Cannabinoids: potential anticancer agents

Cannabinoids — the active components of Cannabis sativa and their derivatives — exert palliative effects in cancer patients by preventing nausea, vomiting and pain and by stimulating appetite. In addition, these compounds have been shown to inhibit the growth of tumour cells in culture and animal models by modulating key cell-signalling pathways. Cannabinoids are usually well tolerated, and do not produce the generalized toxic effects of conventional chemotherapies. So, could cannabinoids be used to develop new anticancer therapies?

[1]  C. Fowler,et al.  Serum-dependent effects of tamoxifen and cannabinoids upon C6 glioma cell viability. , 2000, Biochemical pharmacology.

[2]  A. Yamashita,et al.  2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. , 1995, Biochemical and biophysical research communications.

[3]  I. Galve-Roperh,et al.  De novo‐synthesized ceramide signals apoptosis in astrocytes via extracellular signal‐regulated kinase , 2000, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[4]  I. Galve-Roperh,et al.  Cannabinoids and cell fate. , 2002, Pharmacology & therapeutics.

[5]  D. Piomelli,et al.  Functional role of high-affinity anandamide transport, as revealed by selective inhibition. , 1997, Science.

[6]  J. Haseman,et al.  Toxicity and Carcinogenicity of Δ9-Tetrahydrocannabinol in Fischer Rats and B6C3F1 Mice , 1996 .

[7]  R. Mechoulam,et al.  Cannabinoids and brain injury: therapeutic implications. , 2002, Trends in molecular medicine.

[8]  G. Galloway,et al.  Abuse potential of dronabinol (Marinol). , 1998, Journal of psychoactive drugs.

[9]  J. Borrell,et al.  Cannabinoids Promote Oligodendrocyte Progenitor Survival: Involvement of Cannabinoid Receptors and Phosphatidylinositol-3 Kinase/Akt Signaling , 2002, The Journal of Neuroscience.

[10]  M. Glass,et al.  Concurrent Stimulation of Cannabinoid Cb1 and Dopamine D2 Receptors Augments Camp Accumulation in Striatal Neurons: Evidence for a G S Linkage to the Cb1 Receptor , 1997 .

[11]  S. Mancham,et al.  Anandamide, a natural ligand for the peripheral cannabinoid receptor is a novel synergistic growth factor for hematopoietic cells. , 1997, Blood.

[12]  T. Bonner,et al.  Structure of a cannabinoid receptor and functional expression of the cloned cDNA , 1990, Nature.

[13]  L. Petrocellis,et al.  The endogenous cannabinoid anandamide inhibits human breast cancer cell proliferation. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[14]  P. Novotny,et al.  Phase III clinical trial evaluating low-molecular weight heparin (LMWH) in patients with advanced cancer: A North Central Cancer Treatment Group study , 2005 .

[15]  G. Stein,et al.  Influence of delta9-tetrahydrocannabinol on cell proliferation and macromolecular biosynthesis in human cells. , 1978, Biochemical pharmacology.

[16]  Li Zhu,et al.  Δ-9-Tetrahydrocannabinol Inhibits Antitumor Immunity by a CB2 Receptor-Mediated, Cytokine-Dependent Pathway1 , 2000, The Journal of Immunology.

[17]  G. Velasco,et al.  Mechanism of extracellular signal-regulated kinase activation by the CB(1) cannabinoid receptor. , 2002, Molecular pharmacology.

[18]  A. M. Sánchez,et al.  Activation of phosphoinositide 3-kinase/PKB pathway by CB(1) and CB(2) cannabinoid receptors expressed in prostate PC-3 cells. Involvement in Raf-1 stimulation and NGF induction. , 2003, Cellular signalling.

[19]  A. Howlett,et al.  The CB(1) cannabinoid receptor juxtamembrane C-terminal peptide confers activation to specific G proteins in brain. , 2000, Molecular pharmacology.

