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Journal of Neuroimmune Pharmacology

, Volume 10, Issue 2, pp 255–267 | Cite as

The Antitumor Activity of Plant-Derived Non-Psychoactive Cannabinoids

  • Sean D. McAllister
  • Liliana Soroceanu
  • Pierre-Yves Desprez
INVITED REVIEW

Abstract

As a therapeutic agent, most people are familiar with the palliative effects of the primary psychoactive constituent of Cannabis sativa (CS), Δ9-tetrahydrocannabinol (THC), a molecule active at both the cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptor subtypes. Through the activation primarily of CB1 receptors in the central nervous system, THC can reduce nausea, emesis and pain in cancer patients undergoing chemotherapy. During the last decade, however, several studies have now shown that CB1 and CB2 receptor agonists can act as direct antitumor agents in a variety of aggressive cancers. In addition to THC, there are many other cannabinoids found in CS, and a majority produces little to no psychoactivity due to the inability to activate cannabinoid receptors. For example, the second most abundant cannabinoid in CS is the non-psychoactive cannabidiol (CBD). Using animal models, CBD has been shown to inhibit the progression of many types of cancer including glioblastoma (GBM), breast, lung, prostate and colon cancer. This review will center on mechanisms by which CBD, and other plant-derived cannabinoids inefficient at activating cannabinoid receptors, inhibit tumor cell viability, invasion, metastasis, angiogenesis, and the stem-like potential of cancer cells. We will also discuss the ability of non-psychoactive cannabinoids to induce autophagy and apoptotic-mediated cancer cell death, and enhance the activity of first-line agents commonly used in cancer treatment.

Keywords

Cannabinoid Cannabidiol Cancer Reactive oxygen species 

Notes

Conflict of Interest

The authors declare that they have no conflict of interest.

