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Journal of Neuro-Oncology

, Volume 116, Issue 1, pp 11–24 | Cite as

Systematic review of the literature on clinical and experimental trials on the antitumor effects of cannabinoids in gliomas

  • Francisco Carlos Machado Rocha
  • Jair Guilherme dos Santos Júnior
  • Sergio Carlos Stefano
  • Dartiu Xavier da Silveira
Topic Review

Abstract

To evaluate, through a systematic review of the literature, the antitumoral effects of cannabinoids on gliomas. Research included the following electronic databases: PUBMED, EMBASE, LILACS and The Cochrane Collaboration Controlled Trials Register. All published studies involving the antitumoral effects (cellular and molecular mechanisms) of cannabinoids were considered for this review. The bibliography search strategy included all publications of each of these databases until December 31, 2012. From 2,260 initially identified articles, 35 fulfilled the inclusion criteria for this review. All the studies included in this systematic review were experimental (in vivo and/or in vitro), except for one pilot clinical trial phase I/II involving humans. In all experimental studies included, cannabinoids exerted antitumoral activity in vitro and/or antitumoral evidence in vivo in several models of tumor cells and tumors. The antitumor activity included: antiproliferative effects (cell cycle arrest), decreased viability and cell death by toxicity, apoptosis, necrosis, autophagy, as well as antiangiogenic and antimigratory effects. Antitumoral evidence included: reduction in tumor size, antiangiogenic, and antimetastatic effects. Additionally, most of the studies described that the canabinnoids exercised selective antitumoral action in several distinct tumor models. Thereby, normal cells used as controls were not affected. The safety factor in the cannabinoids’ administration has also been demonstrated in vivo. The various cannabinoids tested in multiple tumor models showed antitumoral effects both in vitro and in vivo. These findings indicate that cannabinoids are promising compounds for the treatment of gliomas.

Keywords

Gliomas Cannabinoids Apoptosis Cell cycle arrest Anti-angiogenesis Anti-metastasis 

Notes

Acknowledgments

Coordination of Improvement of People of Higher Level (CAPES), Cochrane Center.

Conflict of interest

This paper has no conflict of interests.