[20]  J. Manzanares,et al.  Pharmacological and biochemical interactions between opioids and cannabinoids. , 1999, Trends in pharmacological sciences.

[21]  P. Casellas,et al.  A Selective Inverse Agonist for Central Cannabinoid Receptor Inhibits Mitogen-activated Protein Kinase Activation Stimulated by Insulin or Insulin-like Growth Factor 1 , 1997, The Journal of Biological Chemistry.

[22]  R. Kaiko,et al.  Oral morphine and respiratory function amongst hospice inpatients with advanced cancer , 2003, Supportive Care in Cancer.

[23]  Franjo Grotenhermen,et al.  Pharmacokinetics and Pharmacodynamics of Cannabinoids , 2003, Clinical pharmacokinetics.

[24]  Michael T. Fisher,et al.  Targeting CB2 cannabinoid receptors as a novel therapy to treat malignant lymphoblastic disease. , 2002, Blood.

[25]  Raphael Mechoulam,et al.  Cannabidiol: An Overview of Some Pharmacological Aspects , 2002, Journal of clinical pharmacology.

[26]  Dawn Carroll,et al.  Cannabinoids for control of chemotherapy induced nausea and vomiting: quantitative systematic review , 2001, BMJ : British Medical Journal.

[27]  M. L. de Ceballos,et al.  Inhibition of glioma growth in vivo by selective activation of the CB(2) cannabinoid receptor. , 2001, Cancer research.

[28]  P. Casellas,et al.  Cannabinoids enhance human B‐cell growth at low nanomolar concentrations , 1995, FEBS letters.

[29]  C. Sawyers,et al.  The phosphatidylinositol 3-Kinase–AKT pathway in human cancer , 2002, Nature Reviews Cancer.

[30]  D. Piomelli,et al.  A second endogenous cannabinoid that modulates long-term potentiation , 1997, Nature.

[31]  D. Cota,et al.  Endogenous cannabinoid system as a modulator of food intake , 2003, International Journal of Obesity.

[32]  D. Baker,et al.  The therapeutic potential of cannabis in multiple sclerosis , 2003, Expert opinion on investigational drugs.

[33]  M. Vitale,et al.  Control by the endogenous cannabinoid system of ras oncogene‐dependent tumor growth , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[34]  I. Galve-Roperh,et al.  Involvement of the cAMP/protein kinase A pathway and of mitogen‐activated protein kinase in the anti‐proliferative effects of anandamide in human breast cancer cells , 1999, FEBS letters.

[35]  P. Novotny,et al.  Dronabinol versus megestrol acetate versus combination therapy for cancer-associated anorexia: a North Central Cancer Treatment Group study. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[36]  M. Herkenham,et al.  International Union of Pharmacology. XXVII. Classification of Cannabinoid Receptors , 2002, Pharmacological Reviews.

[37]  R. Maldonado,et al.  Cannabinoid Addiction: Behavioral Models and Neural Correlates , 2002, The Journal of Neuroscience.

[38]  P. Robson,et al.  Therapeutic aspects of cannabis and cannabinoids , 2001, British Journal of Psychiatry.

[39]  M. Cabot,et al.  Synergistic cytotoxicity in solid tumor cell lines between N-(4-hydroxyphenyl)retinamide and modulators of ceramide metabolism. , 2000, Journal of the National Cancer Institute.

[40]  R. Pertwee.  Cannabinoid receptor ligands: clinical and neuropharmacological considerations, relevant to future drug discovery and development , 2000, Expert opinion on investigational drugs.

[41]  T. Bisogno,et al.  Suppression of Nerve Growth Factor Trk Receptors and Prolactin Receptors by Endocannabinoids Leads to Inhibition of Human Breast and Prostate Cancer Cell Proliferation* , 2022 .

[42]  A. Makriyannis,et al.  Functional CB 1 cannabinoid receptors in human vascular endothelial cells , 2022 .

