A cannabinoid quinone inhibits angiogenesis by targeting vascular endothelial cells.
Recent findings on the inhibition of angiogenesis and vascular endothelial cell proliferation by anthracycline antibiotics, which contain a quinone moiety, make this type of compound a very promising lead in cancer research/therapy. We have reported that a new cannabinoid anticancer quinone, cannabidiol hydroxyquinone (HU-331), is highly effective against tumor xenografts in nude mice. For evaluation of the antiangiogenic action of cannabinoid quinones, collagen-embedded rat aortic ring assay was used. The ability of cannabinoids to cause endothelial cell apoptosis was assayed by TUNEL staining and flow cytometry analysis. To examine the genes and pathways targeted by HU-331 in vascular endothelial cells, human cDNA microarrays and polymerase chain reaction were used. Immunostaining with anti-CD31 of tumors grown in nude mice served to indicate inhibition of tumor angiogenesis. HU-331 was found to be strongly antiangiogenic, significantly inhibiting angiogenesis at concentrations as low as 300 nM. HU-331 inhibited angiogenesis by directly inducing apoptosis of vascular endothelial cells without changing the expression of pro- and antiangiogenic cytokines and their receptors. A significant decrease in the total area occupied by vessels in HU-331-treated tumors was also observed. These data lead us to consider HU-331 to have high potential as a new antiangiogenic and anticancer drug.
Department of Medicinal Chemistry and Natural Products, Medical Faculty, The Hebrew University, Jerusalem 91120, Israel. natalya@md.huji.ac.il
Natalya M
NM
Kogan
Cristina
C
Blázquez
Luis
L
Alvarez
Ruth
R
Gallily
Michael
M
Schlesinger
Manuel
M
Guzmán
Raphael
R
Mechoulam
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000254:growth & development; D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones / Q000494:pharmacology*; D002185:Cannabidiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D002186:Cannabinoids / Q000494:pharmacology*; D002417:Cattle; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D015870:Gene Expression / Q000235:genetics; D019073:HT29 Cells; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000517:prevention & control; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000235:genetics; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D051381:Rats; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D016227:Benzoquinones; D002186:Cannabinoids; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; C073718:cannabidiol hydroxyquinone; D002185:Cannabidiol; C004532:quinone