkinson's disease. Neurobiol Disease 2005; 19: 96-107.
175. Lamontagne D, Lepicier P, Lagneux C, Bouchard JF. The endogenous cardiac cannabinoid system: a new protective mechanism against myocardial ischemia. Arch Mal Coeur Vaiss 2006; 99: 242-6.
176. Sinor AD, Irvin SM, Greenberg DA. Endocannabinoids protect cerebral cortical neurons from in vitro ischemia in rats. Neurosci Lett 2000; 278: 157-60.
177. Van der Stelt M, Veldhuis WB, van Haaften GW, et al. Exogenous anandamide protects rat brain against acute neuronal injury in vivo. J Neurosci 2001b; 21: 8765-71.
178. Veldhuis WB, van der Stelt M, Wadman MW, et al. Neuroprotection by the endogenous cannabinoid anandamide and arvanil against in vivo excitotoxicity in the rat: role of vanilloid receptors and lipoxygenases. J Neurosci 2003; 23: 4127-33.
179. 2+ release from mitochondria by N-acylethanolamines, a class of lipids synthesized in ischemic heart tissue. J Biol Chem 1982; 257: 1383-91.
180. Gulaya NM, Melnik AA, Balkov DI, et al. The effect of long-chain N-acylethanolamines on some membrane-associated functions of neuroblastoma C1300 N18 cells. Biochim Biophys Acta 1993; 1152: 280-8.
181. Gulaya NM, Smirnov IM, Shmalko YP, et al. Effect of N-palmitoyl- and N-stearoylethanolamines on lipid peroxidation in mouse tissues in metastatic Lewis carcinoma. Ukr Biochem J 1993; 65: 96-101.
182. Gulaya NM., Kuzmenko AI, Margitich VM, et al. Long-chain N-acylethanolamines inhibit lipid peroxidation in rat liver mitochondria under acute hypoxic hypoxia. Chem Phys Lipids 1998; 97: 49-54.
183. Parinandi NL, Schmid HHO. Effects of long-chain N-acylethanolamines on lipid peroxidation in cardiac mitochondria. FEBS Lett 1988; 237: 49-52.
184. Mendizabal VE, Adler-Graschinsky E. Cannabinoids as therapeutic agents in cardiovascular disease: a tale of passions and illusions. Brit J Pharmacol 2007; 151: 427-40.
185. Schmid PC, Krebsbach RJ, Perry SR, et al. Occurrence and postmortem generation of anandamide and other long-chain N-acylethanolamines in mammalian brain. FEBS Lett 1995; 375: 143-7.
186. Natarajan V, Schmid P, Schmid H. N-Acylethanolamine phospholipid metabolism in normal and ischemic rat brain. Biochim Biophys Acta 1986; 878: 32-41.
187. Patel S, Carrier EJ, Ho WS, et al. The postmortal accumulation of brain N-arachidonylethanolamine (anandamide) is dependent upon fatty acid amide hydrolase activity. J Lipid Res 2005; 46: 342-9.
188. 31P NMR study. J Lipid Res 1999; 40: 515-21.
189. Kondo S, Sugiura T, Kodaka T, et al. Accumulation of various N-acylethanolamines including N-arachidonoylethanolamine (anandamide) in cadmium chloride-administered rat testis. Arch Biochem Biophys 1998; 354: 303-10.
190. Hansen HH, Hansen SH, Schousboe A, Hansen HS. Determination of the phospholipid precursor of anandamide and other N-acylethanolamine phospholipids before and after sodium azide-induced toxicity in cultured neocortical neurons. J Neurochem 2000; 75: 861-71.
191. Epps DE, Schmid PC, Natarajan V, Schmid HHO. N-Acylethanolamine accumulation in infarcted myocardium. Biochem Biophys Res Commun 1979; 90: 628-33.
192. Hansen HS, Moesgaard B, Hansen HH, et al. Formation of N-acyl-phosphatidylethanolamine and N-acylethanolamine (including anandamide) during glutamate-induced neurotoxicity. Lipids 1999; 34 (Suppl): 327-30.
193. Berdyshev EV, Schmid PC, Dong Z, Schmid HH. Stress-induced generation of N-acylethanolamines in mouse epidermal JB6 P+ cells. Biochem J 2000; 346 (Pt 2): 369-74.
194. Merkel O, Schmid PC, Paltauf F, Schmid HHO. Presence and potential signaling function of N-acylethanolamines and their phospholipid precursors in the yeast Saccharomyces cerevisiae. Biochim Biophys Acta 2005; 1734: 215-9.
195. Hansen HH, Ikonomidou C, Bittigau P, et al. Accumulation of the anandamide precursor and other N-acylethanolamine phospholipids in infant rat models of in vivo necrotic and apoptotic neuronal death. J Neurochem 2001; 76: 39-46.
196. Marsicano G, Goodenough S, Monory K, et al. CB1 cannabinoid receptors and on-demand defense against excitotoxicity. Science 2003; 302: 84-8.
197. Di Marzo V, Bifulco M, De Petrocellis L. The endocannabinoid system and its therapeutic exploitation. Nat Rev Drug Discov 2004; 3: 771-84.
198. Epps DE, Mandel F, Schwartz A. The alteration of rabbit skeletal sarcoplasmic reticulum function by N-acylethanolamine, a lipid associated with myocardial infarction. Cell Calcium 1982a; 3: 43-53.
199. Zolese G, Gabbianelli R, Bertoli E, et al. Effect of N-acylethanolamines on trout erythrocytes. Chem Phys Lipids 1995; 75: 97-100.
200. Akoka S, Tellier C, le Roux C, et al. A phosphorus magnetic resonance spectroscopy and a differential scanning calorimetry study of the physical properties of N-acylphosphatidylethanolamines in aqueous dispersions. Chem Phys Lipids 1988; 46: 43-50.
201. Wasilewski M, Wieckowski MR, Dymkowska D, Wojtczak L. Effects of N-acylethanolamines on mitochondrial energetics and permeability transition. Biochim Biophys Acta 2004; 1657: 151-63.
202. Sarker KP, Nakata M, Kitajima I, et al. Inhibition of caspase-3 activation by SB 203580, p38 mitogen-activated protein kinase inhibitor in nitric oxide-induced apoptosis of PC-12 cells. J Mol Neurosci 2000; 15 (3): 243-50.
203. + and mitotane effects on steroid hormones labeling in human adrenocortical tissue. Biomedical Res 2001; 22: 191-5.