[43]  Yusuf A. Hannun,et al.  The Ceramide-centric Universe of Lipid-mediated Cell Regulation: Stress Encounters of the Lipid Kind* , 2002, The Journal of Biological Chemistry.

[44]  I. Galve-Roperh,et al.  Control of the cell survival/death decision by cannabinoids , 2001, Journal of Molecular Medicine.

[45]  D. Walsh,et al.  A Phase II Study of Delta-9-Tetrahydrocannabinol for Appetite Stimulation in Cancer-Associated Anorexia , 1994, Journal of palliative care.

[46]  Martin Koltzenburg,et al.  Molecular mechanisms of cancer pain , 2002, Nature Reviews Cancer.

[47]  L. Iversen,et al.  Cannabinoids: a real prospect for pain relief? , 2002, Current opinion in pharmacology.

[48]  P. Soubrié,et al.  The cannabinoid CB1 receptor antagonist SR141716 increases Acrp30 mRNA expression in adipose tissue of obese fa/fa rats and in cultured adipocyte cells. , 2003, Molecular pharmacology.

[49]  I. Galve-Roperh,et al.  Ceramide: a new second messenger of cannabinoid action. , 2001, Trends in pharmacological sciences.

[50]  G. Velasco,et al.  De novo-synthesized ceramide is involved in cannabinoid-induced apoptosis. , 2002, The Biochemical journal.

[51]  R. Kolesnick.  The therapeutic potential of modulating the ceramide/sphingomyelin pathway. , 2002, The Journal of clinical investigation.

[52]  Darrell R. Abernethy,et al.  International Union of Pharmacology: Approaches to the Nomenclature of Voltage-Gated Ion Channels , 2003, Pharmacological Reviews.

[53]  P. Casellas,et al.  Activation of mitogen-activated protein kinases by stimulation of the central cannabinoid receptor CB1. , 1995, The Biochemical journal.

[54]  Soichi Obara,et al.  Anandamide induces apoptosis of PC‐12 cells: involvement of superoxide and caspase‐3 , 2000, FEBS letters.

[55]  Z. Vogel,et al.  Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. , 1995, Biochemical pharmacology.

[56]  J. Ludovic Croxford,et al.  Therapeutic Potential of Cannabinoids in CNS Disease , 2003, CNS drugs.

[57]  V. Marzo,et al.  Targeting the endocannabinoid system in cancer therapy: A call for further research , 2002, Nature Medicine.

[58]  R. DePinho,et al.  Malignant glioma: genetics and biology of a grave matter. , 2001, Genes & development.

[59]  G. Velasco,et al.  The CB1 cannabinoid receptor is coupled to the activation of protein kinase B/Akt. , 2000, The Biochemical journal.

[60]  D. Lewis,et al.  The CB1 Cannabinoid Receptor Can Sequester G-Proteins, Making Them Unavailable to Couple to Other Receptors , 1999, The Journal of Neuroscience.

[61]  J. Walker,et al.  Cannabinoid analgesia. , 2002, Pharmacology & therapeutics.

[62]  J. Folkman,et al.  Clinical translation of angiogenesis inhibitors , 2002, Nature Reviews Cancer.

[63]  M. Mimeault,et al.  Anti‐proliferative and apoptotic effects of anandamide in human prostatic cancer cell lines: Implication of epidermal growth factor receptor down‐regulation and ceramide production , 2003, The Prostate.

[64]  C. Flachskamm,et al.  The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis. , 2003, The Journal of clinical investigation.

[65]  R. Nicoll,et al.  Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses , 2001, Nature.

[66]  G. Portella,et al.  Inhibitory effects of cannabinoid CB1 receptor stimulation on tumor growth and metastatic spreading: actions on signals involved in angiogenesis and metastasis , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[67]  R. Mechoulam,et al.  Isolation, Structure, and Partial Synthesis of an Active Constituent of Hashish , 1964 .

