Planta Med 2018; 84(09/10): 653-661
DOI: 10.1055/a-0587-5991
Biological and Pharmacological Activity
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

A Bivalent Role of Genistein in Sprouting Angiogenesis

Sarah Berndt
1   School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland
,
Mark E. Issa*
1   School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland
,
Gilles Carpentier*
2   Laboratoire CRRET, Faculté des Sciences et Technologie, Université Paris Est Créteil, Créteil Cedex, France
,
Muriel Cuendet
1   School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland
› Author Affiliations
Further Information

Publication History

received 15 November 2017
revised 26 February 2018

accepted 02 March 2018

Publication Date:
14 March 2018 (online)

Abstract

The effects of genistein on angiogenesis remain poorly understood. Some studies claim an antiangiogenic effect and others claim a pro-angiogenic one. Thus, the aim of this study was to determine if genistein may exhibit bivalent angiogenic effects. To address this question, genistein angiogenic modulatory effects were examined using an in vitro 3D angiogenesis model using human umbilical vein endothelial cells. In this model, a bivalent effect of genistein was demonstrated on sprouting angiogenesis, with angiogenic stimulation at low concentrations (0.001 – 1 µM) and inhibition at higher ones (25 – 100 µM). Enhancement of the endothelial tube formation correlated with an increase in human umbilical vein endothelial cell metabolic activity and proliferation. Inhibition of angiogenesis correlated with a decreased metabolic activity, proliferation, and migration. Moreover, high concentrations of genistein influenced human umbilical vein endothelial cell morphology. Expression of genes involved in the angiogenic process in response to genistein was measured to study the mechanism of action. Secretome profiling revealed that angiogenic regulators were modulated with genistein treatment. These results suggested a bivalent effect of genistein on human umbilical vein endothelial cell growth and angiogenesis, and further investigations on the benefit of genistein for cancer chemoprevention, cancer treatment, or pro-angiogenic therapies have to be carefully considered.

* Mark E. Issa and Gilles Carpentier contributed equally to this work.


