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Genistein, a Dietary Ingested Isoflavonoid, Inhibits Cell Proliferation and In Vitro Angiogenesis^1,2,

Theodore Fotsis^3,*, Michael Pepper, Herman Adlercreutz, Tapio Hase^**, Roberto Montesano and Lothar Schweigerer^*

^* Department of Oncology and Immunology, Children's University Hospital, Ruprecht-Karls Universität, INF 150, 6900 Heidelberg, Germany Institute of Histology and Embryology, Department of Morphology, University Medical Center, 1121 Geneva 4, Switzerland Department of Clinical Chemistry, University of Helsinki, Meilahti Hospital, SF-00290 Helsinki, Finland ^** Department of Chemistry, University of Helsinki, Vuorikatu 20, SF-00100 Helsinki, Finland

Consumption of a plant-based diet can prevent the development and progression of chronic diseases that are associated with extensive neovascularization. To determine whether prevention might be associated with dietary derived angiogenesis inhibitors, we have fractionated urine of healthy human subjects consuming a plant-based diet and examined the fractions for their abilities to inhibit the proliferation of vascular endothelial cells. One of the most potent fractions contained several isoflavonoids, which we identified by gas chromatography-mass spectrometry and subsequently synthesized. Of all synthetic compounds, the isoflavonoid genistein was the most potent and inhibited endothelial cell proliferation and in vitro angiogenesis at half maximal concentrations of 5 and 150 µmol/L, respectively. Moreover, genistein inhibited the proliferation of various tumor cells. Genistein excretion in urine of subjects consuming a plant-based diet is in the micromolar range, which is 30-fold higher than that of subjects consuming a traditional Western diet. The high concentrations of genistein in urine of vegetarians and our present results suggest that genistein may contribute to the preventive effect of plant-based diet on chronic diseases, including solid tumors, by inhibiting neovascularization and tumor cell proliferation. Thus genistein may have important applications in the treatment of solid tumors and angiogenic diseases.

KEY WORDS: • diet • endothelial cells • invasion • plasminogen activator • plasminogen-activator inhibitor

¹ Presented at the First International Symposium on the Role of Soy in Preventing and Treating Chronic Disease, held in Mesa, AZ, February 20–23, 1994. The symposium was sponsored by Protein Technologies International, the soybean growers from Nebraska, Indiana, and Iowa and the United Soybean Board. Guest editors for this symposium were Mark Messina, 1543 Lincoln Street, Port Townsend, WA 98368, and John W. Erdman, Jr., Division of Nutritional Sciences, University of Illinois, Urbana, IL 61801-3852.

² Work in Heidelberg was supported by grants from Schwerpunkt "Entzündung" of the Land Baden-Württenberg, Deutsche Krebshilfe and Tumorzentrum Heidelberg-Mannheim, work in Geneva by grants from the Swiss National Science Foundation (31-26625.89) and the Sir Jules Thorn Charitable Overseas Trust and work in Helsinki by grants of the Finnish Cancer Foundation and the Sigrid Juselius Foundation.

³ To whom correspondence should be addressed.