[68]  I. Galve-Roperh,et al.  The CB(1) cannabinoid receptor is coupled to the activation of c-Jun N-terminal kinase. , 2000, Molecular pharmacology.

[69]  O. Mock.  [Animals and humans]. , 1967, Therapie der Gegenwart.

[70]  I. Díaz-Laviada,et al.  Δ9‐Tetrahydrocannabinol induces apoptosis in human prostate PC‐3 cells via a receptor‐independent mechanism , 1999, FEBS letters.

[71]  T. Jang,et al.  Antitumor effects of ajulemic acid (CT3), a synthetic non-psychoactive cannabinoid. , 2001, Biochemical pharmacology.

[72]  D. Lehmann,et al.  γ-Irradiation Enhances Apoptosis Induced by Cannabidiol, a Non-psychotropic Cannabinoid, in Cultured HL-60 Myeloblastic Leukemia Cells , 2003, Leukemia & lymphoma.

[73]  D. Piomelli,et al.  Control of pain initiation by endogenous cannabinoids , 1998, Nature.

[74]  J. Girault,et al.  Regulation of Extracellular Signal-Regulated Kinase by Cannabinoids in Hippocampus , 2003, The Journal of Neuroscience.

[75]  C. Felder,et al.  The endocannabinoid nervous system: unique opportunities for therapeutic intervention. , 2001, Pharmacology & therapeutics.

[76]  M. Herkenham,et al.  Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study , 1991, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[77]  B. Martin,et al.  Cannabis: pharmacology and toxicology in animals and humans. , 1996, Addiction.

[78]  P. Brachet,et al.  Δ9‐Tetrahydrocannabinol induces apoptosis in C6 glioma cells , 1998 .

[79]  Z. Vogel,et al.  Cannabinol derivatives: binding to cannabinoid receptors and inhibition of adenylylcyclase. , 1997, Journal of medicinal chemistry.

[80]  M. Tramèr,et al.  Are cannabinoids an effective and safe treatment option in the management of pain? A qualitative systematic review , 2001, BMJ : British Medical Journal.

[81]  A. Planas,et al.  Inhibition of tumor angiogenesis by cannabinoids , 2002 .

[82]  M. Kathmann,et al.  Modulation of transmitter release via presynaptic cannabinoid receptors. , 2001, Trends in pharmacological sciences.

[83]  J. Schwartz,et al.  Formation and inactivation of endogenous cannabinoid anandamide in central neurons , 1994, Nature.

[84]  M. Roth,et al.  Respiratory and Immunologic Consequences of Marijuana Smoking , 2002, Journal of clinical pharmacology.

[85]  T. Vanderah,et al.  CB2 cannabinoid receptor agonists: pain relief without psychoactive effects? , 2003, Current opinion in pharmacology.

[86]  D. Louis,et al.  Focus on central nervous system neoplasia. , 2002, Cancer cell.

[87]  P. Casellas,et al.  Signaling pathway associated with stimulation of CB2 peripheral cannabinoid receptor. Involvement of both mitogen-activated protein kinase and induction of Krox-24 expression. , 1996, European journal of biochemistry.

[88]  A. Izzo,et al.  Cannabinoids for gastrointestinal diseases: potential therapeutic applications , 2003, Expert opinion on investigational drugs.

[89]  I. Galve-Roperh,et al.  The Endocannabinoid Anandamide Inhibits Neuronal Progenitor Cell Differentiation through Attenuation of the Rap1/B-Raf/ERK Pathway* , 2002, The Journal of Biological Chemistry.

[90]  M. Saraste,et al.  FEBS Lett , 2000 .

[91]  D. Gibson,et al.  Isolation and structure of a brain constituent that binds to the cannabinoid receptor. , 1992, Science.

[92]  M. L. de Ceballos,et al.  Cannabinoids Protect Astrocytes from Ceramide-induced Apoptosis through the Phosphatidylinositol 3-Kinase/Protein Kinase B Pathway* , 2002, The Journal of Biological Chemistry.

