The antitumor action of cannabinoids on glioma tumorigenesis

Histology and Histopathology

Volumn 30, Issue 6, 2015, Pages 629-645

  Zogopoulos, Panagiotis ^a   Korkolopoulou, Penelope ^a   Patsouris, Efstratios ^a   Theocharis, Stamatios ^a  

^a UNIVERSITY OF ATHENS MEDICAL SCHOOL   (Greece)

Author keywords

Cannabinoids; CB1; CB2; Glioma; Tumor

Indexed keywords

ANIMALIA;

CANNABINOID; CANNABINOID 1 RECEPTOR;

BRAIN NEOPLASMS; CARCINOGENESIS; DRUG EFFECTS; GLIOMA; HUMAN; METABOLISM; PATHOLOGY;

BRAIN NEOPLASMS; CANNABINOIDS; CARCINOGENESIS; GLIOMA; HUMANS; RECEPTOR, CANNABINOID, CB1;

EID: 84931840300     PISSN: 02133911     EISSN: None     Source Type: Journal    
DOI: 10.14670/HH-30.629     Document Type: Review

References (158)

1. Adams I.B. and Martin B.R. (1996). Cannabis: pharmacology and toxicology in animals and humans. Addiction 91, 1585-1614
2. Aguado T., Palazuelos J., Monory K., Stella N., Cravatt B., Lutz B., Marsicano G., Kokaia Z., Guzman M. and Galve-Roperh I. (2006). The endocannabinoid system promotes astroglial differentiation by acting on neural progenitor cells. J. Neurosci. 26, 1551-1561.
3. Alexander A., Smith P.F. and Rosengren R.J. (2009). Cannabinoids in the treatment of cancer. Cancer Lett. 285, 6-12.
4. Amantini C., Mosca M., Nabissi M., Lucciarini R., Caprodossi S., Arcella A., Giangaspero F. and Santoni G. (2007). Capsaicin-induced apoptosis of glioma cells is mediated by TRPV1 vanilloid receptor and requires p38 MAPK activation. J. Neurochem. 102, 977-990.
5. Badie B. and Schartner J. (2001). Role of microglia in glioma biology. Microsc. Res. Tech. 54, 106-113.
6. Balkhoyor K.B. and Bernstein M. (2000). Involution of diencephalic pilocytic astrocytoma after partial resection. Report of two cases in adults. J. Neurosurg. 93, 484-486.
7. Bari M., Battista N., Fezza F., Finazzi-Agro A. and Maccarrone M. (2005). Lipid rafts control signaling of type-1 cannabinoid receptors in neuronal cells. Implications for anandamide-induced apoptosis. J. Biol. Chem. 280, 12212-12220.
8. Benito C., Nunez E., Tolon R.M., Carrier E.J., Rabano A., Hillard C.J. and Romero J. (2003). Cannabinoid CB2 receptors and fatty acida mide hydrolase are selectively overexpressed in neuritic plaqueassociated glia in Alzheimer’s disease brains. J. Neurosci. 23, 11136-11141.
9. Benito C., Tolon R.M., Pazos M.R., Nunez E., Castillo A.I. and Romero J. (2008). Cannabinoid CB2 receptors in human brain inflammation. Br. J. Pharmacol. 153, 277-285.
10. Bi ful co M., Mal fi tano A.M., Pi santi S. and Laezza C. (2008). Endocannabinoids in endocrine and related tumors. Endocr. Relat. Cancer 15,391-408.
11. Bíró T., Tóth B.I., Haskó G., Paus R. and Pacher P. (2009). The endocannabinoid system of the skin in health and disease: novel perspectives and therapeutic opportunities. Trends Pharmacol. Sci. 30, 411-420.
12. Blazquez C., Casanova M.L., Planas A., Gomez Del Pulgar T., Villanueva C., Fernandez-Acenero M.J., Aragones J., Huffman J.W., Jorcano J.L. and Guzman M. (2003). Inhi bi ti on of tumor angiogenesis by cannabinoids. FASEB. J. 17, 529-531.
13. Blazquez C., Gonzalez-Feria L., Alvarez L., Haro A., Casanova M.L. and Guzman M. (2004). Cannabi noi ds i nhi bi t the vascul ar endothelial growth factor pathway in gliomas. Cancer Res. 64, -5623.
14. Blazquez C., Salazar M., Carracedo A., Lorente M., Egia A., Gonzalez Feria L., Haro A., Velasco G. and Guzman M. (2008). Cannabinoids i nhi bi t gl i oma cel l i nvasi on by down-regul ati ng matrixmetalloproteinase-2 expression. Cancer Res. 68, 1945-1952.
15. Boiardi A., Silvani A., Pozzi A., Farinotti M., Fariselli L., Broggi G. and Salmaggi A. (1997). Advantage of treating anaplastic gliomas with aggressive protocol combining chemotherapy and radiotherapy. J. Neurooncol. 34, 179-185.
16. Brandes A.A., Scelzi E., Zampieri P., Rigon A., Rotilio A., Amista P., Berti F. and Fiorentino M.V. (1997). Phase II trial with BCNU plus alphainterferon in patients with recurrent high-grade gliomas. Am. J. Clin. Oncol. 20, 364-367.
17. Burnet N.G., Lynch A.G., Jefferies S.J., Price S.J., Jones P.H., Antoun N.M., Xuereb J.H. and Pohl U. (2007). High grade glioma: imaging combined with pathological grade defines management and predicts prognosis. Radiother. Oncol. 85, 371-378.
