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Phloroglucinol suppresses metastatic ability of breast cancer cells by inhibition of epithelial-mesenchymal cell transition.

Kim RK, Suh Y, Yoo KC, Cui YH, Hwang E, Kim HJ, Kang JS, Kim MJ, Lee YY, Lee SJ - Cancer Sci. (2014)

Bottom Line: Importantly, phloroglucinol decreased SLUG through inhibition of PI3K/AKT and RAS/RAF-1/ERK signaling.In agreement with in vitro data, phloroglucinol was also effective against in vivo metastasis of breast cancer cells, drastically suppressing their metastatic ability to lungs, and extending the survival time of mice.Collectively, our findings demonstrate a novel anticancer activity of phloroglucinol against metastasis of breast cancer cells, implicating its clinical relevance.

View Article: PubMed Central - PubMed

Affiliation: Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul, South Korea.

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Phloroglucinol suppresses primary tumor formation and inhibits EMT in vivo. (a) Schematic experimental procedure for the mammary fat pad injection of cancer cells and treatment with vehicle or phloroglucinol. (b) Representative images of primary tumors (left) and tumor growth curves (right). Green fluorescent protein (GFP)-labeled MDA-MB231 cells were injected into mammary fat pad of NSG mice (n = 5) and then were treated four times with phloroglucinol or vehicle by i.p injection. (c) Representative images and quantification of lung metastases foci generated by GFP-labeled metastatic MDA-MB231 cells after mammary fat pad injection. (d) H&E staining and GFP florescence of lung metastases foci after mammary fat pad injection. (e–h) Immunohistochemistry for VIM (e), SLUG (f), p-AKT (g) and p-ERK (h) in fat pad primary tumor tissues. (i) Kaplan–Meier survival curves of mice that was treated with phloroglucinol or vehicle after mammary fat pad injection of cancer cells. Error bars represent mean ± SD. *P < 0.01 vs control.
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fig04: Phloroglucinol suppresses primary tumor formation and inhibits EMT in vivo. (a) Schematic experimental procedure for the mammary fat pad injection of cancer cells and treatment with vehicle or phloroglucinol. (b) Representative images of primary tumors (left) and tumor growth curves (right). Green fluorescent protein (GFP)-labeled MDA-MB231 cells were injected into mammary fat pad of NSG mice (n = 5) and then were treated four times with phloroglucinol or vehicle by i.p injection. (c) Representative images and quantification of lung metastases foci generated by GFP-labeled metastatic MDA-MB231 cells after mammary fat pad injection. (d) H&E staining and GFP florescence of lung metastases foci after mammary fat pad injection. (e–h) Immunohistochemistry for VIM (e), SLUG (f), p-AKT (g) and p-ERK (h) in fat pad primary tumor tissues. (i) Kaplan–Meier survival curves of mice that was treated with phloroglucinol or vehicle after mammary fat pad injection of cancer cells. Error bars represent mean ± SD. *P < 0.01 vs control.

Mentions: Because phloroglucinol inhibited the invasiveness of breast cancer cells in vitro, we next examined whether phloroglucinol could suppress metastasis of breast cancer in vivo. To this end, GFP-labeled metastatic MDA-MB231 cells were transplanted into mammary fat pads of NOD-scid gamma (NSG) mice and phloroglucinol were treated four times on alternate days as indicated in Figure4(a). In tumor volumes, we observed that treatment with phloroglucinol attenuated the primary tumor formation in mammary fat pads (Fig.4b). In parallel, lung metastasis was detected markedly less in phloroglucinol-treated mice than vehicle-treated one (Fig.4c). Not surprisingly, GFP was detected in the tumor tissues, indicating that the tumors had originated from GFP-labeled cancer cells (Fig.4d). When the primary tumors in fat pad were stained by mesenchymal cell marker VIM and regulator SLUG, the expression levels of those proteins were lower in mice that are treated with phloroglucinol, compared to vehicle-treated mice (Fig.4e,f). In a similar way with in vitro data, treatment with phloroglucinol decreased phosphorylation of AKT and ERK in the primary tumors of mice (Fig.4g,h). In agreement with these results, phloroglucinol-treated mice were survived longer than the control mice (Fig.4i).


