Skip to main content

Targeting Cannabinoid Receptors in Brain Tumors

  • Chapter
Cannabinoids and the Brain

Cannabinoids, the active components of Cannabis sativa L., act in the body by mimicking endogenous substances — the endocannabinoids — that activate specific cell surface receptors. Cannabinoids exert various palliative effects in cancer patients. In addition, cannabinoids inhibit the growth of different types of tumor cells, including glioma cells, in laboratory animals. They do so by modulating key cell signaling pathways, mostly the endoplasmic reticulum stress response, thereby inducing antitumoral actions such as the apoptotic death of tumor cells and the inhibition of tumor angiogenesis. Of interest, cannabinoids seem to be selective antitumoral compounds as they kill glioma cells but not their nontransformed astroglial counterparts. On the basis of these preclinical findings, a pilot clinical study of Δ9-tetrahydrocannabinol (Δ9-THC) in patients with recurrent glioblastoma multiforme has been recently run. The fair safety profile of Δ9-THC, together with its possible growth-inhibiting action on tumor cells, may set the basis for future trials aimed at evaluating the potential antitumoral activity of cannabinoids.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Aguado T, Carracedo A, Julien B, Velasco G, Milman G, Mechoulam R, Álvarez L, Guzmán M, Galve-Roperh I (2007) Cannabinoids inhibit glioma stem-like cell differentiation and inhibit gliomagenesis. J Biol Chem 282:6854–6862.

    Article  CAS  PubMed  Google Scholar 

  • Benali-Furet NL, Chami M, Houel L, De Giorgi F, Vernejoul F, Lagorce D, Buscail L, Bartenschlager R, Ichas F, Rizzuto R, Paterlini-Brechot P (2005) Hepatitis C virus core triggers apoptosis in liver cells by inducing ER stress and ER calcium depletion. Oncogene 24:4921–4933.

    Article  CAS  PubMed  Google Scholar 

  • Bifulco M, Di Marzo V (2002) Targeting the endocannabinoid system in cancer therapy: a call for further research. Nat Med 8:547–550.

    Article  CAS  PubMed  Google Scholar 

  • 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 15:2745–2747.

    CAS  PubMed  Google Scholar 

  • Blázquez C, Casanova ML, Planas A, Gómez del Pulgar T, Villanueva C, Fernandez-Acenero MJ, Aragones J, Huffman JW, Jorcano JL, Guzmán M (2003) Inhibition of tumor angiogenesis by cannabinoids. FASEB J 17:529–531.

    PubMed  Google Scholar 

  • Blázquez 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 64:5617–5623.

    Article  PubMed  Google Scholar 

  • Blázquez 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 20:2633–2635.

    Article  PubMed  Google Scholar 

  • Bouaboula M, Poinot-Chazel C, Bourrie B, Canat X, Calandra B, Rinaldi-Carmona M, Le Fur G, Casellas P (1995) Activation of mitogen-activated protein kinases by stimulation of the central cannabinoid receptor CB1. Biochem J 312:637–641.

    CAS  PubMed  Google Scholar 

  • Carracedo A, Geelen MJ, Diez M, Hanada K, Guzman M, Velasco G (2004) Ceramide sensitizes astrocytes to oxidative stress: protective role of cannabinoids. Biochem J 380:435–440.

    Article  CAS  PubMed  Google Scholar 

  • 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 66:6748–6755.

    Article  CAS  PubMed  Google Scholar 

  • Carracedo A, Lorente M, Egia A, Blázquez 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 9:301–312.

    Article  CAS  PubMed  Google Scholar 

  • 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 111:43–50.

    CAS  PubMed  Google Scholar 

  • De Petrocellis L, Melck D, Palmisano A, Bisogno T, Laezza C, Bifulco M, Di Marzo V (1998) The endogenous cannabinoid anandamide inhibits human breast cancer cell proliferation. Proc Natl Acad Sci USA 95:8375–8380.

    Article  PubMed  Google Scholar 

  • Derkinderen P, Toutant M, Burgaya F, Le Bert M, Siciliano JC, de Franciscis V, Gelman M, Girault JA (1996) Regulation of a neuronal form of focal adhesion kinase by anandamide. Science 273:1719–1722.

    Article  CAS  PubMed  Google Scholar 

  • Dinnes J, Cave C, Huang S, Milne R (2002) A rapid and systematic review of the effectiveness of temozolomide for the treatment of recurrent malignant glioma. Br J Cancer 86:501–505.

    Article  CAS  PubMed  Google Scholar 

  • 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 17:25–37.

    Article  CAS  PubMed  Google Scholar 

  • Fernández-Ruiz J, Romero J, Velasco G, Tolon R, Ramos J, Guzmán M (2007) Cannabinoid CB2 receptor: a new target for controlling neural cell survival? Trends Pharmacol Sci 28:39–45.