18. Caffarel M.M., Sarrio D., Palacios J., Guzman M. and Sanchez C. (2006). D9-tetrahydrocannabinol inhibits cell cycle progression in human breast cancer cells through Cdc2 regulation. Cancer Res. 66, 6615-6621.
19. Carracedo A., Gironella M., Lorente M., Garcia S., Guzman M., Velasco G. and Iovanna J.L. (2006a). Cannabinoids induce apoptosis of pancreatic tumor cells via endoplasmic reticulum stress-related genes. Cancer Res. 66, 6748-6755.
20. Carracedo A., Lorente M., Egia A., Blazquez C., Garcia S., Giroux V., Malicet C., Villuendas R., Gironella M., Gonzalez-Feria L., Piris M.A., Iovanna J.L., Guzman M. and Velasco G. (2006b). The stressregulated protein p8 mediates cannabinoid-induced apoptosis of tumor cells. Cancer Cell 9, 301-312.
21. Carrier E.J., Auchampach J.A. and Hillard C.J. (2006). Inhibition of an equilibrative nucleoside transporter by cannabidiol: a mechanism of cannabinoid immunosuppression. Proc. Natl. Acad. Sci. USA 103, 7895-7900.
22. Casanova M.L., Blazquez C., Martinez-Palacio J., Villanueva C., Fernandez-Acenero M.J., Huffman J.W., Jorcano J.L. and Guzman M. (2003). Inhibition of skin tumor growth and angiogenesis in vivo by activation of cannabinoid receptors. J. Clin. Invest. 111, 43-50.
23. Contassot E., Wilmotte R., Tenan M., Belkouch M.C., Schnuriger V., de Tri bol et N.,Burkhardt K. and Di etri ch P.Y. (2004). Arachidonylethanolamide induces apoptosis of human glioma cells through vanilloid receptor-1. J. Neuropathol. Exp. Neurol. 63, 956963.
24. Cudaback E., Marrs W., Moeller T. and Stella N. (2010). The expression level of CB1 and CB2 receptors determines their efficacy at inducing apoptosis in astrocytomas. PLoS One 5, e8702.
25. Cudaback E. and Stella N. (2007). Targeting astrocytomas and invading immune cells with cannabinoids: a promising therapeutic avenue. Mol. Neurobiol. 36, 36-44.
26. Curran N.M., Griffin B.D., O’Toole D., Brady K.J., Fitzgerald S.N. and Moynagh P.N. (2005). The synthetic cannabinoid R(+)WIN 55,212-2 inhibits the interleukin-1 signaling pathway in human astrocytes in a cannabinoid receptor-independent manner. J. Biol. Chem. 280, 35797-35806.
27. De Jesus M.L., Hostalot C., Garibi J.M., Salles J., Meana J.J. and Callado L.F. (2010). Opposite changes in cannabinoid CB1 and CB2 receptor expression in human gliomas. Neurochem. Int. 56, 829-833.
28. De March Z., Zuccato C., Giampa C., Patassini S., Bari M., Gasperi V., De Ceballos M.L., Bernardi G., Maccarrone M., Cattaneo E. and Fusco F.R. (2008). Cortical expression of brain derived neurotrophic factor and type-1 cannabinoid receptor after striatal excitotoxic lesions. Neuroscience 152, 734-740.
29. De Petrocellis L., Melck D., Palmisano A., Bisogno T., Laezza C., Bifulco M. and Di Marzo V. (1998). The endogenous cannabinoid anandamide inhibits human breast cancer cell proliferation. Proc. Natl. Acad. Sci. USA. 95, 8375-8380.
30. Downer E.J., Fogarty M.P. and Campbell V.A. (2003). Tetrahydrocannabinolinduced neurotoxicity depends on CB1 receptor-mediated c-Jun N-terminal kinase activation in cultured cortical neurons. Br. J. Pharmacol. 140, 547-557.
31. Downer E.J., Gowran A., Murphy A.C. and Campbell V.A. (2007). The tumor suppressor protein, p53, is involved in the activation of the apoptotic cascade by Delta9-tetrahydrocannabinol in cultured cortical neurons. Eur. J. Pharmacol. 564, 57-65.
32. Duntsch C., Divi M.K., Jones T., Zhou Q., Krishnamurthy M., Boehm P., Wood G., Sills A. and Moore B.M. (2006). Safety and efficacy of a novel cannabinoid chemotherapeutic, KM-233, for the treatment of high-grade glioma. J. Neuro-Oncol. 77, 143-152.
33. Efird J.T., Friedman G.D., Sidney S., Klatsky A., Habel L.A., Udaltsova N.V., Van den Eeden S. and Nelson L.M. (2004). The risk for malignant primary adult-onset glioma in a large, multiethnic, managed-care cohort: cigarette smoking and other lifestyle behaviors. J. Neurooncol. 68, 57-69.
34. Eichele K., Weinzierl U., Ramer R., Brune K. and Hinz B. (2006). R(+) Methanandami de el i ci ts a cycl ooxygenase-2-dependent mitochondrial apoptosis signaling pathway in human neuroglioma cells. Pharmaceut. Res. 23, 90-94.
35. El-Remessy A.B., Tang Y., Zhu G., Matragoon S., Khalifa Y., Liu E.K., Liu J.Y., Hanson E., Mian S., Fatteh N. and Liou G.I. (2008). Neuroprotective effects of cannabidiol in endotoxin-induced uveitis: critical role of p38 MAPK activation. Mol. Vis. 14, 2190-203.
