8‑bromo‑7‑methoxychrysin induces apoptosis by regulating Akt/FOXO3a pathway in cisplatin‑sensitive and resistant ovarian cancer cells

Ding,Qing; Chen,Yi; Zhang,Qing; Guo,Yanling; Huang,Zhi; Dai,Liqing; Cao,Sudan

doi:10.3892/mmr.2015.4039

8‑bromo‑7‑methoxychrysin induces apoptosis by regulating Akt/FOXO3a pathway in cisplatin‑sensitive and resistant ovarian cancer cells

Authors:
- Qing Ding
- Yi Chen
- Qing Zhang
- Yanling Guo
- Zhi Huang
- Liqing Dai
- Sudan Cao
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Affiliations: Hunan University of Traditional Chinese Medicine, Changsha, Hunan 410208, P.R.China
Published online on: July 3, 2015 https://doi.org/10.3892/mmr.2015.4039
Pages: 5100-5108
Copyright: © Ding et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

8‑bromo‑7‑methoxychrysin (BrMC), a novel chrysin analog, was reported to have anti‑cancer activities. The aim of the present study was to investigate the molecular mechanism of 8‑bromo‑7‑methoxychrysin (BrMC)‑induced apoptosis via the Akt/forkhead box O3a (FOXO3a) pathway in cisplatin (DDP)‑sensitive and ‑resistant ovarian cancer cells. The human ovarian cancer cell lines A2780 and A2780/DDP were cultured in vitro. Various molecular techniques were used to assess the expression of FOXO3a and B cell lymphoma 2 (Bcl‑2)‑interacting mediator of cell death (Bim) in cisplatin‑sensitive and ‑resistant ovarian cancer cells. Different concentrations of BrMC induced apoptosis in cisplatin‑sensitive and ‑resistant ovarian cancer cells. BrMC‑induced apoptotic cell death occurred mainly by the activation of Akt, which was accompanied by the overexpression of transcription factor FOXO3a, with a concomitant increase in the expression levels of Bim. Silencing Bim expression by using small interfering RNA, attenuated the induction of apoptosis by BrMC treatment. The results indicated that BrMC‑induced apoptosis in cisplatin‑sensitive and ‑resistant ovarian cancer cells may occur via the regulation of Akt/FOXO3a, leading to Bim transcription.

