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

Wittig C, Scheuer C, Parakenings J, Menger MD, Laschke MW - PLoS ONE (2015)

Bottom Line: In vitro, geraniol reduced the migratory activity of endothelial-like eEND2 cells.In addition, geraniol significantly reduced vascular sprout formation in a rat aortic ring assay.Immunohistochemical analyses confirmed a decreased number of Ki67-positive cells and CD31-positive microvessels with reduced VEGFR-2 expression within geraniol-treated tumors.

View Article: PubMed Central - PubMed

Affiliation: Institute for Clinical & Experimental Surgery, University of Saarland, Homburg/Saar, Germany.

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.

No MeSH data available.


Related in: MedlinePlus

Geraniol action on protein expression.A: Western blot analysis of PCNA, Casp-3 and VEGFR-2 protein expression (optical density (OD)*mm²) of eEND2 cells, which were exposed for 24h to vehicle (white bars; n = 3) or 200μM (grey bars; n = 3) and 400μM geraniol (black bars; n = 3). B: Western blot analysis of pAKT/AKT and pERK/ERK protein expression ratio of eEND2 cells, which were exposed for 24h to vehicle (white bars; n = 3) or 200μM (grey bars; n = 3) and 400μM geraniol (black bars; n = 3). Means ± SEM. *P<0.05 vs. control.
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pone.0131946.g004: Geraniol action on protein expression.A: Western blot analysis of PCNA, Casp-3 and VEGFR-2 protein expression (optical density (OD)*mm²) of eEND2 cells, which were exposed for 24h to vehicle (white bars; n = 3) or 200μM (grey bars; n = 3) and 400μM geraniol (black bars; n = 3). B: Western blot analysis of pAKT/AKT and pERK/ERK protein expression ratio of eEND2 cells, which were exposed for 24h to vehicle (white bars; n = 3) or 200μM (grey bars; n = 3) and 400μM geraniol (black bars; n = 3). Means ± SEM. *P<0.05 vs. control.

Mentions: We additionally examined the impact of geraniol treatment on the expression of marker proteins for cell proliferation, angiogenesis and apoptosis by Western blotting. We found that geraniol dose-dependently reduced the expression of PCNA and VEGFR-2 in eEND2 cells when compared to vehicle-treated controls (Fig 4A). In contrast, expression of the cleaved form of caspase-3 was elevated in eEND2 cells, which were exposed to geraniol (Fig 4A). These differences in protein expression were associated with a significantly reduced pAKT/AKT and pERK/ERK ratio (Fig 4B), indicating the suppression of VEGFR-2-induced phospho-regulated signaling pathways in geraniol-treated cells.


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

Wittig C, Scheuer C, Parakenings J, Menger MD, Laschke MW - PLoS ONE (2015)

Geraniol action on protein expression.A: Western blot analysis of PCNA, Casp-3 and VEGFR-2 protein expression (optical density (OD)*mm²) of eEND2 cells, which were exposed for 24h to vehicle (white bars; n = 3) or 200μM (grey bars; n = 3) and 400μM geraniol (black bars; n = 3). B: Western blot analysis of pAKT/AKT and pERK/ERK protein expression ratio of eEND2 cells, which were exposed for 24h to vehicle (white bars; n = 3) or 200μM (grey bars; n = 3) and 400μM geraniol (black bars; n = 3). Means ± SEM. *P<0.05 vs. control.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4496091&req=5

pone.0131946.g004: Geraniol action on protein expression.A: Western blot analysis of PCNA, Casp-3 and VEGFR-2 protein expression (optical density (OD)*mm²) of eEND2 cells, which were exposed for 24h to vehicle (white bars; n = 3) or 200μM (grey bars; n = 3) and 400μM geraniol (black bars; n = 3). B: Western blot analysis of pAKT/AKT and pERK/ERK protein expression ratio of eEND2 cells, which were exposed for 24h to vehicle (white bars; n = 3) or 200μM (grey bars; n = 3) and 400μM geraniol (black bars; n = 3). Means ± SEM. *P<0.05 vs. control.
Mentions: We additionally examined the impact of geraniol treatment on the expression of marker proteins for cell proliferation, angiogenesis and apoptosis by Western blotting. We found that geraniol dose-dependently reduced the expression of PCNA and VEGFR-2 in eEND2 cells when compared to vehicle-treated controls (Fig 4A). In contrast, expression of the cleaved form of caspase-3 was elevated in eEND2 cells, which were exposed to geraniol (Fig 4A). These differences in protein expression were associated with a significantly reduced pAKT/AKT and pERK/ERK ratio (Fig 4B), indicating the suppression of VEGFR-2-induced phospho-regulated signaling pathways in geraniol-treated cells.

Bottom Line: In vitro, geraniol reduced the migratory activity of endothelial-like eEND2 cells.In addition, geraniol significantly reduced vascular sprout formation in a rat aortic ring assay.Immunohistochemical analyses confirmed a decreased number of Ki67-positive cells and CD31-positive microvessels with reduced VEGFR-2 expression within geraniol-treated tumors.

View Article: PubMed Central - PubMed

Affiliation: Institute for Clinical & Experimental Surgery, University of Saarland, Homburg/Saar, Germany.

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.

No MeSH data available.


Related in: MedlinePlus