    Article  PubMed  Google Scholar 

  • Galve-Roperh I, Sanchez C, Cortes ML, Gómez del Pulgar T, Izquierdo M, Guzmán M (2000) Anti-tumoral action of cannabinoids: involvement of sustained ceramide accumulation and extracellular signal-regulated kinase activation. Nat Med 6:313–319.

    Article  CAS  PubMed  Google Scholar 

  • Gaoni Y, Mechoulam R (1964) Isolation, structure and partial synthesis of an active constituent of hashish. J Am Chem Soc 86:1646–1647.

    Article  CAS  Google Scholar 

  • Gómez del Pulgar T, Velasco G, Guzman M (2000) The CB1 cannabinoid receptor is coupled to the activation of protein kinase B/Akt. Biochem J 347:369–373.

    Article  PubMed  Google Scholar 

  • Gómez del Pulgar T, De Ceballos ML, Guzmán M, 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.

    Article  PubMed  Google Scholar 

  • Gómez del Pulgar T, Velasco G, Sánchez C, Haro A, Guzman M (2002b) De novo-synthesized ceramide is involved in cannabinoid-induced apoptosis. Biochem J 363:183–188.

    Article  PubMed  Google Scholar 

  • 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 312:363–373.

    Article  CAS  PubMed  Google Scholar 

  • Guzmán M (2003) Cannabinoids: potential anticancer agents. Nat Rev Cancer 3:745–755.

    Article  PubMed  Google Scholar 

  • Guzmán 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 delta-9-tetrahydrocannabinol in patients with recurrent glioblastoma multiforme. Br J Cancer 95:197–203.

    Article  PubMed  Google Scholar 

  • Hall W, Christie M, Currow D (2005) Cannabinoids and cancer: causation, remediation, and palliation. Lancet Oncol 6:35–42.

    CAS  PubMed  Google Scholar 

  • Herrera B, Carracedo A, Diez-Zaera M, Gomez del Pulgar T, Guzmán M, Velasco G (2006) The CB2 cannabinoid receptor signals apoptosis via ceramide-dependent activation of the mitochondrial intrinsic pathway. Exp Cell Res 312:2121–2131.

    Article  CAS  PubMed  Google Scholar 

  • 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 receptors. Pharmacol Rev 54:161–202.

    Article  CAS  PubMed  Google Scholar 

  • Jordan CT, Guzmán ML, Noble M (2006) Cancer stem cells. N Engl J Med 355:1253–1261.

    Article  CAS  PubMed  Google Scholar 

  • Kleihues P, Louis DN, Scheithauer BW, Rorke LB, Reifenberger G, Burger PC, Cavenee WK (2002). The WHO classification of tumors of the nervous system. J Neuropathol Exp Neurol 61:215–225.

    PubMed  Google Scholar 

  • Kogan NM, Blázquez C, Alvarez L, Gallily R, Schlesinger M, Guzman M, Mechoulam R (2006) A cannabinoid quinone inhibits angiogenesis by targeting vascular endothelial cells. Mol Pharmacol 70:51–59.

    CAS  PubMed  Google Scholar 

  • Li J, Holbrook NJ (2004) Elevated gadd153/chop expression and enhanced c-Jun N-terminal protein kinase activation sensitizes aged cells to ER stress. Exp Gerontol 39:735–744.

    Article  CAS  PubMed  Google Scholar 

  • Liu J, Gao B, Mirshahi F, Sanyal AJ, Khanolkar AD, Makriyannis A, Kunos G (2000) Functional CB1 cannabinoid receptors in human vascular endothelial cells. Biochem J 346:835–840.

    Article  CAS  PubMed  Google Scholar 

  • Lombard C, Nagarkatti M, Nagarkatti PS (2005) Targeting cannabinoid receptors to treat leukemia: role of cross-talk between extrinsic and intrinsic pathways in Delta9-tetrahydrocannabinol (THC)-induced apoptosis of Jurkat cells. Leuk Res 29:915–922.

    Article  CAS  PubMed  Google Scholar 

  • Lonardi S, Tosoni A, Brandes AA (2005) Adjuvant chemotherapy in the treatment of high grade gliomas. Cancer Treat Rev 31:79–89.

    Article  CAS  PubMed  Google Scholar 

  • Maher EA, Furnari FB, Bachoo RM, Rowitch DH, Louis DN, Cavenee WK, DePinho RA (2001) Malignant glioma: genetics and biology of a grave matter. Genes Dev 15:1311–1333.

    Article  CAS  PubMed  Google Scholar 

  • Mallo GV, Fiedler F, Calvo EL, Ortiz EM, Vasseur S, Keim V, Morisset J, Iovanna JL (1997) Cloning and expression of the rat p8 cDNA, a new gene activated in pancreas during the acute phase of pancreatitis, pancreatic development, and regeneration, and which promotes cellular growth. J Biol Chem 272:32360–32369.

    Article  CAS  PubMed  Google Scholar 

  • Mandic A, Hansson J, Linder S, Shoshan MC (2003) Cisplatin induces endoplasmic reticulum stress and nucleus-independent apoptotic signaling. J Biol Chem 278:9100–9106.

