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J Steroid Biochem Mol Biol. 2005 Apr;94(5):461-7. Epub 2005 Mar 16.
Mammalian lignans and genistein decrease the activities of aromatase and 17beta-hydroxysteroid dehydrogenase in MCF-7 cells. Brooks JD, Thompson LU.
Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, 150 College St., Toronto, Ont., Canada M5S 3E2.
Estrogen plays a major role in breast cancer development and progression. Breast tissue and cell lines contain the necessary enzymes for estrogen synthesis, including aromatase and 17beta-hydroxysteroid dehydrogenase (17beta-HSD). These enzymes can influence tissue exposure to estrogen and therefore have become targets for breast cancer treatment and prevention. This study determined whether the isoflavone genistein (GEN) and the mammalian lignans enterolactone (EL) and enterodiol (ED) would inhibit the activity of aromatase and 17beta-HSD type 1 in MCF-7 cancer cells, thereby decreasing the amount of estradiol (E2) produced and consequently cell proliferation. Results showed that 10 microM EL, ED and GEN significantly decreased the amount of estrone (E1) produced via the aromatase pathway by 37%, 81% and 70%, respectively. Regarding 17beta-HSD type 1, 50 microM EL and GEN maximally inhibited E2 production by 84% and 59%, respectively. The reduction in E1 and E2 production by EL and the reduction in E2 production by GEN were significantly related to a reduction in MCF-7 cell proliferation. 4-Hydroxyandrostene-3,17-dione (50 microM) did not inhibit aromatase but inhibited the conversion of E1 to E2 by 78%, suggesting that it is a 17beta-HSD type 1 inhibitor. In conclusion, modulation of local E2 synthesis is one potential mechanism through which ED, EL and GEN may protect against breast cancer.
PMID: 15876411 [PubMed - indexed for MEDLINE]
Mammalian lignans and genistein decrease the activ...[J Steroid Biochem Mol Biol. 2005] - PubMed Result
ScienceDirect - The Journal of Steroid Biochemistry and Molecular Biology : Mammalian lignans and genistein decrease the activities of aromatase and 17β-hydroxysteroid dehydrogenase in MCF-7 cells
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"Flaxseed's lignans
There is substantial evidence that flaxseed and its lignans (components in the fiber) inhibit estradiol carcinogenic effects.
Researchers at the Division of Oncology, Faculty of Health Sciences, University Hospital, Linkoping, Sweden, found that certain phytoestrogens in flaxseeds (enterodiol and enterolactone) counteracted the effects of estradiol (E2) and thereby inhibited the growth and angiogenesis (growth of blood vessels) in solid tumors in mice. Both flaxseed phytoestrogens (lignan derived) decreases the secretion of VEGF – vascular endothelial growth factor – in human breast cancer cells.
The researchers concluded that flaxseed and its lignans have potent anti-estrogenic effects on estrogen receptors positive breast cancer and may prove to be beneficial in breast cancer prevention in the future.
One of the main sources of phytoestrogens in the western diet is lignans. Plant lignans such as in flaxseeds or sesame seeds appear in their naturally occurring state in a form of a compound called SDG (secoisolariciresinol diglucoside). SDG is metabolized by gut bacteria (microflora) to the more bioactive mammalian lignans enterodiol and enterolactone."
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J Steroid Biochem Mol Biol. 1994 Aug;50(3-4):205-12.
Lignans and flavonoids inhibit aromatase enzyme in human preadipocytes. Wang C, Mäkelä T, Hase T, Adlercreutz H, Kurzer MS.
Department of Food Science and Nutrition, University of Minnesota, St Paul 55108.
Lignans and flavonoids are naturally-occurring diphenolic compounds found in high concentrations in whole grains, legumes, fruits and vegetables. Seven lignans and six flavonoids were evaluated for their abilities to inhibit aromatase enzyme activity in a human preadipose cell culture system. The lignan, enterolactone (Enl) and its theoretical precursors, 3'-demethoxy-3O-demethylmatairesinol (DMDM) and didemethoxymatairesinol (DDMM) decreased aromatase enzyme activity, with Ki values of 14.4, 5.0 and 7.3 microM, respectively. The flavonoids, coumestrol, luteolin and kaempferol also decreased aromatase enzyme activity, with Ki values of 1.3, 4.8 and 27.2 microM, respectively. Aminoglutethimide, a pharmaceutical aromatase inhibitor, showed a Ki value of 0.5 microM. Kinetic studies showed the inhibition by all compounds to be competitive. Smaller decreases in aromatase activity were observed with the lignan, enterodiol (End) and its theoretical precursors, O-demethylsecoisolariciresinol (ODSI), demethoxysecoisolariciresinol (DMSI) and didemethylsecoisolariciresinol (DDSI). The flavonoids, O-demethylangolensin (O-Dma), fisetin and morin showed no inhibitory effects. The inhibition of human preadipocyte aromatase activity by lignans and flavonoids suggests a mechanism by which consumption of lignan- and flavonoid-rich plant foods may contribute to reduction of estrogen-dependent disease, such as breast cancer.
