Skip to main content
Erschienen in: Cancer Chemotherapy and Pharmacology 6/2017

12.05.2017 | Original Article

CYT-Rx20 inhibits ovarian cancer cells in vitro and in vivo through oxidative stress-induced DNA damage and cell apoptosis

verfasst von: Yen-Yun Wang, Yuk-Kwan Chen, Stephen Chu-Sung Hu, Ya-Ling Hsu, Chun-Hao Tsai, Tsung-Chen Chi, Wan-Ling Huang, Pei-Wen Hsieh, Shyng-Shiou F. Yuan

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 6/2017

Einloggen, um Zugang zu erhalten

Abstract

Purpose

The β-nitrostyrene family has been previously reported to possess anticancer property. However, the biological effects of β-nitrostyrenes on ovarian cancer and the underlying mechanisms involved remain unclear. In the present study, we synthesized a β-nitrostyrene derivative, CYT-Rx20 3′-hydroxy-4′-methoxy-β-methyl-β-nitrostyrene), and investigated its anticancer effects and the putative pathways of action in ovarian cancer.

Methods

The effects of CYT-Rx20 were analyzed using cell viability assay, reactive oxygen species (ROS) generation assay, FACS analysis, annexin V staining, immunostaining, comet assay, immunoblotting, soft agar assay, migration assay, nude mice xenograft study and immunohistochemistry.

Results

CYT-Rx20 induced cytotoxicity in ovarian cancer cells by promoting cell apoptosis via ROS generation and DNA damage. CYT-Rx20-induced cell apoptosis, ROS generation and DNA damage were reversed by thiol antioxidants. In addition, CYT-Rx20 inhibited ovarian cancer cell migration by regulating the expression of epithelial to mesenchymal transition (EMT) markers. In nude mice, CYT-Rx20 inhibited ovarian tumor growth accompanied by increased expression of DNA damage marker γH2AX and decreased expression of EMT marker Vimentin.

