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Endocannabinoids and Cancer

  • Guillermo Velasco
  • Cristina Sánchez
  • Manuel Guzmán
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 231)

Abstract

A large body of evidence shows that cannabinoids, in addition to their well-known palliative effects on some cancer-associated symptoms, can reduce tumour growth in animal models of cancer. They do so by modulating key cell signalling pathways involved in the control of cancer cell proliferation and survival. In addition, cannabinoids inhibit angiogenesis and cell proliferation in different types of tumours in laboratory animals. By contrast, little is known about the biological role of the endocannabinoid system in cancer physio-pathology, and several studies suggest that it may be over-activated in cancer. In this review, we discuss our current understanding of cannabinoids as antitumour agents, focusing on recent advances in the molecular mechanisms of action, including resistance mechanisms and opportunities for combination therapy approaches.

Keywords

Angiogenesis Apoptosis Autophagy Cancer Cannabinoid Cell proliferation Cell signalling Combinational therapy 

Abbreviations

2-AG

2-Arachidonoylglycerol

ALK

Anaplastic lymphoma kinase

ATF-4

Activating transcription factor 4

CB1

Cannabinoid CB1 receptor

CB2

Cannabinoid CB2 receptor

CBD

Cannabidiol

CHOP

C/EBP homologous protein

EGFR

Epidermal growth factor receptor

ER

Endoplasmic reticulum

ERK

Extracellular signal-regulated kinase

MDK

Midkine

mTORC1

Mammalian target of rapamycin complex 1

mTORC2

Mammalian target of rapamycin complex 2

THC

Δ9-tetrahydrocannabinol

TRIB3

Tribbles-homologue 3

TRPV1

Transient receptor potential cation channel subfamily V member 1

VEGF

Vascular endothelial growth factor

Notes

Acknowledgements

Research in the groups of the authors is supported by grants from Spanish Ministry of Economy and Competitiveness (MINECO) (PI12/02248, FR2009-0052 and IT2009-0053 to GV; and PI11/00295 to CS), Comunidad de Madrid (S2011/BMD-2308 to MG), GW Pharmaceuticals (to GV, CS and MG); Fundación Mutua Madrileña (AP101042012 to GV) and Fundació Telemarató (20134031 to GV)

Potential Conflict of Interest

We declare that GW Pharmaceuticals funded part of the research of our laboratory. Likewise, part of the data obtained by the authors in relation with the antitumour action of cannabinoids is included in three patent applications presented by GW Pharmaceuticals.

