Daidzein exerts anticancer activity towards SKOV3 human ovarian cancer cells by inducing apoptosis and cell cycle arrest, and inhibiting the Raf/MEK/ERK cascade Retraction in /10.3892/ijmm.2021.4929

Hua,Fu; Li,Chang‑Hua; Chen,Xiao‑Gang; Liu,Xiao‑Ping

doi:10.3892/ijmm.2018.3531

Daidzein exerts anticancer activity towards SKOV3 human ovarian cancer cells by inducing apoptosis and cell cycle arrest, and inhibiting the Raf/MEK/ERK cascade

Retraction in: /10.3892/ijmm.2021.4929

Authors:
- Fu Hua
- Chang‑Hua Li
- Xiao‑Gang Chen
- Xiao‑Ping Liu
View Affiliations

Affiliations: Department of Gynecology, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, Jiangsu 223300, P.R. China, Department of Orthopaedics, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, Jiangsu 223300, P.R. China
Published online on: March 5, 2018 https://doi.org/10.3892/ijmm.2018.3531
Pages: 3485-3492

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

Ovarian cancer is the main cause of gynecological cancer‑associated mortality around the world. Despite initial responses to chemotherapy, frequent relapse occurs. Daidzein is an important flavonoid and has been shown to exhibit a diversity of pharmacological properties, including antimicrobial and anticancer activities. However, information on the anticancer activity of daidzein against ovarian cancer remains limited. Therefore, the present study evaluated the anticancer activity of daidzein against a panel of human ovarian cancer cell lines and one normal ovarian cell line (Moody). The results revealed that daidzein exhibited potent anticancer activity against SKVO3 cells with a half‑maximal inhibitory concentration (IC50) of 20 µM. However, it exhibited comparatively lower activity against normal ovarian Moody cells, which had an IC50 of 100 µM. Daidzein induced morphological changes in SKOV3 cells and mitochondrial apoptosis, as evident from DAPI, AO/EB and Annexin V/propidium iodide staining. This was associated with the upregulation of B‑cell lymphoma 2‑associated X protein, cytochrome c, cleaved caspase‑3 and ‑9, and cleaved poly (ADP‑ribose) polymerase. Daidzein also triggered G2/M cell arrest through the downregulation of pCdc25c, Cdc25c, pCdc2, Cdc2 and cyclin B1. The effect of daidzein on the migration of SKOV3 cells was also determined, the results of which indicated that daidzein inhibited cell migration in a concentration‑dependent manner and was coupled with concomitant decrease in the expression of matrix metalloproteinase (MMP)‑2 and ‑9. Additionally, daidzein‑inhibited cell growth was simultaneous with suppression of the expression of phosphorylated mitogen‑activated protein kinase kinase and phosphorylated extracellular signal‑regulated kinase. The present study also examined whether daidzein exerts similar activity against SKOV3 cells in nude mouse xenograft models and it was revealed that daidzein considerably reduced the tumorigenesis in vivo, indicative of the potential for daidzein as a lead molecule in the development of ovarian cancer chemotherapy.