36. El l ert-Mi kl aszewska A.,Kami nska B. and Konarska L. (2005). Cannabinoids down-regulate PI3K/Akt and Erk signalling pathways and activate proapoptotic function of Bad protein. Cell. Signal. 17, 25-37.
37. Ellert-Miklaszewska A., Grajkowska W., Gabrusiewicz K., Kaminska B. and Konarska L. (2007). Distinctive pattern of cannabinoid receptor type II (CB2) expression in adult and pediatric brain tumors. Brain Res. 1137, 161-169.
38. Elsohly M.A. and Slade D. (2005). Chemical constituents of marijuana: the complex mixture of natural cannabinoids. Life Sci 78, 539-548.
39. Endsley M.P., Aggarwal N., Isbell M.A., Wheelock C.E., Hammock B.D., Falck J.R., Campbell W.B. and Nithipatikom K. (2007). Diverse roles of 2-arachidonoylglycerol in invasion of prostate carcinoma cells: Location, hydrolysis and 12-lipoxygenase metabolism. Int. J. Cancer 121, 984-991.
40. Endsley M.P., Thill R., Choudhry I., Williams C.L., Kajdacsy-Balla A., Campbell W.B. and Nithipatikom K. (2008). Expression and function of fatty acid amide hydrolase in prostate cancer. Int. J. Cancer 123, 1318-1326.
41. Felder C. and Mitchell R. (1995). Comparison of the signal transduction of the human cannabinoid CB1 and CB2 receptors. ASPET. 48, 443-450.
42. Fernandez-Ruiz J., Romero J., Velasco G., Tolon R.M., Ramos J.A. and Guzman M. (2007). Cannabinoid CB2 receptor: a new target for controlling neural cell survival. Trends Pharmacol. Sci. 28, 39-45.
43. Fisher P.G. and Buffler P.A. (2005). Malignant gliomas in 2005: where to GO from here? JAMA 293, 615-617.
44. Fomchenko E.I. and Holland E.C. (2006a). Mouse models of brain tumors and their applications in preclinical trials. Clin. Cancer Res. 12, 5288-5297.
45. Fomchenko E.I. and Holland E.C. (2006b). Origins of brain tumors-a disease of stem cells? Nat. Clin. Pract. Neurol. 2, 288-289.
46. Foroughi M., Hendson G., Sargent M.A. and Steinbok P. (2011). Spontaneous regression of septum pellucidum/forniceal pilocytic astrocytomas—possible role of Cannabis inhalation. Childs Nerv. Syst. 27, 671-679.
47. Fowler C.J., Jonsson K.O., Andersson A., Juntunen J., Jarvinen T., Vandevoorde S., Lambert D.M., Jerman J.C. and Smart D. (2003). Inhibition of C6 glioma cell proliferation by anandamide, 1arachidonoylglycerol, and by a water soluble phosphate ester of anandamide: variability in response and involvement of arachidonic acid. Biochem. Pharmacol. 66, 757-767.
48. Freimuth N., Ramer R. and Hinz B. (2010). Antitumorigenic effects of cannabinoids beyond apoptosis. J. Pharmacol. Exp. Ther. 332, 336 344.
49. Galanis E. and Buckner J.C. (2000). Chemotherapy of brain tumors. Curr. Opin. Neurol. 13, 619-625.
50. Galve-Roperh I., Sanchez C., Cortes M.L., Gomez del Pulgar T., Izquierdo M. and Guzman M. (2000). Anti-tumoral action of cannabinoids: involvement of sustained ceramide accumulation and extracellular signal-regulated kinase activation. Nat. Med. 6, 313-319.
51. Gilbert G.L., Kim H.J., Waataja J.J. and Thayer S.A. (2007). Delta9 tetrahydrocannabi nol protects hi ppocampal neurons from excitotoxicity. Brain Res. 1128, 61-69.
52. Gomez Del Pulgar T., De Ceballos M.L., Guzman M. and Velasco G. (2002a). Cannabinoids protect astrocytes from ceramide-induced apoptosis through the phosphatidylinositol 3-kinase/protein kinase B pathway. J. Biol. Chem. 277, 36527-36533.
53. Gomez del Pulgar T., Velasco G., Sanchez C., Haro A. and Guzman M. (2002b). De novo-synthesized ceramide is involved in cannabinoidinduced apoptosis. Biochem. J. 363, 183-188.
54. Gong J.P., Onaivi E.S., Ishiguro H., Liu Q.R., Tagliaferro P.A., Brusco A. and Uhl G.R. (2006). Cannabi noi d CB2 receptors: immunohistochemical localization in rat brain. Brain Res. 1071, 1023.
55. Grant R., Liang B.C., Page M.A., Crane D.L., Greenberg H.S. and Junck L. (1995). Age influences chemotherapy response in astrocytomas. Neurology 45, 929-933.
56. Green S.B., Byar D.P., Walker M.D., Pistenmaa D.A., Alexander E. Jr, Batzdorf U., Brooks W.H., Hunt W.E., Mealey J. Jr, Odom G.L., Paoletti P., Ransohoff J. II, Robertson J.T., Selker R.G., Shapiro W.R., Smi th K.R. Jr, Wi l son C.B. and Stri ke T.A. (1983). Compari sons of carmusti ne, procarbazi ne, and hi gh-dose methylprednisolone as additions to surgery and radiotherapy for the treatment of malignant glioma. Cancer Treat. Rep. 67, 121-132.