References

  1. Atwood BK, Huffman J, Straiker A, Mackie K (2010) JWH018, a common constituent of ‘Spice’ herbal blends, is a potent and efficacious cannabinoid CB receptor agonist. Br J Pharmacol 160:585–593PubMedCentralCrossRefPubMedGoogle Scholar
  2. Bifulco M, Laezza C, Portella G, Vitale M, Orlando P, De Petrocellis L, Di Marzo V (2001) Control by the endogenous cannabinoid system of ras oncogene-dependent tumor growth. FASEB J 15:2745–2747PubMedGoogle Scholar
  3. Blazquez C, Casanova ML, Planas A, Gómez del Pulgar T, Villanueva C, Fernandez-Acenero MJ, Aragones J, Huffman JW, Jorcano JL, Guzman M (2003) Inhibition of tumor angiogenesis by cannabinoids. FASEB J 17:529–531PubMedGoogle Scholar
  4. Blazquez C, Gonzalez-Feria L, Alvarez L, Haro A, Casanova ML, Guzman M (2004) Cannabinoids inhibit the vascular endothelial growth factor pathway in gliomas. Cancer Res 64:5617–5623CrossRefPubMedGoogle Scholar
  5. Blazquez C, Carracedo A, Barrado L, Real PJ, Fernandez-Luna JL, Velasco G, Malumbres M, Guzman M (2006) Cannabinoid receptors as novel targets for the treatment of melanoma. FASEB J 20:2633–2635CrossRefPubMedGoogle Scholar
  6. Blazquez C, Salazar M, Carracedo A, Lorente M, Egia A, Gonzalez-Feria L, Haro A, Velasco G, Guzman M (2008) Cannabinoids inhibit glioma cell invasion by down-regulating matrix metalloproteinase-2 expression. Cancer Res 68:1945–1952CrossRefPubMedGoogle Scholar
  7. Burstein SH, Zurier RB (2009) Cannabinoids, endocannabinoids, and related analogs in inflammation. AAPS J 11:109–119PubMedCentralCrossRefPubMedGoogle Scholar
  8. Caffarel MM, Sarrio D, Palacios J, Guzman M, Sanchez C (2006) Delta9-tetrahydrocannabinol inhibits cell cycle progression in human breast cancer cells through Cdc2 regulation. Cancer Res 66:6615–6621CrossRefPubMedGoogle Scholar
  9. Caffarel MM, Moreno-Bueno G, Cerutti C, Palacios J, Guzman M, Mechta-Grigoriou F, Sanchez C (2008) JunD is involved in the antiproliferative effect of Delta9-tetrahydrocannabinol on human breast cancer cells. Oncogene 27:5033–5044CrossRefPubMedGoogle Scholar
  10. Caffarel MM, Andradas C, Perez-Gomez E, Guzman M, Sanchez C (2012) Cannabinoids: a new hope for breast cancer therapy? Cancer Treat Rev 38:911–918CrossRefPubMedGoogle Scholar
  11. Carracedo A, Gironella M, Lorente M, Garcia S, Guzman M, Velasco G, Iovanna JL (2006a) Cannabinoids induce apoptosis of pancreatic tumor cells via endoplasmic reticulum stress-related genes. Cancer Res 66:6748–6755CrossRefPubMedGoogle Scholar
  12. Carracedo A, Lorente M, Egia A, Blazquez C, Garcia S, Giroux V, Malicet C, Villuendas R, Gironella M, Gonzalez-Feria L, Piris MA, Iovanna JL, Guzman M, Velasco G (2006b) The stress-regulated protein p8 mediates cannabinoid-induced apoptosis of tumor cells. Cancer Cell 9:301–312CrossRefPubMedGoogle Scholar
  13. Casanova ML, Blazquez C, Martinez-Palacio J, Villanueva C, Fernandez-Acenero MJ, Huffman JW, Jorcano JL, Guzman M (2003) Inhibition of skin tumor growth and angiogenesis in vivo by activation of cannabinoid receptors. J Clin Invest 111:43–50PubMedCentralCrossRefPubMedGoogle Scholar
  14. Chan PC, Sills RC, Braun AG, Haseman JK, Bucher JR (1996) Toxicity and carcinogenicity of delta 9-tetrahydrocannabinol in Fischer rats and B6C3F1 mice. Fundam Appl Toxicol 30:109–117CrossRefPubMedGoogle Scholar
  15. Cudaback E, Marrs W, Moeller T, Stella N (2010) The expression level of CB1 and CB2 receptors determines their efficacy at inducing apoptosis in astrocytomas. PLoS One 5, e8702PubMedCentralCrossRefPubMedGoogle Scholar