References

  1. Agurell S, Carlsson S, Lindgren JE, Ohlsson A, Gillespie H, Hollister LE (1981) Interactions of delta 1-tetrahydrocannabinol with cannabinol and cannabidiol following oral administration in man. Assay of cannabinol and cannabidiol by mass fragmentography. Experientia 37:1090–1092PubMedCrossRefGoogle Scholar
  2. Albanese C, Johnson J, Watanabe G, Eklund N, Vu D, Arnold A, Pestell RG (1995) Transforming p21ras mutants and c-Ets-2 activate the cyclin D1 promoter through distinguishable regions. J Biol Chem 270:23589–23597PubMedCrossRefGoogle Scholar
  3. Alozie SO, Martin BR, Harris LS, Dewey WL (1980) 3H-delta 9-Tetrahydrocannabinol, 3H-cannabinol and 3H-cannabidiol: penetration and regional distribution in rat brain. Pharmacol Biochem Behav 12:217–218PubMedCrossRefGoogle Scholar
  4. Armstrong JL, Hill DS, McKee CS, Hernandez-Tiedra S, Lorente M, Lopez-Valero I, Eleni Anagnostou M, Babatunde F, Corazzari M, Redfern CP, Velasco G and Lovat PE (2015) Exploiting Cannabinoid-Induced Cytotoxic Autophagy to Drive Melanoma Cell Death. J Invest DermatolGoogle Scholar
  5. Baldwin JM (1994) Structure and function of receptors coupled to G proteins. Curr Opin Cell Biol 6Google Scholar
  6. Bifulco M, Di Marzo V (2002) Targeting the endocannabinoid system in cancer therapy: a call for further research. Nat Med 8:547–550PubMedCrossRefGoogle Scholar
  7. Bornheim LM, Grillo MP (1998) Characterization of cytochrome P450 3A inactivation by cannabidiol: possible involvement of cannabidiol-hydroxyquinone as a P450 inactivator. Chem Res Toxicol 11:1209–1216PubMedCrossRefGoogle Scholar
  8. Brady KT, Balster RL (1980) The effects of delta 9-tetrahydrocannabinol alone and in combination with cannabidiol on fixed-interval performance in rhesus monkeys. Psychopharmacology 72:21–26PubMedCrossRefGoogle Scholar
  9. Caffarel MM, Andradas C, Mira E, Perez-Gomez E, Cerutti C, Moreno-Bueno G, Flores JM, Garcia-Real I, Palacios J, Manes S, Guzman M, Sanchez C (2010) Cannabinoids reduce ErbB2-driven breast cancer progression through Akt inhibition. Mol Cancer 9:196PubMedCentralPubMedCrossRefGoogle Scholar
  10. Cardaci S, Filomeni G, Ciriolo MR (2012) Redox implications of AMPK-mediated signal transduction beyond energetic clues. J Cell Sci 125:2115–2125PubMedCrossRefGoogle 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 66:6748–6755PubMedCrossRefGoogle 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 9:301–312PubMedCrossRefGoogle Scholar
  13. Dalton WS, Martz R, Lemberger L, Rodda BE, Forney RB (1976) Influence of cannabidiol on delta-9-tetrahydrocannabinol effects. Clin Pharmacol Ther 19:300–309PubMedGoogle Scholar
  14. Dando I, Donadelli M, Costanzo C, Dalla Pozza E, D’Alessandro A, Zolla L, Palmieri M (2013) Cannabinoids inhibit energetic metabolism and induce AMPK-dependent autophagy in pancreatic cancer cells. Cell Death Dis 4:e664PubMedCentralPubMedCrossRefGoogle Scholar
  15. Davis WM, Hatoum NS (1983) Neurobehavioral actions of cannabichromene and interactions with delta 9-tetrahydrocannabinol. Gen Pharmacol 14:247–252PubMedCrossRefGoogle Scholar
  16. De Petrocellis L, Ligresti A, Schiano Moriello A, Iappelli M, Verde R, Stott CG, Cristino L, Orlando P, Di Marzo V (2013) Non-THC cannabinoids inhibit prostate carcinoma growth in vitro and in vivo: pro-apoptotic effects and underlying mechanisms. Br J Pharmacol 168:79–102PubMedCentralPubMedCrossRefGoogle Scholar
  17. 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:e152PubMedCentralPubMedCrossRefGoogle Scholar
  18. Edery H, Grunfeld Y, Ben-Zvi Z, Mechoulam R (1971) Structural requirements for cannabinoid activity. Ann NY Acad Sci 191:40–53CrossRefGoogle Scholar
