title: Targeting multiple cannabinoid anti-tumour pathways with a resorcinol derivative leads to inhibition of advanced stages of breast cancer.
abstract: OBJECTIVE
  The psychoactive cannabinoid Δ(9) -tetrahydrocannabinol (THC) and the non-psychoactive cannabinoid cannabidiol (CBD) can both reduce cancer progression, each through distinct anti-tumour pathways. Our goal was to discover a compound that could efficiently target both cannabinoid anti-tumour pathways.
  
  
  METHODS
  To measure breast cancer cell proliferation/viability and invasion, MTT and Boyden chamber assays were used. Modulation of reactive oxygen species (ROS) and apoptosis was measured using dichlorodihydrofluorescein and annexin/propidium iodide, respectively, in combination with cell flow cytometry. Changes in protein levels were evaluated using Western analysis. Orthotopic and i.v. mouse models of breast cancer metastasis were used to test the activity of cannabinoids in vivo.
  
  
  RESULTS
  CBD reduced breast cancer metastasis in advanced stages of the disease as the direct result of down-regulating the transcriptional regulator Id1. However, this was associated with moderate increases in survival. We therefore screened for analogues that could co-target cannabinoid anti-tumour pathways (CBD- and THC-associated) and discovered the compound O-1663. This analogue inhibited Id1, produced a marked stimulation of ROS, up-regulated autophagy and induced apoptosis. Of all the compounds tested, it was the most potent at inhibiting breast cancer cell proliferation and invasion in culture and metastasis in vivo.
  
  
  CONCLUSIONS
  O-1663 prolonged survival in advanced stages of breast cancer metastasis. Developing compounds that can simultaneously target multiple cannabinoid anti-tumour pathways efficiently may provide a novel approach for the treatment of patients with metastatic breast cancer.
authors.affiliation: California Pacific Medical Center, Research Institute, San Francisco, CA, USA.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Murase
authors.forename: Rumi
authors.initials: R
authors.lastname: Kawamura
authors.forename: Eric
authors.initials: E
authors.lastname: Singer
authors.forename: Arash
authors.initials: A
authors.lastname: Pakdel
authors.forename: Pranamee
authors.initials: P
authors.lastname: Sarma
authors.forename: Jonathon
authors.initials: J
authors.lastname: Judkins
authors.forename: Eiman
authors.initials: E
authors.lastname: Elwakeel
authors.forename: Sonali
authors.initials: S
authors.lastname: Dayal
authors.forename: Esther
authors.initials: E
authors.lastname: Martinez-Martinez
authors.forename: Mukkanti
authors.initials: M
authors.lastname: Amere
authors.forename: Ramesh
authors.initials: R
authors.lastname: Gujjar
authors.forename: Anu
authors.initials: A
authors.lastname: Mahadevan
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Desprez
authors.forename: Sean D
authors.initials: SD
authors.lastname: McAllister
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002185:Cannabidiol / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000556:secondary; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D017382:Reactive Oxygen Species / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000378:metabolism; D012118:Resorcinols / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; C497453:ID1 protein, human; D051798:Inhibitor of Differentiation Protein 1; D017382:Reactive Oxygen Species; D043885:Receptor, Cannabinoid, CB2; D012118:Resorcinols; D002185:Cannabidiol