Conclusions

CYT-Rx20 inhibits ovarian cancer cells in vitro and in vivo, and has the potential to be further developed into an anti-ovarian cancer drug clinically.
Anhänge
Nur mit Berechtigung zugänglich
Literatur
5.
Zurück zum Zitat Chen IH, Chang FR, Wu YC, Kung PH, Wu CC (2015) 3,4-Methylenedioxy-beta-nitrostyrene inhibits adhesion and migration of human triple-negative breast cancer cells by suppressing beta1 integrin function and surface protein disulfide isomerase. Biochimie 110:81–92. doi:10.1016/j.biochi.2015.01.006 CrossRefPubMed Chen IH, Chang FR, Wu YC, Kung PH, Wu CC (2015) 3,4-Methylenedioxy-beta-nitrostyrene inhibits adhesion and migration of human triple-negative breast cancer cells by suppressing beta1 integrin function and surface protein disulfide isomerase. Biochimie 110:81–92. doi:10.​1016/​j.​biochi.​2015.​01.​006 CrossRefPubMed
6.
Zurück zum Zitat Rahmani-Nezhad S, Safavi M, Pordeli M, Ardestani SK, Khosravani L, Pourshojaei Y, Mahdavi M, Emami S, Foroumadi A, Shafiee A (2014) Synthesis, in vitro cytotoxicity and apoptosis inducing study of 2-aryl-3-nitro-2H-chromene derivatives as potent anti-breast cancer agents. Eur J Med Chem 86:562–569. doi:10.1016/j.ejmech.2014.09.017 CrossRefPubMed Rahmani-Nezhad S, Safavi M, Pordeli M, Ardestani SK, Khosravani L, Pourshojaei Y, Mahdavi M, Emami S, Foroumadi A, Shafiee A (2014) Synthesis, in vitro cytotoxicity and apoptosis inducing study of 2-aryl-3-nitro-2H-chromene derivatives as potent anti-breast cancer agents. Eur J Med Chem 86:562–569. doi:10.​1016/​j.​ejmech.​2014.​09.​017 CrossRefPubMed
8.
Zurück zum Zitat He Y, Varadarajan S, Munoz-Planillo R, Burberry A, Nakamura Y, Nunez G (2014) 3,4-Methylenedioxy-beta-nitrostyrene inhibits NLRP3 inflammasome activation by blocking assembly of the inflammasome. J Biol Chem 289(2):1142–1150. doi:10.1074/jbc.M113.515080 CrossRefPubMed He Y, Varadarajan S, Munoz-Planillo R, Burberry A, Nakamura Y, Nunez G (2014) 3,4-Methylenedioxy-beta-nitrostyrene inhibits NLRP3 inflammasome activation by blocking assembly of the inflammasome. J Biol Chem 289(2):1142–1150. doi:10.​1074/​jbc.​M113.​515080 CrossRefPubMed
9.
Zurück zum Zitat Carter KC, Finnon YS, Daeid NN, Robson DC, Waddell R (2002) The effect of nitrostyrene on cell proliferation and macrophage immune responses. Immunopharmacol Immunotoxicol 24(2):187–197. doi:10.1081/iph-120003749 CrossRefPubMed Carter KC, Finnon YS, Daeid NN, Robson DC, Waddell R (2002) The effect of nitrostyrene on cell proliferation and macrophage immune responses. Immunopharmacol Immunotoxicol 24(2):187–197. doi:10.​1081/​iph-120003749 CrossRefPubMed
10.
Zurück zum Zitat Zeng Z, Sun Z, Huang M, Zhang W, Liu J, Chen L, Chen F, Zhou Y, Lin J, Huang F, Xu L, Zhuang Z, Guo S, Alitongbieke G, Xie G, Xu Y, Lin B, Cao X, Su Y, Zhang XK, Zhou H (2015) Nitrostyrene derivatives act as RXRalpha ligands to inhibit TNFalpha activation of NF-kappaB. Cancer Res 75(10):2049–2060. doi:10.1158/0008-5472.can-14-2435 CrossRefPubMedPubMedCentral Zeng Z, Sun Z, Huang M, Zhang W, Liu J, Chen L, Chen F, Zhou Y, Lin J, Huang F, Xu L, Zhuang Z, Guo S, Alitongbieke G, Xie G, Xu Y, Lin B, Cao X, Su Y, Zhang XK, Zhou H (2015) Nitrostyrene derivatives act as RXRalpha ligands to inhibit TNFalpha activation of NF-kappaB. Cancer Res 75(10):2049–2060. doi:10.​1158/​0008-5472.​can-14-2435 CrossRefPubMedPubMedCentral
11.
Zurück zum Zitat Hung AC, Tsai CH, Hou MF, Chang WL, Wang CH, Lee YC, Ko A, Hu SC, Chang FR, Hsieh PW, Yuan SS (2016) The synthetic beta-nitrostyrene derivative CYT-Rx20 induces breast cancer cell death and autophagy via ROS-mediated MEK/ERK pathway. Cancer Lett 371(2):251–261. doi:10.1016/j.canlet.2015.11.035 CrossRefPubMed Hung AC, Tsai CH, Hou MF, Chang WL, Wang CH, Lee YC, Ko A, Hu SC, Chang FR, Hsieh PW, Yuan SS (2016) The synthetic beta-nitrostyrene derivative CYT-Rx20 induces breast cancer cell death and autophagy via ROS-mediated MEK/ERK pathway. Cancer Lett 371(2):251–261. doi:10.​1016/​j.​canlet.​2015.​11.​035 CrossRefPubMed
12.
13.
Zurück zum Zitat Chen HM, Wu YC, Chia YC, Chang FR, Hsu HK, Hsieh YC, Chen CC, Yuan SS (2009) Gallic acid, a major component of Toona sinensis leaf extracts, contains a ROS-mediated anti-cancer activity in human prostate cancer cells. Cancer Lett 286(2):161–171. doi:10.1016/j.canlet.2009.05.040 CrossRefPubMed Chen HM, Wu YC, Chia YC, Chang FR, Hsu HK, Hsieh YC, Chen CC, Yuan SS (2009) Gallic acid, a major component of Toona sinensis leaf extracts, contains a ROS-mediated anti-cancer activity in human prostate cancer cells. Cancer Lett 286(2):161–171. doi:10.​1016/​j.​canlet.​2009.​05.​040 CrossRefPubMed
14.
Zurück zum Zitat Yuan SS, Hou MF, Hsieh YC, Huang CY, Lee YC, Chen YJ, Lo S (2012) Role of MRE11 in cell proliferation, tumor invasion, and DNA repair in breast cancer. J Natl Cancer Inst 104(19):1485–1502. doi:10.1093/jnci/djs355 CrossRefPubMed Yuan SS, Hou MF, Hsieh YC, Huang CY, Lee YC, Chen YJ, Lo S (2012) Role of MRE11 in cell proliferation, tumor invasion, and DNA repair in breast cancer. J Natl Cancer Inst 104(19):1485–1502. doi:10.​1093/​jnci/​djs355 CrossRefPubMed