57. Grossman S.A., O’Neill A. and Grunnet M. (2000). Phase III study comparing three cycles of infusional BCNU/cisplatin followed by radiation with radiation and concurrent BCNU for patients with newly diagnosed supratentorial glioblastoma multiforme. Proc. Am. Soc. Clin. Oncol. 19, A612.
58. Grotenhermen F. (2005). Cannabinoids. Curr. Drug Targets CNS Neurol. Disord. 4, 507-530.
59. Gunny R.S., Hayward R.D., Phipps K.P., Harding B.N. and Saunders D.E. (2005). Spontaneous regression of residual low-grade cerebellar pilocytic astrocytomas in children. Pediatr. Radiol. 35, 1086-1091.
60. Gustafsson K., Wang X., Severa D., Eriksson M., Kimby E., Merup M., Christensson B., Flygare J. and Sander B. (2008). Expression of cannabinoid receptors type 1 and type 2 in non-hodgkin lymphoma: growth inhibition by receptor activation. Int. J. Cancer 123, 1025-1033.
61. Gustafsson K., Sander B., Bielawski J., Hannun Y.A. and Flygare J. (2009). Potentiation of cannabinoid-induced cytotoxicity in mantle cell lymphoma through modulation of ceramide metabolism. Mol. Cancer Res. 7, 1086-1098.
62. Guzman M. (2003). Cannabinoids: potential anticancer agents. Nat. Rev. Cancer. 3, 745-755.
63. Guzman M., Sanchez C. and Galve-Roperh I. (2002). Cannabinoids and cell fate. Pharmacol. Ther. 95, 175-184.
64. Hall W. and Solowij N. (1998). Adverse effects of Cannabis. Lancet 352, 1611-1616.
65. Halperin E.C., Herndon J., Schold S.C., Brown M., Vick N., Cairncross J.G., Macdonald D.R., Gaspar L., Fischer B., Dropcho E., Rosenfeld S., Morowitz R., Piepmeier J., Hait W., Byrne T., Salter M., Imperato J., Khandekar J., Paleologos N., Burger P., Bentel G.C. and Friedman A. (1996). A phase III randomized prospective trial of external beam radiotherapy, mitomycin C, carmustine, and 6mercaptopurine for the treatment of adults with anaplastic glioma of the brain CNS. Cancer Consortium. Int. J. Radiat. Oncol. Biol. Phys. 34, 793-802.
66. Hambardzumyan D., Squatrito M., Carbajal E. and Holland E.C. (2008). Glioma formation, cancer stem cells, and akt signaling. Stem Cell Rev. 4, 203-210.
67. Hart S., Fischer O.M. and Ullrich A. (2004). Cannabinoids induce cancer cell proliferation via tumor necrosis factor alpha-converting enzyme (TACE/ADAM17)-mediated transactivation of the epidermal growth factor receptor. Cancer Res. 64, 1943-1950.
68. Held-Feindt J., Dorner L., Sahan G., Mehdorn H.M. and Mentlein R. (2006). Cannabinoid receptors in human astroglial tumors. J. Neurochem. 98, 886-893.
69. Herrera B., Carracedo A., Diez-Zaera M., Gomez del Pulgar T., Guzman M. and Velasco G. (2006). The CB2 cannabinoid receptor signals apoptosis via ceramide-dependent activation of the mitochondrial intrinsic pathway. Exp. Cell Res. 312, 2121-2131.
70. Hildebrand J., Sahmoud T., Mignolet F., Brucher J.M. and Afra D. (1994). Adjuvant therapy with dibromodulcitol and BCNU increases survival of adults with malignant gliomas. EORTC Brain Tumor Group. Neurology 44, 1479-1483.
71. Hinz B., Ramer R., Eichele K., Weinzierl U. and Brune K. (2004a). R(+) Methanandamide-induced cyclooxygenase-2 expression in H4 human neuroglioma cells: possible involvement of membrane lipid rafts. Bioch. Bioph. Res. Commun. 324, 621-626.
72. Hinz B., Ramer R., Eichele K., Weinzierl U. and Brune K. (2004b). Upregulation of cyclooxygenase-2 expression is involved in R(+)methanandamide-induced apoptotic death of human neuroglioma cells. Mol. Pharmacol. 66, 1643-1651.
73. Hosli P., Sappino A.P., de Tribolet N. and Dietrich P.Y. (1998). Mal i gnant gl i oma: shoul d chemotherapy be overthrown by experimental treatments? Ann. Oncol. 9, 589-600.
74. Howlett A.C. (2002). The cannabinoid receptors. Prostaglandins Other Lipid Mediat. (68,69), 619-631.
75. Huffman J.W., Liddle J. and Yu S. (1999). 3-(1,1-Dimethylbutyl)-1 deoxy-delta-8,9-tetrahydrocannabinol and related compounds: synthesis of selective ligands for the CB2 receptor. Bioorg. Med. Chem. Lett. 7, 2905-2914.
76. Iversen L.L. (2000). The science of marijuana. New York: Oxford University Press.
77. Jacobsson S.O., Rongard E., Stridh M., Tiger G. and Fowler C.J. (2000). Serum-dependent effects of tamoxifen and cannabinoids upon C6 glioma cell viability. Biochem. Pharmacol. 60, 1807-1813.