  16. de Bono JS, Ashworth A (2010) Translating cancer research into targeted therapeutics. Nature 467:543–549CrossRefPubMedGoogle Scholar
  17. 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 258:1946–1949CrossRefPubMedGoogle Scholar
  18. Donadelli M, Dando I, Zaniboni T, Costanzo C, Dalla Pozza E, Scupoli MT, Scarpa A, Zappavigna S, Marra M, Abbruzzese A, Bifulco M, Caraglia M, Palmieri M (2011) Gemcitabine/cannabinoid combination triggers autophagy in pancreatic cancer cells through a ROS-mediated mechanism. Cell Death Dis 2, e152PubMedCentralCrossRefPubMedGoogle Scholar
  19. Du K, Herzig S, Kulkarni RN, Montminy M (2003) TRB3: a tribbles homolog that inhibits Akt/PKB activation by insulin in liver. Science 300:1574–1577CrossRefPubMedGoogle Scholar
  20. Eisenberg-Lerner A, Bialik S, Simon HU, Kimchi A (2009) Life and death partners: apoptosis, autophagy and the cross-talk between them. Cell Death Differ 16:966–975CrossRefPubMedGoogle Scholar
  21. Ellert-Miklaszewska A, Kaminska B, Konarska L (2005) Cannabinoids down-regulate PI3K/Akt and Erk signalling pathways and activate proapoptotic function of Bad protein. Cell Signal 17:25–37CrossRefPubMedGoogle Scholar
  22. Encinar JA, Mallo GV, Mizyrycki C, Giono L, Gonzalez-Ros JM, Rico M, Canepa E, Moreno S, Neira JL, Iovanna JL (2001) Human p8 is a HMG-I/Y-like protein with DNA binding activity enhanced by phosphorylation. J Biol Chem 276:2742–2751CrossRefPubMedGoogle Scholar
  23. Fernandez-Ruiz J, Romero J, Velasco G, Tolon RM, Ramos JA, Guzman M (2007) Cannabinoid CB2 receptor: a new target for controlling neural cell survival? Trends Pharmacol Sci 28:39–45CrossRefPubMedGoogle Scholar
  24. Galve-Roperh I, Sanchez C, Cortes ML, Gómez del Pulgar T, Izquierdo M, Guzman M (2000) Anti-tumoral action of cannabinoids: involvement of sustained ceramide accumulation and extracellular signal-regulated kinase activation. Nat Med 6:313–319CrossRefPubMedGoogle Scholar
  25. Galve-Roperh I, Aguado T, Palazuelos J, Guzman M (2008) Mechanisms of control of neuron survival by the endocannabinoid system. Curr Pharm Des 14:2279–2288CrossRefPubMedGoogle Scholar
  26. Gaoni Y, Mechoulam R (1964) Isolation, structure and partial synthesis of an active constituent of hashish. J Am Chem Soc 86:1646–1647CrossRefGoogle Scholar
  27. Gomez del Pulgar T, Velasco G, Sanchez C, Haro A, Guzman M (2002) De novo-synthesized ceramide is involved in cannabinoid-induced apoptosis. Biochem J 363:183–188PubMedCentralCrossRefPubMedGoogle Scholar
  28. Grande E, Bolos MV, Arriola E (2011) Targeting oncogenic ALK: a promising strategy for cancer treatment. Mol Cancer Ther 10:569–579CrossRefPubMedGoogle Scholar
  29. Grimaldi C, Pisanti S, Laezza C, Malfitano AM, Santoro A, Vitale M, Caruso MG, Notarnicola M, Iacuzzo I, Portella G, Di Marzo V, Bifulco M (2006) Anandamide inhibits adhesion and migration of breast cancer cells. Exp Cell Res 312:363–373CrossRefPubMedGoogle Scholar
  30. Guindon J, Hohmann AG (2011) The endocannabinoid system and cancer: therapeutic implication. Br J Pharmacol 163:1447–1463PubMedCentralCrossRefPubMedGoogle Scholar
  31. Gustafsson SB, Lindgren T, Jonsson M, Jacobsson SO (2009) Cannabinoid receptor-independent cytotoxic effects of cannabinoids in human colorectal carcinoma cells: synergism with 5-fluorouracil. Cancer Chemother Pharmacol 63:691–701CrossRefPubMedGoogle Scholar
  32. Guzman M (2003) Cannabinoids: potential anticancer agents. Nat Rev Cancer 3:745–755CrossRefPubMedGoogle Scholar