References

  1. 1.
    Munson AE, Harris LS, Friedman MA, Dewey WL, Carchman RA (1975) Antineoplastic activity of cannabinoids. J Natl Cancer Inst 55:597–602PubMedGoogle Scholar
  2. 2.
    Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, Gibson D, Mandelbaum A, Etinger A, Mechoulam R (1992) Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258:1946–1949PubMedCrossRefGoogle Scholar
  3. 3.
    Mechoulam R, Ben Shabat S, Hanus L, Ligumsky M, Kaminski NE, Schatz AR, Gopher A, Almog S, Martin BR, Compton DR, Pertwee RG, Griffin G, Bayewitch M, Barg J, Vogel Z (1995) Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol 50:83–90PubMedCrossRefGoogle Scholar
  4. 4.
    Sugiura T, Kondo S, Sukagawa A, Nakane S, Shinoda A, Itoh K, Yamashita A, Waku K (1995) 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem Biophys Res Commun 215:89–97PubMedCrossRefGoogle Scholar
  5. 5.
    Sun Y, Alexander SP, Garle MJ, Gibson CL, Hewitt K, Murphy SP, Kendall DA, Bennet AJ (2007) Cannabinoid activation of PPARα; a novel neuroprotective mechanism. Br J Pharmacol 152:734–743PubMedCrossRefGoogle Scholar
  6. 6.
    Piomelli D (2003) The molecular logic of endocannabinoid signaling. Nat Rev Neurosci 4:873–878PubMedCrossRefGoogle Scholar
  7. 7.
    Felder CC, Glass M (1998) Cannabinoid receptors nand their endogenous agonists. Annu Rev Pharmacol Toxicol 38:179–200PubMedCrossRefGoogle Scholar
  8. 8.
    Guzmán M (2003) Cannabinoids: potential anticancer agents. Nat Rev Cancer 3:745–755PubMedCrossRefGoogle Scholar
  9. 9.
    Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, Felder CC, Herkenham M, Mackie K, Martin BR, Mechoulam R, Pertwee RG (2002) International Union of Pharmacology. XXVII. Classification of cannabinoid receptor. Pharmacol Rev 54:161–202PubMedCrossRefGoogle Scholar
  10. 10.
    Velasco G, Galve-Roperh I, Sánchez C, Blázquez C, Guzmán M (2004) Hypothesis: cannabinoid therapy for the treatment of gliomas? Neuropharmacology 47:315–323PubMedCrossRefGoogle Scholar
  11. 11.
    Bifulco M, Laezza C, Gazzerro P, Pentimalli F (2007) Endocannabinoids as emerging suppressors of angiogenesis and tumor invasion (review). Oncol Rep 17(Suppl4):813–816PubMedGoogle Scholar
  12. 12.
    Cook DJ, Mulrow CD, Haynes RB (1997) Systematic Reviews: synthesis of best evidence for clinical decisions. Ann Intern Med 126:364–371CrossRefGoogle Scholar
  13. 13.
    Jadad A, Moore A, Carrol D, Jenkinson C, Reynolds DJM, Gavaghan DJ, McQuay HJ (1996) Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 17:1–12PubMedCrossRefGoogle Scholar
  14. 14.
    Guzmán M, Duarte MJ, Blázquez C, Ravina J, Rosa MC, Galve-Roperh I, Sánchez C, Velasco G, González-Feria L (2006) A pilot clinical study of delta-9-tetrahydrocannabinoi in patients with recurrent glioblastoma multiforme. Br J Cancer 95:197–203PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Galve-Roperh I, Sánchez C, Cortés ML, Del Pulgar TG, Izquierdo M, Guzmán M (2000) Anti-tumoral action of cannabinoids: involvement of sustained ceramide accumulation and extracellular signal-regulated kinase activation. Nat Med 6(Suppl3):313–319PubMedGoogle Scholar
  16. 16.
    Recht LD, Salmonsen R, Rosetti R, Jang T, Pipia G, Kubiatowski T, Karim P, Ross AH, Zurier R, Litofsky NS, Burstein S (2001) Antitumor effects of ajulemic acid (CT3), a synthetic non-psychoactive cannabinoid. Biochem Pharmacol 62:755–763PubMedCrossRefGoogle Scholar
  17. 17.
    Sánchez C, Ceballos ML, del Pulgar TG, Rueda D, Corbacho C, Velasco G, Galve-Roperh I, Huffman JW, Ramon y Cajal S, Guzmán M (2001) Inhibition of glioma growth in vivo by selective activation of the CB2 cannabinoid receptor. Cancer Res 61:5784–5789PubMedGoogle Scholar
  18. 18.
    Blásquez C, Casanova L, Planas A, del Pulgar TG, Villanueva C, Aceñero MJ, Aragonês J, Huffman JW, Jorcano JL, Guzmán M (2003) Inhibition of tumor angiogenesis by cannabinoids. FASEB J 17(Suppl3):529–531Google Scholar
  19. 19.
    Blásquez C, González-Feria L, Álvarez L, Haro A, Casanova ML, Guzmán M (2004) Cannabinoids inhibit the vascular endothelial growth factor pathway in gliomas. Cancer Res 64:5617–5623CrossRefGoogle Scholar