View Figures

View References

1	Siegel R, Ma J, Zou Z and Jemal A: Cancer statistics, 2014. CA Can J Clin. 64:9–29. 2014. View Article : Google Scholar
2	Bast RC Jr, Urban N, Shridhar V, Smith D, Zhang Z, Skates S, Lu K, Liu J, Fishman D and Mills G: Early detection of ovarian cancer: Promise and reality. Cancer Treat Res. 107:61–97. 2002.PubMed/NCBI
3	Berek JS: Ovarian cancer. Practical Gynecologic Oncology. Berek JS and Hacker NF: Lippincott Williams & Wilkins; Philadelphia, PA: pp. 443epp. 5112005
4	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
5	Newman DJ and Cragg GM: Natural products as sources of new drugs over the 30 years from 1981 to 2010. J Nat Prod. 75:311–35. 2012. View Article : Google Scholar : PubMed/NCBI
6	Over B, Wetzel S, Grütter C, Nakai Y, Renner S, Rauh D and Waldmann H: Natural-product-derived fragments for fragment-based ligand discovery. Nat Chem. 5:21–28. 2013. View Article : Google Scholar
7	Clough J, Chen S, Gordon EM, Hackbarth C, Lam S, Trias J, White RJ, Candiani G, Donadio S, Romanò G, et al: Combinatorial modification of natural products: Synthesis and in vitro analysis of derivatives of thiazole peptide antibiotic GE2270 A: A-ring modifications. Biorg Med Chem Lett. 13:3409–3414. 2003. View Article : Google Scholar
8	Cordier C, Morton D, Murrison S, Nelson A and O'Leary-Steele C: Natural products as an inspiration in the diversity-oriented synthesis of bioactive compound libraries. Nat Prod Rep. 25:719–737. 2008. View Article : Google Scholar : PubMed/NCBI
9	Newman DJ and Cragg GM: Natural products as sources of new drugs over the last 25 years. J Nat Prod. 70:461–477. 2007. View Article : Google Scholar : PubMed/NCBI
10	Cragg GM, Grothaus PG and Newman DJ: Impact of natural products on developing new anti-cancer agents. Chem Rev. 109:3012–3043. 2009. View Article : Google Scholar : PubMed/NCBI
11	Shah U, Shah R, Acharya S and Acharya N: Novel anticancer agents from plant sources. Chin J Nat Med. 11:16–23. 2013. View Article : Google Scholar
12	Zhang X, Chen LX, Ouyang L, Cheng Y and Liu B: Plant natural compounds: Targeting pathways of autophagy as anti-cancer therapeutic agents. Cell Prolif. 45:466–476. 2012. View Article : Google Scholar : PubMed/NCBI
13	Liggins J, Bluck LJ, Runswick S, Atkinson C, Coward WA and Bingham SA: Daidzein and genistein contents of vegetables. British J Nutr. 84:717–725. 2000.
14	Liggins J, Bluck LJ, Runswick S, Atkinson C, Coward WA and Bingham SA: Bingham Daidzein and genistein content of fruits and nuts. J Nutr Biochem. 11:326–331. 2000. View Article : Google Scholar : PubMed/NCBI
15	Cancer Genome Atlas Research Network: Integrated genomic analyses of ovarian carcinoma. Nature. 474:609–615. 2011. View Article : Google Scholar : PubMed/NCBI
16	Siegel R, Naishadham D and Jemal A: Cancer statistics, 2012. CA Cancer J Clin. 62:10–29. 2012. View Article : Google Scholar : PubMed/NCBI
17	Ullah MF, Ahmad A, Bhat SH, Khan HY, Zubair H, Sarkar FH and Hadi SM: Simulating hypoxia-induced acidic environment in cancer cells facilitates mobilization and redox-cycling of genomic copper by daidzein leading to pro-oxidant cell death: Implications for the sensitization of resistant hypoxic cancer cells to therapeutic challenges. Biometals. 29:299–310. 2016. View Article : Google Scholar : PubMed/NCBI
18	Choi EJ and Kim GH: Daidzein causes cell cycle arrest at the G1 and G2/M phases in human breast cancer MCF-7 and MDA-MB-453 cells. Phytomedicine. 15:683–690. 2008. View Article : Google Scholar : PubMed/NCBI
19	Jin S, Zhang QY, Kang XM, Wang JX and Zhao WH: Daidzein induces MCF-7 breast cancer cell apoptosis via the mitochondrial pathway. Ann Oncol. 21:263–268. 2009. View Article : Google Scholar : PubMed/NCBI
20	Zhang M, Liu Y, Gao Y and Li S: Silibinin-induced glioma cell apoptosis by PI3K-mediated but Akt-independent down-regulation of FoxM1 expression. Euro J Pharmacol. 765:346–354. 2015. View Article : Google Scholar
21	Lee HG, Park WJ, Shin SJ, Kwon SH, Cha SD, Seo YH, Jeong JH, Lee JY and Cho CH: Hsp90 inhibitor SY-016 induces G2/M arrest and apoptosis in paclitaxel-resistant human ovarian cancer cells. Oncol Lett. 13:2817–2822. 2017. View Article : Google Scholar
22	Gautier J, Solomon MJ, Booher RN, Bazan JF and Kirschner MW: cdc25 is a specific tyrosine phosphatase that directly activates p34^cdc2. Cell. 67:197–211. 1991. View Article : Google Scholar : PubMed/NCBI
23	Sancar A, Lindsey-Boltz LA, Unsal-Kaçmaz K and Linn S: Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Ann Rev Biochem. 73:39–85. 2004. View Article : Google Scholar : PubMed/NCBI
24	Harper JW, Adami GR, Wei N, Keyomarsi K and Elledge SJ: The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell. 75:805–816. 1993. View Article : Google Scholar : PubMed/NCBI
25	Baus F, Gire V, Fisher D, Piette J and Dulić V: Permanent cell cycle exit in G₂ phase after DNA damage in normal human fibro-blasts. EMBO J. 22:3992–4002. 2003. View Article : Google Scholar : PubMed/NCBI
26	Hsu YL, Kuo PL, Lin LT and Lin CC: Asiatic acid, a triterpene, induces apoptosis and cell cycle arrest through activation of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase pathways in human breast cancer cells. J Pharmacol Exp Ther. 313:333–344. 2005. View Article : Google Scholar : PubMed/NCBI
27	Sun SY, Hail N Jr and Lotan R: Apoptosis as a novel target for cancer chemoprevention. J Natl Can Inst. 96:662–672. 2004. View Article : Google Scholar
28	Singer G, Oldt R III, Cohen Y, Wang BG, Sidransky D and Kurman RJ; Shih IeM: Mutations in BRAF and KRAS characterize the development of low-grade ovarian serous carcinoma. J Natl Cancer Inst. 95:484–486. 2003. View Article : Google Scholar : PubMed/NCBI
29	Auner V, Kriegshäuser G, Tong D, Horvat R, Reinthaller A, Mustea A and Zeillinger R: KRAS mutation analysis in ovarian samples using a high sensitivity biochip assay. BMC Can. 9:1112009. View Article : Google Scholar
30	Scholzen T and Gerdes J: The Ki-67 protein: From the known and the unknown. J Cell Physiol. 182:311–322. 2000. View Article : Google Scholar : PubMed/NCBI
31	Noble P, Vyas M, Al-Attar A, Durrant S, Scholefield J and Durrant L: High levels of cleaved caspase-3 in colorectal tumour stroma predict good survival. Br J Cancer. 108:2097–2105. 2013. View Article : Google Scholar : PubMed/NCBI