Mechanisms of the antiangiogenic activity by the hop flavonoid xanthohumol: NF-kappaB and Akt as targets.
Xanthohumol (XN), the principal flavonoid of the hop plant (Humulus lupulus L.) and a constituent of beer, has been suggested to have potential cancer chemopreventive activities. We have observed that most cancer chemopreventive agents show antiangiogenic properties in vitro and in vivo, a concept we termed "angioprevention." Here we show for the first time that XN can inhibit growth of a vascular tumor in vivo. Histopathology and in vivo angiogenesis assays indicated that tumor angiogenesis inhibition was involved. Further, we show the mechanisms for its inhibition of angiogenesis in vivo and related endothelial cell activities in vitro. XN repressed both the NF-kappaB and Akt pathways in endothelial cells, indicating that components of these pathways are major targets in the molecular mechanism of XN. Moreover, using in vitro analyses, we show that XN interferes with several points in the angiogenic process, including inhibition of endothelial cell invasion and migration, growth, and formation of a network of tubular-like structures. Our results suggest that XN can be added to the expanding list of antiangiogenic chemopreventive drugs whose potential in cancer prevention and therapy should be evaluated.
Albini
Adriana
A
Molecular Oncology Laboratory, Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
Dell'Eva
Raffaella
R
Vené
Roberta
R
Ferrari
Nicoletta
N
Buhler
Donald R
DR
Noonan
Douglas M
DM
Fassina
Gianfranco
G
D016475:3T3 Cells / Q000378:metabolism; D000284:Administration, Oral; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002633:Chemotaxis / Q000187:drug effects; D003094:Collagen; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004338:Drug Combinations; D004354:Drug Screening Assays, Antitumor; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D004730:Endothelium, Vascular / Q000187:drug effects; D005419:Flavonoids; D006801:Humans; D027582:Humulus / Q000737:chemistry*; D020672:I-kappa B Proteins / Q000378:metabolism; D007797:Laminin; D051379:Mice; D008819:Mice, Nude; D009024:Morphogenesis / Q000187:drug effects; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009368:Neoplasm Transplantation; D010766:Phosphorylation / Q000187:drug effects; D011427:Propiophenones / Q000494:pharmacology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D011509:Proteoglycans; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D012514:Sarcoma, Kaposi / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology
D020533:Angiogenesis Inhibitors; D017077:Culture Media, Conditioned; D004338:Drug Combinations; D005419:Flavonoids; D020672:I-kappa B Proteins; D007797:Laminin; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D011427:Propiophenones; D011509:Proteoglycans; C059485:matrigel; D000072000:NF-KappaB Inhibitor alpha; D003094:Collagen; D051057:Proto-Oncogene Proteins c-akt; C104536:xanthohumol