78. Jacobsson S.O., Wallin T. and Fowler C.J. (2001). Inhibition of rat C6 glioma cell proliferation by endogenous and synthetic cannabinoids. Relative involvement of cannabinoid and vanilloid receptors. J. Pharmacol. Exp. Ther. 299, 951-959.
79. Jemal A., Thomas A., Murray T. and Thun M. (2002). Cancer statistics. C.A. Cancer. J. Clin. 52, 23-47.
80. Jones S. and Howl J. (2003). Cannabi noi d receptor systems: therapeutic targets for tumor intervention. Expert. Opin. Ther. Targets 7, 749-758.
81. Jonsson K.O., Andersson A., Jacobsson S.O., Vandevoorde S., Lambert D.M. and Fowler C.J. (2003). AM404 and VDM 11 nonspecifically inhibit C6 glioma cell proliferation at concentrations used to block the cellular accumulation of the endocannabinoid anandamide. Arch. Toxicol. 77, 201-207.
82. Khaspekov L.G., Brenz Verca M.S., Frumkina L.E., Hermann H., Marsicano G. and Lutz B. (2004). Involvement of brain-derived neurotrophic factor in cannabinoid receptor-dependent protection against excitotoxicity. Eur. J.Neurosci. 19, 1691-1698.
83. Kleihues P., Louis D.N., Scheithauer B.W., Rorke L.B., Reifenberger G., Burger P.C. and Cavenee W.K. (2002). The WHO classification of tumors of the nervous system. J. Neuropathol. Exp. Neurol. 61, 215-225.
84. Kogan N.M. (2005). Cannabinoids and cancer. Mini. Rev. Med. Chem. 5, 941-952.
85. Laperriere N., Zuraw L. and Cairncross G. (2002). Radiotherapy for newly diagnosed malignant glioma in adults: a systematic review. Radiother. Oncol. 64, 259-273.
86. Levin V.A., Maor M.H., Thall P.F., Yung W.K., Bruner J., Sawaya R., Kyritsis A.P., Leeds N., Woo S. and Rodriguez L. (1995). Phase II study of accelerated fractionation radiation therapy with carboplatin fol l owed by vi ncri sti ne chemotherapy for the treatment of glioblastoma multiforme. Int. J. Radiat. Oncol. Biol. Phys. 33, 357-364.
87. Levin V.A., Yung W.K., Bruner J., Kyritsis A., Leeds N., Gleason M.J., Hess K.R., Meyers C.A., Ictech S.A., Chang E. and Maor M.H. (2000). Phase II study of accelerated fractionation radiation therapy with carboplatin followed by PCV for the treatment of anaplastic gliomas. Neurooncology 2, 278.
88. Liu J. and Lin A. (2005). Role of JNK activation in apoptosis: a doubleedged sword. Cell. Res. 15, 36-42.
89. Maccarrone M., Lorenzon T., Bari M., Melino G. and Finazzi-Agro A. (2000). Anandamide induces apoptosis in human cells via vanilloid receptors. Evidence for a protective role of cannabinoid receptors. J. Biol. Chem. 275, 31938-31945.
90. Maccarrone M., Pauselli R., Di Rienzo M. and Finazzi-Agro A. (2002). Binding, degradation and apoptotic activity of stearoylethanolamide in rat C6 glioma cells. Biochem. J. 366, 137-144.
91. Massi P., Vaccani A., Ceruti S., Colombo A., Abbracchio M.P. and Parol aro D. (2004). Anti tumor effects of cannabi di ol, a nonpsychoactive cannabinoid, on human glioma cell lines. J. Pharmacol. Exp. Ther. 308, 838-845.
92. McAllister S.D. and Glass M. (2002). CB(1) and CB(2) receptormediated signalling: a focus on endocannabinoids. Prostaglandins Leukot. Essent. Fatty Acids 66, 161-171.
93. McAllister S.D., Chan C., Taft R.J., Luu T., Abood M.E., Moore D.H., Aldape K. and Yount G. (2005). Cannabinoids selectively inhibit proliferation and induce death of cultured human glioblastoma multiforme cells. J. Neurooncol. 74, 31-40.
94. McKallip R.J., Lombard C., Fisher M., Martin B.R., Ryu S., Grant S., Nagarkatti P.S. and Nagarkatti M. (2002). Targeti ng CB2 cannabinoid receptors as a novel therapy to treat malignant lymphoblastic disease. Blood 100, 627-634.
95. McKallip R.J., Nagarkatti M. and Nagarkatti P.S. (2005). Delta-9 tetrahydrocannabi nol enhances breast cancer growth and metastasis by suppression of the antitumor immune response. J. Immunol. 174, 3281-3289.
96. Melck D., De Petrocellis L., Orlando P., Bisogno T., Laezza C., Bifulco M. and Di Marzo V. (2000). Suppression of nerve growth factor Trk receptors and prolactin receptors by endocannabinoids leads to inhibition of human breast and prostate cancer cell proliferation. Endocrinology 141, 118-126.
97. Middeke M., Hoffmann S., Hassan I., Wunderlich A., Hofbauer L.C. and Zielke A. (2002). In vitro and in vivo angiogenesis in PC12 pheochromocytoma cells is mediated by vascular endothelial growth factor. Exp. Clin. Endocrinol. Diab. 110, 386-392.
98. Mimeault M., Pommery N., Wattez N., Bailly C. and Hénichart J.P. (2003). Anti-proliferative and apoptotic effects of anandamide in human prostatic cancer cell lines: implication of epidermal growth factor receptor down-regulation and ceramide production. Prostate 56, 1-12.
