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Flavonoids, Dietary-Derived Inhibitors of Cell Proliferation and in Vitro Angiogenesis' Theodorefotsis,2Michaels

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Flavonoids, Dietary-Derived Inhibitors of Cell Proliferation and in Vitro Angiogenesis' Theodorefotsis,2Michaels CANCER RESEARCH 57. 2916-2921. July 15. 19971 Flavonoids, Dietary-derived Inhibitors of Cell Proliferation and in Vitro Angiogenesis' TheodoreFotsis,2MichaelS. Pepper,ErkanAktas,StephenBreit,3Sirpa Rasku,HermanAdlercreutz, Kristiina Wähälä,Roberto Montesano, and Lothar Schweigerer@ Division of Hema:olog@ and Oncologe. Children ‘sHospital, Ruprecht-Karls Universir-v, INF 150, 69120 Heidelberg, Germany (T. F.. E. A., S. B., L SI: Institute of Histology and Embryology. Departnient of Morphology. Unis'ersitv Medical Center, 1121 Geneva 4, Switzerland (M. S. P., R. MI; Department of C'hemistrv, Organic C'hemistry Laboratory, P. 0. Box 55. University of Helsinki, FIN-IXXJI4Helsinki. Finland (S. R., K. WI: Department of Clinical Chemistry. Meilahti Hospital. University of Helsinki. SF-00290 Helsinki. Finland jH. A.! ABSTRACT diseases (8); however, an increased risk for these diseases accompa nies a change toward a Westernized diet (9). These data indicate that Consumption of a plant-based diet can prevent the development and certain plant-derived dietary groups might contain compounds that progression of chronic diseases associated with extensive neovasculariza exert antimitotic and antitumorigenic effects, thereby offering anti tion, including solid malignant tumors. In previous studies, we have shown that the plant-derived isoflavonoid genistein is a potent inhibitor of cell cancer protection to individuals consuming such diets. Identification proliferation and in vitroangiogenesis. In the present study, we report that and characterization of such compounds might provide us with addi certain structurally related flavonoids are more potent inhibitors than tional chemotherapeutic agents for pharmacological intervention in genistein. Indeed, 3-hydroxyflavone, 3',4'-dihydroxyflavone, 2',3'-dihy cancer. droxyflavone, fisetin, apigenin, and luteolin inhibited the proliferation of The idea that dietary ingested compounds could modulate prolifer normal and tumor cells, as well as in vitro angiogenesis, at half-maximal ation of tumor cells and pathological angiogenesis appeared to us to concentrations in the low micromolar range. We have previously demon be an important possibility meriting further investigation. If dietary strated that genistein concentrations in the urine of subjects consuming a compounds were to inhibit angiogenesis, this could explain, at least in plant-based diet Is 30-fold higher than in subjects consuming a traditional part, the long-known preventive effect of plant-based diets on tumor Western diet. The wider distribution and the more abundant presence of igenesis and other chronic diseases, such as inflammation (5). In flavonoids in the plant kingdom, together with the present results, suggest that flavonoids may contribute to the preventive effect of a plant-based previous studies, we examined this possibility by screening the urine diet on chronic diseases, including solid tumors. of human subjects consuming a diet rich in plant products for the presence of antimitotic and antiangiogenic compounds. This work led to the identification of the isoflavonoid genistein as a potent inhibitor INTRODUCTION of cell proliferation and in vitro angiogenesis (10, 11). Further studies Angiogenesis, the generation of new capillaries from preexisting showed that the excretion of genistein in urine of vegetarians is vessels, is virtually absent in the healthy adult organism in which it is 30-fold higher than that of omnivores (12—14).In the present study, restricted to a few conditions including wound healing and the for we extended these observations by investigating the antimitotic and mation of corpus luteum, endometrium, and placenta. These condi antiangiogenic effects of flavonoids, a group of compounds that are tions of physiological angiogenesis represent ordered, tightly regu isomeric to isoflavonoids. Flavonoid aglycones all consist of a ben bated, and self-limited processes ( I). However, in certain pathological zene ring (A) fused with a six-member ring (C) that in position 2 conditions, angiogenesis is dramatically enhanced and loses its self carries a phenyb ring (B) as a substituent (Table I), whereas isofla limiting capacity (2). Although pathological angiogenesis is seen vonoids carry the B ring in position 3. Flavonoids are more widely during the development and progression of many diseases, such as distributed in the plant kingdom (15—17),rendering them a very rheumatoid arthritis, psoriasis, and diabetic retinopathy, from a din attractive target for further studies. ical perspective, probably the most important manifestation of path obogical angiogenesis is that induced by solid tumors (3). Well MATERIALS AND METHODS vascularized tumors expand both locally and by metastasis, whereas avascular tumors do not grow beyond a diameter of 1—2mm (1, 4). Materials and Instrumentation. All flavonoids except 2',3'-dihydroxy Dietary factors contribute to about one-third of potentially prevent flavone, 3',4'-dihydroxyflavone, coumarin, and catechin were obtained from able cancers (5), and the long-known preventive effect of plant-based Roth Chemikalien (Karlsruhe, Germany). 