Effects of 5‑hydroxy‑4'‑nitro‑7‑propionyloxy‑genistein on inhibiting proliferation and invasion via activating reactive oxygen species in human ovarian cancer A2780/DDP cells

Bai,Jun; Yang,Bin‑Jian; Luo,Xin

doi:10.3892/ol.2018.7938

Effects of 5‑hydroxy‑4'‑nitro‑7‑propionyloxy‑genistein on inhibiting proliferation and invasion via activating reactive oxygen species in human ovarian cancer A2780/DDP cells

Authors:
- Jun Bai
- Bin‑Jian Yang
- Xin Luo
View Affiliations

Affiliations: Department of Obstetrics and Gynecology, The First Clinical School of Jinan University, Guangzhou, Guangdong 510632, P.R. China
Published online on: February 2, 2018 https://doi.org/10.3892/ol.2018.7938
Pages: 5227-5235

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

5‑hydroxy‑4'‑nitro‑7‑propionyloxy‑genistein (HNPG), a novel synthetic isoflavone derivative, was demonstrated to possess antitumor activity in gastric cancer and breast cancer in vitro, but its antitumor effect and mechanism in ovarian cancer has not been characterized. The aim of the present study was to investigate the effects of HNPG on inhibiting the proliferation and invasion in human ovarian cancer A2780 cell lines of cisplatin resistance (A2780/DDP) and elucidate its underlying molecular mechanism. The results indicated that HNPG presented with marked antitumor activity against A2780/DDP cells in vitro, significantly inhibited the rates of proliferation, clone formation, invasion and metastasis, and markedly induced apoptosis in dose‑ and time‑dependent manner. Simultaneously, levels of reactive oxygen species (ROS) were increased and mitochondrial membrane potential was decreased. In addition, Bcl‑2 expression was downregulated, Bax expression was upregulated, and the ratio of Bcl‑2/Bax was decreased. Concurrently, levels of Cyt‑C were markedly enhanced and the caspase cascade was triggered. Taken together, the results suggested that HNPG exerted anticancer effects through promoting ROS accumulation in cells, triggering mitochondrial apoptotic pathways and ultimately resulting in cells apoptosis. Therefore, HNPG serves as a potential candidate in the chemoprevention and/or treatment of cisplatin‑resistant human ovarian cancer.

