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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 metastatic ability of breast cancer cells to lung. (a) Schematic experimental procedure for tail vein injection of cancer cells into athymic nude mice and treatment with vehicle or phloroglucinol. (b) Quantification of lung metastases foci generated by green fluorescent protein (GFP)-labeled metastatic MDA-MB231 cells after tail vein injection (n = 4). (c) H&E staining and GFP florescence of lung metastases foci after tail vein injection. (d, e) Immunohistochemistry for p-AKT (d) and p-ERK (e) in lung metastasized tumor tissues. (f) Kaplan–Meier survival curves of mice that were treated with phloroglucinol or vehicle after tail vein injection of cancer cells. Error bars represent mean ± SD. *P < 0.01 vs control.
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fig05: Phloroglucinol suppresses metastatic ability of breast cancer cells to lung. (a) Schematic experimental procedure for tail vein injection of cancer cells into athymic nude mice and treatment with vehicle or phloroglucinol. (b) Quantification of lung metastases foci generated by green fluorescent protein (GFP)-labeled metastatic MDA-MB231 cells after tail vein injection (n = 4). (c) H&E staining and GFP florescence of lung metastases foci after tail vein injection. (d, e) Immunohistochemistry for p-AKT (d) and p-ERK (e) in lung metastasized tumor tissues. (f) Kaplan–Meier survival curves of mice that were treated with phloroglucinol or vehicle after tail vein injection of cancer cells. Error bars represent mean ± SD. *P < 0.01 vs control.

Mentions: Since phloroglucinol attenuated tumor formation as well as the metastasis, the less lung metastasis in phloroglucinol-treated mice could be caused by inhibition of primary tumor formation. Thus, to clarify the more direct effect of phloroglucinol on metastatic ability of breast cancer cells, we introduced GFP-labeled metastatic MDA-MB231 cells into athymic nude mice by intravenous injection. Mice were then treated with vehicle or phloroglucinol by i.p injection four times on alternate days (Fig.5a). By 5 weeks, we analyzed the frequency of lung metastasis in mice that were treated with phloroglucinol. Notably, treatment with phloroglucinol effectively attenuated lung metastasis of MDA-MB231 cells, compared to counterpart control in mice (Fig.5b). Again, GFP was detected in the tumor tissues, indicating that the tumors had originated from GFP-labeled MDA-MB231 cells (Fig.5c). By immunohistochemistry, we observed that AKT and ERK were highly activated in lung metastasized tumors, compared to counterpart normal tissues (Fig.5d,e). However, AKT and ERK were less phosphorylated in the tumors of mice that are treated with phloroglucinol (Fig.5d,e), indicating that phloroglucinol also inhibits AKT and ERK signaling in vivo. In agreement, the survival rate was higher in mice that are treated with phloroglucinol, compared to vehicle-treated mice (Fig.5f). Taken together, these results suggest that phloroglucinol inhibits in vivo metastatic ability of breast cancer cells.


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 metastatic ability of breast cancer cells to lung. (a) Schematic experimental procedure for tail vein injection of cancer cells into athymic nude mice and treatment with vehicle or phloroglucinol. (b) Quantification of lung metastases foci generated by green fluorescent protein (GFP)-labeled metastatic MDA-MB231 cells after tail vein injection (n = 4). (c) H&E staining and GFP florescence of lung metastases foci after tail vein injection. (d, e) Immunohistochemistry for p-AKT (d) and p-ERK (e) in lung metastasized tumor tissues. (f) Kaplan–Meier survival curves of mice that were treated with phloroglucinol or vehicle after tail vein 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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Show All Figures
getmorefigures.php?uid=PMC4317783&req=5

fig05: Phloroglucinol suppresses metastatic ability of breast cancer cells to lung. (a) Schematic experimental procedure for tail vein injection of cancer cells into athymic nude mice and treatment with vehicle or phloroglucinol. (b) Quantification of lung metastases foci generated by green fluorescent protein (GFP)-labeled metastatic MDA-MB231 cells after tail vein injection (n = 4). (c) H&E staining and GFP florescence of lung metastases foci after tail vein injection. (d, e) Immunohistochemistry for p-AKT (d) and p-ERK (e) in lung metastasized tumor tissues. (f) Kaplan–Meier survival curves of mice that were treated with phloroglucinol or vehicle after tail vein injection of cancer cells. Error bars represent mean ± SD. *P < 0.01 vs control.
Mentions: Since phloroglucinol attenuated tumor formation as well as the metastasis, the less lung metastasis in phloroglucinol-treated mice could be caused by inhibition of primary tumor formation. Thus, to clarify the more direct effect of phloroglucinol on metastatic ability of breast cancer cells, we introduced GFP-labeled metastatic MDA-MB231 cells into athymic nude mice by intravenous injection. Mice were then treated with vehicle or phloroglucinol by i.p injection four times on alternate days (Fig.5a). By 5 weeks, we analyzed the frequency of lung metastasis in mice that were treated with phloroglucinol. Notably, treatment with phloroglucinol effectively attenuated lung metastasis of MDA-MB231 cells, compared to counterpart control in mice (Fig.5b). Again, GFP was detected in the tumor tissues, indicating that the tumors had originated from GFP-labeled MDA-MB231 cells (Fig.5c). By immunohistochemistry, we observed that AKT and ERK were highly activated in lung metastasized tumors, compared to counterpart normal tissues (Fig.5d,e). However, AKT and ERK were less phosphorylated in the tumors of mice that are treated with phloroglucinol (Fig.5d,e), indicating that phloroglucinol also inhibits AKT and ERK signaling in vivo. In agreement, the survival rate was higher in mice that are treated with phloroglucinol, compared to vehicle-treated mice (Fig.5f). Taken together, these results suggest that phloroglucinol inhibits in vivo metastatic ability of breast cancer cells.

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