phytoestrogens and hydroxymatairesinol

Lignans are plant polyphenols which may possess anticancer, antioxidant, antimicrobial, anti-inflammatory and immunomodulatory activities. In particular, the lignan 7-hydroxymatairesinol (HMR/lignan, HMR) is a novel precursor of the mammalian lignan enterolactone (EL). In the present study, we investigated the estrogenicity of HMR and of EL in comparison to estradiol (E2), by measuring their effects on growth and apoptotic markers in the human estrogen-sensitive cell line MCF-7. HMR, EL and E2 concentration-dependently increased the percentage of MCF-7 cells in the S phase of the cell cycle, with the following relative potencies: E2 congruent with EL>>HMR, and efficacies: E2>HMR>>EL. Treatment of MCF-7 cells with either HMR, EL or E2 also increased the Bcl-2/Bax mRNA ratio. The effects of HMR and EL were reduced in the presence of the estrogen receptor (ER) antagonist tamoxifene. We conclude that both HMR and its metabolite EL are endowed with estrogenic activity, which is likely to be exerted through the contribution of ER-dependent pathways and to target the same intracellular mechanisms acted upon by E2. The estrogenicity of HMR and EL is however milder than that of E2, as indicated by the lower potencies and efficacies of both lignans. The present results support the notion that dietary supplementation with HMR may result in a mild estrogenic activity, both directly and by providing a suitable source for endogenous EL.

Topics: 4-Butyrolactone; Antioxidants; Apoptosis; bcl-2-Associated X Protein; Breast Neoplasms; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Estradiol; Estrogen Antagonists; Female; Gene Expression Regulation, Neoplastic; Humans; Lignans; Phytoestrogens; Picea; Proto-Oncogene Proteins c-bcl-2; RNA, Messenger; Tamoxifen

Cyclooxygenase (COX)-2 is an inducible isoform, expressed in inflamed leukocytes and cancer cells. It is known that estrogen causes prostate dysplasia, but little is known about COX-2 expression and its influence on male reproductivity. In this study, we show that COX-2 was abolished in the distal end of the vas deferens in neonatally estrogenized (diethylstilbestrol, NeoDES) Sprague-Dawley (SD) rats at age of 15 mo, but the control normal rats were found to remain constitutive expression at the same age, while the levels of COX-1 in these rats remained intact. Furthermore, BAX, an indicator of sperm quality, was observed in the endothelium of vas deferens and sperm of the aged rats. However, COX-2 was not detected in the inflamed lesions of NeoDES rat's prostate by immunohistochemistry. In addition to estrogen, hydroxymatairesinol (HMR), a phytoestrogen, was analyzed in vitro for possible regulation on COX-2. Through Western blot analysis, HMR was shown to have no inhibitory affect on COX-2 expression. These results indicated that estrogen treatment strongly influences the expression of COX-2 that is associated with fertility, but no induction of COX-2 by estrogen may not exclude COX-2's role in prostatitis, and the anti-tumor mechanism of HMR largely remains elusive.

Topics: Animals; Animals, Newborn; bcl-2-Associated X Protein; Blotting, Western; Cell Line; Cellular Senescence; Cyclooxygenase 1; Cyclooxygenase 2; Diethylstilbestrol; Enzyme Induction; Estrogens; Gene Expression Regulation, Enzymologic; Genitalia, Male; Immunohistochemistry; Lignans; Lipopolysaccharides; Macrophage Activation; Macrophages; Male; Membrane Proteins; Phytoestrogens; Prostate; Rats; Spermatozoa; Vas Deferens

Clinical intervention studies and experimental studies with lignan-rich diets suggest that lignans may have inhibitory effects on prostate cancer, but no clinical or experimental studies with purified lignans have been published. The purpose of this study was to investigate the effect of a plant lignan 7-hydroxymatairesinol (HMR) on LNCaP human prostate cancer xenografts in athymic mice. Athymic nude male mice were injected subcutaneously with LNCaP cells. Starting 3 days after tumor cell injections, a control diet or a control diet supplemented with 0.15% or 0.30% of HMR was administered to mice and the tumor take rate and growth was observed for 9 weeks. HMR diet inhibited the growth of LNCaP tumors. Mice treated with HMR had smaller tumor volume, lower tumor take rate, increased proportion of nongrowing tumors, and higher tumor cell apoptotic index compared with controls. Furthermore, the cell proliferation index was reduced in mice receiving the 0.30% HMR diet compared with mice receiving the control diet. Our results suggest that dietary HMR started at the early phase of the tumor development inhibits the growth of the LNCaP human prostate cancer xenografts in athymic male mice.

Topics: Animals; Anticarcinogenic Agents; Apoptosis; Carcinoma; Cell Proliferation; Diet; Disease Models, Animal; Humans; Isoflavones; Lignans; Male; Mice; Mice, Nude; Models, Biological; Neoplasm Transplantation; Phytoestrogens; Prostate-Specific Antigen; Prostatic Neoplasms; Time Factors; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

The chemopreventive effects of hydroxymatairesinol (HMR), a lignan extracted from Norway spruce (Picea abies), on the development of mammary carcinoma induced by 7,12-dimethylbenz[a]anthracene (DMBA) was studied in rats. HMR administered via diet in an average daily dose of 4.7 mg/kg body wt starting before DMBA induction reduced tumor volume and tumor growth, but no significant reduction in tumor multiplicity (number of tumors/rat) was observed. The predominant histological type in the control group was type B (well-differentiated adenocarcinoma, 78%). The proportion of type B tumors decreased to 35% in the HMR group, while the type A (poorly differentiated) and type C (atrophic) tumor proportions increased. Anticarcinogenic effects of dietary HMR (4.7 mg/kg) were also evident when the administration started after DMBA induction and was seen as growth inhibition of established tumors. Dietary HMR supplementation significantly increased serum and urinary enterolactone and HMR concentrations but had no significant effect on the uterine weight, suggesting that HMR or its major metabolite enterolactone did not have an antiestrogenic effect. Further studies are warranted to further clarify and verify HMR action and the associated mechanisms in mammary tumorigenesis.

Topics: 4-Butyrolactone; 9,10-Dimethyl-1,2-benzanthracene; Adenocarcinoma; Animals; Anticarcinogenic Agents; Diet; Estrogens, Non-Steroidal; Female; Isoflavones; Lignans; Mammary Neoplasms, Experimental; Organ Size; Phytoestrogens; Plant Preparations; Rats; Rats, Sprague-Dawley; Uterus