PMID: 8049151 [PubMed - indexed for MEDLINE
Lignans and flavonoids inhibit aromatase enzyme in...[J Steroid Biochem Mol Biol. 1994] - PubMed Result
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J Endocrinol. 1995 Nov;147(2):295-302.
Inhibition of 5 alpha-reductase in genital skin fibroblasts and prostate tissue by dietary lignans and isoflavonoids.
Evans BA, Griffiths K, Morton MS.
Department of Child Health, University of Wales College of Medicine, Health Park, Cardiff, UK.
Isoflavonoids and lignans, constituents of many plant foods, have been proposed as protective agents in those populations with a low incidence of hormone-dependent cancers. They may act by their inhibition of the metabolism of growth-promoting steroid hormones. This report describes the inhibition of 5 alpha-reductase and 17 beta-hydroxysteroid dehydrogenase by six isoflavonoids and two lignans in human genital skin fibroblast monolayers and homogenates, and in benign prostatic hyperplasia tissue homogenates. In genital skin fibroblasts, genistein, biochanin A and equol were the most potent inhibitors of 5 alpha-reductase activity, each resulting in greater than 80% inhibition at a concentration of 100 microM. The IC50 values for genistein and a seven-compound mixture were approximately 35 microM and 20 microM (2.9 microM of each compound) respectively. Of the lignans, enterolactone was the most potent inhibitor. Inhibition by biochanin A was shown to be reversible. When genital skin fibroblast homogenates were used, biochanin A was found to inhibit 5 alpha-reductase isozymes 1 and 2 to differing extents (30% and 75% respectively). Genistein was shown to inhibit 5 alpha-reductase 2 in a non-competitive nature (Vmax and Km values without and with inhibitor were 30 and 20 pmol/mg protein per h and 177 and 170 nM respectively). All of the compounds tested inhibited 17 beta-hydroxysteroid dehydrogenase activity in genital skin fibroblast monolayers. When prostate tissue homogenates were used, the compounds tested were better inhibitors of 5 alpha-reductase 1 than 2.(ABSTRACT TRUNCATED AT 250 WORDS)
PMID: 7490559 [PubMed - indexed for MEDLINE]
Inhibition of 5 alpha-reductase in genital skin fi...[J Endocrinol. 1995] - PubMed Result
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Clinical Cancer Research 13, 1061-1067, February 1, 2007. doi: 10.1158/1078-0432.CCR-06-1651
© 2007 American Association for Cancer Research
Cancer Therapy: Preclinical
Flaxseed and Its Lignans Inhibit Estradiol-Induced Growth, Angiogenesis, and Secretion of Vascular Endothelial Growth Factor in Human Breast Cancer Xenografts In vivo
Malin Bergman Jungeström1, Lilian U. Thompson2 and Charlotta Dabrosin1
Authors' Affiliations: 1 Divison of Oncology, Faculty of Health Sciences, University Hospital, Linköping, Sweden and 2 Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
Requests for reprints: Charlotta Dabrosin, Division of Oncology, Faculty of Health Sciences, University Hospital, S-581 85 Linköping, Sweden. Phone: 46-13-22-85-95; Fax: 46-13-22-44-60; E-mail: chada{at}ibk.liu.se.
Purpose: Vascular endothelial growth factor (VEGF) is a potent stimulator of angiogenesis, which is crucial in cancer progression. We have previously shown that estradiol (E2) increases VEGF in breast cancer. Phytoestrogens are potential compounds in breast cancer prevention and treatment by poorly understood mechanisms. The main phytoestrogens in Western diet are lignans, and flaxseed is a rich source of the mammalian lignans enterodiol and enterolactone.
Experimental Design: In the present study, ovariectomized mice were treated with continuous release of E2. MCF-7 tumors were established and mice were fed with basal diet or 10% flaxseed, and two groups that were fed basal diet received daily injections with enterodiol or enterolactone (15 mg/kg body weight).
Results: We show that flaxseed, enterodiol, and enterolactone counteracted E2-induced growth and angiogenesis in solid tumors. Extracellular VEGF in vivo, sampled using microdialysis, in all intervention groups was significantly decreased compared with tumors in the basal diet group. Our in vivo findings were confirmed in vitro. By adding enterodiol or enterolactone, E2-induced VEGF secretion in MCF-7 cells decreased significantly without agonistic effects. The increased VEGF secretion by E2 in MCF-7 cells increased the expression of VEGF receptor-2 in umbilical vein endothelial cells, suggesting a proangiogenic effect by E2 by two different mechanisms, both of which were inhibited by the addition of lignans.
Conclusions: Our results suggest that
flaxseed and its lignans have potent antiestrogenic effects on estrogen receptor–positive breast cancer and may prove to be beneficial in breast cancer prevention strategies in the future.
Flaxseed and Its Lignans Inhibit Estradiol-Induced Growth, Angiogenesis, and Secretion of Vascular Endothelial Growth Factor in Human Breast Cancer Xenografts In vivo -- Bergman Jungeström et al. 13 (3): 1061 -- Clinical Cancer Research