  20. 20.
    Massi P, Vaccani A, Ceruti S, Colombo A, Abbracchio MP, Parolaro D (2004) Antitumor effects of cannabidiol, a nonpsychoactive cannabinoid, on human glioma cell lines. J Pharmacol Exp Ther 308:838–845PubMedCrossRefGoogle Scholar
  21. 21.
    Duntsch C, Divi MK, Jones T, Zhou Q, Krishnamurthy M, Boehm P, Wood G, Sills A, Moore BM II (2006) Safety and efficacy of a novel cannabinoid chemotherapeutic, KM-233, for the treatment of high-grade glioma. J Neurooncol 77:143–152PubMedCrossRefGoogle Scholar
  22. 22.
    Carracedo A, Lorente M, Egia A, Blázquez C, Garcia S, Giroux V, Malicet C, Villuendas R, Gironella M, Gonzáliz-Feria L, Piris MA, Iovanna JL, Guzmán M, Velasco G (2006) The stress-regulated protein p8 mediates cannabinoid-induced apoptosis of tumor cells. Cancer Cell 9:301–312PubMedCrossRefGoogle Scholar
  23. 23.
    Massi P, Valenti M, Vaccani A, Gasperi V, Marras E, Fezza F, Macarrone M, Parolaro D (2008) 5-Lipoxygenase and anandamide hydrolase (FAAH) mediate the antitumor activity of cannabidiol, a non-psychoactive cannabinoid. J Neurochem 104:1091–1100PubMedCrossRefGoogle Scholar
  24. 24.
    Blázquez C, Carracedo A, Salazar M, Lorente M, Egia A, González-Feria L, Haro A, Velasco G, Guzmán M (2008) Down-regulation of tissue inhibitor of metalloproteinases-1 in gliomas: a new marker of cannabinoid antitumoral activity? Neuropharmacology 54:235–243PubMedCrossRefGoogle Scholar
  25. 25.
    Blázquez C, Salazar M, Carracedo A, Lorente M, Egia A, González-Feria L, Haro A, Velasco G, Guzmán M (2008) Cannabinoids inhibit glioma cell invasion by down-regulating matrix metalloproteinase-2 expression. Cancer Res 68(Suppl6):1945–1952PubMedCrossRefGoogle Scholar
  26. 26.
    Salazar M, Carracedo A, Salanueva IJ, Hernández-Tiedra S, Lorente M, Egia A, Vázquez P, Blázquez C, Torres S, Garcia S, Nowak J, Fimia GM, Piacentini M, Cecconi F, Pandolfi PP, González-Feria L, Iovanna JL, Guzmán M, Boya P, Velasco G (2009) Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells. J Clin Invest 119:1359–1372PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Torres S, Lorente M, Rodríguez-Fornés F, Hernández-Tiedra S, Salazar M, Garcia-Taboada E, Barcia J, Guzmán M, Velasco G (2011) A combined preclinical therapy of cannabinoids and temozolomide against glioma. Mol Cancer Ther 10(Suppl1):90–103PubMedCrossRefGoogle Scholar
  28. 28.
    Soroceanu L, Murase R, Limbad C, Singer E, Allison J, Adrados I, Kawamura R, Pakdel A, Fukuyo Y, Nguyen D, Khan S, Arauz R, Yount GL, Moore DH, Desprez PY, McAllister SD (2013) Id-1 is a key transcriptional regulator of glioblastoma aggressiveness and a novel therapeutic target. Cancer Res 73:1559–1569PubMedCrossRefGoogle Scholar
  29. 29.
    Gurley SN, Abidi AH, Allison P, Guan P, Duntsch C, Robertson JH, Kosanke SD, Keir ST, Bigner DD, Elberger AJ, Moore BM II (2012) Mechanism of anti-glioma activity and in vivo efficacy of the cannabinoid ligand KM-233. J Neurooncol 110(Suppl2):163–177PubMedCrossRefGoogle Scholar
  30. 30.
    Dolecek TA, Propp JM, Stroup NE, Kruchko C (2012) CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2005–2009. Neurooncology 14(Suppl5):v1–v49Google Scholar
  31. 31.
    Kleihues P, Louis DN, Scheithauer BW, Rorke LB, Reifenberger G, Burger PC, Cavence WK (2002) The WHO classification of tumors of the nervous system. J Neuropathol Exp Neurol 61:215–225PubMedGoogle Scholar
  32. 32.
    Massi P, Vaccani A, Bianchessi S, Costa B, Macchi P, Parolaro D (2006) The non-psychoactive cannabidiol triggers caspase activation and oxidative stress in human glioma cells. Cell Mol Life Sci 63:2057–2066PubMedCrossRefGoogle Scholar
  33. 33.
    Jacobsson SOP, Wallin T, Fowler CJ (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(Suppl3):951–959PubMedGoogle Scholar
  34. 34.
    Bari M, Battista N, Fezza G, Finazzi-Agrò A, Macarrone M (2005) Lipid rafts control signaling of type-1 cannabinoid receptors in neuronal cells. Implications for anandamide-induced apoptosis. J Biol Chem 280(Suppl13):12212–12220PubMedGoogle Scholar
