title: Perillyl alcohol is an angiogenesis inhibitor.
abstract: Aberrant angiogenesis is essential for the progression of solid tumors and hematological malignancies. Thus, antiangiogenic therapy is one of the most promising approaches to control cancer. In the present work, we examined the ability of perillyl alcohol (POH), a dietary monoterpene with well-established tumor chemopreventive and chemotherapeutic activity, to interfere with the process of angiogenesis. POH remarkably prevented new blood vessel growth in the in vivo chicken embryo chorioallantoic membrane assay and proved to be effective in inhibiting the morphogenic differentiation of cultured endothelial cells into capillary-like networks both in collagen gel and Matrigel models. In addition, POH reduced the cell number in a proliferation assay and induced apoptosis of endothelial cells as indicated by the POH-mediated increase of caspase-3 activity and DNA fragmentation. Consistent with the observed antisurvival effect, POH treatment resulted in a significant inhibition of Akt phosphorylation in endothelial cells. Finally, POH was able to differentially modulate the release of two important angiogenic regulators: vascular endothelial growth factor (VEGF) and angiopoietin 2 (Ang2). POH decreased the release of VEGF from cancer cells but stimulated the expression of Ang2 by endothelial cells, indicating that it might suppress neovascularization and induce vessel regression. Overall, these data underscore the antiangiogenic potential of POH and suggest that POH, in addition to its anticancer activity, may be an effective agent in the treatment of angiogenesis-dependent diseases.
authors.affiliation: Laboratory for Molecular Pharmacology, Department of Pharmacy, University of Patras, Patras, Greece 26504.
authors.forename: Heleni
authors.initials: H
authors.lastname: Loutrari
authors.forename: Maria
authors.initials: M
authors.lastname: Hatziapostolou
authors.forename: Vassoula
authors.initials: V
authors.lastname: Skouridou
authors.forename: Evangelia
authors.initials: E
authors.lastname: Papadimitriou
authors.forename: Charis
authors.initials: C
authors.lastname: Roussos
authors.forename: Fragiskos N
authors.initials: FN
authors.lastname: Kolisis
authors.forename: Andreas
authors.initials: A
authors.lastname: Papapetropoulos
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D042702:Angiopoietin-2 / Q000378:metabolism; D000818:Animals; D002417:Cattle; D002452:Cell Count; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D015870:Gene Expression / Q000187:drug effects; D039821:Monoterpenes / Q000494:pharmacology*; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D042702:Angiopoietin-2; D039821:Monoterpenes; D011518:Proto-Oncogene Proteins; D042461:Vascular Endothelial Growth Factor A; C032208:perillyl alcohol; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt