title: Cannabidiol inhibits angiogenesis by multiple mechanisms.
abstract: OBJECTIVE
  Several studies have demonstrated anti-proliferative and pro-apoptotic actions of cannabinoids on various tumours, together with their anti-angiogenic properties. The non-psychoactive cannabinoid cannabidiol (CBD) effectively inhibits the growth of different types of tumours in vitro and in vivo and down-regulates some pro-angiogenic signals produced by glioma cells. As its anti-angiogenic properties have not been thoroughly investigated to date, and given its very favourable pharmacological and toxicological profile, here, we evaluated the ability of CBD to modulate tumour angiogenesis.
  
  
  METHODS
  Firstly, we evaluated the effect of CBD on human umbilical vein endothelial cell (HUVEC) proliferation and viability - through [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay and FACS analysis - and in vitro motility - both in a classical Boyden chamber test and in a wound-healing assay. We next investigated CBD effects on different angiogenesis-related proteins released by HUVECs, using an angiogenesis array kit and an ELISA directed at MMP2. Then we evaluated its effects on in vitro angiogenesis in treated HUVECs invading a Matrigel layer and in HUVEC spheroids embedded into collagen gels, and further characterized its effects in vivo using a Matrigel sponge model of angiogenesis in C57/BL6 mice.
  
  
  RESULTS
  CBD induced HUVEC cytostasis without inducing apoptosis, inhibited HUVEC migration, invasion and sprouting in vitro, and angiogenesis in vivo in Matrigel sponges. These effects were associated with the down-modulation of several angiogenesis-related molecules.
  
  
  CONCLUSIONS
  This study reveals that CBD inhibits angiogenesis by multiple mechanisms. Its dual effect on both tumour and endothelial cells supports the hypothesis that CBD has potential as an effective agent in cancer therapy.
authors.affiliation: Department of Biomedical, Computer and Communication Sciences, University of Insubria, Busto Arsizio (VA), Italy.
authors.forename: M
authors.initials: M
authors.lastname: Solinas
authors.forename: P
authors.initials: P
authors.lastname: Massi
authors.forename: A R
authors.initials: AR
authors.lastname: Cantelmo
authors.forename: M G
authors.initials: MG
authors.lastname: Cattaneo
authors.forename: R
authors.initials: R
authors.lastname: Cammarota
authors.forename: D
authors.initials: D
authors.lastname: Bartolini
authors.forename: V
authors.initials: V
authors.lastname: Cinquina
authors.forename: M
authors.initials: M
authors.lastname: Valenti
authors.forename: L M
authors.initials: LM
authors.lastname: Vicentini
authors.forename: D M
authors.initials: DM
authors.lastname: Noonan
authors.forename: A
authors.initials: A
authors.lastname: Albini
authors.forename: D
authors.initials: D
authors.lastname: Parolaro
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D002185:Cannabidiol / Q000494:pharmacology / Q000627:therapeutic use*; D002465:Cell Movement / Q000187:drug effects; D006493:Heparin; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000139:chemically induced / Q000188:drug therapy*; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A
chemical_list: D020533:Angiogenesis Inhibitors; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D002185:Cannabidiol; D006493:Heparin