Ellagic acid inhibits human glioblastoma growth in vitro and in vivo

Wang,Dongliang; Chen,Qianxue; Tan,Yinqiu; Liu,Baohui; Liu,Chao

doi:10.3892/or.2016.5331

Ellagic acid inhibits human glioblastoma growth in vitro and in vivo

Authors:
- Dongliang Wang
- Qianxue Chen
- Yinqiu Tan
- Baohui Liu
- Chao Liu
View Affiliations

Affiliations: Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
Published online on: December 22, 2016 https://doi.org/10.3892/or.2016.5331
Pages: 1084-1092

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Ellagic acid (EA) is present in various fruits and plants and has recently been found to possess anticarcinogenic effects. The objective of this study was to investigate the anti‑glioblastoma effect of EA and its mechanisms in vitro and in vivo. We first studied the anticancer activity of EA in U87 and U118 human glioblastoma cell lines. The cell viability and cell proliferation were examined by Cell Counting Kit-8 (CCK-8) assay and 5-ethynyl-2'-deoxyuridine staining respectively. The cell cycle was detected with propidium iodide staining method by flow cytometry and the DNA damage of the cells caused by EA exposure was evaluated by detection of γ-H2AX foci. Then we examined the effect of EA on tumor growth in glioblastoma xenografted mice, and expression of Akt and Notch signaling and their target gene products were detected by immunohistochemistry and western blot analysis. As a result, we found that the cell viability and proliferation of glioblastoma cells treated with EA were significantly suppressed compared with the control; EA significantly increased the proportion of cells in the S phase accompanied by a decrease in the population in the G1 and G2/M phase in both cell lines. Meanwhile, the level of DNA damage in the EA-treated group was significantly higher than that of the control. Treatment of glioblastoma in xenografted mice by EA led to a significant suppression in tumor growth. EA upregulated the expression of E-cadherin and inhibited the expression of Snail, matrix metalloproteinase (MMP)-2 and MMP-9. EA also inhibited the expression of Bcl-2, cyclin D1, cyclin-dependent kinase (CDK)2 and CDK6 in U87 xenograft tissues. In addition, significant suppression of Akt and Notch was found in the xenografts of the tumor-bearing mice treated with EA. These data indicate that EA can suppress glioblastoma proliferation and invasion by inhibiting the Akt and Notch signaling pathways, which suggests that EA may be beneficial for the treatment of glioblastoma.

