Flaxseed, Lignans, And Inhibiting Cancer

Pubs Related to Flaxseed AND Cancer 1: Clin Cancer Res. 2007 Feb 1;13(3):1061-7. Related Articles, Links Click here to read 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 M, Thompson LU, Dabrosin C. Divison of Oncology, Faculty of Health Sciences, University Hospital, Linköping, Sweden. 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. Publication Types: * Research Support, Non-U.S. Gov't PMID: 17289903 [PubMed - indexed for MEDLINE] 2: Clin Transl Oncol. 2006 Nov;8(11):812-20.

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HER2 (erbB-2)-targeted effects of the omega-3 polyunsaturated fatty acid, alpha-linolenic acid (ALA; 18:3n-3), in breast cancer cells: the "fat features" of the "Mediterranean diet" as an "antiHER2 cocktail". Menéndez JA, Vázquez-Martín A, Ropero S, Colomer R, Lupu R. Fundació d'Investigació Biomédica de Girona Dr. Josep Trueta (IdIBGi), Girona, Catalonia. Spain. [email protected] BACKGROUND: Data derived from epidemiological and experimental studies suggest that alphalinolenic acid (ALA; 18:3n-3), the main omega-3 polyunsaturated fatty acid (PUFA) present in the Western diet, may have protective effects in breast cancer risk and metastatic progression. A recent pilot clinical trial assessing the effects of ALA-rich dietary flaxseed on tumor biological markers in postmenopausal patients with primary breast cancer demonstrated significant reductions in tumor growth and in HER2 (erbB-2) oncogene expression. HYPOTHESIS: The molecular mechanism by which ALA inhibits breast cancer cell growth and metastasis formation

may involve a direct regulation of HER2, a well-characterized oncogene playing a key role in the etiology, progression and response to some chemo- and endocrine therapies in approximately 20% of breast carcinomas. METHODS: Using HER2-specific ELISA, flow cytometry, immunofluorescence microscopy, Western blotting, RT-PCR and HER2 promoter-reporter analyses, we characterized the effects of exogenous supplementation with ALA on the expression of HER2 oncogene, a master key player in the onset and metastasis formation of breast cancer disease. Metabolic status (MTT) assays were performed to evaluate the nature of the cytotoxic interaction between ALA and the humanized anti-HER2 monoclonal antibody trastuzumab (Herceptin). To study these issues we used BT-474 and SKBr-3 breast cancer cells, which naturally exhibit amplification of the HER2 oncogene. RESULTS: ALA treatment dramatically suppressed the expression of HER2-coded p185Her-2/neu oncoprotein as determined by ELISA, flow cytometry, immunofluorescence microscopy and immunoblotting techniques. Interestingly, ALA-induced down-regulation of p185Her-2/neu correlated with a transcriptional response as no HER2 mRNA signal could be detected by RT-PCR upon treatment with optimal concentrations of ALA (up to 20 microM). Consistent with these findings, ALA exposure was found to dramatically repress the activity of a Luciferase reporter gene driven by the HER2 promoter. Moreover, the nature of the cytotoxic interaction between ALA and trastuzumab (Herceptin) revealed a significant synergism as assessed by MTT-based cell viability assays. CONCLUSIONS: i) These findings reveal that the omega-3 PUFA ALA suppresses overexpression of HER2 oncogene at the transcriptional level, which, in turn, interacts synergistically with anti-HER2 trastuzumab- based immunotherapy. ii) Our results molecularly support a recent randomized double-blind placebocontrolled clinical trial suggesting that ALA may be a potential dietary alternative or adjunct to currently used drugs in the management of HER2-positive breast carcinomas. iii) Considering our previous findings demonstrating the <> of the omega-6 PUFA linolenic acid (LA; 18:2n-6) and the <> of the omega-3 PUFA docosahexaenoic acid (DHA; 22:6n-3) and of the omega-9 monounsaturated fatty acid oleic acid (OA; 18:1n-9), it is reasonable to suggest that a low omega-6/omega-3 PUFA ratio and elevated MUFA levels, the two prominent <> of the <<Mediterranean diet>>, should be extremely efficient at blocking HER2 expression in breast cancer cells. Publication Types: * Research Support, N.I.H., Extramural * Research Support, Non-U.S. Gov't PMID: 17134970 [PubMed - indexed for MEDLINE] 3: J Nutr. 2006 Apr;136(4):906-12. Related Articles, Links Click here to read Sesamin is one of the major precursors of mammalian lignans in sesame seed (Sesamum indicum) as observed in vitro and in rats. Liu Z, Saarinen NM, Thompson LU. Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, M5S 3E2, Canada. Plant lignans occur in many foods, with flaxseed presently recognized as the richest source. Some plant lignans can be converted by intestinal microbiota to the mammalian lignans, enterodiol and enterolactone, which may have protective effects against hormone-related diseases such as breast cancer. This study determined whether plant lignans in sesame seed, particularly sesamin, could be metabolized to the mammalian lignans. The total plant lignan concentration in sesame seed (2180 micromol/100 g) was higher than that in flaxseed (820 micromol/100 g). In vitro fermentation with human fecal inoculum showed conversion of sesamin to the mammalian lignans, although at a lower rate (1.1%) compared with that of