  19. Elbaz M, Nasser MW, Ravi J, Wani NA, Ahirwar DK, Zhao H, Oghumu S, Satoskar AR, Shilo K, Carson WE, 3rd and Ganju RK (2015) Modulation of the tumor microenvironment and inhibition of EGF/EGFR pathway: Novel anti-tumor mechanisms of Cannabidiol in breast cancer. Mol OncolGoogle Scholar
  20. Emery SM, Alotaibi MR, Tao Q, Selley DE, Lichtman AH, Gewirtz DA (2014) Combined antiproliferative effects of the aminoalkylindole WIN55,212-2 and radiation in breast cancer cells. J Pharmacol Exp Ther 348:293–302PubMedCrossRefGoogle Scholar
  21. Flygare J, Sander B (2008) The endocannabinoid system in cancer-potential therapeutic target? Semin Cancer Biol 18:176–189PubMedCrossRefGoogle Scholar
  22. Fong S, Itahana Y, Sumida T, Singh J, Coppe JP, Liu Y, Richards PC, Bennington JL, Lee NM, Debs RJ, Desprez PY (2003) Id-1 as a molecular target in therapy for breast cancer cell invasion and metastasis. Proc Natl Acad Sci U S A 100:13543–13548PubMedCentralPubMedCrossRefGoogle Scholar
  23. Freimuth N, Ramer R, Hinz B (2010) Antitumorigenic effects of cannabinoids beyond apoptosis. J Pharmacol Exp Ther 332:336–344PubMedCrossRefGoogle Scholar
  24. Galve-Roperh I, Sanchez C, Cortes ML, del Pulgar TG, Izquierdo M, Guzman M (2000) Anti-tumoral action of cannabinoids: involvement of sustained ceramide accumulation and extracellular signal-regulated kinase activation. Nat Med 6:313–319PubMedCrossRefGoogle Scholar
  25. Guimaraes FS, de Aguiar JC, Mechoulam R, Breuer A (1994) Anxiolytic effect of cannabidiol derivatives in the elevated plus-maze. Gen Pharmacol 25:161–164PubMedCrossRefGoogle Scholar
  26. Guindon J, Hohmann AG (2011) The endocannabinoid system and cancer: therapeutic implication. Br J Pharmacol 163:1447–1463PubMedCentralPubMedCrossRefGoogle Scholar
  27. Gupta GP, Perk J, Acharyya S, de Candia P, Mittal V, Todorova-Manova K, Gerald WL, Brogi E, Benezra R, Massague J (2007) ID genes mediate tumor reinitiation during breast cancer lung metastasis. Proc Natl Acad Sci U S A 104:19506–19511PubMedCentralPubMedCrossRefGoogle Scholar
  28. Hampson AJ, Grimaldi M, Axelrod J, Wink D (1998) Cannabidiol and (-)Delta9-tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl Acad Sci U S A 95:8268–8273PubMedCentralPubMedCrossRefGoogle Scholar
  29. Hiltunen AJ, Jarbe TU, Wangdahl K (1988) Cannabinol and cannabidiol in combination: temperature, open-field activity, and vocalization. Pharmacol Biochem Behav 30:675–678PubMedCrossRefGoogle Scholar
  30. Hiltunen AJ, Jarbe TU, Kamkar MR, Archer T (1989) Behaviour in rats maintained by low differential reinforcement rate: effects of delta 1-tetrahydrocannabinol, cannabinol and cannabidiol, alone and in combination. Neuropharmacology 28:183–189PubMedCrossRefGoogle Scholar
  31. Holland ML, Panetta JA, Hoskins JM, Bebawy M, Roufogalis BD, Allen JD, Arnold JC (2006) The effects of cannabinoids on P-glycoprotein transport and expression in multidrug resistant cells. Biochem Pharmacol 71:1146–1154PubMedCrossRefGoogle Scholar
  32. Holland ML, Lau DT, Allen JD, Arnold JC (2007) The multidrug transporter ABCG2 (BCRP) is inhibited by plant-derived cannabinoids. Br J Pharmacol 152:815–824PubMedCentralPubMedCrossRefGoogle Scholar
  33. Hollister LE, Gillespie H (1975) Interactions in man of delta-9-tetrahydrocannabinol. II. Cannabinol and cannabidiol. Clin Pharmacol Ther 18:80–83PubMedGoogle Scholar
  34. Howlett AC (1987) Cannabinoid inhibition of adenylate cyclase: relative activity of the constituents and metabolites of marijuana. Neuropharmacology 26:507–512PubMedCrossRefGoogle Scholar
