Plant flavonoid taxifolin inhibits the growth, migration and invasion of human osteosarcoma cells

Chen,Xin; Gu,Na; Xue,Chao; Li,Ban‑Ruo

doi:10.3892/mmr.2017.8271

Plant flavonoid taxifolin inhibits the growth, migration and invasion of human osteosarcoma cells

Authors:
- Xin Chen
- Na Gu
- Chao Xue
- Ban‑Ruo Li
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Affiliations: Department of Orthopedics, Hanzhong Centre Hospital, Hanzhong, Shaanxi 723000, P.R. China, Department of Respiratory Medicine, Hanzhong Centre Hospital, Hanzhong, Shaanxi 723000, P.R. China
Published online on: December 12, 2017 https://doi.org/10.3892/mmr.2017.8271
Pages: 3239-3245

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Abstract

The aim of the present study was to investigate the anti-cancer effects of the natural plant flavonoid, taxifolin, on human osteosarcoma cancer cells. Taxifolin was demonstrated to exhibit anti‑cancer effects on U2OS and Saos‑2 osteosarcoma cell lines. Treatment of cells with taxifolin inhibited proliferation and diminished colony formation in soft agar in a dose‑dependent manner. In vivo, intraperitoneal administration of taxifolin in nude mice bearing U2OS xenograft tumors, significantly inhibited tumor growth. In addition, taxifolin treatment was demonstrated to promote G1 cell cycle arrest and cell apoptosis in U2OS and Saos‑2 cell lines, as demonstrated by flow cytometry analysis. Western blot analysis demonstrated that taxifolin treatment was associated with a reduction in the expression levels of AKT serine/threonine kinase 1 (AKT), phosphorylated (p‑Ser473) AKT, v‑myc avian myelocytomatosis viral oncogene homolog (c‑myc) and S‑phase kinase associated protein 2 (SKP‑2) in U2OS and Saos‑2 cell lines. Overexpression of AKT considerably reversed the taxifolin‑induced decrease in AKT, c‑myc and SKP‑2 protein expression and the decrease in AKT phosphorylation, suggesting that inactivation of AKT was a mediator of taxifolin‑induced inhibition of c‑myc and SKP‑2. Furthermore, overexpression of SKP‑2 in U2OS cells partially reversed the growth inhibition mediated by taxifolin. Finally, taxifolin treatment repressed cell migration and invasion in U2OS cells and this effect was markedly reversed by SKP‑2 overexpression. The results of the present study indicate that taxifolin may present a potential novel therapeutic agent for osteosarcoma treatment.

