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Quercetin inhibits angiogenesis mediated human prostate tumor growth by targeting VEGFR- 2 regulated AKT/mTOR/P70S6K signaling pathways.

Pratheeshkumar P, Budhraja A, Son YO, Wang X, Zhang Z, Ding S, Wang L, Hitron A, Lee JC, Xu M, Chen G, Luo J, Shi X - PLoS ONE (2012)

Bottom Line: Quercetin (20 mg/kg/d) significantly reduced the volume and the weight of solid tumors in prostate xenograft mouse model, indicating that quercetin inhibited tumorigenesis by targeting angiogenesis.Furthermore, quercetin reduced the cell viability and induced apoptosis in prostate cancer cells, which were correlated with the downregulation of AKT, mTOR and P70S6K expressions.Collectively the findings in the present study suggest that quercetin inhibits tumor growth and angiogenesis by targeting VEGF-R2 regulated AKT/mTOR/P70S6K signaling pathway, and could be used as a potential drug candidate for cancer therapy.

View Article: PubMed Central - PubMed

Affiliation: Graduate Center for Toxicology, College of Medicine, University of Kentucky, Lexington, Kentucky, United States of America.

ABSTRACT
Angiogenesis is a crucial step in the growth and metastasis of cancers, since it enables the growing tumor to receive oxygen and nutrients. Cancer prevention using natural products has become an integral part of cancer control. We studied the antiangiogenic activity of quercetin using ex vivo, in vivo and in vitro models. Rat aortic ring assay showed that quercetin at non-toxic concentrations significantly inhibited microvessel sprouting and exhibited a significant inhibition in the proliferation, migration, invasion and tube formation of endothelial cells, which are key events in the process of angiogenesis. Most importantly, quercetin treatment inhibited ex vivo angiogenesis as revealed by chicken egg chorioallantoic membrane assay (CAM) and matrigel plug assay. Western blot analysis showed that quercetin suppressed VEGF induced phosphorylation of VEGF receptor 2 and their downstream protein kinases AKT, mTOR, and ribosomal protein S6 kinase in HUVECs. Quercetin (20 mg/kg/d) significantly reduced the volume and the weight of solid tumors in prostate xenograft mouse model, indicating that quercetin inhibited tumorigenesis by targeting angiogenesis. Furthermore, quercetin reduced the cell viability and induced apoptosis in prostate cancer cells, which were correlated with the downregulation of AKT, mTOR and P70S6K expressions. Collectively the findings in the present study suggest that quercetin inhibits tumor growth and angiogenesis by targeting VEGF-R2 regulated AKT/mTOR/P70S6K signaling pathway, and could be used as a potential drug candidate for cancer therapy.

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Quercetin inhibits the VEGF induced cell proliferation in HUVECs.(a) Chemical structure of quercetin. (b) Effect of quercetin on HUVECs viability in culture. HUVECs (5000 cells/well) were plated in a 96 well titer plate with different concentrations of quercetin and incubated for 48 h. Relative cell viability was determined by MTT assay. Values are means ± SD (mean of triplicate). *p<0.05 denotes a statistically significant difference from untreated controls. (c) Quercetin inhibits the VEGF induced proliferation of endothelial cells. HUVECs (5000 cells/well) in 96-well flat bottomed titer plate with different concentrations of quercetin and VEGF and incubated for 24 h. Relative cell proliferation was determined by MTT assay. Values are means ± SD (mean of triplicate). *p<0.05 denotes a statistically significant difference from untreated controls; #p<0.05 denotes a statistically significant difference from VEGF control.
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pone-0047516-g001: Quercetin inhibits the VEGF induced cell proliferation in HUVECs.(a) Chemical structure of quercetin. (b) Effect of quercetin on HUVECs viability in culture. HUVECs (5000 cells/well) were plated in a 96 well titer plate with different concentrations of quercetin and incubated for 48 h. Relative cell viability was determined by MTT assay. Values are means ± SD (mean of triplicate). *p<0.05 denotes a statistically significant difference from untreated controls. (c) Quercetin inhibits the VEGF induced proliferation of endothelial cells. HUVECs (5000 cells/well) in 96-well flat bottomed titer plate with different concentrations of quercetin and VEGF and incubated for 24 h. Relative cell proliferation was determined by MTT assay. Values are means ± SD (mean of triplicate). *p<0.05 denotes a statistically significant difference from untreated controls; #p<0.05 denotes a statistically significant difference from VEGF control.