  35. 35.
    Hinz B, Ramer R, Eichele K, Weinzierl U, Brune K (2004) Up-regulation of cyclooxygenase-2 expression is involved in R(+)-methanandamide-induced apoptotic death of human neuroglioma cells. Mol Pharmacol 66:1643–1651PubMedCrossRefGoogle Scholar
  36. 36.
    Vaccani A, Massi P, Colombo A, Rubino T, Parolaro D (2005) Cannabidiol inhibits human glioma cell migration through a cannabinoid receptor-independent mechanism. Br J Pharmacol 144:1032–1036PubMedCrossRefGoogle Scholar
  37. 37.
    Molinari M (2000) Cell cycle checkpoints and their inactivation in human cancer. Cell Prolif 33:261–274PubMedCrossRefGoogle Scholar
  38. 38.
    Gómez del Pulgar T, de Ceballos ML, Guzmán M, Velasco G (2002) Cannabinoids protect astrocytes from ceramide-induced apoptosis through the phosphatidylinositol 3-kinase/protein kinase B pathway. J Biol Chem 277:36527–36533PubMedCrossRefGoogle Scholar
  39. 39.
    Gómez Del Pulgar TG, Velasco G, Sánchez C, Haro A, Guzmán M (2002) De novo-synthesized ceramide is involved in cannabinoid-induced apoptosis. Biochem J 363:183–188PubMedCrossRefGoogle Scholar
  40. 40.
    Guzmán M, Galve-Roperh I, Sánchez C (2001) Ceramide: a new second messenger of cannabinoid action. Trends Pharmacol Sci 22:19–22PubMedCrossRefGoogle Scholar
  41. 41.
    Gustafsson K, Sander B, Bielawski J, Hannun YA, Flygare J (2009) Potentiation of canabinoi-induced cytotoxicity in mantle cell lymphoma through modulation of ceramide metabolism. Mol Cancer Res 7(Suppl7):1086–1098PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Galanti G, Fisher T, Kventsel I, Shoham J, Gallily R, Mechoulam R, Lavie G, Amariglio N, Rechavi G, Toren A (2008) 9-Tetrahydrocannabinol inhibits cell cycle progression by downregulation of E2F1 in human glioblastoma multiforme cells. Acta Oncol 47(Suppl6):1062–1070PubMedCrossRefGoogle Scholar
  43. 43.
    Costello JF, Berger MS, Huang H-JS, Cavenee WK (1996) Silencing of p16/CDKN2 expression in human gliomas by methylation and chromatin condensation. Cancer Res 56:2405–2410PubMedGoogle Scholar
  44. 44.
    Casanova ML, Larcher F, Casanova B, Murillas R, Fernández-Aceñero MJ, Villanueva C, Martinez-Palacio J, Ullrich A, Conti CJ, Jorcano JL (2002) A critical role for ras-mediated, EGFR-dependent angiogenesis in mouse skin carcinogenesis. Cancer Res 62:3402–3407PubMedGoogle Scholar
  45. 45.
    Ros J, Clària J, To-Figueiras J, Planagumá A, Cejudo-Martín P, Fernández-Varo G, Martín-Ruiz R, Arroyo V, Rivera F, Rodes J, Jiménez W (2002) Endogenous cannabinoids: a new system involved in the homeostasis of arterial pressure in experimental cirrhosis in the rat. Gastroenterology 122:85–93PubMedCrossRefGoogle Scholar
  46. 46.
    Nakada M, Nakada S, Demuth T, Tran NL, Hoelzinger DB, Berens ME (2007) Molecular targets of glioma invasion. Cell Mol Life Sci 64:458–478PubMedCrossRefGoogle Scholar
  47. 47.
    Deryugina EI, Quigley JP (2006) Matrix metalloproteinases and tumor metastasis. Cancer Metastasis Rev 25:9–34PubMedCrossRefGoogle Scholar
  48. 48.
    Joseph J, Niggemann B, Zaenker KS, Entschladen F (2004) Anandamide is an endogenous inhibitor for the migration of tumor cells ant T lymphocytes. Cancer Immunol Immunother 53:723–728PubMedCrossRefGoogle Scholar
  49. 49.
    Pisanti S, Borselli C, Oliviero O, Laezza C, Gazzerro P, Bifulco M (2006) Antiangiogenic activity of the endocannabinoid anandamide: correlation in its tumor-suppressor efficacy. J Cell Physiol 211:495–503CrossRefGoogle Scholar
  50. 50.
    Zhu LX, Sharma S, Stolina M, Gardner B, Roth MD, Tashkin DP, Dubinett SM (2000) Delta-9-Tetrahydrocannabinol inhibits antitumor immunity by a CB2 receptor-mediated, cytokine-dependent pathway. J Immunol 165:373–380PubMedGoogle Scholar
  51. 51.
    Widmer M, Hanemann CO, Zajicek J (2008) High concentrations of cannabinoids activate apoptosis in human U373MG glioma cells. J Neurosci Res 86:3212–3220PubMedCrossRefGoogle Scholar
  52. 52.
