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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 stress fiber formation and cell migration.A, B: Fluorescence microscopic images of eEND2 cells, which were exposed for 24h to vehicle (A) or 400μM geraniol (B). The cells were stained with Alexa Fluor 568-conjugated phalloidin (red) for the detection of the cytoskeleton. The cell nuclei were stained with Hoechst 33342 (blue). Note that in contrast to the geraniol-treated cells (B) many of the vehicle-treated cells exhibit typical actin stress fibers (A, arrows). Scale bars: 30μm. C-F: Light microscopic images of eEND2 cells, which have migrated through the 8μm pores of the PET filters of the transwell migration assay to the lower membrane surface. The cells were exposed for 24h to vehicle (C), 100μM (D), 200μM (E) or 400μM geraniol (F) and visualized by Diff-Quick staining. Scale bars: 70μm. G: Cell migration (cells/ROI) of eEND2 cells, which were exposed for 24h to different doses (100–400μM; n = 4) of geraniol or vehicle (control; n = 4), as assessed by the transwell migration assay. Means ± SEM. *P<0.05 vs. control.
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pone.0131946.g003: Geraniol action on stress fiber formation and cell migration.A, B: Fluorescence microscopic images of eEND2 cells, which were exposed for 24h to vehicle (A) or 400μM geraniol (B). The cells were stained with Alexa Fluor 568-conjugated phalloidin (red) for the detection of the cytoskeleton. The cell nuclei were stained with Hoechst 33342 (blue). Note that in contrast to the geraniol-treated cells (B) many of the vehicle-treated cells exhibit typical actin stress fibers (A, arrows). Scale bars: 30μm. C-F: Light microscopic images of eEND2 cells, which have migrated through the 8μm pores of the PET filters of the transwell migration assay to the lower membrane surface. The cells were exposed for 24h to vehicle (C), 100μM (D), 200μM (E) or 400μM geraniol (F) and visualized by Diff-Quick staining. Scale bars: 70μm. G: Cell migration (cells/ROI) of eEND2 cells, which were exposed for 24h to different doses (100–400μM; n = 4) of geraniol or vehicle (control; n = 4), as assessed by the transwell migration assay. Means ± SEM. *P<0.05 vs. control.

Mentions: The analysis of the cytoskeleton of eEND2 cells showed that geraniol treatment reduced the fraction of cells with actin stress fibers (36 ± 3%; n = 4; P<0.05) when compared to vehicle-treated controls (50 ± 3%; n = 4) (Fig 3A and 3B). Moreover, the migration rate of geraniol-treated eEND2 cells was significantly reduced in the transwell migration assay when compared to vehicle-treated controls (Fig 3C–3G).


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 stress fiber formation and cell migration.A, B: Fluorescence microscopic images of eEND2 cells, which were exposed for 24h to vehicle (A) or 400μM geraniol (B). The cells were stained with Alexa Fluor 568-conjugated phalloidin (red) for the detection of the cytoskeleton. The cell nuclei were stained with Hoechst 33342 (blue). Note that in contrast to the geraniol-treated cells (B) many of the vehicle-treated cells exhibit typical actin stress fibers (A, arrows). Scale bars: 30μm. C-F: Light microscopic images of eEND2 cells, which have migrated through the 8μm pores of the PET filters of the transwell migration assay to the lower membrane surface. The cells were exposed for 24h to vehicle (C), 100μM (D), 200μM (E) or 400μM geraniol (F) and visualized by Diff-Quick staining. Scale bars: 70μm. G: Cell migration (cells/ROI) of eEND2 cells, which were exposed for 24h to different doses (100–400μM; n = 4) of geraniol or vehicle (control; n = 4), as assessed by the transwell migration assay. 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.g003: Geraniol action on stress fiber formation and cell migration.A, B: Fluorescence microscopic images of eEND2 cells, which were exposed for 24h to vehicle (A) or 400μM geraniol (B). The cells were stained with Alexa Fluor 568-conjugated phalloidin (red) for the detection of the cytoskeleton. The cell nuclei were stained with Hoechst 33342 (blue). Note that in contrast to the geraniol-treated cells (B) many of the vehicle-treated cells exhibit typical actin stress fibers (A, arrows). Scale bars: 30μm. C-F: Light microscopic images of eEND2 cells, which have migrated through the 8μm pores of the PET filters of the transwell migration assay to the lower membrane surface. The cells were exposed for 24h to vehicle (C), 100μM (D), 200μM (E) or 400μM geraniol (F) and visualized by Diff-Quick staining. Scale bars: 70μm. G: Cell migration (cells/ROI) of eEND2 cells, which were exposed for 24h to different doses (100–400μM; n = 4) of geraniol or vehicle (control; n = 4), as assessed by the transwell migration assay. Means ± SEM. *P<0.05 vs. control.
Mentions: The analysis of the cytoskeleton of eEND2 cells showed that geraniol treatment reduced the fraction of cells with actin stress fibers (36 ± 3%; n = 4; P<0.05) when compared to vehicle-treated controls (50 ± 3%; n = 4) (Fig 3A and 3B). Moreover, the migration rate of geraniol-treated eEND2 cells was significantly reduced in the transwell migration assay when compared to vehicle-treated controls (Fig 3C–3G).

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