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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 tumor angiogenesis in vivo by suppressing AKT/mTOR/p70S6K pathway.(a) Quercetin inhibited the activation of AKT/mTOR/p70S6K pathway in vivo. Proteins from tumor tissue was tested by western blotting and probed with specific antibodies. Experiments were repeated for three times. Quercetin inhibited tumor angiogenesis as evident from (b) CD31 and (c) CD34 immunohistochemistry. Tumor sections (5 µm) were incubated with a rabbit anti-CD31 and mouse anti-CD34 antibodies and were subsequently incubated with biotinylated anti-rabbit/anti-mouse secondary antibody, followed by staining with Vectastain ABC Kit.
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pone-0047516-g007: Quercetin inhibits tumor angiogenesis in vivo by suppressing AKT/mTOR/p70S6K pathway.(a) Quercetin inhibited the activation of AKT/mTOR/p70S6K pathway in vivo. Proteins from tumor tissue was tested by western blotting and probed with specific antibodies. Experiments were repeated for three times. Quercetin inhibited tumor angiogenesis as evident from (b) CD31 and (c) CD34 immunohistochemistry. Tumor sections (5 µm) were incubated with a rabbit anti-CD31 and mouse anti-CD34 antibodies and were subsequently incubated with biotinylated anti-rabbit/anti-mouse secondary antibody, followed by staining with Vectastain ABC Kit.

Mentions: To further investigate whether quercetin inhibited tumor growth by suppressing tumor angiogenesis, we performed western blot and immunohistochemical analysis of solid tumors (Fig. 7). Tumors from quercetin treated animals showed a suppressed activation of AKT, mTOR and P70S6K proteins (Fig. 7a). We also observed a large number of CD31 (Fig. 7b) and CD34 (Fig. 7c) positive cells in untreated control group whereas a small number in quercetin treated group. All these observations indicate the antiangiogenic efficacy of quercetin in vivo that strongly support the above ex vivo and in vitro studies.


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 tumor angiogenesis in vivo by suppressing AKT/mTOR/p70S6K pathway.(a) Quercetin inhibited the activation of AKT/mTOR/p70S6K pathway in vivo. Proteins from tumor tissue was tested by western blotting and probed with specific antibodies. Experiments were repeated for three times. Quercetin inhibited tumor angiogenesis as evident from (b) CD31 and (c) CD34 immunohistochemistry. Tumor sections (5 µm) were incubated with a rabbit anti-CD31 and mouse anti-CD34 antibodies and were subsequently incubated with biotinylated anti-rabbit/anti-mouse secondary antibody, followed by staining with Vectastain ABC Kit.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3475699&req=5

pone-0047516-g007: Quercetin inhibits tumor angiogenesis in vivo by suppressing AKT/mTOR/p70S6K pathway.(a) Quercetin inhibited the activation of AKT/mTOR/p70S6K pathway in vivo. Proteins from tumor tissue was tested by western blotting and probed with specific antibodies. Experiments were repeated for three times. Quercetin inhibited tumor angiogenesis as evident from (b) CD31 and (c) CD34 immunohistochemistry. Tumor sections (5 µm) were incubated with a rabbit anti-CD31 and mouse anti-CD34 antibodies and were subsequently incubated with biotinylated anti-rabbit/anti-mouse secondary antibody, followed by staining with Vectastain ABC Kit.
Mentions: To further investigate whether quercetin inhibited tumor growth by suppressing tumor angiogenesis, we performed western blot and immunohistochemical analysis of solid tumors (Fig. 7). Tumors from quercetin treated animals showed a suppressed activation of AKT, mTOR and P70S6K proteins (Fig. 7a). We also observed a large number of CD31 (Fig. 7b) and CD34 (Fig. 7c) positive cells in untreated control group whereas a small number in quercetin treated group. All these observations indicate the antiangiogenic efficacy of quercetin in vivo that strongly support the above ex vivo and in vitro studies.

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