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.
Highlights
Angiogenesis, i.e. the formation of new blood vessels from pre-existing ones, is a key process in tumor pathogenesis
In a first step we examined the effect of different doses of geraniol on the viability of eEND2 cells by means of a Water-soluble tetrazolium (WST)-1 assay
Treatment of the cells in this dose range only showed a significant Lactate dehydrogenase (LDH) release into the culture medium at a geraniol concentration of 400μM (Fig 1B). The extent of this LDH release (~10%) was rather low. These findings were confirmed by flow cytometric analyses of propidium iodide (PI)- and annexin V-stained eEND2 cells, which were exposed to 200 or 400μM geraniol (Fig 1C–1H)
Summary
Angiogenesis, i.e. the formation of new blood vessels from pre-existing ones, is a key process in tumor pathogenesis. Growing tumors are crucially dependent on an adequate blood supply, providing them with oxygen and essential nutrients [1]. A newly developing tumor microvasculature enables metastatically-competent cells to depart from the primary tumor site and colonize initially unaffected organs [2]. Based on these considerations, antiangiogenic therapy has rapidly evolved within the last three decades and is an integral component of current standard treatment regimens in clinical oncology [3, 4]. There is a continuous search for novel compounds, which suppress angiogenesis and exhibit a tolerable side effect profile.
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