title: Geraniol Suppresses Angiogenesis by Downregulating Vascular Endothelial Growth Factor (VEGF)/VEGFR-2 Signaling.
abstract: Geraniol exerts several direct pharmacological effects on tumor cells and, thus, has been suggested as a promising anti-cancer compound. Because vascularization is a major precondition for tumor growth, we analyzed in this study the anti-angiogenic action of geraniol. In vitro, geraniol reduced the migratory activity of endothelial-like eEND2 cells. Western blot analyses further revealed that geraniol downregulates proliferating cell nuclear antigen (PCNA) and upregulates cleaved caspase-3 (Casp-3) expression in eEND2 cells. Moreover, geraniol blocked vascular endothelial growth factor (VEGF)/VEGFR-2 signal transduction, resulting in a suppression of downstream AKT and ERK signaling pathways. In addition, geraniol significantly reduced vascular sprout formation in a rat aortic ring assay. In vivo, geraniol inhibited the vascularization of CT26 tumors in dorsal skinfold chambers of BALB/c mice, which was associated with a smaller tumor size when compared to vehicle-treated controls. Immunohistochemical analyses confirmed a decreased number of Ki67-positive cells and CD31-positive microvessels with reduced VEGFR-2 expression within geraniol-treated tumors. Taken together, these findings indicate that geraniol targets multiple angiogenic mechanisms and, therefore, is an attractive candidate for the anti-angiogenic treatment of tumors.
authors.affiliation: Institute for Clinical & Experimental Surgery, University of Saarland, Homburg/Saar, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Wittig
authors.affiliation: Institute for Clinical & Experimental Surgery, University of Saarland, Homburg/Saar, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Scheuer
authors.affiliation: Institute for Clinical & Experimental Surgery, University of Saarland, Homburg/Saar, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Parakenings
authors.affiliation: Institute for Clinical & Experimental Surgery, University of Saarland, Homburg/Saar, Germany.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Menger
authors.affiliation: Institute for Clinical & Experimental Surgery, University of Saarland, Homburg/Saar, Germany.
authors.forename: Matthias W
authors.initials: MW
authors.lastname: Laschke
mesh_terms: D000080462:Acyclic Monoterpenes; D000818:Animals; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008297:Male; D008807:Mice, Inbred BALB C; D055806:Microvessels / Q000187:drug effects / Q000473:pathology; D009369:Neoplasms / Q000098:blood supply / Q000473:pathology / Q000503:physiopathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D022502:Stress Fibers / Q000187:drug effects / Q000378:metabolism; D013729:Terpenes / Q000494:pharmacology* / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
chemical_list: D000080462:Acyclic Monoterpenes; D013729:Terpenes; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; C007836:geraniol