  35. Hu H, Han HY, Wang YL, Zhang XP, Chua CW, Wong YC, Wang XF, Ling MT, Xu KX (2009) The role of Id-1 in chemosensitivity and epirubicin-induced apoptosis in bladder cancer cells. Oncol Rep 21:1053–1059PubMedGoogle Scholar
  36. Huffman JW, Shu Y, Showalter V, Abood ME, Wiley JL, Compton DR, Martin BR, Bramblett DR, Reggio PH (1996) Synthesis and pharmacology of a very potent cannabinoid lacking a phenolic hydroxyl with high affinity for the CB2 receptor. J Med Chem 39:3875–3877PubMedCrossRefGoogle Scholar
  37. Hunt CA, Jones RT, Herning RI, Bachman J (1981) Evidence that cannabidiol does not significantly alter the pharmacokinetics of tetrahydrocannabinol in man. J Pharmacokinet Biopharm 9:245–260PubMedCrossRefGoogle Scholar
  38. Jacobsson SO, Rongard E, Stridh M, Tiger G, Fowler CJ (2000) Serum-dependent effects of tamoxifen and cannabinoids upon C6 glioma cell viability. Biochem Pharmacol 60:1807–1813PubMedCrossRefGoogle Scholar
  39. Jaeger W, Benet LZ, Bornheim LM (1996) Inhibition of cyclosporine and tetrahydrocannabinol metabolism by cannabidiol in mouse and human microsomes. Xenobiotica 26:275–284PubMedCrossRefGoogle Scholar
  40. Jarbe TU, Hiltunen AJ (1987) Cannabimimetic activity of cannabinol in rats and pigeons. Neuropharmacology 26:219–228PubMedCrossRefGoogle Scholar
  41. Karler R, Turkanis SA (1979) Cannabis and epilepsy. In: Nahas GG, Paton WDM (eds) Marihuana: biological effects, analysis, metabolism, cellular responses, reproduction and brain. Pergamon Press, Oxford, pp 619–641CrossRefGoogle Scholar
  42. Klein TW (2005) Cannabinoid-based drugs as anti-inflammatory therapeutics. Nat Rev Immunol 5:400–411PubMedCrossRefGoogle Scholar
  43. Kogan NM, Rabinowitz R, Levi P, Gibson D, Sandor P, Schlesinger M, Mechoulam R (2004) Synthesis and antitumor activity of quinonoid derivatives of cannabinoids. J Med Chem 47:3800–3806PubMedCrossRefGoogle Scholar
  44. Kogan NM, Schlesinger M, Priel E, Rabinowitz R, Berenshtein E, Chevion M, Mechoulam R (2007) HU-331, a novel cannabinoid-based anticancer topoisomerase II inhibitor. Mol Cancer Ther 6:173–183PubMedCrossRefGoogle Scholar
  45. Laurent A, Nicco C, Chereau C, Goulvestre C, Alexandre J, Alves A, Levy E, Goldwasser F, Panis Y, Soubrane O, Weill B, Batteux F (2005) Controlling tumor growth by modulating endogenous production of reactive oxygen species. Cancer Res 65:948–956PubMedGoogle Scholar
  46. 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 318:1375–1387PubMedCrossRefGoogle Scholar
  47. Malfait AM, Gallily R, Sumariwalla PF, Malik AS, Andreakos E, Mechoulam R, Feldmann M (2000) The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis. Proc Natl Acad Sci U S A 97:9561–9566PubMedCentralPubMedCrossRefGoogle Scholar
  48. Mao P, Joshi K, Li J, Kim SH, Li P, Santana-Santos L, Luthra S, Chandran UR, Benos PV, Smith L, Wang M, Hu B, Cheng SY, Sobol RW, Nakano I (2013) Mesenchymal glioma stem cells are maintained by activated glycolytic metabolism involving aldehyde dehydrogenase 1A3. Proc Natl Acad Sci U S A 110:8644–8649PubMedCentralPubMedCrossRefGoogle 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 9:180–189PubMedCentralPubMedCrossRefGoogle Scholar
  50. 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
  51. 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
  52. Massi P, Valenti M, Vaccani A, Gasperi V, Perletti G, Marras E, Fezza F, Maccarrone M and Parolaro D (2008) 5-Lipoxygenase and anandamide hydrolase (FAAH) mediate the antitumor activity of cannabidiol, a non-psychoactive cannabinoid. J Neurochem 104:1091–1100Google Scholar
  53. Massi P, Solinas M, Cinquina V, Parolaro D (2012) Cannabidiol as potential anticancer drug. Br J Clin Pharmacol 75:303–312PubMedCentralCrossRefGoogle Scholar
  54. Mato S, Victoria Sanchez-Gomez M, Matute C (2010) Cannabidiol induces intracellular calcium elevation and cytotoxicity in oligodendrocytes. Glia 58:1739–1747Google Scholar
  55. 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 6:2921–2927PubMedCrossRefGoogle Scholar
  56. 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 (2010) Pathways mediating the effects of cannabidiol on the reduction of breast cancer cell proliferation, invasion, and metastasis. Breast Cancer Res Treat 129:37–47PubMedCentralPubMedCrossRefGoogle Scholar
  57. McKallip RJ, Jia W, Schlomer J, Warren JW, Nagarkatti PS, Nagarkatti M (2006) Cannabidiol-induced apoptosis in human leukemia cells: a novel role of cannabidiol in the regulation of p22phox and Nox4 expression. Mol Pharmacol 70:897–908PubMedCrossRefGoogle Scholar
  58. McPartland JM, Russo EB (2001) Cannabis and cannabis extract: greater than the sum of the parts? J Cannabis Therapeut 1:103–132CrossRefGoogle Scholar
  59. Mechoulam R, Ben-Shabat S, Hanus S, Ligumsky M, Kaminski NE, Schatz AR, Gopher A, Almong S, Martin BR, Compton DR, Pertwee RG, Griffin G, Bayewitch M, Barg J, Vogel Z (1995) Identification of a 2-mono-glyceride, present in canine gut, that biinds to cannabinoid receptors. Biochem Pharmacol 50:83–90PubMedCrossRefGoogle Scholar
  60. Minn AJ, Gupta GP, Siegel PM, Bos PD, Shu W, Giri DD, Viale A, Olshen AB, Gerald WL, Massague J (2005) Genes that mediate breast cancer metastasis to lung. Nature 436:518–524PubMedCentralPubMedCrossRefGoogle Scholar
  61. Murase R, Kawamura R, Singer E, Pakdel A, Sarma P, Judkins J, Elwakeel E, Dayal S, Martinez-Martinez E, Amere M, Gujjar R, Mahadevan A, Desprez PY, McAllister SD (2014) Targeting multiple cannabinoid antitumor pathways with a resorcinol derivative leads to inhibition of advanced stages of breast cancer. Br J Pharmacol 171:4464–4477PubMedCrossRefGoogle Scholar
  62. Nasser MW, Qamri Z, Deol YS, Smith D, Shilo K, Zou X, Ganju RK (2011) Crosstalk between chemokine receptor CXCR4 and cannabinoid receptor CB2 in modulating breast cancer growth and invasion. PLoS One 6:e23901PubMedCentralPubMedCrossRefGoogle Scholar
  63. Ohlsson A, Lindgren JE, Wahlen A, Agurell S, Hollister LE, Gillespie HK (1980) Plasma delta-9 tetrahydrocannabinol concentrations and clinical effects after oral and intravenous administration and smoking. Clin Pharmacol Ther 28:409–416PubMedCrossRefGoogle Scholar
  64. Perez-Reyes M, Timmons MC, Davis KH, Wall EM (1973) A comparison of the pharmacological activity in man of intraveneously administered D9-tetrahydrocannabinol, cannabinol, and cannabidiol. Experientia 29:1368–1369PubMedCrossRefGoogle Scholar
  65. Pertwee RG (1997) Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol Ther 74:129–180PubMedGoogle Scholar
  66. Pertwee RG (2006) Cannabinoid pharmacology: the first 66 years. Br J Pharmacol 147(Suppl 1):S163–S171PubMedCentralPubMedGoogle Scholar
  67. Piomelli D (2003) The molecular logic of endocannabinoid signalling. Nat Rev Neurosci 4:873–884PubMedCrossRefGoogle Scholar
  68. Ponz-Sarvise M, Nguewa PA, Pajares MJ, Agorreta J, Lozano MD, Redrado M, Pio R, Behrens C, Wistuba II, Garcia-Franco CE, Garcia-Foncillas J, Montuenga LM, Calvo A, Gil-Bazo I (2011) Inhibitor of differentiation-1 as a novel prognostic factor in NSCLC patients with adenocarcinoma histology and its potential contribution to therapy resistance. Clin Cancer Res 17:4155–4166PubMedCrossRefGoogle Scholar
  69. Preet A, Qamri Z, Nasser MW, Prasad A, Shilo K, Zou X, Groopman JE, Ganju RK (2011) Cannabinoid receptors, CB1 and CB2, as novel targets for inhibition of non-small cell lung cancer growth and metastasis. Cancer Prev Res (Phila) 4:65–75CrossRefGoogle Scholar
