Phenoxodiol, an experimental anticancer drug, shows potent antiangiogenic properties in addition to its antitumour effects.
Phenoxodiol (2H-1-benzopyran-7-0,1, 3-[4-hydroxyphenyl], PXD) is a synthetic analogue of the naturally-occurring plant isoflavone and anticancer agent, genistein. PXD directly induces mitotic arrest and apoptosis in most cancer cells and is currently undergoing clinical trials, as a chemotherapeutic in ovarian and prostate cancers. We show here that PXD also exhibits potent antiangiogenic properties. Thus, it inhibited endothelial cell proliferation, migration and capillary tube formation and inhibited expression of the matrix metalloproteinase MMP-2, a major matrix degrading enzyme. Importantly, we demonstrate that PXD is functional in vivo since it inhibited the extent of capillary tube invasion in an in vivo model of angiogenesis. We show that phenoxodiol inhibits hallmarks of endothelial cell activation, namely TNF or IL-1 induced E-selectin and VCAM-1 expression and IL-8 secretion. However, PXD had no effect on unstimulated endothelial cells. We also describe that PXD inhibits the lipid kinase sphingosine kinase, which recently has been implicated in endothelial cell activation and angiogenesis as well as oncogenesis. Thus, our results suggest that PXD may be an effective anticancer drug targeting the two drivers of tumour growth--the proliferation of the tumour cells themselves and the angiogenic and inflammatory stimulation of the vasculature.
Gamble
Jennifer R
JR
Division of Human Immunology, Hanson Institute, Institute of Medical and Veterinary Science, and Division of Human Immunology, the University of Adelaide 5000, Australia. Jennifer.Gamble@imvs.sa.gov.au
Xia
Pu
P
Hahn
Christopher N
CN
Drew
Jenny J
JJ
Drogemuller
Christopher J
CJ
Brown
David
D
Vadas
Mathew A
MA
D000818:Animals; D002196:Capillaries / Q000166:cytology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D005260:Female; D006801:Humans; D007249:Inflammation; D007529:Isoflavones / Q000494:pharmacology*; D051379:Mice; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy; D009389:Neovascularization, Pathologic; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000378:metabolism; D014470:Umbilical Cord / Q000098:blood supply; D000099157:Sphingosine Kinase
D007529:Isoflavones; D017853:Phosphotransferases (Alcohol Group Acceptor); D000099157:Sphingosine Kinase; C471183:phenoxodiol