View Figures

View References

1	Wijdeven RH, Pang B, Assaraf YG and Neefjes J: Old drugs, novel ways out: Drug resistance toward cytotoxic chemotherapeutics. Drug Resist Updat. 28:65–81. 2016. View Article : Google Scholar : PubMed/NCBI
2	Bergamini A, Pisano C, Di Napoli M, Arenare L, Della Pepa C, Tambaro R, Facchini G, Gargiulo P, Rossetti S, Mangili G, et al: Cisplatin can be safely administered to ovarian cancer patients with hypersensitivity to carboplatin. Gynecol Oncol. 144:72–76. 2017. View Article : Google Scholar : PubMed/NCBI
3	Brozovic A: The relationship between platinum drug resistance and epithelial-mesenchymal transition. Arch Toxicol. 91:605–619. 2017. View Article : Google Scholar : PubMed/NCBI
4	Jin L, Xu M, Luo XH and Zhu XF: Stephania tetrandra and ginseng-containing Chinese herbal formulation NSENL reverses cisplatin resistance in lung cancer xenografts. Am J Chin Med. 45:385–401. 2017. View Article : Google Scholar : PubMed/NCBI
5	Henklewska M, Pawlak A, Pruchnik H and Obminska-Mrukowicz B: Complex of platinum(II) with tris(2-carboxyethyl) phosphine induces apoptosis in canine lymphoma/leukemia cell lines. Anticancer Res. 37:539–546. 2017. View Article : Google Scholar : PubMed/NCBI
6	Chen Y, Cass SL, Kutty SK, Yee EM, Chan DS, Gardner CR, Vittorio O, Pasquier E, Black DS and Kumar N: Synthesis, biological evaluation and structure-activity relationship studies of isoflavene based mannich bases with potent anti-cancer activity. Bioorg Med Chem Lett. 25:5377–5383. 2015. View Article : Google Scholar : PubMed/NCBI
7	Uesawa Y, Sakagami H, Kagaya H, Yamashita M, Takao K and Sugita Y: Quantitative structure-cytotoxicity relationship of 3-benzylidenechromanones. Anticancer Res. 36:5803–5812. 2016. View Article : Google Scholar : PubMed/NCBI
8	Wootten D, Simms J, Koole C, Woodman OL, Summers RJ, Christopoulos A and Sexton PM: Modulation of the glucagon-like peptide-1 receptor signaling by naturally occurring and synthetic flavonoids. J Pharmacol Exp Ther. 336:540–550. 2011. View Article : Google Scholar : PubMed/NCBI
9	Nagib DA and MacMillan DW: Trifluoromethylation of arenes and heteroarenes by means of photoredox catalysis. Nature. 480:224–228. 2011. View Article : Google Scholar : PubMed/NCBI
10	Lv H, Yang J, Wang C, Yu F, Huang D and Ye L: The WNT7B protein promotes the migration and differentiation of human dental pulp cells partly through WNT/beta-catenin and c-Jun N-terminal kinase signalling pathways. Arch Oral Biol. 87:54–61. 2017. View Article : Google Scholar : PubMed/NCBI
11	Wang JH, Gao CJ and Meng Lk: Study on the synthesis and antitumor effects of 5-Hydroxy-4′-nitro-7-propionyloxy-isoflavone. China Pharmacist. 15:1378–1385. 2012.(In Chinese).
12	Jin YS, Liu CM, Wu QY, Yao B, Dai Y, Zhang LR and Shen XL: Design and synthesis of genistein derivatives 5-hydroxy-4′-nitro-7-substituted acyloxy isoflavone and their antitumor effects. Acad J Mil Med Univ. 26:182–185. 2005.(In Chinese).
13	Singh S, Guetzko M and Resnick K: Preoperative predictors of delay in initiation of adjuvant chemotherapy in patients undergoing primary debulking surgery for ovarian cancer. Gynecol Oncol. 143:241–245. 2016. View Article : Google Scholar : PubMed/NCBI
14	Xu Z, Mei J and Tan Y: Baicalin attenuates DDP (cisplatin) resistance in lung cancer by downregulating MARK2 and p-Akt. Int J Oncol. 50:93–100. 2017. View Article : Google Scholar : PubMed/NCBI
15	Solmaz Hasdemir P and Guvena T: Borderline ovarian tumors A contemporary review of clinicopathological characteristics, diagnostic methods and therapeutic options. J Buon. 21:780–786. 2016.PubMed/NCBI
16	Erdogan S, Turkekul K, Serttas R and Erdogan Z: The natural flavonoid apigenin sensitizes human CD44+ prostate cancer stem cells to cisplatin therapy. Biomed Pharmacother. 88:210–217. 2017. View Article : Google Scholar : PubMed/NCBI
17	Mirzaei MR, Mahmoodi M, Hassanshahi G and Ahmadi Z: Down-regulation of anti-apoptotic genes in tumor cell lines is facilitated by suppression of OCT4B1. Adv Med Sci. 62:97–102. 2016. View Article : Google Scholar : PubMed/NCBI
18	Jian KL, Zhang C, Shang ZC, Yang L and Kong LY: Eucalrobusone C suppresses cell proliferation and induces ROS-dependent mitochondrial apoptosis via the p38 MAPK pathway in hepatocellular carcinoma cells. Phytomedicine. 25:71–82. 2017. View Article : Google Scholar : PubMed/NCBI
19	Han X, Zhen S, Ye Z, Lu J, Wang L, Li P, Li J, Zheng X, Li H, Chen W, et al: A feedback loop between miR-30a/c-5p and DNMT1 mediates cisplatin resistance in ovarian cancer cells. Cell Physiol Biochem. 41:973–986. 2017. View Article : Google Scholar : PubMed/NCBI
20	Bauer G: Central signaling elements of intercellular reactive oxygen/nitrogen species-dependent induction of apoptosis in malignant cells. Anticancer Res. 37:499–513. 2017. View Article : Google Scholar : PubMed/NCBI
21	Pluchino LA, Choudhary S and Wang HC: Reactive oxygen species-mediated synergistic and preferential induction of cell death and reduction of clonogenic resistance in breast cancer cells by combined cisplatin and FK228. Cancer Lett. 381:124–132. 2016. View Article : Google Scholar : PubMed/NCBI
22	Bauer D, Werth F, Nguyen HA, Kiecker F and Eberle J: Critical role of reactive oxygen species (ROS) for synergistic enhancement of apoptosis by vemurafenib and the potassium channel inhibitor TRAM-34 in melanoma cells. Cell Death Dis. 8:e25942017. View Article : Google Scholar : PubMed/NCBI
23	Zajac J, Kostrhunova H, Novohradsky V, Vrana O, Raveendran R, Gibson D, Kasparkova J and Brabec V: Potentiation of mitochondrial dysfunction in tumor cells by conjugates of metabolic modulator dichloroacetate with a Pt (IV) derivative of oxaliplatin. J Inorg Biochem. 156:89–97. 2016. View Article : Google Scholar : PubMed/NCBI
24	Vijayarathna S, Oon CE, Chen Y, Kanwar JR and Sasidharan S: Polyalthia longifolia methanolic leaf extracts (PLME) induce apoptosis, cell cycle arrest and mitochondrial potential depolarization by possibly modulating the redox status in hela cells. Biomed Pharmacother. 89:499–514. 2017. View Article : Google Scholar : PubMed/NCBI
25	Nasser MI, Masood M, Wei W and Li X, Zhou Y, Liu B, Li J and Li X: Cordycepin induces apoptosis in SGC-7901 cells through mitochondrial extrinsic phosphorylation of PI3K/Akt by generating ROS. Int J Oncol. 50:911–919. 2017. View Article : Google Scholar : PubMed/NCBI
26	Hsin IL, Wang SC, Li JR, Ciou TC, Wu CH, Wu HM and Ko JL: Immunomodulatory proteins FIP-gts and chloroquine induce caspase-independent cell death via autophagy for resensitizing cisplatin-resistant urothelial cancer cells. Phytomedicine. 23:1566–1573. 2016. View Article : Google Scholar : PubMed/NCBI
27	Leekha A, Gurjar BS, Tyagi A, Rizvi MA and Verma AK: Vitamin C in synergism with cisplatin induces cell death in cervical cancer cells through altered redox cycling and p53 upregulation. J Cancer Res Clin Oncol. 142:2503–2514. 2016. View Article : Google Scholar : PubMed/NCBI