15.
Zurück zum Zitat Krajewska M, Krajewski S, Epstein JI, Shabaik A, Sauvageot J, Song K, Kitada S, Reed JC (1996) Immunohistochemical analysis of bcl-2, bax, bcl-X, and mcl-1 expression in prostate cancers. Am J Pathol 148(5):1567–1576PubMedPubMedCentral Krajewska M, Krajewski S, Epstein JI, Shabaik A, Sauvageot J, Song K, Kitada S, Reed JC (1996) Immunohistochemical analysis of bcl-2, bax, bcl-X, and mcl-1 expression in prostate cancers. Am J Pathol 148(5):1567–1576PubMedPubMedCentral
19.
Zurück zum Zitat Kuo LJ, Yang LX (2008) Gamma-H2AX-a novel biomarker for DNA double-strand breaks. In vivo 22(3):305–309PubMed Kuo LJ, Yang LX (2008) Gamma-H2AX-a novel biomarker for DNA double-strand breaks. In vivo 22(3):305–309PubMed
24.
Zurück zum Zitat Pan ST, Qin Y, Zhou ZW, He ZX, Zhang X, Yang T, Yang YX, Wang D, Qiu JX, Zhou SF (2015) Plumbagin induces G2/M arrest, apoptosis, and autophagy via p38 MAPK- and PI3 K/Akt/mTOR-mediated pathways in human tongue squamous cell carcinoma cells. Drug Des Devel Ther 9:1601–1626. doi:10.2147/dddt.s76057 PubMedPubMedCentral Pan ST, Qin Y, Zhou ZW, He ZX, Zhang X, Yang T, Yang YX, Wang D, Qiu JX, Zhou SF (2015) Plumbagin induces G2/M arrest, apoptosis, and autophagy via p38 MAPK- and PI3 K/Akt/mTOR-mediated pathways in human tongue squamous cell carcinoma cells. Drug Des Devel Ther 9:1601–1626. doi:10.​2147/​dddt.​s76057 PubMedPubMedCentral
25.
Zurück zum Zitat Armstrong JS, Steinauer KK, Hornung B, Irish JM, Lecane P, Birrell GW, Peehl DM, Knox SJ (2002) Role of glutathione depletion and reactive oxygen species generation in apoptotic signaling in a human B lymphoma cell line. Cell Death Differ 9(3):252–263. doi:10.1038/sj.cdd.4400959 CrossRefPubMed Armstrong JS, Steinauer KK, Hornung B, Irish JM, Lecane P, Birrell GW, Peehl DM, Knox SJ (2002) Role of glutathione depletion and reactive oxygen species generation in apoptotic signaling in a human B lymphoma cell line. Cell Death Differ 9(3):252–263. doi:10.​1038/​sj.​cdd.​4400959 CrossRefPubMed
27.
31.
Zurück zum Zitat Yang X, Zheng F, Xing H, Gao Q, Wei W, Lu Y, Wang S, Zhou J, Hu W, Ma D (2004) Resistance to chemotherapy-induced apoptosis via decreased caspase-3 activity and overexpression of antiapoptotic proteins in ovarian cancer. J Cancer Res Clin Oncol 130(7):423–428. doi:10.1007/s00432-004-0556-9 CrossRefPubMed Yang X, Zheng F, Xing H, Gao Q, Wei W, Lu Y, Wang S, Zhou J, Hu W, Ma D (2004) Resistance to chemotherapy-induced apoptosis via decreased caspase-3 activity and overexpression of antiapoptotic proteins in ovarian cancer. J Cancer Res Clin Oncol 130(7):423–428. doi:10.​1007/​s00432-004-0556-9 CrossRefPubMed
32.
Zurück zum Zitat Nicholson DW, Thornberry NA (1997) Caspases: killer proteases. Trends Biochem Sci 22(8):299–306CrossRefPubMed Nicholson DW, Thornberry NA (1997) Caspases: killer proteases. Trends Biochem Sci 22(8):299–306CrossRefPubMed
33.
Zurück zum Zitat Voulgari A, Pintzas A (2009) Epithelial-mesenchymal transition in cancer metastasis: mechanisms, markers and strategies to overcome drug resistance in the clinic. Biochim Biophys Acta 1796(2):75–90. doi:10.1016/j.bbcan.2009.03.002 PubMed Voulgari A, Pintzas A (2009) Epithelial-mesenchymal transition in cancer metastasis: mechanisms, markers and strategies to overcome drug resistance in the clinic. Biochim Biophys Acta 1796(2):75–90. doi:10.​1016/​j.​bbcan.​2009.​03.​002 PubMed
34.
Zurück zum Zitat Haslehurst AM, Koti M, Dharsee M, Nuin P, Evans K, Geraci J, Childs T, Chen J, Li J, Weberpals J, Davey S, Squire J, Park PC, Feilotter H (2012) EMT transcription factors snail and slug directly contribute to cisplatin resistance in ovarian cancer. BMC Cancer 12:91. doi:10.1186/1471-2407-12-91 CrossRefPubMedPubMedCentral Haslehurst AM, Koti M, Dharsee M, Nuin P, Evans K, Geraci J, Childs T, Chen J, Li J, Weberpals J, Davey S, Squire J, Park PC, Feilotter H (2012) EMT transcription factors snail and slug directly contribute to cisplatin resistance in ovarian cancer. BMC Cancer 12:91. doi:10.​1186/​1471-2407-12-91 CrossRefPubMedPubMedCentral
Metadaten
Titel
CYT-Rx20 inhibits ovarian cancer cells in vitro and in vivo through oxidative stress-induced DNA damage and cell apoptosis
verfasst von
Yen-Yun Wang
Yuk-Kwan Chen
Stephen Chu-Sung Hu
Ya-Ling Hsu
Chun-Hao Tsai
Tsung-Chen Chi
Wan-Ling Huang
Pei-Wen Hsieh
Shyng-Shiou F. Yuan
Publikationsdatum
12.05.2017
Verlag
Springer Berlin Heidelberg
Erschienen in
Cancer Chemotherapy and Pharmacology / Ausgabe 6/2017
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-017-3330-9

Weitere Artikel der Ausgabe 6/2017

Cancer Chemotherapy and Pharmacology 6/2017 Zur Ausgabe

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.