secoisolariciresinol diglucoside (57.2%). However, when fed to female Sprague-Dawley rats for 10 d, sesamin (15 mg/kg body weight) and a 10% sesame seed diet resulted in greater (P < 0.05) urinary mammalian lignan excretion (3.2 and 11.2 micromol/d, respectively), than the control (< 0.05 micromol/d). We conclude that sesame seed is a rich source of mammalian lignan precursors and sesamin is one of them. From intermediate metabolites of sesamin identified in rat urine by GC-MS, a tentative metabolic pathway of sesamin to mammalian lignans is suggested. Publication Types: * Research Support, Non-U.S. Gov't PMID: 16549449 [PubMed - indexed for MEDLINE] 4: Int J Cancer. 2005 Sep 20;116(5):793-8. Related Articles, Links Click here to read The inhibitory effect of flaxseed on the growth and metastasis of estrogen receptor negative human breast cancer xenograftsis attributed to both its lignan and oil components. Wang L, Chen J, Thompson LU. Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada. Our previous studies have shown that dietary flaxseed (FS) can reduce the growth and metastasis of human estrogen receptor negative (ER-) breast cancer in nude mice. The aims of our study were to determine (i) whether the tumor inhibitory effect of FS was due to its oil (FO), lignan secoisolariciresinol diglycoside (SDG), or both components, and (ii) whether the effect on tumor growth was related to increased lipid peroxidation. Athymic nude mice were orthotopically injected with ER- breast cancer cells (MDA-MB-435) and 8 weeks later were fed either the basal diet (BD) or BD supplemented with 10% FS, SDG, FO, or combined SDG and FO (SDG + FO) for 6 weeks. The SDG and FO levels were equivalent to the amounts in the 10% FS. Compared to the BD group, the tumor growth rate was significantly lower (p < 0.05) in the FS, FO, and SDG + FO groups, in concordance with decreased cell proliferation and increased apoptosis; however, these did not significantly relate to the lipid peroxidation, indexed as malonaldehyde (MDA), in the primary tumors. Lung metastasis incidence was reduced (16-70%) by all treatments, significantly in the FS and SDG + FO groups. The distant lymph node metastasis was significantly decreased (52%) only in the FO group. Although the total metastasis incidence was lowered (42%) significantly only in the SDG + FO group, all treatment groups did not differ significantly. In conclusion, FS reduced the growth and metastasis of established ER- human breast cancer in part due to its lignan and FO components, and not to lipid peroxidation. (c) 2005 Wiley-Liss, Inc. PMID: 15849746 [PubMed - indexed for MEDLINE] 5: Clin Cancer Res. 2005 May 15;11(10):3828-35. Related Articles, Links Click here to read Dietary flaxseed alters tumor biological markers in postmenopausal breast cancer. Thompson LU, Chen JM, Li T, Strasser-Weippl K, Goss PE. Department of Nutritional Sciences, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada. PURPOSE: Flaxseed, the richest source of mammalian lignan precursors, has previously been shown to reduce the growth of tumors in rats. This study examined, in a randomized double-blind placebo-controlled clinical trial, the effects of dietary flaxseed on tumor biological markers and

urinary lignan excretion in postmenopausal patients with newly diagnosed breast cancer. EXPERIMENTAL DESIGN: Patients were randomized to daily intake of either a 25 g flaxseedcontaining muffin (n = 19) or a control (placebo) muffin (n = 13). At the time of diagnosis and again at definitive surgery, tumor tissue was analyzed for the rate of tumor cell proliferation (Ki-67 labeling index, primary end point), apoptosis, c-erbB2 expression, and estrogen and progesterone receptor levels. Twenty-four-hour urine samples were analyzed for lignans, and 3day diet records were evaluated for macronutrient and caloric intake. Mean treatment times were 39 and 32 days in the placebo and flaxseed groups, respectively. RESULTS: Reductions in Ki-67 labeling index (34.2%; P = 0.001) and in c-erbB2 expression (71.0%; P = 0.003) and an increase in apoptosis (30.7%; P = 0.007) were observed in the flaxseed, but not in the placebo group. No significant differences in caloric and macronutrient intake were seen between groups and between pre- and posttreatment periods. A significant increase in mean urinary lignan excretion was observed in the flaxseed group (1,300%; P < 0.01) compared with placebo controls. The total intake of flaxseed was correlated with changes in c-erbB2 score (r = -0.373; P = 0.036) and apoptotic index (r = 0.495; P < 0.004). CONCLUSION: Dietary flaxseed has the potential to reduce tumor growth in patients with breast cancer. Publication Types: * Clinical Trial * Randomized Controlled Trial * Research Support, Non-U.S. Gov't PMID: 15897583 [PubMed - indexed for MEDLINE] 6: Anticancer Res. 2005 May-Jun;25(3A):1817-22.