View Figures

View References

1	Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, et al: European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 352:987–996. 2005. View Article : Google Scholar : PubMed/NCBI
2	Cuddapah VA, Robel S, Watkins S and Sontheimer H: A neurocentric perspective on glioma invasion. Nat Rev Neurosci. 15:455–465. 2014. View Article : Google Scholar : PubMed/NCBI
3	Yang JA, Li JQ, Shao LM, Yang Q, Liu BH, Wu TF, Wu P, Yi W and Chen QX: Puerarin inhibits proliferation and induces apoptosis in human glioblastoma cell lines. Int J Clin Exp Med. 8:10132–10142. 2015.PubMed/NCBI
4	Lee DH, Kim DW, Jung CH, Lee YJ and Park D: Gingerol sensitizes TRAIL-induced apoptotic cell death of glioblastoma cells. Toxicol Appl Pharmacol. 279:253–265. 2014. View Article : Google Scholar : PubMed/NCBI
5	Son YG, Kim EH, Kim JY, Kim SU, Kwon TK, Yoon AR, Yun CO and Choi KS: Silibinin sensitizes human glioma cells to TRAIL-mediated apoptosis via DR5 up-regulation and down-regulation of c-FLIP and survivin. Cancer Res. 67:8274–8284. 2007. View Article : Google Scholar : PubMed/NCBI
6	Vattem DA and Shetty K: Biological function of ellagic acid: A Review. J Food Biochem. 29:234–266. 2005. View Article : Google Scholar
7	Zaveri NT: Green tea and its polyphenolic catechins: Medicinal uses in cancer and noncancer applications. Life Sci. 78:2073–2080. 2006. View Article : Google Scholar : PubMed/NCBI
8	Seeram NP, Adams LS, Henning SM, Niu Y, Zhang Y, Nair MG and Heber D: In vitro antiproliferative, apoptotic and antioxidant activities of punicalagin, ellagic acid and a total pomegranate tannin extract are enhanced in combination with other polyphenols as found in pomegranate juice. J Nutr Biochem. 16:360–367. 2005. View Article : Google Scholar : PubMed/NCBI
9	Han DH, Lee MJ and Kim JH: Antioxidant and apoptosis-inducing activities of ellagic acid. Anticancer Res 26 (5A). 3601–3606. 2006.
10	Strati A, Papoutsi Z, Lianidou E and Moutsatsou P: Effect of ellagic acid on the expression of human telomerase reverse transcriptase (hTERT) α+β+ transcript in estrogen receptor-positive MCF-7 breast cancer cells. Clin Biochem. 42:1358–1362. 2009. View Article : Google Scholar : PubMed/NCBI
11	Saiko P, Steinmann MT, Schuster H, Graser G, Bressler S, Giessrigl B, Lackner A, Grusch M, Krupitza G, Bago-Horvath Z, et al: Epigallocatechin gallate, ellagic acid, and rosmarinic acid perturb dNTP pools and inhibit de novo DNA synthesis and proliferation of human HL-60 promyelocytic leukemia cells: Synergism with arabinofuranosylcytosine. Phytomedicine. 22:213–222. 2015. View Article : Google Scholar : PubMed/NCBI
12	Arulmozhi V, Pandian K and Mirunalini S: Ellagic acid encapsulated chitosan nanoparticles for drug delivery system in human oral cancer cell line (KB). Colloids Surf B Biointerfaces. 110:313–320. 2013. View Article : Google Scholar : PubMed/NCBI
13	Zhao M, Tang SN, Marsh JL, Shankar S and Srivastava RK: Ellagic acid inhibits human pancreatic cancer growth in Balb c nude mice. Cancer Lett. 337:210–217. 2013. View Article : Google Scholar : PubMed/NCBI
14	Okla M, Kang I, Kim DM, Gourineni V, Shay N, Gu L and Chung S: Ellagic acid modulates lipid accumulation in primary human adipocytes and human hepatoma Huh7 cells via discrete mechanisms. J Nutr Biochem. 26:82–90. 2015. View Article : Google Scholar : PubMed/NCBI
15	Umesalma S and Sudhandiran G: Ellagic acid prevents rat colon carcinogenesis induced by 1, 2 dimethyl hydrazine through inhibition of AKT-phosphoinositide-3 kinase pathway. Eur J Pharmacol. 660:249–258. 2011. View Article : Google Scholar : PubMed/NCBI
16	Guo W, Li A, Jia Z, Yuan Y, Dai H and Li H: Transferrin modified PEG-PLA-resveratrol conjugates: In vitro and in vivo studies for glioma. Eur J Pharmacol. 718:41–47. 2013. View Article : Google Scholar : PubMed/NCBI
17	Purow B: Notch inhibition as a promising new approach to cancer therapy. Adv Exp Med Biol. 727:305–319. 2012. View Article : Google Scholar : PubMed/NCBI
18	Koch U and Radtke F: Notch and cancer: A double-edged sword. Cell Mol Life Sci. 64:2746–2762. 2007. View Article : Google Scholar : PubMed/NCBI
19	Cory S, Huang DC and Adams JM: The Bcl-2 family: Roles in cell survival and oncogenesis. Oncogene. 22:8590–8607. 2003. View Article : Google Scholar : PubMed/NCBI
20	Steeg PS: Tumor metastasis: Mechanistic insights and clinical challenges. Nat Med. 12:895–904. 2006. View Article : Google Scholar : PubMed/NCBI
21	Pavelic S Kraljevic, Sedic M, Bosnjak H, Spaventi S and Pavelic K: Metastasis: New perspectives on an old problem. Mol Cancer. 10:222011. View Article : Google Scholar : PubMed/NCBI
22	McCarthy N: Metastasis: Route master. Nat Rev Cancer. 9:610–611. 2009. View Article : Google Scholar : PubMed/NCBI
23	McCarthy N: Metastasis: Influencing bad behaviour. Nat Rev Cancer. 9:6092009. View Article : Google Scholar : PubMed/NCBI
24	Nguyen DX, Bos PD and Massagué J: Metastasis: From dissemination to organ-specific colonization. Nat Rev Cancer. 9:274–284. 2009. View Article : Google Scholar : PubMed/NCBI
25	Grossman SA and Batara JF: Current management of glioblastoma multiforme. Semin Oncol. 31:635–644. 2004. View Article : Google Scholar : PubMed/NCBI
26	Landete JM: Ellagitannins, ellagic acid and their derived metabolites: A review about source, metabolism, functions and health. Food Res Int. 44:1150–1160. 2011. View Article : Google Scholar
27	Hernández L, Terradas M, Martín M, Tusell L and Genescà A: Highly sensitive automated method for DNA damage assessment: gamma-H2AX foci counting and cell cycle sorting. Int J Mol Sci. 14:15810–15826. 2013. View Article : Google Scholar : PubMed/NCBI
28	Koseoglu S, Lu Z, Kumar C, Kirschmeier P and Zou J: AKT1, AKT2 and AKT3-dependent cell survival is cell line-specific and knockdown of all three isoforms selectively induces apoptosis in 20 human tumor cell lines. Cancer Biol Ther. 6:755–762. 2007. View Article : Google Scholar : PubMed/NCBI
29	Wang D, Chen Q, Liu B, Li Y, Tan Y and Yang B: Ellagic acid inhibits proliferation and induces apoptosis in human glioblastoma cells. Acta Cir Bras. 31:143–149. 2016. View Article : Google Scholar : PubMed/NCBI
30	Palena C, Hamilton DH and Fernando RI: Influence of IL-8 on the epithelial-mesenchymal transition and the tumor microenvironment. Future Oncol. 8:713–722. 2012. View Article : Google Scholar : PubMed/NCBI