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1	Duong LM and Richardson LC: Descriptive epidemiology of malignant primary osteosarcoma using population-based registries, United States, 1999–2008. J Registry Manag. 40:59–64. 2013.PubMed/NCBI
2	Savage SA, Woodson K, Walk E, Modi W, Liao J, Douglass C, Hoover RN and Chanock SJ; National Osteosarcoma Etiology Study Group, : Analysis of genes critical for growth regulation identifies insulin-like growth factor 2 receptor variations with possible functional significance as risk factors for osteosarcoma. Cancer Epidemiol Biomarkers Prev. 16:1667–1674. 2007. View Article : Google Scholar : PubMed/NCBI
3	Longhi A, Errani C, De Paolis M, Mercuri M and Bacci G: Primary bone osteosarcoma in the pediatric age: State of the art. Cancer Treat Rev. 32:423–436. 2006. View Article : Google Scholar : PubMed/NCBI
4	Longhi A, Fabbri N, Donati D, Capanna R, Briccoli A, Biagini R, Bernini G, Ferrari S, Versari M and Bacci G: Neoadjuvant chemotherapy for patients with synchronous multifocal osteosarcoma: Results in eleven cases. J Chemother. 13:324–330. 2001. View Article : Google Scholar : PubMed/NCBI
5	Collins M, Wilhelm M, Conyers R, Herschtal A, Whelan J, Bielack S, Kager L, Kühne T, Sydes M, Gelderblom H, et al: Benefits and adverse events in younger versus older patients receiving neoadjuvant chemotherapy for osteosarcoma: Findings from a meta-analysis. J Clin Oncol. 31:2303–2312. 2013. View Article : Google Scholar : PubMed/NCBI
6	Middleton E Jr, Kandaswami C and Theoharides TC: The effects of plant flavonoids on mammalian cells: Implications for inflammation, heart disease, and cancer. Pharmacol Rev. 52:673–751. 2000.PubMed/NCBI
7	Dajas F, Rivera F, Blasina F, Arredondo F, Echeverry C, Lafon L, Morquio A and Heizen H: Cell culture protection and in vivo neuroprotective capacity of flavonoids. Neurotox Res. 5:425–432. 2003. View Article : Google Scholar : PubMed/NCBI
8	Slimestad R, Fossen T and Vågen IM: Onions: A source of unique dietary flavonoids. J Agric Food Chem. 55:10067–10080. 2007. View Article : Google Scholar : PubMed/NCBI
9	Guo H, Zhang X, Cui Y, Zhou H, Xu D, Shan T, Zhang F, Guo Y, Chen Y and Wu D: Taxifolin protects against cardiac hypertrophy and fibrosis during biomechanical stress of pressure overload. Toxicol Appl Pharmacol. 287:168–177. 2015. View Article : Google Scholar : PubMed/NCBI
10	Liang L, Gao C, Luo M, Wang W, Zhao C, Zu Y, Efferth T and Fu Y: Dihydroquercetin (DHQ) induced HO-1 and NQO1 expression against oxidative stress through the Nrf2-dependent antioxidant pathway. J Agric Food Chem. 61:2755–2761. 2013. View Article : Google Scholar : PubMed/NCBI
11	Zhang ZR, Al Zaharna M, Wong MM, Chiu SK and Cheung HY: Taxifolin enhances andrographolide-induced mitotic arrest and apoptosis in human prostate cancer cells via spindle assembly checkpoint activation. PLoS One. 8:e545772013. View Article : Google Scholar : PubMed/NCBI
12	Kim YJ, Choi SE, Lee MW and Lee CS: Taxifolin glycoside inhibits dendritic cell responses stimulated by lipopolysaccharide and lipoteichoic acid. J Pharm Pharmacol. 60:1465–1472. 2008. View Article : Google Scholar : PubMed/NCBI
13	Ahn JY, Choi SE, Jeong MS, Park KH, Moon NJ, Joo SS, Lee CS, Choi YW, Li K, Lee MK, et al: Effect of taxifolin glycoside on atopic dermatitis-like skin lesions in NC/Nga mice. Phytother Res. 24:1071–1077. 2010.PubMed/NCBI
14	Rogovskiĭ VS, Matiushin AI, Shimanovskiĭ NL, Semeĭkin AV, Kukhareva TS, Koroteev AM, Koroteev MP and Nifant'ev EE: Antiproliferative and antioxidant activity of new dihydroquercetin derivatives. Eksp Klin Farmakol. 73:39–42. 2010.(In Russian).
15	Vrba J, Gažák R, Kuzma M, Papoušková B, Vacek J, Weiszenstein M, Křen V and Ulrichová J: A novel semisynthetic flavonoid 7-O-galloyltaxifolin upregulates heme oxygenase-1 in RAW264.7 cells via MAPK/Nrf2 pathway. J Med Chem. 56:856–866. 2013. View Article : Google Scholar : PubMed/NCBI