  33. Guzman M, Duarte MJ, Blazquez C, Ravina J, Rosa MC, Galve-Roperh I, Sanchez C, Velasco G, Gonzalez-Feria L (2006) A pilot clinical study of Delta9-tetrahydrocannabinol in patients with recurrent glioblastoma multiforme. Br J Cancer 95:197–203PubMedCentralCrossRefPubMedGoogle Scholar
  34. Hart S, Fischer OM, 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 64:1943–1950CrossRefPubMedGoogle Scholar
  35. Hegde VL, Nagarkatti M, Nagarkatti PS (2010) Cannabinoid receptor activation leads to massive mobilization of myeloid-derived suppressor cells with potent immunosuppressive properties. Eur J Immunol 40:3358–3371PubMedCentralCrossRefPubMedGoogle Scholar
  36. Herrera B, Carracedo A, Diez-Zaera M, Gomez del Pulgar T, Guzman M, Velasco G (2006) The CB2 cannabinoid receptor signals apoptosis via ceramide-dependent activation of the mitochondrial intrinsic pathway. Exp Cell Res 312:2121–2131CrossRefPubMedGoogle Scholar
  37. Izzo AA, Aviello G, Petrosino S, Orlando P, Marsicano G, Lutz B, Borrelli F, Capasso R, Nigam S, Capasso F, Di Marzo V (2008) Increased endocannabinoid levels reduce the development of precancerous lesions in the mouse colon. J Mol Med (Berl) 86:89–98CrossRefGoogle Scholar
  38. Joosten M, Valk PJ, Jorda MA, Vankan-Berkhoudt Y, Verbakel S, van den Broek M, Beijen A, Lowenberg B, Delwel R (2002) Leukemic predisposition of pSca-1/Cb2 transgenic mice. Exp Hematol 30:142–149CrossRefPubMedGoogle Scholar
  39. Kadomatsu K (2005) The midkine family in cancer, inflammation and neural development. Nagoya J Med Sci 67:71–82PubMedGoogle Scholar
  40. Katona I, Freund TF (2008) Endocannabinoid signaling as a synaptic circuit breaker in neurological disease. Nat Med 14:923–930CrossRefPubMedGoogle Scholar
  41. 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 125:677–687CrossRefPubMedGoogle Scholar
  42. Ligresti A, Moriello AS, Starowicz K, Matias I, Pisanti S, De Petrocellis L, Laezza C, Portella G, Bifulco M, Di Marzo V (2006) Antitumor activity of plant cannabinoids with emphasis on the effect of cannabidiol on human breast carcinoma. J Pharmacol Exp Ther 318:1375–1387CrossRefPubMedGoogle Scholar
  43. Liu WM, Fowler DW, Dalgleish AG (2010) Cannabis-derived substances in cancer therapy—an emerging anti-inflammatory role for the cannabinoids. Curr Clin Pharmacol 5:281–287CrossRefPubMedGoogle Scholar
  44. Lonardi S, Tosoni A, Brandes AA (2005) Adjuvant chemotherapy in the treatment of high grade gliomas. Cancer Treat Rev 31:79–89CrossRefPubMedGoogle Scholar
  45. Lorente M, Carracedo A, Torres S, Natali F, Egia A, Hernandez-Tiedra S, Salazar M, Blazquez C, Guzman M, Velasco G (2009) Amphiregulin is a factor for resistance of glioma cells to cannabinoid-induced apoptosis. Glia 57:1374–1385CrossRefPubMedGoogle Scholar
  46. Lorente M, Torres S, Salazar M, Carracedo A, Hernandez-Tiedra S, Rodriguez-Fornes F, Garcia-Taboada E, Melendez B, Mollejo M, Campos-Martin Y, Lakatosh SA, Barcia J, Guzman M, Velasco G (2011) Stimulation of the midkine/ALK axis renders glioma cells resistant to cannabinoid antitumoral action. Cell Death Differ 18:959–973PubMedCentralCrossRefPubMedGoogle Scholar
  47. Lu T, Newton C, Perkins I, Friedman H, Klein TW (2006) Cannabinoid treatment suppresses the T-helper cell-polarizing function of mouse dendritic cells stimulated with Legionella pneumophila infection. J Pharmacol Exp Ther 319:269–276CrossRefPubMedGoogle Scholar
  48. Malfitano AM, Ciaglia E, Gangemi G, Gazzerro P, Laezza C, Bifulco M (2011) Update on the endocannabinoid system as an anticancer target. Expert Opin Ther Targets 15:297–308CrossRefPubMedGoogle Scholar