99. Molina-Holgado E., Vela J.M., Arevalo-Martin A., Almazan G., Molina Holgado F., Borrell J. and Guaza C. (2002). Cannabinoids promote oligodendrocyte progenitor survival: involvement of cannabinoid receptors and phosphatidylinositol-3 kinase/Akt signaling. J. Neurosci. 22, 9742-9753.
100. Moore T.H., Zammit S., Lingford-Hughes A., Barnes T.R., Jones P.B., Burke M. and Lewis G. (2007). Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review. Lancet 370, 319-328.
101. Morelli M.B., Offidani M., Alesiani F., Discepoli G., Liberati S., Olivieri A., Santoni M., Santoni G., Leoni P. and Nabissi M. (2014). The effects of cannabidiol and its synergism with bortezomib in multiple myeloma cell lines. A role for transient receptor potential vanilloid type-2. Int. J. Cancer 134, 2534-2546.
102. Morioka N., Abdin J.M., Morita K., Kitayama T., Nakata Y. and Dohi T. (2008). The regul ati on of gl yci ne transporter GLYT1 i s mainlymediated by protein kinase Calpha in C6 glioma cells. Neurochem. Int. 53, 248-254.
103. Munson A.E., Harris L.S., Friedman M.A., Dewey W.L. and Carchman R.A.. (1975). Antineoplastic activity of cannabinoids. J. Natl. Cancer Inst. 55, 597-602.
104. Nabissi M., Morelli M.B., Amantini C., Farfariello V., Ricci-Vitiani L., Caprodossi S., Arcella A., Santoni M., Giangaspero F., De Maria R. and Santoni G. (2010). TRPV2 channel negatively controls glioma cell proliferation and resistance to fas-induced apoptosis in ERKdependent manner. Carcinogenesis 31, 794-803.
105. Nelson D.F., Diener-West M., Horton J., Chang C.H., Schoenfeld D. and Nelson J.S. (1988). Combined modality approach to treatment of malignant gliomas - re-evaluation of RTOG 7401/ECOG 1374 with long-term follow-up: a joint study of the Radiation Therapy Oncology Group and the Eastern Cooperative Oncology Group. NCI Monogr. 6, 279-284.
106. Nithipatikom K., Endsley M.P., Isbell M.A., Falck J.R., Iwamoto Y., Hillard C.J. and Campbell W.B. (2004). 2-arachidonoylglycerol: a novel inhibitor of androgen-independent prostate cancer cell invasion. Cancer Res. 64, 8826-8830.
107. Nithipatikom K., Endsley M.P., Isbell M.A., Wheelock C.E., Hammock B.D. and Campbell WB. (2005). A new class of inhibitors of 2arachidonoylglycerol hydrolysis and invasion of prostate cancer cells. Biochem. Biophys. Res. Commun. 332, 1028-1033.
108. Nunez E., Benito C., Pazos M.R., Barbachano A., Fajardo O., Gonzalez S., Tolon R.M. and Romero J. (2004). Cannabinoid CB2 receptors are expressed by perivascular microglial cells in the human brain: an immunohistochemical study. Synapse 53, 208-213.
109. Ohgaki H. and Kleihues P. (2005). Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas. J. Neuropathol. Exp. Neurol. 64, 479-489.
110. Pacher P., Batkai S. and Kunos G. (2006). The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol. Rev. 58, 389-462.
111. Palazuelos J., Aguado T., Egia A., Mechoulam R., Guzman M. and Galve-Roperh I. (2006). Non-psychoactive CB2 cannabinoid agonists stimulate neural progenitor proliferation. FASEB J. 20, 1773-1779.
112. Palma L., Celli P. and Mariottini A. (2004). Long-term follow-up of childhood cerebellar astrocytomas after incomplete resection with particular reference to arrested growth or spontaneous tumor regression. Acta Neurochir. (Wien) 146, 581-588.
113. Pasquariello N., Catanzaro G., Marzano V., Amadio D., Barcaroli D., Oddi S., Federici G., Urbani A., Finazzi Agro A. and Maccarrone M. (2009). Characterization of the endocannabinoid system in human neuronal cells and proteomic analysis of anandamide-induced apoptosis. J. Biol. Chem. 284, 29413-29426.
114. Pertwee R.G. (1997). Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol. Therap. 74, 129-180.
115. Pertwee R.G. and Ross R.A. (2002). Cannabinoid receptors and their ligands. Prostaglandins Leukot. Essent. Fatty Acids 66, 101-121.
116. Pertwee R.G., Howlett A.C., Abood M.E., Alexander S.P., Di Marzo V., Elphick M.R., Greasley P.J., Hansen H.S., Kunos G., Mackie K., Mechoulam R. and Ross R.A. (2010). International union of basic and clinical pharmacology. LXXIX. cannabinoid receptors and their ligands: beyond CB and CB. Pharmacol. Rev. 62, 588-631.
117. Petersen G., Moesgaard B., Schmid P.C., Schmid H.H.O., Broholm H., Kosteljanetz M. and Hansen H.S. (2005). Endocannabinoid metabolism in human glioblastomas and meningiomas compared to human non-tumor brain tissue. J. Neurochem. 93, 299-309.
118. Portella G., Laezza C., Laccetti P., De Petrocellis L., Di Marzo V. and Bifulco M. (2003). Inhibitory effects of cannabinoid CB1 receptor stimulation on tumor growth and metastatic spreading: actions on signals involved in angiogenesis and metastasis. FASEB J. 17, 1771-1773.
