title: Cannabidiol enhances the inhibitory effects of delta9-tetrahydrocannabinol on human glioblastoma cell proliferation and survival.
abstract: The cannabinoid 1 (CB(1)) and cannabinoid 2 (CB(2)) receptor agonist Delta(9)-tetrahydrocannabinol (THC) has been shown to be a broad-range inhibitor of cancer in culture and in vivo, and is currently being used in a clinical trial for the treatment of glioblastoma. It has been suggested that other plant-derived cannabinoids, which do not interact efficiently with CB(1) and CB(2) receptors, can modulate the actions of Delta(9)-THC. There are conflicting reports, however, as to what extent other cannabinoids can modulate Delta(9)-THC activity, and most importantly, it is not clear whether other cannabinoid compounds can either potentiate or inhibit the actions of Delta(9)-THC. We therefore tested cannabidiol, the second most abundant plant-derived cannabinoid, in combination with Delta(9)-THC. In the U251 and SF126 glioblastoma cell lines, Delta(9)-THC and cannabidiol acted synergistically to inhibit cell proliferation. The treatment of glioblastoma cells with both compounds led to significant modulations of the cell cycle and induction of reactive oxygen species and apoptosis as well as specific modulations of extracellular signal-regulated kinase and caspase activities. These specific changes were not observed with either compound individually, indicating that the signal transduction pathways affected by the combination treatment were unique. Our results suggest that the addition of cannabidiol to Delta(9)-THC may improve the overall effectiveness of Delta(9)-THC in the treatment of glioblastoma in cancer patients.
authors.affiliation: California Pacific Medical Center Research Institute, San Francisco, California 94107, USA.
authors.forename: Jahan P
authors.initials: JP
authors.lastname: Marcu
authors.forename: Rigel T
authors.initials: RT
authors.lastname: Christian
authors.forename: Darryl
authors.initials: D
authors.lastname: Lau
authors.forename: Anne J
authors.initials: AJ
authors.lastname: Zielinski
authors.forename: Maxx P
authors.initials: MP
authors.lastname: Horowitz
authors.forename: Jasmine
authors.initials: J
authors.lastname: Lee
authors.forename: Arash
authors.initials: A
authors.lastname: Pakdel
authors.forename: Juanita
authors.initials: J
authors.lastname: Allison
authors.forename: Chandani
authors.initials: C
authors.lastname: Limbad
authors.forename: Dan H
authors.initials: DH
authors.lastname: Moore
authors.forename: Garret L
authors.initials: GL
authors.lastname: Yount
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Desprez
authors.forename: Sean D
authors.initials: SD
authors.lastname: McAllister
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002185:Cannabidiol / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D013759:Dronabinol / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005909:Glioblastoma / Q000201:enzymology / Q000473:pathology*; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002185:Cannabidiol; D020169:Caspases; D013759:Dronabinol; D020928:Mitogen-Activated Protein Kinases; D009363:Neoplasm Proteins; D017382:Reactive Oxygen Species; D043885:Receptor, Cannabinoid, CB2; C491643:NUPR1 protein, human