  49. Marcu JP, Christian RT, Lau D, Zielinski AJ, Horowitz MP, Lee J, Pakdel A, Allison J, Limbad C, Moore DH, Yount GL, Desprez PY, McAllister SD (2010) Cannabidiol enhances the inhibitory effects of delta9-tetrahydrocannabinol on human glioblastoma cell proliferation and survival. Mol Cancer Ther 9:180–189PubMedCentralCrossRefPubMedGoogle Scholar
  50. 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 63:2057–2066CrossRefPubMedGoogle Scholar
  51. Massi P, Valenti M, Vaccani A, Gasperi V, Perletti G, Marras E, Fezza F, Maccarrone M, Parolaro D (2008) 5-Lipoxygenase and anandamide hydrolase (FAAH) mediate the antitumor activity of cannabidiol, a non-psychoactive cannabinoid. J Neurochem 104:1091–1100CrossRefPubMedGoogle Scholar
  52. Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI (1990) Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346:561–564CrossRefPubMedGoogle Scholar
  53. McAllister SD, Christian RT, Horowitz MP, Garcia A, Desprez PY (2007) Cannabidiol as a novel inhibitor of Id-1 gene expression in aggressive breast cancer cells. Mol Cancer Ther 6:2921–2927CrossRefPubMedGoogle Scholar
  54. McAllister SD, Murase R, Christian RT, Lau D, Zielinski AJ, Allison J, Almanza C, Pakdel A, Lee J, Limbad C, Liu Y, Debs RJ, Moore DH, Desprez PY (2011) Pathways mediating the effects of cannabidiol on the reduction of breast cancer cell proliferation, invasion, and metastasis. Breast Cancer Res Treat 129:37–47PubMedCentralCrossRefPubMedGoogle Scholar
  55. McKallip RJ, Lombard C, Fisher M, Martin BR, Ryu S, Grant S, Nagarkatti PS, Nagarkatti M (2002) Targeting CB2 cannabinoid receptors as a novel therapy to treat malignant lymphoblastic disease. Blood 100:627–634CrossRefPubMedGoogle Scholar
  56. McKallip RJ, Nagarkatti M, Nagarkatti PS (2005) Delta-9-tetrahydrocannabinol enhances breast cancer growth and metastasis by suppression of the antitumor immune response. J Immunol 174:3281–3289CrossRefPubMedGoogle Scholar
  57. Mechoulam R, Ben-Shabat S, Hanus L, Ligumsky M, Kaminski NE, Schatz AR, Gopher A, Almog S, Martin BR, Compton DR, Pertweee RG, Griffine G, Bayewitchf M, Bargf J, Vogelf Z (1995) Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol 50:83–90CrossRefPubMedGoogle Scholar
  58. Mirkin BL, Clark S, Zheng X, Chu F, White BD, Greene M, Rebbaa A (2005) Identification of midkine as a mediator for intercellular transfer of drug resistance. Oncogene 24:4965–4974CrossRefPubMedGoogle Scholar
  59. Miyato H, Kitayama J, Yamashita H, Souma D, Asakage M, Yamada J, Nagawa H (2009) Pharmacological synergism between cannabinoids and paclitaxel in gastric cancer cell lines. J Surg Res 155:40–47CrossRefPubMedGoogle Scholar
  60. Mizushima N, Levine B, Cuervo AM, Klionsky DJ (2008) Autophagy fights disease through cellular self-digestion. Nature 451:1069–1075PubMedCentralCrossRefPubMedGoogle Scholar
  61. Munro S, Thomas KL, Abu-Shaar M (1993) Molecular characterization of a peripheral receptor for cannabinoids. Nature 365:61–65CrossRefPubMedGoogle Scholar
  62. Nabissi M, Morelli MB, Santoni M, Santoni G (2012) Triggering of the TRPV2 channel by cannabidiol sensitizes glioblastoma cells to cytotoxic chemotherapeutic agents. Carcinogenesis 34:48–57CrossRefPubMedGoogle Scholar
  63. Newton CA, Chou PJ, Perkins I, Klein TW (2009) CB(1) and CB(2) cannabinoid receptors mediate different aspects of delta-9-tetrahydrocannabinol (THC)-induced T helper cell shift following immune activation by Legionella pneumophila infection. J Neuroimmune Pharmacol 4:92–102CrossRefPubMedGoogle Scholar
  64. Nieder C, Adam M, Molls M, Grosu AL (2006) Therapeutic options for recurrent high-grade glioma in adult patients: recent advances. Crit Rev Oncol Hematol 60:181–193CrossRefPubMedGoogle Scholar