119. Prados M.D., Larson D.A., Lamborn K., McDermott M.W., Sneed P.K., Wara W.M., Chang S.M., Mack E.E., Krouwer H.G., Chandler K.L., Warnick R.E., Davis R.L., Rabbitt J.E., Malec M., Levin V.A., Gutin P.H., Phillips T.L. and Wilson C.B. (1998). Radiation therapy and hydroxyurea followed by the combination of 6-thioguanine and BCNU for the treatment of primary malignant brain tumors. Int. J. Radiat. Oncol. Biol. Phys. 40, 57-63.
120. Ramer R., Brune K., Pahl A. and Hinz B. (2001). R(+)-methanandamide induces cyclooxygenase-2 expression in human neuroglioma cells via a non-cannabinoid receptor-mediated mechanism. Biochem. Biophys. Res. Commun 286, 1144-1152.
121. Recht L.D., Salmonsen R., Rosetti R., Jang T., Pipia G., Kubiatowski T., Karim P., Ross A.H., Zurier R., Litofsky N.S. and Burstein S. (2001). Anti tumor effects of aj ul emi c aci d (CT3), a syntheti c nonpsychoactive cannabinoid. Biochem. Pharmacol. 62, 755-763.
122. Rich J.N. and Bigner D.D. (2004). Development of novel targeted therapies in the treatment of malignant glioma. Nat. Rev. Drug Discov. 3, 430-446.
123. Rozen W.M., Joseph S. and Lo P.A. (2008). Spontaneous regression of low-grade gliomas in pediatric patients without neurofibromatosis. Pediatr. Neurosurg. 44, 324-328.
124. Rubovitch V., Gafni M. and Sarne Y. (2004). The involvement of VEGF receptors and MAPK in the cannabinoid potentiation of Ca(2+) flux into N18TG2 neuroblastoma cells. Brain Res. Mol. Brain Res. 120, 138-144.
125. Rueda D., Galve-Roperh I., Haro A. and Guzman M. (2000). The CB(1) cannabinoid receptor is coupled to the activation of c-Jun N-terminal kinase. Mol. Pharmacol. 58, 814-820.
126. Rui z L., Mi guel A. and Di az-Lavi ada I. (1999). Del ta9 tetrahydrocannabinol induces apoptosis in human prostate PC-3 cells via a receptorindependent mechanism. FEBS. Lett. 458, 400-404.
127. Salazar M., Carracedo A., Salanueva I., Hernandez-Tiedra S., Lorente M., Egia A., Vazquez P., Blazquez C., Torres S., Garcia S., Nowak J., Fimia G.M, Piacentini M, Cecconi F., Pandolfi P.P., GonzalezFeria L., Iovanna J.L., Guzman M., Boya P. and Velasco G. (2009). Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells. J. Clin. Invest. 119, 1359-1372.
128. Samoto K., Ikezaki K., Ono M., Shono T., Kohno K., Kuwano M. and Fukui M. (1995). Expression of vascular endothelial growth factor and its possible relation with neovascularization in human brain tumors. Cancer Res. 55, 1189-1193.
129. Sanchez C., Galve-Roperh I., Canova C., Brachet P. and Guzman M. (1998). Delta9-tetrahydrocannabinol induces apoptosis in C6 glioma cells. FEBS Lett. 436, 6-10.
130. Sanchez C., de Ceballos M.L., del Pulgar T.G., Rueda D., Corbacho C., Velasco G., Galve-Roperh I., Huffman J.W., Ramon y. Cajal S. and Guzman M. (2001). Inhibition of glioma growth in vivo by selective activation of the CB(2) cannabinoid receptor. Cancer Res. 61, 5784-5789.
131. Sanchez M.G., Sanchez A.M., Ruiz-Llorente L. and Diaz-Laviada I. (2003). Enhancement of androgen receptor expression induced by (R)-methanandamide in prostate LNCaP cells. FEBS Lett. 555, 561-566.
132. Sarfaraz S., Afaq F., Adhami V.M. and Mukhtar H. (2005). Cannabinoid receptor as a novel target for the treatment of prostate cancer. Cancer Res. 65, 1635-1641.
133. Sarfaraz S., Afaq F., Adhami V.M., Malik A. and Mukhtar H. (2006). 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. 281, 39480-39491.
134. Sarfaraz S., Adhami V.M., Syed D.N., Afaq F. and Mukhtar H. (2008). Cannabinoids for cancer treatment: progress and promise. Cancer Res. 68, 339-342.
135. Saunders D.E., Phipps K.P., Wade A.M. and Hayward R.D. (2005). Survei l l ance i magi ng strategi es fol l owi ng surgery and/or radiotherapy for childhood cerebellar low-grade astrocytoma. J. Neurosurg. 102, 172-178.
136. Schley M., Ständer S., Kerner J., Vajkoczy P., Schόpfer G., Dusch M., Schmelz M. and Konrad C. (2009). Predominant CB2 receptor expression in endothelial cells of glioblastoma in humans. Brain Res. Bull. 79, 333-337.
137. Schmidt N.O., Westphal M., Hagel C., Ergun S., Stavrou D., Rosen E.M. and Lamszus K. (1999). Levels of vascular endothelial growth factor, hepatocyte growth factor/scatter factor and basic fibroblast growth factor in human gliomas and their relation to angiogenesis. Int. J. Cancer 84, 10-18.