Supporting Information

 
  • References

  • 1 Weis SM, Cheresh DA. Tumor angiogenesis: molecular pathways and therapeutic targets. Nat Med 2011; 17: 1359-1370
  • 2 Bridges EM, Harris AL. The angiogenic process as a therapeutic target in cancer. Biochem Pharmacol 2011; 81: 1183-1191
  • 3 Banerjee S, Li YW, Wang ZW, Sarkar FH. Multi-targeted therapy of cancer by genistein. Cancer Lett 2008; 269: 226-242
  • 4 Lee JH, Khor TO, Shu L, Su ZY, Fuentes F, Kong NT. Dietary phytochemicals and cancer prevention: Nrf2 signaling, epigenetics, and cell death mechanisms in blocking cancer initiation and progression. Pharmacol Ther 2013; 137: 153-171
  • 5 Lakshman M, Xu L, Ananthanarayanan V, Cooper J, Takimoto CH, Helenowski I, Pelling JC, Bergan RC. Dietary genistein inhibits metastasis of human prostate cancer in mice. Cancer Res 2008; 68: 2024-2032
  • 6 Hsieh CY, Santell RC, Haslam SZ, Helferich WG. Estrogenic effects of genistein on the growth of estrogen receptor-positive human breast cancer (MCF-7) cells in vitro and in vivo . Cancer Res 1998; 58: 3833-3838
  • 7 Constantinou AI, Krygier AE, Mehta RR. Genistein induces maturation of cultured human breast cancer cells and prevents tumor growth in nude mice. Am J Clin Nutr 1998; 68: 1426S-1430S
  • 8 Zhou JR, Gugger ET, Tanaka T, Guo Y, Blackburn GL, Clinton SK. Soybean phytochemicals inhibit the growth of transplantable human prostate carcinoma and tumor angiogenesis in mice. J Nutr 1999; 129: 1628-1635
  • 9 Farina HG, Pomies M, Alonso DF, Gomez DE. Antitumor and antiangiogenic activity of soy isoflavone genistein in mouse models of melanoma and breast cancer. Oncol Rep 2006; 16: 885-892
  • 10 Lee SH, Lee JH, Asahara T, Kim YS, Jeong HC, Ahn Y, Jung JS, Kwon SM. Genistein promotes endothelial colony-forming cell (ECFC) bioactivities and cardiac regeneration in myocardial infarction. PLoS One 2014; 9: e96155
  • 11 Bouker KB, Hilakivi-Clarke L. Genistein: does it prevent or promote breast cancer?. Environ Health Perspect 2000; 108: 701-708
  • 12 Park S, Sorenson CM, Sheibani N. PECAM-1 isoforms, eNOS and endoglin axis in regulation of angiogenesis. Clin Sci (Lond) 2015; 129: 217-234
  • 13 Kim SH, Kim CW, Jeon SY, Go RE, Hwang KA, Choi KC. Chemopreventive and chemotherapeutic effects of genistein, a soy isoflavone, upon cancer development and progression in preclinical animal models. Lab Anim Res 2014; 30: 143-150
  • 14 Khan N, Afaq F, Mukhtar H. Cancer chemoprevention through dietary antioxidants: progress and promise. Antioxid Redox Signal 2008; 10: 475-510
  • 15 Dixon RA, Ferreira D. Genistein. Phytochemistry 2002; 60: 205-211
  • 16 Martinez ME. Primary prevention of colorectal cancer: lifestyle, nutrition, exercise. Recent Results Cancer Res 2005; 166: 177-211
  • 17 Morton MS, Arisaka O, Miyake N, Morgan LD, Evans BA. Phytoestrogen concentrations in serum from Japanese men and women over forty years of age. J Nutr 2002; 132: 3168-3171
  • 18 deVere White RW, Tsodikov A, Stapp EC, Soares SE, Fujii H, Hackman RM. Effects of a high dose, aglycone-rich soy extract on prostate-specific antigen and serum isoflavone concentrations in men with localized prostate cancer. Nutr Cancer 2010; 62: 1036-1043
  • 19 Rabiau N, Kossai M, Braud M, Chalabi N, Satih S, Bignon YJ, Bernard-Gallon DJ. Genistein and daidzein act on a panel of genes implicated in cell cycle and angiogenesis by polymerase chain reaction arrays in human prostate cancer cell lines. Cancer Epidemiol 2010; 34: 200-206
  • 20 Su SJ, Yeh TM, Chuang WJ, Ho CL, Chang KL, Cheng HL, Liu HS, Cheng HL, Hsu PY, Chow NH. The novel targets for anti-angiogenesis of genistein on human cancer cells. Biochem Pharmacol 2005; 69: 307-318
  • 21 Cao G, OʼBrien CD, Zhou Z, Sanders SM, Greenbaum JN, Makrigiannakis A, DeLisser HM. Involvement of human PECAM-1 in angiogenesis and in vitro endothelial cell migration. Am J Physiol Cell Physiol 2002; 282: C1181-C1190
  • 22 Touil YS, Fellous A, Scherman D, Chabot GG. Flavonoid-induced morphological modifications of endothelial cells through microtubule stabilization. Nutr Cancer 2009; 61: 310-321
  • 23 Hwang KA, Choi KC. Anticarcinogenic effects of dietary phytoestrogens and their chemopreventive mechanisms. Nutr Cancer 2015; 67: 796-803
  • 24 Mizushina Y, Shiomi K, Kuriyama I, Takahashi Y, Yoshida H. Inhibitory effects of a major soy isoflavone, genistein, on human DNA topoisomerase II activity and cancer cell proliferation. Int J Oncol 2013; 43: 1117-1124
  • 25 Peterson G. Evaluation of the biochemical targets of genistein in tumor cells. The J Nutr 1995; 125: 784S-789S
  • 26 Banerjee S, Li Y, Wang Z, Sarkar FH. Multi-targeted therapy of cancer by genistein. Cancer Lett 2008; 269: 226-242
  • 27 Fotsis T, Pepper M, Adlercreutz H, Hase T, Montesano R, Schweigerer L. Genistein, a dietary ingested isoflavonoid, inhibits cell proliferation and in vitro angiogenesis. J Nutr 1995; 125: 790S-797S
  • 28 Wang Z, Zhang Y, Li Y, Banerjee S, Liao J, Sarkar FH. Down-regulation of Notch-1 contributes to cell growth inhibition and apoptosis in pancreatic cancer cells. Mol Cancer Ther 2006; 5: 483-493
  • 29 Domigan CK, Warren CM, Antanesian V, Happel K, Ziyad S, Lee S, Krall A, Duan L, Torres-Collado AX, Castellani LW, Elashoff D, Christofk HR, van der Bliek AM, Potente M, Iruela-Arispe ML. Autocrine VEGF maintains endothelial survival through regulation of metabolism and autophagy. J Cell Sci 2015; 128: 2236-2248
  • 30 Nakatsu MN, Hughes CC. An optimized three-dimensional in vitro model for the analysis of angiogenesis. Methods Enzymol 2008; 443: 65-82
  • 31 Issa ME, Berndt S, Carpentier G, Pezzuto JM, Cuendet M. Bruceantin inhibits multiple myeloma cancer stem cell proliferation. Cancer Biol Ther 2016; 17: 966-975
  • 32 Carpentier G. Angiogenesis analyzer. Faculté des Sciences et Technologie, Université Paris Est Creteil, Val de Marne, France. Available at https://imagej.nih.gov/ij/macros/toolsets/Angiogenesis Analyzer.txt Accessed November 9, 2017
  • 33 Carpentier G. Protein array analyzer for ImageJ. Faculté des Sciences et Technologie, Université Paris Est Creteil, Val de Marne, France Available at http://image.bio.methods.free.fr/ImageJ/?Protein-Array-Analyzer-for-ImageJ.html Accessed November 9, 2017