  65. Nomura DK, Long JZ, Niessen S, Hoover HS, Ng SW, Cravatt BF (2010) Monoacylglycerol lipase regulates a fatty acid network that promotes cancer pathogenesis. Cell 140:49–61PubMedCentralCrossRefPubMedGoogle Scholar
  66. Pacher P, Batkai S, Kunos G (2006) The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev 58:389–462PubMedCentralCrossRefPubMedGoogle Scholar
  67. Palmer RH, Vernersson E, Grabbe C, Hallberg B (2009) Anaplastic lymphoma kinase: signalling in development and disease. Biochem J 420:345–361PubMedCentralCrossRefPubMedGoogle Scholar
  68. Pertwee RG (2008) The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol 153:199–215PubMedCentralCrossRefPubMedGoogle Scholar
  69. Pertwee RG (2009) Emerging strategies for exploiting cannabinoid receptor agonists as medicines. Br J Pharmacol 156:397–411PubMedCentralCrossRefPubMedGoogle Scholar
  70. Pertwee RG, Howlett AC, Abood ME, Alexander SP, Di Marzo V, Elphick MR, Greasley PJ, Hansen HS, Kunos G, Mackie K, Mechoulam R, Ross RA (2010) International union of basic and clinical pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB1 and CB2. Pharmacol Rev 62:588–631PubMedCentralCrossRefPubMedGoogle Scholar
  71. Pisanti S, Borselli C, Oliviero O, Laezza C, Gazzerro P, Bifulco M (2007) Antiangiogenic activity of the endocannabinoid anandamide: correlation to its tumor-suppressor efficacy. J Cell Physiol 211:495–503CrossRefPubMedGoogle Scholar
  72. Portella G, Laezza C, Laccetti P, De Petrocellis L, Di Marzo V, 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 17:1771–1773PubMedGoogle Scholar
  73. Preet A, Ganju RK, Groopman JE (2008) Delta9-Tetrahydrocannabinol inhibits epithelial growth factor-induced lung cancer cell migration in vitro as well as its growth and metastasis in vivo. Oncogene 27:339–346CrossRefPubMedGoogle Scholar
  74. Purow B, Schiff D (2009) Advances in the genetics of glioblastoma: are we reaching critical mass? Nat Rev Neurol 5:419–426PubMedCentralCrossRefPubMedGoogle Scholar
  75. Qamri Z, Preet A, Nasser MW, Bass CE, Leone G, Barsky SH, Ganju RK (2009) Synthetic cannabinoid receptor agonists inhibit tumor growth and metastasis of breast cancer. Mol Cancer Ther 8:3117–3129PubMedCentralCrossRefPubMedGoogle Scholar
  76. Ramer R, Hinz B (2008) Inhibition of cancer cell invasion by cannabinoids via increased expression of tissue inhibitor of matrix metalloproteinases-1. J Natl Cancer Inst 100:59–69CrossRefPubMedGoogle Scholar
  77. Salazar M, Carracedo A, Salanueva IJ, Hernandez-Tiedra S, Lorente M, Egia A, Vazquez P, Blazquez C, Torres S, Garcia S, Nowak J, Fimia GM, Piacentini M, Cecconi F, Pandolfi PP, Gonzalez-Feria L, Iovanna JL, Guzman 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 119:1359–1372PubMedCentralCrossRefPubMedGoogle Scholar
  78. Salazar M, Lorente M, Garcia-Taboada E, Hernandez-Tiedra S, Davila D, Francis SE, Guzman M, Kiss-Toth E, Velasco G (2013) The pseudokinase tribbles homologue-3 plays a crucial role in cannabinoid anticancer action. Biochim Biophys Acta 1831:1573–1578CrossRefPubMedGoogle Scholar
  79. Sanchez C, de Ceballos ML, del Pulgar TG, Rueda D, Corbacho C, Velasco G, Galve-Roperh I, Huffman JW, Ramon y Cajal S, Guzman M (2001) Inhibition of glioma growth in vivo by selective activation of the CB(2) cannabinoid receptor. Cancer Res 61:5784–5789PubMedGoogle Scholar
  80. Sarfaraz S, Afaq F, Adhami VM, Malik A, 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 281:39480–39491CrossRefPubMedGoogle Scholar