[93]  I. Galve-Roperh,et al.  The CB1 Cannabinoid Receptor Is Coupled to the Activation of c-Jun N-Terminal Kinase , 2000 .

[94]  R. Noyes,et al.  The analgesic properties of delta‐9‐tetrahydrocannabinol and codeine , 1975, Clinical pharmacology and therapeutics.

[95]  Alexander J Stokes,et al.  Differential Roles of CB1 and CB2 Cannabinoid Receptors in Mast Cells1 , 2003, The Journal of Immunology.

[96]  S. Munro,et al.  Molecular characterization of a peripheral receptor for cannabinoids , 1993, Nature.

[97]  I. Galve-Roperh,et al.  Involvement of sphingomyelin hydrolysis and the mitogen-activated protein kinase cascade in the Delta9-tetrahydrocannabinol-induced stimulation of glucose metabolism in primary astrocytes. , 1998, Molecular pharmacology.

[98]  J. Girault,et al.  Cannabinoids activate p38 mitogen‐activated protein kinases through CB1 receptors in hippocampus , 2001, Journal of neurochemistry.

[99]  T. Klein,et al.  Delta9-tetrahydrocannabinol induces apoptosis in macrophages and lymphocytes: involvement of Bcl-2 and caspase-1. , 1998, The Journal of pharmacology and experimental therapeutics.

[100]  G. Melino,et al.  Anandamide Induces Apoptosis in Human Cells via Vanilloid Receptors , 2000, The Journal of Biological Chemistry.

[101]  M. Cortés,et al.  Anti-tumoral action of cannabinoids: Involvement of sustained ceramide accumulation and extracellular signal-regulated kinase activation , 2000, Nature Medicine.

[102]  D. Piomelli,et al.  A Peripheral Mechanism for CB1 Cannabinoid Receptor-Dependent Modulation of Feeding , 2002, The Journal of Neuroscience.

[103]  E. Berry,et al.  Tetrahydrocannabinol and endocannabinoids in feeding and appetite. , 2002, Pharmacology & therapeutics.

[104]  H. Bönisch,et al.  Direct inhibition by cannabinoids of human 5‐HT3A receptors: probable involvement of an allosteric modulatory site , 2002, British journal of pharmacology.

[105]  R. Carchman,et al.  Antineoplastic activity of cannabinoids. , 1975, Journal of the National Cancer Institute.

[106]  D. Walsh,et al.  Established and potential therapeutic applications of cannabinoids in oncology , 2003, Supportive Care in Cancer.

[107]  F. Blanco,et al.  Anadamide, an endogenous cannabinoid receptor agonist inhibits lymphocyte proliferation and induces apoptosis , 1994, Journal of Neuroimmunology.

[108]  D. Piomelli,et al.  The endocannabinoid system as a target for therapeutic drugs. , 2000, Trends in pharmacological sciences.

[109]  I. Galve-Roperh,et al.  The CB(1) cannabinoid receptor of astrocytes is coupled to sphingomyelin hydrolysis through the adaptor protein fan. , 2001, Molecular pharmacology.

[110]  M. Yamakuchi,et al.  ASK1–p38 MAPK/JNK signaling cascade mediates anandamide‐induced PC12 cell death , 2003, Journal of neurochemistry.

[111]  A. Makriyannis,et al.  Functional CB1 cannabinoid receptors in human vascular endothelial cells. , 2000, The Biochemical journal.

[112]  M. Karin,et al.  Mammalian MAP kinase signalling cascades , 2001, Nature.

[113]  Stephen P. Mayfield,et al.  Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides , 1996, Nature.

[114]  Cristina Blázquez,et al.  Inhibition of skin tumor growth and angiogenesis in vivo by activation of cannabinoid receptors. , 2003, The Journal of clinical investigation.

[115]  N. Radin.  Killing tumours by ceramide-induced apoptosis: a critique of available drugs. , 2003, The Biochemical journal.