Mentions: Natural products are a tremendous source of active therapeutic agents, including anticancer agents. Cancer prevention using natural products has become an integral part of cancer control. Phytochemicals are potential novel leads for developing antiangiogenic drugs [11], [12]. Flavonoids are polyphenolic substances, widely distributed in almost every food plant, that possess antiviral, antimicrobial, anti-inflammatory, anti-allergic, anti-thrombotic, antimutagenic, antineoplasic, and cytoprotective effects on different cell types, both in animal and human models [13]. Epidemiologic studies have suggested that high consumption of flavonoids may be associated with decreased risk of several types of cancer [14]. Quercetin (Quer) (Fig. 1a) is found in a variety of plant-based foods such as red onions, apples, tea (Camelia sinensis), broccoli, capers, lovage, parsley, red grapes and a number of berries [15]. The potential chemopreventive effects of quercetin have been attributed to various mechanisms including its anti-oxidative activity as well as its capacity to inhibit enzymes that activate carcinogens, to modify signal transduction pathways, and to interact with and regulate cell receptors and other proteins [16]. In the present study, we analyzed the effect of quercetin on the inhibition of tumor specific angiogenesis in vivo as well as in vitro models. We found that quercetin can inhibit VEGF induced chemotactic migration, invasion, proliferation, and tube formation of HUVECs by suppressing VEGFR-2-regulated AKT/mTOR/P70S6K activation. Quercetin also blocks micro-vessel out growth in rat aortic ring and vascular density in CAM. Moreover, quercetin inhibits cancer growth and angiogenesis in human prostate xenograft mouse model.


Quercetin inhibits angiogenesis mediated human prostate tumor growth by targeting VEGFR- 2 regulated AKT/mTOR/P70S6K signaling pathways.

Pratheeshkumar P, Budhraja A, Son YO, Wang X, Zhang Z, Ding S, Wang L, Hitron A, Lee JC, Xu M, Chen G, Luo J, Shi X - PLoS ONE (2012)

Quercetin inhibits the VEGF induced cell proliferation in HUVECs.(a) Chemical structure of quercetin. (b) Effect of quercetin on HUVECs viability in culture. HUVECs (5000 cells/well) were plated in a 96 well titer plate with different concentrations of quercetin and incubated for 48 h. Relative cell viability was determined by MTT assay. Values are means ± SD (mean of triplicate). *p<0.05 denotes a statistically significant difference from untreated controls. (c) Quercetin inhibits the VEGF induced proliferation of endothelial cells. HUVECs (5000 cells/well) in 96-well flat bottomed titer plate with different concentrations of quercetin and VEGF and incubated for 24 h. Relative cell proliferation was determined by MTT assay. Values are means ± SD (mean of triplicate). *p<0.05 denotes a statistically significant difference from untreated controls; #p<0.05 denotes a statistically significant difference from VEGF control.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3475699&req=5