  81. Sarfaraz S, Adhami VM, Syed DN, Afaq F, Mukhtar H (2008) Cannabinoids for cancer treatment: progress and promise. Cancer Res 68:339–342CrossRefPubMedGoogle Scholar
  82. Shrivastava A, Kuzontkoski PM, Groopman JE, Prasad A (2011) Cannabidiol induces programmed cell death in breast cancer cells by coordinating the cross-talk between apoptosis and autophagy. Mol Cancer Ther 10:1161–1172CrossRefPubMedGoogle Scholar
  83. 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 (2012) Id-1 is a key transcriptional regulator of glioblastoma aggressiveness and a novel therapeutic target. Cancer Res 73:1559–1569PubMedCentralCrossRefPubMedGoogle Scholar
  84. Steffens S, Veillard NR, Arnaud C, Pelli G, Burger F, Staub C, Karsak M, Zimmer A, Frossard JL, Mach F (2005) Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice. Nature 434:782–786CrossRefPubMedGoogle Scholar
  85. Stupp R, Pavlidis N, Jelic S (2005) ESMO minimum clinical recommendations for diagnosis, treatment and follow-up of malignant glioma. Ann Oncol 16(Suppl 1):i64–i65CrossRefPubMedGoogle Scholar
  86. 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 215:89–97CrossRefPubMedGoogle Scholar
  87. Thors L, Bergh A, Persson E, Hammarsten P, Stattin P, Egevad L, Granfors T, Fowler CJ (2010) Fatty acid amide hydrolase in prostate cancer: association with disease severity and outcome, CB1 receptor expression and regulation by IL-4. PLoS One 5, e12275PubMedCentralCrossRefPubMedGoogle Scholar
  88. Torres S, Lorente M, Rodriguez-Fornes F, Hernandez-Tiedra S, Salazar M, Garcia-Taboada E, Barcia J, Guzman M, Velasco G (2011) A combined preclinical therapy of cannabinoids and temozolomide against glioma. Mol Cancer Ther 10:90–103CrossRefPubMedGoogle Scholar
  89. Vara D, Salazar M, Olea-Herrero N, Guzman M, Velasco G, Diaz-Laviada I (2011) Anti-tumoral action of cannabinoids on hepatocellular carcinoma: role of AMPK-dependent activation of autophagy. Cell Death Differ 18:1099–1111PubMedCentralCrossRefPubMedGoogle Scholar
  90. Velasco G, Sanchez C, Guzman M (2012) Towards the use of cannabinoids as antitumour agents. Nat Rev Cancer 12:436–444CrossRefPubMedGoogle Scholar
  91. Verfaillie T, Salazar M, Velasco G, Agostinis P (2010) Linking ER stress to autophagy: potential implications for cancer therapy. Int J Cell Biol 2010:930509PubMedCentralCrossRefPubMedGoogle Scholar
  92. Wang D, Wang H, Ning W, Backlund MG, Dey SK, DuBois RN (2008) Loss of cannabinoid receptor 1 accelerates intestinal tumor growth. Cancer Res 68:6468–6476PubMedCentralCrossRefPubMedGoogle Scholar
  93. Zheng D, Bode AM, Zhao Q, Cho YY, Zhu F, Ma WY, Dong Z (2008) The cannabinoid receptors are required for ultraviolet-induced inflammation and skin cancer development. Cancer Res 68:3992–3998PubMedCentralCrossRefPubMedGoogle Scholar
  94. 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 165:373–380CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Guillermo Velasco
    • 1
    • 2
    • 3
    • 4
  • Cristina Sánchez
    • 1
    • 4
    • 5
  • Manuel Guzmán
    • 1
    • 2
    • 4
    • 6
  1. 1.Department of Biochemistry and Molecular Biology I, School of BiologyComplutense UniversityMadridSpain
  2. 2.Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED)MadridSpain
  3. 3.Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC)MadridSpain
  4. 4.Instituto Universitario de Investigación Neuroquímica (IUIN)MadridSpain
  5. 5.Instituto de Investigación Hospital 12 de Octubre (i + 12)MadridSpain
  6. 6.Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS)MadridSpain

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