  70. 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 8:3117–3129PubMedCentralPubMedCrossRefGoogle Scholar
  71. 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 100:59–69PubMedCrossRefGoogle Scholar
  72. Ramer R, Merkord J, Rohde H, Hinz B (2010a) Cannabidiol inhibits cancer cell invasion via upregulation of tissue inhibitor of matrix metalloproteinases-1. Biochem Pharmacol 79:955–966PubMedCrossRefGoogle Scholar
  73. Ramer R, Rohde A, Merkord J, Rohde H, Hinz B (2010b) Decrease of plasminogen activator inhibitor-1 may contribute to the anti-invasive action of cannabidiol on human lung cancer cells. Pharm Res 27:2162–2174PubMedCrossRefGoogle Scholar
  74. Ramer R, Bublitz K, Freimuth N, Merkord J, Rohde H, Haustein M, Borchert P, Schmuhl E, Linnebacher M, Hinz B (2011) Cannabidiol inhibits lung cancer cell invasion and metastasis via intercellular adhesion molecule-1. FASEB J 26:1535–1548PubMedCrossRefGoogle Scholar
  75. Ramer R, Heinemann K, Merkord J, Rohde H, Salamon A, Linnebacher M, Hinz B (2013) COX-2 and PPAR-gamma confer cannabidiol-induced apoptosis of human lung cancer cells. Mol Cancer Ther 12:69–82PubMedCrossRefGoogle Scholar
  76. Rimmerman N, Ben-Hail D, Porat Z, Juknat A, Kozela E, Daniels MP, Connelly PS, Leishman E, Bradshaw HB, Shoshan-Barmatz V, Vogel Z (2013) Direct modulation of the outer mitochondrial membrane channel, voltage-dependent anion channel 1 (VDAC1) by cannabidiol: a novel mechanism for cannabinoid-induced cell death. Cell Death Dis 4:e949PubMedCentralPubMedCrossRefGoogle Scholar
  77. Ryan D, Drysdale AJ, Lafourcade C, Pertwee RG, Platt B (2009) Cannabidiol targets mitochondria to regulate intracellular Ca2+ levels. J Neurosci 29:2053–2063PubMedCrossRefGoogle Scholar
  78. 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 119:1359–1372PubMedCentralPubMedCrossRefGoogle Scholar
  79. 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 281:39480–39491PubMedCrossRefGoogle Scholar
  80. Sarfaraz S, Adhami VM, Syed DN, Afaq F, Mukhtar H (2008) Cannabinoids for cancer treatment: progress and promise. Cancer Res 68:339–342PubMedCrossRefGoogle Scholar
  81. Sarker KP, Maruyama I (2003) Anandamide induces cell death independently of cannabinoid receptors or vanilloid receptor 1: possible involvement of lipid rafts. Cell Mol Life Sci 60:1200–1208PubMedGoogle Scholar
  82. Scott KA, Dalgleish AG, Liu WM (2014) The combination of cannabidiol and Delta9-tetrahydrocannabinol enhances the anticancer effects of radiation in an orthotopic murine glioma model. Mol Cancer Ther 13:2955–2967PubMedCrossRefGoogle Scholar
  83. 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 10:1161–1172PubMedCrossRefGoogle Scholar
  84. Singer E, Judkins J, Salomonis N, Matlaf L, Soteropoulos P, McAllister S, Soroceanu L (2015) Reactive oxygen species-mediated therapeutic response and resistance in glioblastoma. Cell Death Dis 6:e1601PubMedCrossRefGoogle Scholar
  85. Solinas M, Massi P, Cantelmo AR, Cattaneo MG, Cammarota R, Bartolini D, Cinquina V, Valenti M, Vicentini LM, Noonan DM, Albini A, Parolaro D (2012) Cannabidiol inhibits angiogenesis by multiple mechanisms. Br J Pharmacol 167:1218–1231PubMedCentralPubMedCrossRefGoogle Scholar
  86. Soroceanu L, Murase R, Limbad C, Singer EL, Allison J, Adrados I, Kawamura R, Pakdel A, Fukuyo Y, Nguyen D, Khan S, Arauz R, Yount GL, Moore D, Desprez PY, McAllister SD (2013) Id-1 is a Key transcriptional regulator of glioblastoma aggressiveness and a novel therapeutic target. Cancer Res 73:1559–1569Google Scholar
  87. Srivastava MD, Srivastava BI, Brouhard B (1998) Delta9 tetrahydrocannabinol and cannabidiol alter cytokine production by human immune cells. Immunopharmacology 40:179–185PubMedCrossRefGoogle Scholar