pone-0047516-g001: Quercetin inhibits the VEGF induced cell proliferation in HUVECs.(a) Chemical structure of quercetin. (b) Effect of quercetin on HUVECs viability in culture. HUVECs (5000 cells/well) were plated in a 96 well titer plate with different concentrations of quercetin and incubated for 48 h. Relative cell viability was determined by MTT assay. Values are means ± SD (mean of triplicate). *p<0.05 denotes a statistically significant difference from untreated controls. (c) Quercetin inhibits the VEGF induced proliferation of endothelial cells. HUVECs (5000 cells/well) in 96-well flat bottomed titer plate with different concentrations of quercetin and VEGF and incubated for 24 h. Relative cell proliferation was determined by MTT assay. Values are means ± SD (mean of triplicate). *p<0.05 denotes a statistically significant difference from untreated controls; #p<0.05 denotes a statistically significant difference from VEGF control.
Mentions: Natural products are a tremendous source of active therapeutic agents, including anticancer agents. Cancer prevention using natural products has become an integral part of cancer control. Phytochemicals are potential novel leads for developing antiangiogenic drugs [11], [12]. Flavonoids are polyphenolic substances, widely distributed in almost every food plant, that possess antiviral, antimicrobial, anti-inflammatory, anti-allergic, anti-thrombotic, antimutagenic, antineoplasic, and cytoprotective effects on different cell types, both in animal and human models [13]. Epidemiologic studies have suggested that high consumption of flavonoids may be associated with decreased risk of several types of cancer [14]. Quercetin (Quer) (Fig. 1a) is found in a variety of plant-based foods such as red onions, apples, tea (Camelia sinensis), broccoli, capers, lovage, parsley, red grapes and a number of berries [15]. The potential chemopreventive effects of quercetin have been attributed to various mechanisms including its anti-oxidative activity as well as its capacity to inhibit enzymes that activate carcinogens, to modify signal transduction pathways, and to interact with and regulate cell receptors and other proteins [16]. In the present study, we analyzed the effect of quercetin on the inhibition of tumor specific angiogenesis in vivo as well as in vitro models. We found that quercetin can inhibit VEGF induced chemotactic migration, invasion, proliferation, and tube formation of HUVECs by suppressing VEGFR-2-regulated AKT/mTOR/P70S6K activation. Quercetin also blocks micro-vessel out growth in rat aortic ring and vascular density in CAM. Moreover, quercetin inhibits cancer growth and angiogenesis in human prostate xenograft mouse model.

Bottom Line: Quercetin (20 mg/kg/d) significantly reduced the volume and the weight of solid tumors in prostate xenograft mouse model, indicating that quercetin inhibited tumorigenesis by targeting angiogenesis.Furthermore, quercetin reduced the cell viability and induced apoptosis in prostate cancer cells, which were correlated with the downregulation of AKT, mTOR and P70S6K expressions.Collectively the findings in the present study suggest that quercetin inhibits tumor growth and angiogenesis by targeting VEGF-R2 regulated AKT/mTOR/P70S6K signaling pathway, and could be used as a potential drug candidate for cancer therapy.

View Article: PubMed Central - PubMed

Affiliation: Graduate Center for Toxicology, College of Medicine, University of Kentucky, Lexington, Kentucky, United States of America.

ABSTRACT
Angiogenesis is a crucial step in the growth and metastasis of cancers, since it enables the growing tumor to receive oxygen and nutrients. Cancer prevention using natural products has become an integral part of cancer control. We studied the antiangiogenic activity of quercetin using ex vivo, in vivo and in vitro models. Rat aortic ring assay showed that quercetin at non-toxic concentrations significantly inhibited microvessel sprouting and exhibited a significant inhibition in the proliferation, migration, invasion and tube formation of endothelial cells, which are key events in the process of angiogenesis. Most importantly, quercetin treatment inhibited ex vivo angiogenesis as revealed by chicken egg chorioallantoic membrane assay (CAM) and matrigel plug assay. Western blot analysis showed that quercetin suppressed VEGF induced phosphorylation of VEGF receptor 2 and their downstream protein kinases AKT, mTOR, and ribosomal protein S6 kinase in HUVECs. Quercetin (20 mg/kg/d) significantly reduced the volume and the weight of solid tumors in prostate xenograft mouse model, indicating that quercetin inhibited tumorigenesis by targeting angiogenesis. Furthermore, quercetin reduced the cell viability and induced apoptosis in prostate cancer cells, which were correlated with the downregulation of AKT, mTOR and P70S6K expressions. Collectively the findings in the present study suggest that quercetin inhibits tumor growth and angiogenesis by targeting VEGF-R2 regulated AKT/mTOR/P70S6K signaling pathway, and could be used as a potential drug candidate for cancer therapy.

Show MeSH
Related in: MedlinePlus