Geraniol Suppresses Angiogenesis by Downregulating Vascular Endothelial Growth Factor (VEGF)/VEGFR-2 Signaling

• Published in: PloS one Vol. 10; no. 7; p. e0131946
• Main Authors: Wittig, Christine, Scheuer, Claudia, Parakenings, Julia, Menger, Michael D., Laschke, Matthias W.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 08.07.2015; Public Library of Science (PLoS)
• Subjects: AKT protein; Alcohol; Analysis; Angiogenesis; Animals; Aorta; Apoptosis; Cancer; Caspase; Caspase-3; Cell culture; Cell cycle; Cell Line; Cell Movement - drug effects; Cell Proliferation - drug effects; Cell Survival - drug effects; Cellular signal transduction; Cytotoxicity; Down-Regulation - drug effects; Flow cytometry; Hemodynamics - drug effects; Humans; Immunohistochemistry; In Vitro Techniques; Male; Mice, Inbred BALB C; Microvessels - drug effects; Microvessels - pathology; Neoplasms - blood supply; Neoplasms - pathology; Neoplasms - physiopathology; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - pathology; Neovascularization, Physiologic - drug effects; Penicillin; Pharmacology; Proliferating cell nuclear antigen; Rats, Sprague-Dawley; Signal transduction; Signal Transduction - drug effects; Signaling; Stress Fibers - drug effects; Stress Fibers - metabolism; Surgery; Terpenes - pharmacology; Terpenes - therapeutic use; Tumor cells; Tumors; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - metabolism; Vascular Endothelial Growth Factor Receptor-2 - metabolism; Vascular endothelial growth factor receptors; Vascularization
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0131946

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.