16	Chuu CP and Lin HP: Antiproliferative effect of LXR agonists T0901317 and 22(R)-hydroxycholesterol on multiple human cancer cell lines. Anticancer Res. 30:3643–3648. 2010.PubMed/NCBI
17	Wilson JK, Sargent JM, Elgie AW, Hill JG and Taylor CG: Feasibility study of the MTT assay for chemosensitivity testing in ovarian malignancy. Br J Cancer. 62:189–194. 1990. View Article : Google Scholar : PubMed/NCBI
18	Chuu CP, Kokontis JM, Hiipakka RA, Fukuchi J, Lin HP, Lin CY, Huo C, Su LC and Liao S: Androgen suppresses proliferation of castration-resistant LNCaP 104-R2 prostate cancer cells through androgen receptor, Skp2, and c-Myc. Cancer Sci. 102:2022–2028. 2011. View Article : Google Scholar : PubMed/NCBI
19	Ye J, Yin L, Xie P, Wu J, Huang J, Zhou G, Xu H, Lu E and He X: Antiproliferative effects and molecular mechanisms of troglitazone in human cervical cancer in vitro. Onco Targets Ther. 8:1211–1218. 2015.PubMed/NCBI
20	Zhang A, He S, Sun X, Ding L, Bao X and Wang N: Wnt5a promotes migration of human osteosarcoma cells by triggering a phosphatidylinositol-3 kinase/Akt signals. Cancer Cell Int. 14:152014. View Article : Google Scholar : PubMed/NCBI
21	Lin HP, Lin CY, Liu CC, Su LC, Huo C, Kuo YY, Tseng JC, Hsu JM, Chen CK and Chuu CP: Caffeic acid phenethyl ester as a potential treatment for advanced prostate cancer targeting akt signaling. Int J Mol Sci. 14:5264–5283. 2013. View Article : Google Scholar : PubMed/NCBI
22	Kreisberg JI, Malik SN, Prihoda TJ, Bedolla RG, Troyer DA, Kreisberg S and Ghosh PM: Phosphorylation of Akt (Ser473) is an excellent predictor of poor clinical outcome in prostate cancer. Cancer Res. 64:5232–5236. 2004. View Article : Google Scholar : PubMed/NCBI
23	Liu CC, Hsu JM, Kuo LK and Chuu CP: Caffeic acid phenethyl ester as an adjuvant therapy for advanced prostate cancer. Med Hypotheses. 80:617–619. 2013. View Article : Google Scholar : PubMed/NCBI
24	Kokontis J, Takakura K, Hay N and Liao S: Increased androgen receptor activity and altered c-myc expression in prostate cancer cells after long-term androgen deprivation. Cancer Res. 54:1566–1573. 1994.PubMed/NCBI
25	Han G, Wang Y and Bi W: C-Myc overexpression promotes osteosarcoma cell invasion via activation of MEK-ERK pathway. Oncol Res. 20:149–156. 2012. View Article : Google Scholar : PubMed/NCBI
26	Edwards J, Krishna NS, Witton CJ and Bartlett JM: Gene amplifications associated with the development of hormone-resistant prostate cancer. Clin Cancer Res. 9:5271–5281. 2003.PubMed/NCBI
27	Grad JM, Dai JL, Wu S and Burnstein KL: Multiple androgen response elements and a Myc consensus site in the androgen receptor (AR) coding region are involved in androgen-mediated up-regulation of AR messenger RNA. Mol Endocrinol. 13:1896–1911. 1999. View Article : Google Scholar : PubMed/NCBI
28	Liu Z, Zhang G, Li J, Liu J and Lv P: The tumor-suppressive microRNA-135b targets c-myc in osteoscarcoma. PLoS One. 9:e1026212014. View Article : Google Scholar : PubMed/NCBI
29	Field JK and Spandidos DA: The role of ras and myc oncogenes in human solid tumours and their relevance in diagnosis and prognosis (review). Anticancer Res. 10:1–22. 1990.PubMed/NCBI
30	Matthews GM, Lefebure M, Doyle MA, Shortt J, Ellul J, Chesi M, Banks KM, Vidacs E, Faulkner D, Atadja P, et al: Preclinical screening of histone deacetylase inhibitors combined with ABT-737, rhTRAIL/MD5-1 or 5-azacytidine using syngeneic Vk*MYC multiple myeloma. Cell Death Dis. 4:e7982013. View Article : Google Scholar : PubMed/NCBI
31	Carrano AC, Eytan E, Hershko A and Pagano M: SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27. Nat Cell Biol. 1:193–199. 1999. View Article : Google Scholar : PubMed/NCBI
32	Tsvetkov LM, Yeh KH, Lee SJ, Sun H and Zhang H: p27(Kip1) ubiquitination and degradation is regulated by the SCF (Skp2) complex through phosphorylated Thr187 in p27. Curr Biol. 9:661–664. 1999. View Article : Google Scholar : PubMed/NCBI
33	Elledge SJ and Harper JW: Cdk inhibitors: On the threshold of checkpoints and development. Curr Opin Cell Biol. 6:847–852. 1994. View Article : Google Scholar : PubMed/NCBI