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1	Lan C, Chenggang W, Yulan B, Xiaohui D, Junhui Z and Xiao W: Aberrant expression of WWOX protein in epithelial ovarian cancer: a clinicopathologic and immunohistochemical study. Int J Gynecol Pathol. 31:125–132. 2012. View Article : Google Scholar : PubMed/NCBI
2	Vlahovic G, Meadows KL, Uronis HE, et al: A phase I study of bevacizumab, everolimus and panitumumab in advanced solid tumors. Cancer Chemother Pharmacol. 70:95–102. 2012. View Article : Google Scholar : PubMed/NCBI
3	Egawa-Takata T, Endo H, Fujita M, et al: Early reduction of glucose uptake after cisplatin treatment is a marker of cisplatin sensitivity in ovarian cancer. Cancer Sci. 101:2171–2178. 2010. View Article : Google Scholar : PubMed/NCBI
4	Park SS, Bae I and Lee YJ: Flavonoids-induced accumulation of hypoxia-inducible factor (HIF)-1alpha/2alpha is mediated through chelation of iron. J Cell Biochem. 103:1989–1998. 2008. View Article : Google Scholar
5	Shin EK, Kwon HS, Kim YH, Shin HK and Kim JK: Chrysin, a natural flavone, improves murine inflammatory bowel diseases. Biochem Biophys Res Commun. 381:502–507. 2009. View Article : Google Scholar : PubMed/NCBI
6	Lotito SB and Frei B: Dietary flavonoids attenuate tumor necrosis factor alpha-induced adhesion molecule expression in human aortic endothelial cells. Structure-function relationships and activity after first pass metabolism. J Biol Chem. 281:37102–37110. 2006. View Article : Google Scholar : PubMed/NCBI
7	Lee SJ, Yoon JH and Song KS: Chrysin inhibited stem cell factor (SCF)/c-Kit complex-induced cell proliferation in human myeloid leukemia cells. Biochem Pharmacol. 74:215–225. 2007. View Article : Google Scholar : PubMed/NCBI
8	Zhang T, Chen X, Qu L, Wu J, Cui R and Zhao Y: Chrysin and its phosphate ester inhibit cell proliferation and induce apoptosis in Hela cells. Bioorg Med Chem. 12:6097–6105. 2004. View Article : Google Scholar : PubMed/NCBI
9	Monasterio A, Urdaci MC, Pinchuk IV, López-Moratalla N and Martínez-Irujo JJ: Flavonoids induce apoptosis in human leukemia U937 cells through caspase- and caspase-calpain-dependent pathways. Nutr Cancer. 50:90–100. 2004. View Article : Google Scholar : PubMed/NCBI
10	Khoo BY, Chua SL and Balaram P: Apoptotic effects of chrysin in human cancer cell lines. Int J Mol Sci. 11:2188–2199. 2010. View Article : Google Scholar : PubMed/NCBI
11	Zheng X, Meng WD, Xu YY, Cao JG and Qing FL: Synthesis and anticancer effect of chrysin derivatives. Bioorg Med Chem Lett. 13:881–884. 2003. View Article : Google Scholar : PubMed/NCBI
12	Zheng X, Cao JG, Liao DF, Zhu BY and Liu HT: Synthesis and anticancer effect of gem-difluoromethylenated chrysin derivatives. Chin Chem Lett. 11:1431–1442. 2006.In Chinese.
13	Xiang H, Zheng X and Cao J: Induction of apoptosis of human gastric carcinoma SGC-7901 cell line by 8-bromo-7-methoxychrysin. Zhongguo Yaolixue Tongbao. 24:1370–1373. 2008.
14	Ai XH, Zheng X, Tang XQ, et al: Induction of apoptosis of human gastric carcinoma SGC-7901 cell line by 5, 7-dihydroxy-8-nitrochrysin in vitro. World J Gastroenterol. 13:3824–3828. 2007.PubMed/NCBI
15	Yang XH, Zheng X, Cao JG, Xiang HL, Liu F and Lv Y: 8-Bromo-7-methoxychrysin-induced apoptosis of hepatocellular carcinoma cells involves ROS and JNK. World J Gastroenterol. 16:3385–3393. 2010. View Article : Google Scholar : PubMed/NCBI
16	Xiao G, Tang X, Yao C and Wang C: Potentiation of arsenic trioxide-induced apoptosis by 8-bromo-7-methoxychrysin in human leukemia cells involves depletion of intracellular reduced glutathione. Acta Biochim Biophys Sin (Shanghai). 43:712–721. 2011. View Article : Google Scholar
17	Staal SP: Molecular cloning of the akt oncogene and its human homologues AKT1 and AKT2: amplification of AKT1 in a primary human gastric adenocarcinoma. Proc Natl Acad Sci U S A. 84:5034–5037. 1987. View Article : Google Scholar : PubMed/NCBI
18	Bast RC Jr, Hennessy B and Mills GB: The biology of ovarian cancer: new opportunities for translation. Nat Rev Cancer. 9:415–428. 2009. View Article : Google Scholar : PubMed/NCBI
19	Levanon K, Crum C and Drapkin R: New insights into the pathogenesis of serous ovarian cancer and its clinical impact. J Clin Oncol. 26:5284–5293. 2008. View Article : Google Scholar : PubMed/NCBI
20	Landen CN Jr, Birrer MJ and Sood AK: Early events in the pathogenesis of epithelial ovarian cancer. J Clin Oncol. 26:995–1005. 2008. View Article : Google Scholar : PubMed/NCBI