138. Showalter V.M., Compton D.R., Martin B.R. and Abood M.E. (1996). Evaluation of binding in a transfected cell line expressing a peripheral cannabinoid receptor (CB2): identification of cannabinoid receptor subtype selective ligands. J. Pharmacol. Exp. Ther. 278, 989-999.
139. Stei nbok P. (1994). Management and outcome of l ow-grade astrocytomas of the midline in children: a retrospective review. Neurosurgery 35, 342-343.
140. Steinbok P., Poskitt K. and Hendson G. (2006). Spontaneous regression of cerebellar astrocytoma after subtotal resection. Childs Nerv. Syst. 22, 572-576.
141. Stupp R., Dietrich P.Y., Ostermann Kraljevic S., Pica A., Maillard I., Maeder P., Meuli R., Janzer R., Pizzolato G., Miralbell R., Porchet F., Regli L., de Tribolet N., Mirimanoff R.O. and Leyvraz S. (2002). Promising survival for patients with newly diagnosed glioblastoma multiforme treated with concomitant radiation plus temozolomide followed by adjuvant temozolomide. J. Clin. Oncol. 20, 1375-1382.
142. Tanaka T., Hosokawa M., Yasui Y., Ishigamori R. and Miyashita K. (2011). Cancer chemopreventive ability of conjugated linolenic acids. Int. J. Mol. Sci. 12, 7495-509.
143. Torres S., Lorente M., Rodríguez-Fornes F., Hernandez-Tiedra S., Salazar M., García-Taboada E., Barcia J., Guzman M. and Velasco G. (2011). A Combined Preclinical Therapy of Cannabinoids and Temozolomide against Glioma. Mol. Cancer Ther. 10, 90-103.
144. Turner W.M and Tsuang M.T. (1990). Impact of substance abuse on the course and outcome of schizophrenia. Schizophr. Bull. 16, 87-95.
145. Valenzano K.J., Tafesse L., Lee G., Harrison J.E., Boulet J.M., Gottshall S.L., Mark L., Pearson M.S., Miller W., Shan S., Rabadi L., Rotshteyn Y., Chaffer S.M., Turchin P.I., Elsemore D.A., Toth M., Koetzner L. And Whiteside G.T. (2005). Pharmacological and pharmacokinetic characterization of the cannabinoid receptor 2 agonist, GW405833, utilizing rodent models of acute and chronic pain, anxiety, ataxia and catalepsy. Neuropharmacology 48, 658-672.
146. Vara D., Salazar M., Olea-Herrero N., Guzman M., Velasco G. and Diaz-Laviada I. (2011). Antitumoral action of cannabinoids on hepatocellular carcinoma: role of AMPK-dependent activation of autophagy. Cell. Death Differ. 18, 1099-1111.
147. Velasco L., Ruiz L., Sanchez M.G. and Diaz-Laviada I. (2001). Δ(9) Tetrahydrocannabinol increases nerve growth factor production by prostate PC-3 cells. Involvement of CB1 cannabinoid receptor and Raf-1. Eur. J. Biochem. 268, 531-535.
148. Velasco G., Galve-Roperh I., Sanchez C., Blazquez C. and Guzman M. (2004). Hypothesis: cannabinoid therapy for the treatment of gliomas? Neuropharmacology 47, 315-323.
149. Velasco G., Carracedo A., Blazquez C., Lorente M., Aguado T., Haro A., Sanchez C., Galve-Roperh I. and Guzman M. (2007). Cannabinoids and gliomas. Mol. Neurobiol. 36, 60-67.
150. Velasco G., Sanchez C. and Guzman M. (2012). Towards the use of cannabinoids as antitumour agents. Nat. Rev. Cancer 12, 436-444.
151. Wahle K.W.J., Heys S.D. and Rotondo D. (2004). Conjugated linoleic acids: are they beneficial or detrimental to health? Prog. Lipid. Res. 43, 553-587.
152. Wang X., Dow-Edwards D., Keller E. and Hurd Y.L. (2003). Preferential limbic expression of the cannabinoid receptor mRNA in the human fetal brain. Neuroscience 118, 681-694.
153. Wen P.Y. and Kesari S. (2008). Malignant gliomas in adults. N. Engl. J. Med. 359, 492-507.
154. White A.C., Munson J.A., Munson A.E. and Carchman R.A. (1976). Effects of del ta9-tetrahydrocannabi nol i n Lewi s l ung adenocarcinoma cells in tissue culture. J. Natl. Cancer Inst. 56, 655-658.
155. Widmer M., Hanemann C.O. and Zajicek J. (2008). High concentrations of cannabinoids activate apoptosis in human U373MG glioma cells. J. Neurosci. Res. 86, 3212-3220.
156. Woodfin A., Voisin M.B. and Nourshargh S. (2007). PECAM-1: a multifuncti onal mol ecul e i n i nfl ammati on and vascul ar bi ol ogy. Arterioscler. Thromb. Vasc. Biol. 27, 2514-2523.
157. Zogopoulos P., Vasileiou I., Patsouris E. and Theocharis S. (2013a). The role of endocannabinoids in pain modulation. Fundam. Clin. Pharmacol. 27, 64-80.
158. Zogopoulos P., Vasileiou I., Patsouris E. and Theocharis S. (2013b). The neuroprotective role of endocannabinoids against chemicalinduced injury and other adverse effects. J. Appl. Toxicol. 33, 246-264.