    Article  CAS  PubMed  Google Scholar 

  • 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 100:627–634.

    Article  CAS  PubMed  Google Scholar 

  • Mechoulam R, Spatz M, Shohami E (2002) Endocannabinoids and neuroprotection. Sci STKE 2002:RE5.

    Google Scholar 

  • Melck D, De Petrocellis L, Orlando P, Bisogno T, Laezza C, Bifulco M, 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.

    Article  CAS  PubMed  Google Scholar 

  • Mimeault M, Pommery N, Wattez N, Bailly C, Henichart JP (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.

    Article  CAS  PubMed  Google Scholar 

  • Molina-Holgado E, Vela JM, Arevalo-Martin A, Almazan G, Molina-Holgado F, Borrell J, Guaza C (2002) Cannabinoids promote oligodendrocyte progenitor survival: involvement of cannabinoid receptors and phosphatidylinositol-3 kinase/Akt signaling. J Neurosci 22:9742–9753.

    CAS  PubMed  Google Scholar 

  • Munson AE, Harris LS, Friedman MA, Dewey WL, Carchman RA (1975) Antineoplastic activity of cannabinoids. J Natl Cancer Inst 55:597–602.

    CAS  PubMed  Google Scholar 

  • Ogretmen B, Hannun YA (2004). Biologically active sphingolipids in cancer pathogenesis and treatment. Nat Rev Cancer 4:604–616.

    Article  CAS  PubMed  Google Scholar 

  • Ohoka N, Yoshii S, Hattori T, Onozaki K, Hayashi H (2005) TRB3, a novel ER stress-inducible gene, is induced via ATF4-CHOP pathway and is involved in cell death. EMBO J 24:1243–1255.

    Article  CAS  PubMed  Google Scholar 

  • Piomelli D (2003) The molecular logic of endocannabinoid signalling. Nat Rev Neurosci 4:873–884.

    Article  CAS  PubMed  Google Scholar 

  • 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 17:1771–1773.

    CAS  PubMed  Google Scholar 

  • Reardon DA, Wen PY (2006) Therapeutic advances in the treatment of glioblastoma: rationale and potential role of targeted agents. Oncologist 11:152–164.

    Article  CAS  PubMed  Google Scholar 

  • Rueda D, Galve-Roperh I, Haro A, Guzman M (2000) The CB1 cannabinoid receptor is coupled to the activation of c-Jun N-terminal kinase. Mol Pharmacol 58:814–820.

    CAS  PubMed  Google Scholar 

  • Sánchez C, Galve-Roperh I, Canova C, Brachet P, Guzmán M (1998) Delta-9-tetrahydrocannabinol induces apoptosis in C6 glioma cells. FEBS Lett 436:6–10.

    Article  PubMed  Google Scholar 

  • Sánchez C, de Ceballos ML, del Pulgar TG, Rueda D, Corbacho C, Velasco G, Galve-Roperh I, Huffman W, Ramon y Cajal S, Guzmán M (2001a)Inhibition of glioma growth in vivo by selective activation of the CB2 cannabinoid receptor. Cancer Res 61:5784–5789.

    PubMed  Google Scholar 

  • Sánchez C, Rueda D, Segui B, Galve-Roperh I, Levade T, Guzmán M (2001b) The CB1 cannabinoid receptor of astrocytes is coupled to sphingomyelin hydrolysis through the adaptor protein fan. Mol Pharmacol 59:955–959.

    PubMed  Google Scholar 

  • Schroder M, Kaufman RJ (2005). The mammalian unfolded protein response. Annu Rev Biochem 74:739–789.

    Article  PubMed  Google Scholar 

  • Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996.

    Article  CAS  PubMed  Google Scholar 

  • Tajiri S, Oyadomari S, Yano S, Morioka M, Gotoh T, Hamada JI, Ushio Y, Mori M (2004) Ischemia-induced neuronal cell death is mediated by the endoplasmic reticulum stress pathway involving CHOP. Cell Death Differ 11:403–415.

    Article  CAS  PubMed  Google Scholar 

  • Tramer MR, Carroll D, Campbell FA, Reynolds DJ, Moore RA, McQuay HJ (2001) Cannabinoids for control of chemotherapy induced nausea and vomiting: quantitative systematic review. Br Med J 323:16–21.

    Article  CAS  Google Scholar 

  • Vescovi AL, Galli R, Reynolds BA (2006) Brain tumour stem cells. Nat Rev Cancer 6:425–436.

    Article  CAS  PubMed  Google Scholar 

  • Yamanaka R (2006) Novel immunotherapeutic approaches to glioma. Curr Opin Mol Ther 8:46–51.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2008 Springer

About this chapter

Cite this chapter

Velasco, G. et al. (2008). Targeting Cannabinoid Receptors in Brain Tumors. In: Köfalvi, A. (eds) Cannabinoids and the Brain. Springer, Boston, MA. https://doi.org/10.1007/978-0-387-74349-3_17

Download citation

Publish with us

Policies and ethics