    Marcu JP, Christian RT, Lau D, Zielinski AJ, Horowitz MP, Lee J, Pakdel A, Allison J, Limbad C, Moore DH, Yount GL, Desprez P-Y, McAllister SD (2010) Cannabidiol enhances the inhibitory effects of delta-9-tetrahydrocannabinol on human glioblastoma cell proliferation and survival. Mol Cancer Ther 9(Suppl1):180–189PubMedCentralPubMedCrossRefGoogle Scholar
  53. 53.
    Russo E, Guy GW (2006) A tale of two cannabinoids: the therapeutic rationale for combining tetrahydrocannabinol and cannabidiol. Med Hypotheses 66(Suppl2):234–246PubMedCrossRefGoogle Scholar
  54. 54.
    Ligresti A, Bisogno T, Matias I, De Petrocellis L, Cascio MG, Cosenza V, D’Argenio G, Scaglione G, Bifulco M, Sorrentini I, Di Marzo V (2003) Possible endocannabinoid control of colorectal cancer growth. Gastroenterology 125:677–687PubMedCrossRefGoogle Scholar
  55. 55.
    Eichele K, Ramer R, Hinz B (2009) R(+)-methanandamide-induced apoptosis of human cervical carcinoma cells involves a cyclooxygenase-2-dependent pathway. Pharm Res 26:346–355PubMedCrossRefGoogle Scholar
  56. 56.
    Morales A, Lee H, Goni FM, Kolesnick R, Fernandez-Checa JC (2007) Sphingolipids and cell death. Apoptosis 12:923–939PubMedCrossRefGoogle Scholar
  57. 57.
    Nabissi N, Morelli MB, Santoni M, Santoni G (2013) Triggering of the TRPV2 channel by cannabidiol sensitizes glioblastoma cells to cytotoxic chemotherapeutic agents. Carcinogenesis 34(Suppl1):48–57PubMedCrossRefGoogle Scholar
  58. 58.
    End DW, Thoursen K, Dewey WL, Carchman RA (1977) A comparative study of the disposition of (-)-delta9-tetrahydrocannabinol in neuroblastoma and glioma cells in tissue culture: relation to cellular impairment. Mol Pharmacol 13:864–871PubMedGoogle Scholar
  59. 59.
    Sánchez C, Galve-Roperh I, Casanova C, Brachet P, Guzmán M (1998) Delta9-tetrahydrocannabinol induces apoptosis in C6 glioma cells. FEBS Lett 436(Suppl1):6–10PubMedCrossRefGoogle Scholar
  60. 60.
    Macarrone M, Pauselli R, Di Rienzo M, Finazzi-Agró A (2002) Binding, degradation and apoptotic activity of stearoylethanolamide in rat C6 glioma cells. Biochem J 366:137–144Google Scholar
  61. 61.
    Fowler CJ, Jonsson KO, Andersson A, Juntunen J, Järvinen T, Vandevoorde S, Lambert DM, Jerman JC, Smart D (2003) Inhibition of C6 glioma cell proliferation by anandamide, 1-arachidonoylglycerol, and by a water soluble phosphate ester of anandamide: variability in response and involvement of arachidonic acid. Biochem Pharmacol 66:757–767PubMedCrossRefGoogle Scholar
  62. 62.
    Contassot E, Wilmotte R, Tenan M, Belkouch MC, Schnüriger V, Tribolet N, Bourkhardt K, Dietrich PY (2004) Arachidonylethanolamide induces apoptosis of human glioma cells through vanilloid receptor-1. J Neuropathol Exp Neurol 63(Suppl9):956–963PubMedGoogle Scholar
  63. 63.
    Goncharov I, Weiner L, Vogel Z (2005) Delta9-tetrahydrocannabinol increases C6 glioma cell death produced by oxidative stress. Neuroscience 134:567–574PubMedCrossRefGoogle Scholar
  64. 64.
    McAllister SD, Chan C, Taft RJ, Luu T, Abood ME, Moore DH, Aldape K, Yount G (2005) Cannabinoids selectively inhibit proliferation and induce death of cultured human glioblastoma multiforme cells. J Neurooncol 74:31–40PubMedCrossRefGoogle Scholar
  65. 65.
    Ellert-Miklaszewska A, Kaminska B, Konarska L (2005) Cannabinoids down-regulate P13K/Akt and Erk signaling pathways and activate proapoptotic function of bad protein. Cell Signal 17:25–37PubMedCrossRefGoogle Scholar
  66. 66.
    Eichele K, Weinzierl U, Ramer R, Brune K, Hinz B (2006) R(+)-methanandamide elicits a cyclooxygenase-2-dependent mitochondrial apoptosis signalling pathway in human neuroglioma cells. Pharm Res 23(Suppl1):90–94PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Francisco Carlos Machado Rocha
    • 1
  • Jair Guilherme dos Santos Júnior
    • 2
  • Sergio Carlos Stefano
    • 1
  • Dartiu Xavier da Silveira
    • 1
  1. 1.Paulista School of MedicineFederal University of São PauloSão PauloBrazil
  2. 2.Faculty of Medical Sciences of Santa Casa of São PauloSão PauloBrazil

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