  88. Sugiura T, Kondo S, Sukagawa A, Nakane S, Shinoda A, Itoh K, Yamashita A, Waku K (1995) 2-Arachidonoylglycerol: a possible cannabinoid receptor ligand in the brain. Biochem Biophys Res Commun 215:89–97PubMedCrossRefGoogle Scholar
  89. Sui X, Chen R, Wang Z, Huang Z, Kong N, Zhang M, Han W, Lou F, Yang J, Zhang Q, Wang X, He C, Pan H (2013) Autophagy and chemotherapy resistance: a promising therapeutic target for cancer treatment. Cell Death Dis 4:e838PubMedCentralPubMedCrossRefGoogle Scholar
  90. Swarbrick A, Roy E, Allen T, Bishop JM (2008) Id1 cooperates with oncogenic Ras to induce metastatic mammary carcinoma by subversion of the cellular senescence response. Proc Natl Acad Sci U S A 105:5402–5407PubMedCentralPubMedCrossRefGoogle Scholar
  91. Timmerman LA, Holton T, Yuneva M, Louie RJ, Padro M, Daemen A, Hu M, Chan DA, Ethier SP, van’t Veer LJ, Polyak K, McCormick F, Gray JW (2013) Glutamine sensitivity analysis identifies the xCT antiporter as a common triple-negative breast tumor therapeutic target. Cancer Cell 24:450–465PubMedCentralPubMedCrossRefGoogle Scholar
  92. 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 10:90–103PubMedCrossRefGoogle Scholar
  93. Turkanis SA, Karler R (1975) Influence of anticonvulsant cannabinoids on posttetanic potentiation at isolated bullfrog ganglia. Life Sci 17:569–578PubMedCrossRefGoogle Scholar
  94. Turner CE, Elsohly MA, Boeren EG (1980) Constituents of Cannabis sativa L. XVII. A review of the natural constituents. J Nat Prod 43:169–234PubMedCrossRefGoogle Scholar
  95. 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 144:1032–1036PubMedCentralPubMedCrossRefGoogle Scholar
  96. Velasco G, Galve-Roperh I, Sanchez C, Blazquez C, Guzman M (2004) Hypothesis: cannabinoid therapy for the treatment of gliomas? Neuropharmacology 47:315–323PubMedCrossRefGoogle Scholar
  97. Velasco G, Sanchez C, Guzman M (2012) Towards the use of cannabinoids as antitumour agents. Nat Rev Cancer 12:436–444PubMedCrossRefGoogle Scholar
  98. Ward SJ, McAllister SD, Kawamura R, Murase R, Neelakantan H, Walker EA (2014) Cannabidiol inhibits paclitaxel-induced neuropathic pain through 5-HT(1A) receptors without diminishing nervous system function or chemotherapy efficacy. Br J Pharmacol 171:636–645PubMedCentralPubMedCrossRefGoogle Scholar
  99. Wilson RI, Nicoll RA (2002) Endocannabinoid signaling in the brain. Science 296:678–682PubMedCrossRefGoogle Scholar
  100. Wondrak GT (2009) Redox-directed cancer therapeutics: molecular mechanisms and opportunities. Antioxid Redox Signal 11:3013–3069PubMedCentralPubMedCrossRefGoogle Scholar
  101. Yoshikawa M, Tsuchihashi K, Ishimoto T, Yae T, Motohara T, Sugihara E, Onishi N, Masuko T, Yoshizawa K, Kawashiri S, Mukai M, Asoda S, Kawana H, Nakagawa T, Saya H, Nagano O (2013) xCT inhibition depletes CD44v-expressing tumor cells that are resistant to EGFR-targeted therapy in head and neck squamous cell carcinoma. Cancer Res 73:1855–1866PubMedCrossRefGoogle Scholar
  102. Zhu HJ, Wang JS, Markowitz JS, Donovan JL, Gibson BB, Gefroh HA, Devane CL (2006) Characterization of P-glycoprotein inhibition by major cannabinoids from marijuana. J Pharmacol Exp Ther 317:850–857PubMedCrossRefGoogle Scholar
  103. Zuardi AW (2008) Cannabidiol: from an inactive cannabinoid to a drug with wide spectrum of action. Rev Bras Psiquiatr 30:271–280PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Sean D. McAllister
    • 1
  • Liliana Soroceanu
    • 1
  • Pierre-Yves Desprez
    • 1
  1. 1.California Pacific Medical Center Research InstituteSan FranciscoUSA

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