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Flax-seed extracts with phytoestrogenic effects on a hormone receptor-positive tumour cell line. Waldschläger J, Bergemann C, Ruth W, Effmert U, Jeschke U, Richter DU, Kragl U, Piechulla B, Briese V. Department of Obstetrics and Gynaecology, University of Rostock, Germany. [email protected] The higher soy intake in the Asian population compared to Europeans is believed to be an essential factor for the lower incidence of hormone-dependent tumours in Asia. It has already been shown that soya beans, with their ingredients genistein and daidzein from the isoflavonoid group, have protective effects on hormone-caused diseases. Lignans are another, less investigated, group of phytoestrogens. The aim of this study was to investigate the effects of flaxseed, which is typically found in Northern European diets, on the proliferation and hormone production of an estrogen receptor (ER)-positive trophoblast tumour cell line. MATERIALS AND METHODS: Trophoblast tumour cells of the cell line Jeg3 were incubated with 2 different concentrations of the isolated crude extract of flax-seed and 7 chemically partitioned extract fractions. Untreated cells were used as controls. After 48 h of stimulation, cell proliferation was measured using the BrdU method. The concentrations of hCG and progesterone produced by the trophoblast tumour cells were measured 48 h after stimulation. Extract fractions with antiproliferative effects in the BrdU- test were analysed by HPLC-MS. RESULTS: Our study showed an inhibitory influence of some of the isolated flax-seed fractions on the Jeg3 tumour cells. Proliferation of the Jeg3 cells was decreased by flax-seed fractions I, V, VI and VII in a dose-dependent manner. Inhibition of hCG production by flax-seed extracts III, V, VI and VII was also dose-dependent. Extract fractions V and VI decreased the production of progesterone by 58% to 86%. Some extract fractions showed a stimulating effect on hormone production and cell proliferation. HPLC-MS analysis showed the presence of matairesinol and biochanin A in flax-

seed fraction VI. DISCUSSION: Flax-seed seems to have similar inhibitory effects to soya on hormone production and proliferation of hormone-sensitive tumour cells. Our results showed a dose-dependent inhibition by isolated flax-seed extracts on the Jeg3 cell line. Matairesinol and biochanin A seem to be useful candidates for extended tests on other tumour cell lines and normal tissues to evaluate the potential benefit of a lignan-containing therapy in hormonedependent diseases. PMID: 16033105 [PubMed - indexed for MEDLINE] 7: Forum Nutr. 2005;(57):100-11.

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Health effects of phytoestrogens. Branca F, Lorenzetti S. National Institute for Research on Food and Nutrition, Rome, Italy. [email protected] Phytoestrogens are naturally occurring plant-derived phytochemicals, whose common biological roles are to protect plants from stress or to act as part of a plant's defense mechanism. Although composed of a wide group of nonsteroidal compounds of diverse structure, phytoestrogens have been shown to bind estrogen receptors and to behave as weak agonist/antagonist in both animals and humans. Phytoestrogens include mainly isoflavones (IF), coumestans, and lignans. These compounds are known to be present in fruits, vegetables, and whole grains commonly consumed by humans. IF are found in legumes--mainly soybeans-whereas flaxseed is a major source of lignans, and coumestans are significantly present in clover, alfalfa and soybean sprouts. 8-Prenyl flavonoids are common in vegetables. Bioavailability of IF requires an initial hydrolysis of the sugar moiety by intestinal beta-glucosidases to allow the following uptake by enterocytes and the flow through the peripheral circulation. Following absorption, IF are then reconjugated mainly to glucuronic acid and to a lesser degree to sulphuric acid. Gut metabolism seems key to the determination of the potency of action. Several epidemiological studies correlated high dose consumptions of soy IF with multiple beneficial effects on breast and prostate cancers, menopausal symptoms, osteoporosis, atherosclerosis and stroke, and neurodegeneration. For the relief of menopausal symptoms a consumption of 60 mg aglycones/day has been suggested; for cancer prevention a consumption between 50 and 110 mg aglycones/day is considered beneficial to reduce risks of breast, colon and prostate cancer; to decrease cardiovascular risk a minimum intake of 40-60 mg aglycones/day, together with about 25 g of soy protein has been suggested. For improvement in bone mineral density, 60100 mg aglycones/day for a period of at least 6-12 months could be beneficial. Publication Types: * Review PMID: 15702593 [PubMed - indexed for MEDLINE]