21	O'Connor L, Strasser A, O'Reilly LA, et al: Bim: a novel member of the Bcl-2 family that promotes apoptosis. EMBO J. 17:384–395. 1998. View Article : Google Scholar : PubMed/NCBI
22	Qi XJ, Wildey GM and Howe PH: Evidence that Ser87 of BimEL is phosphorylated by Akt and regulates BimEL apoptotic function. J Biol Chem. 281:813–823. 2006. View Article : Google Scholar
23	Fletcher JI and Huang DC: Controlling the cell death mediators Bax and Bak: puzzles and conundrums. Cell Cycle. 7:39–44. 2008. View Article : Google Scholar : PubMed/NCBI
24	van Gorp AG, Pomeranz KM, Birkenkamp KU, Hui RC, Lam EW and Coffer PJ: Chronic protein kinase B (PKB/c-akt) activation leads to apoptosis induced by oxidative stress-mediated Foxo3a transcriptional up-regulation. Cancer Res. 66:10760–10769. 2006. View Article : Google Scholar : PubMed/NCBI
25	Essafi A, Fernàndez de Mattos S, Hassen YA, et al: Direct transcriptional regulation of Bim by FoxO3a mediates STI571-induced apoptosis in Bcr-Abl-expressing cells. Oncogene. 24:2317–2329. 2005. View Article : Google Scholar : PubMed/NCBI
26	Cardone MH, Roy N, Stennicke HR, et al: Regulation of cell death protease caspase-9 by phosphorylation. Science. 282:1318–1321. 1998. View Article : Google Scholar : PubMed/NCBI
27	Sunters A, Fernàndez de Mattos S, Stahl M, et al: FoxO3a transcriptional regulation of Bim controls apoptosis in paclitaxel-treated breast cancer cell lines. J Biol Chem. 278:49795–49805. 2003. View Article : Google Scholar : PubMed/NCBI
28	Simonin K, Brotin E, Dufort S, et al: Mcl-1 is an important determinant of the apoptotic response to the BH3-mimetic molecule HA14-1 in cisplatin-resistant ovarian carcinoma cells. Mol Cancer Ther. 8:3162–3170. 2009. View Article : Google Scholar : PubMed/NCBI
29	Zhang N, Wu ZM, McGowan E, et al: Arsenic trioxide and cisplatin synergism increase cytotoxicity in human ovarian cancer cells: therapeutic potential for ovarian cancer. Cancer Sci. 100:2459–2464. 2009. View Article : Google Scholar : PubMed/NCBI
30	Wang Z, Ahmad A, Banerjee S, et al: FoxM1 is a novel target of a natural agent in pancreatic cancer. Pharm Res. 27:1159–1168. 2010. View Article : Google Scholar : PubMed/NCBI
31	Ning Y, Li Q, Xiang H, Liu F and Cao J: Apoptosis induced by 7-difluoromethoxyl-5,4′-di-n-octyl genistein via the inactivation of FoxM1 in ovarian cancer cells. Oncol Rep. 27:1857–1864. 2012.PubMed/NCBI
32	Polier G, Ding J, Konkimalla BV, et al: Wogonin and related natural flavones are inhibitors of CDK9 that induce apoptosis in cancer cells by transcriptional suppression of Mcl-1. Cell Death Dis. 2:e1822011. View Article : Google Scholar : PubMed/NCBI
33	Zhao XC, Cao XC, Liu F, et al: Regulation of the FOXO3a/Bim signaling pathway by 5,7-dihydroxy-8-nitrochrysin in MDA-MB-453 breast cancer cells. Oncol Lett. 5:929–934. 2013.PubMed/NCBI
34	Yuan Z, Wang F, Zhao Z, et al: BIM-mediated Akt phosphorylation is a key modulator of arsenic trioxide-induced apoptosis in cisplatin-sensitive and -resistant ovarian cancer cells. PLoS One. 6:e205862011. View Article : Google Scholar : PubMed/NCBI
35	Chen KF, Yeh PY, Yeh KH, Lu YS, Huang SY and Cheng AL: Down-regulation of phospho-Akt is a major molecular determinant of bortezomib-induced apoptosis in hepatocellular carcinoma cells. Cancer Res. 68:6698–6707. 2008. View Article : Google Scholar : PubMed/NCBI
36	Woo KJ, Jeong YJ, Park JW and Kwon TK: Chrysin-induced apoptosis is mediated through caspase activation and Akt inactivation in U937 leukemia cells. Biochem Biophys Res Commun. 325:1215–1222. 2004. View Article : Google Scholar : PubMed/NCBI
37	Fraser M, Bai T and Tsang BK: Akt promotes cisplatin resistance in human ovarian cancer cells through inhibition of p53 phosphorylation and nuclear function. Int J Cancer. 122:534–546. 2008. View Article : Google Scholar
38	Liu W, Akhand AA, Takeda K, et al: Protein phosphatase 2A-linked and -unlinked caspase-dependent pathways for downregulation of Akt kinase triggered by 4-hydroxynonenal. Cell Death Differ. 10:772–781. 2003. View Article : Google Scholar : PubMed/NCBI
39	Ramos AM, Fernández C, Amràn D, Sancho P, de Blas E and Aller P: Pharmacologic inhibitors of PI3K/Akt potentiate the apoptotic action of the antileukemic drug arsenic trioxide via glutathione depletion and increased peroxide accumulation in myeloid leukemia cells. Blood. 105:4013–4020. 2005. View Article : Google Scholar : PubMed/NCBI
40	Kornblau SM, Singh N, Qiu Y, et al: Highly phosphorylated FOX03A is an adverse prognostic factor in acute myeloid leukemia. Clin Cancer Res. 16:1865–1874. 2010. View Article : Google Scholar : PubMed/NCBI