Phloroglucinol suppresses metastatic ability of breast cancer cells by inhibition of epithelial-mesenchymal cell transition.

Kim RK, Suh Y, Yoo KC, Cui YH, Hwang E, Kim HJ, Kang JS, Kim MJ, Lee YY, Lee SJ - Cancer Sci. (2014)

Phloroglucinol suppresses primary tumor formation and inhibits EMT in vivo. (a) Schematic experimental procedure for the mammary fat pad injection of cancer cells and treatment with vehicle or phloroglucinol. (b) Representative images of primary tumors (left) and tumor growth curves (right). Green fluorescent protein (GFP)-labeled MDA-MB231 cells were injected into mammary fat pad of NSG mice (n = 5) and then were treated four times with phloroglucinol or vehicle by i.p injection. (c) Representative images and quantification of lung metastases foci generated by GFP-labeled metastatic MDA-MB231 cells after mammary fat pad injection. (d) H&E staining and GFP florescence of lung metastases foci after mammary fat pad injection. (e–h) Immunohistochemistry for VIM (e), SLUG (f), p-AKT (g) and p-ERK (h) in fat pad primary tumor tissues. (i) Kaplan–Meier survival curves of mice that was treated with phloroglucinol or vehicle after mammary fat pad injection of cancer cells. Error bars represent mean ± SD. *P < 0.01 vs control.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig04: Phloroglucinol suppresses primary tumor formation and inhibits EMT in vivo. (a) Schematic experimental procedure for the mammary fat pad injection of cancer cells and treatment with vehicle or phloroglucinol. (b) Representative images of primary tumors (left) and tumor growth curves (right). Green fluorescent protein (GFP)-labeled MDA-MB231 cells were injected into mammary fat pad of NSG mice (n = 5) and then were treated four times with phloroglucinol or vehicle by i.p injection. (c) Representative images and quantification of lung metastases foci generated by GFP-labeled metastatic MDA-MB231 cells after mammary fat pad injection. (d) H&E staining and GFP florescence of lung metastases foci after mammary fat pad injection. (e–h) Immunohistochemistry for VIM (e), SLUG (f), p-AKT (g) and p-ERK (h) in fat pad primary tumor tissues. (i) Kaplan–Meier survival curves of mice that was treated with phloroglucinol or vehicle after mammary fat pad injection of cancer cells. Error bars represent mean ± SD. *P < 0.01 vs control.
Mentions: Because phloroglucinol inhibited the invasiveness of breast cancer cells in vitro, we next examined whether phloroglucinol could suppress metastasis of breast cancer in vivo. To this end, GFP-labeled metastatic MDA-MB231 cells were transplanted into mammary fat pads of NOD-scid gamma (NSG) mice and phloroglucinol were treated four times on alternate days as indicated in Figure4(a). In tumor volumes, we observed that treatment with phloroglucinol attenuated the primary tumor formation in mammary fat pads (Fig.4b). In parallel, lung metastasis was detected markedly less in phloroglucinol-treated mice than vehicle-treated one (Fig.4c). Not surprisingly, GFP was detected in the tumor tissues, indicating that the tumors had originated from GFP-labeled cancer cells (Fig.4d). When the primary tumors in fat pad were stained by mesenchymal cell marker VIM and regulator SLUG, the expression levels of those proteins were lower in mice that are treated with phloroglucinol, compared to vehicle-treated mice (Fig.4e,f). In a similar way with in vitro data, treatment with phloroglucinol decreased phosphorylation of AKT and ERK in the primary tumors of mice (Fig.4g,h). In agreement with these results, phloroglucinol-treated mice were survived longer than the control mice (Fig.4i).

Bottom Line: Importantly, phloroglucinol decreased SLUG through inhibition of PI3K/AKT and RAS/RAF-1/ERK signaling.In agreement with in vitro data, phloroglucinol was also effective against in vivo metastasis of breast cancer cells, drastically suppressing their metastatic ability to lungs, and extending the survival time of mice.Collectively, our findings demonstrate a novel anticancer activity of phloroglucinol against metastasis of breast cancer cells, implicating its clinical relevance.

View Article: PubMed Central - PubMed

Affiliation: Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul, South Korea.

Show MeSH
Related in: MedlinePlus