2',3'-Dihydroxyflavone and 3',4'- diets on tumorigenesis and other chronic diseases is well documented dihydroxyflavone were synthesized as described below. The various (6). Breast, prostate, and endometnal cancer belong to a group of flavonoids were prepared in 10 mM stock solutions. Apigenin, chrysin, hormone-dependent cancers that, like colon cancer and coronary heart 3',4'-dihydroxyflavone, 3',4'—dihydroxyflavone, luteolin-7-glucoside, and disease, are among those chronic diseases that have a bower incidence 3-hydroxyflavone were dissolved in ethanol. All the other compounds were in Asia than in Western countries (7). Immigrants from Asia who dissolved in ethanol: DMSO (1:1, v/v). DMSO was obtained from Merck (Darmstadt, Germany). When stored at 4°C,stocksolutions of the substances maintain their traditional diet do not increase their risk of these remained bioactive for more than I month. ‘Hand‘3CNMR4spectra were recorded on a Varian GEMINI-200 FT Received I/7/97; accepted 5/13/97. spectrometer. Mass spectra were obtained with a JEOL JMS SX1O2 mass The costs of publication of this article were defrayed in part by the payment of page spectrometer operating at 70 eV. Samples were introduced by a direct inlet charges. This article must therefore be hereby marked advertisement in accordance with I8 U.S.C. Section 1734 solely to indicate this fact. probe. The UV spectra were recorded with a CARY SE UV-VIS-NIR spec I Work in Heidelberg was supported by grants from Deutsche Forschungsgemein tophotometer. Melting points were determined in open capillary tubes with an schaft, Kulemann-Stiftung, and Deutsche Krebshilfe; work in Geneva by Grant 31- Electrothermal apparatus and are uncorrected. TLC was conducted on Merck 43364.95 from the Swiss National Science Foundation; and work in Helsinki by grants from the Finnish Cancer Foundation and the Sigrid Juselius Foundation. 2To whom requests for reprints should be addressed, at Laboratory of Biological 4 The abbreviationsusedare: NMR, nuclearmagneticresonance;THF, tetrahydrofu Chemistry. Medical School. University of loannina, 451 10 loannina, Greece. Phone: ran; LiHMDS, lithium bis(trimethylsilyl)amide; BBCE, brain capillary endothelial; ACE, (30)65 1 28388; Fax: (30)65 1 33442; E-mail: [email protected]. adrenal cortex endothelial; BAE, bovine aorta endothelial; HUVE, human umbilical vein 3 Present address: Department of Hematology, Oncology and Endocrinology. Chil endothelial; FGF, fibroblast growth factor; bFGF, basic FGF; BME, bovine microvascular dren's Hospital. University of Essen, Hufelandstrasse 55. 45 122 Essen. Germany. endothelial; VEGF, vascular endothelial growth factor. 2916 Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1997 American Association for Cancer Research. FLAVONOIDS INHIBIT IN VITROANGIOGENESIS silica gel 60 P254 plates. THF was distilled over CaH2. LiHMDS was titrated Heidelberg, Germany). MCF-7 cells were cultured in MEM with nonessential before use with 1-pyreneacetic acid (18). amino acids, sodium pyruvate (1 mmol/liter), bovine insulin (10 @xg/liter),10% Synthesis of 2',3'-Dlhydroxyflavone and 3',4'-Dihydroxyflavone. 2',3'- fetal bovine serum, and antibiotics. Tumor cells from human neuroblastoma Dihydroxyflavone was synthesized via 2',3'-dimethoxyflavone as follows. A (SH-EP) and their MYCN oncogene stable transfectants (WAC 2) were a gift solution of 0.81 MLiHMDS in THF (38 ml, 30.6 mmol) was added dropwise from Prof. M. Schwab (DKFZ) and maintained in RPMI 1640 with 10% to 2-hydroxyacetophenone (0.46 ml, 3.8 mmol) in dry THF (15 ml) under newborn calf serum and antibiotics. In the cultures of WAC 2 cells, the argon at —78°C.Themixture was stirred at —78°CforI h and then at —10°C antibiotic geneticin (200 @xg/ml) was also added for selection. for 2 h. Methyl 2,3-dimethoxybenzoate [prepared from 2,3-dimethoxybenzoic Cell Proliferation Assay. Stock cultureswere trypsinized(25), cells were acid with methanol and H2S04 (cat.) at room temperature; 0.75 g, 3.8 mmoll adjusted to a density of 5 X l0@cells/mI (or 2 X l0@cells/mI in the case of in dry THF (3 ml) was added at —78°Cin one portion. The reaction was HUVE cells) in their respective media, and seeded in 1-mI aliquots into continued at —78°Cfor I h and then at room temperature for 20 h (TLC 12-well cluster dishes. After 16 h, wells received 5-pi aliquots of either solvent
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