Estrogen receptor beta (ERβ) is one of the two key receptors (ERα, ERβ) that facilitate biological actions of 17β-estradiol (E2). ERβ is widely expressed in many tissues, and its expression is reduced or lost during progression of many tumors. ERβ facilitates estrogen signaling by both genomic (classical and non-classical) and extra-nuclear signaling. Emerging evidence suggests that ERβ functions as a tissue-specific tumor suppressor with anti-proliferative actions. Recent studies have identified a number of naturally available selective ERβ agonists. Targeting ERβ using its naturally available ligands is an attractive approach for treating and preventing cancers. This review presents the beneficial actions of ERβ signaling and clinical utility of several natural ERβ ligands as potential cancer therapy.
Antineoplastic Agents, Phytogenic ; pharmacology ; therapeutic use ; Equol ; pharmacology ; therapeutic use ; Estrogen Receptor beta ; antagonists & inhibitors ; metabolism ; Flavanones ; pharmacology ; therapeutic use ; Genistein ; pharmacology ; therapeutic use ; Glycyrrhiza ; chemistry ; Humans ; Ligands ; Neoplasms ; drug therapy ; metabolism ; Phytotherapy ; Plant Extracts ; pharmacology ; therapeutic use ; Soybeans ; chemistry

Thyroid carcinogenesis is accompanied by loss of thyroid-specific functions and refractory to radioiodine and thyroid stimulating hormone (TSH) suppression therapy. Redifferentiating agents have been shown to inhibit tumor growth and improve the response to conventional therapy. Polyphenol phytochemicals (PPs) in fruits and vegetables have been reported to inhibit cancer initiation, promotion, progression and induce redifferentiation in selected types. In this study we examined PPs induce redifferentiation in thyroid cancer cell lines. We investigated the effects of genistein, resveratrol, quercetin, kaempferol, and resorcinol on the F9 embryonal carcinoma cell differentiation model. The thyroid cancer cell lines, TPC-1, FTC-133, NPA, FRO, and ARO, displayed growth inhibition in response to genistein, resveratrol, quercetin. We further demonstrated that genistein decreased the dedifferention marker CD97 in NPA cells and resveratrol decreased CD97 in FTC-133, NPA, FRO cells and quercetin decreased CD97 in all cell lines. We observed increased expression of differentiation marker NIS in FTC-133 cells in response to genistein, and resveratrol but no change in NPA, FRO, ARO cells. Quercetin increased or induced NIS in FTC-133, NPA, FRO cells. These findings suggest that PPs may provide a useful therapeutic intervention in thyroid cancer redifferentiation therapy.
Antigens, CD/metabolism ; Antineoplastic Agents/*pharmacology/therapeutic use ; Carcinoma, Embryonal/*drug therapy/metabolism ; Cell Differentiation/*drug effects ; Cell Line, Tumor ; Cell Proliferation/*drug effects ; Flavonoids/*pharmacology/therapeutic use ; Gene Expression Regulation, Neoplastic ; Genistein/pharmacology/therapeutic use ; Humans ; Kaempferols/pharmacology/therapeutic use ; Models, Biological ; Phenols/*pharmacology/therapeutic use ; Quercetin/pharmacology/therapeutic use ; Resorcinols/pharmacology/therapeutic use ; Stilbenes/pharmacology/therapeutic use ; Symporters/metabolism ; Thyroid Neoplasms/*drug therapy/metabolism

OBJECTIVETo investigate the preventive effect of genistein on the malignant transformation of oral leukoplakia in hamster cheek pouch.

METHODSSixty male Syrian golden hamsters were randomly divided into 4 groups, with two of 20 and two of 10. DMBA solution (0.5% in acetone) was applied topically to the left cheek pouch of male Syrian golden hamsters in group A and B, while animals in group C were painted with acetone, 3 times a week for 6 weeks. For the next 12 weeks, animals in group B received genistein (10 mg.kg(-1).d(-1)) daily by gavage; animals in group A and C received same volume of saline; animals in group D serving as blank control. At the end of the experiment, animals were sacrificed and tissue samples were collected for histopathological examination.

RESULTSNo significant differences in the tumor latency and tumor incidence were observed between the control and genistein treated group.

CONCLUSIONSNo inhibitory effect of genistein on the transformation of oral leukoplakia was observed in hamster.

Animals ; Cricetinae ; Genistein ; pharmacology ; therapeutic use ; Leukoplakia, Oral ; pathology ; prevention & control ; Male ; Mesocricetus ; Mouth Mucosa ; drug effects ; pathology ; Precancerous Conditions ; pathology ; prevention & control

Animals ; Asthma ; drug therapy ; metabolism ; Genistein ; pharmacology ; therapeutic use ; Guinea Pigs ; Interleukin-4 ; genetics ; metabolism ; Janus Kinase 1 ; genetics ; metabolism ; Lung ; metabolism ; Male ; Protein Kinase Inhibitors ; pharmacology ; therapeutic use

OBJECTIVETo detect the effect of genistein on mandible metabolism in ovariectomized rats.

METHODSForty 12 week-old female SD rats were randomly assigned to four groups: (1) sham operated; (2) ovariectomized; (3) ovariectomized and treated with estradiol; (4) ovariectomized and received genistein, 45 mg/kg body weight per day. After 12 weeks, bone mineral density (BMD), serum level of alkaline phosphatase (ALP), acid phosphatase (ACP), osteocalcin, IL-1beta, TNF-alpha, IL-6 and calcitonin (CT) were evaluated. In addition, the serum estradiol and the weight of uteri were also examined to indicate the side effect of genistein to the uteri.

RESULTSOvariectomized animals had a significant decrease in BMD, and increased serum level of ALP, ACP, IL-1beta and osteocalcin compared with sham rats. After treated with genistein, BMD and the serum level of ALP, ACP, osteocalcin increased significantly, while the serum level of IL-1beta and TNF-alpha decreased. Especially, the increase of ALP and osteocalcin was higher than that of estradiol-treated animal. Additionally, the uterus weight index and the serum estradiol in genistein-treated rats were lower significantly than those of estradiol-treated rats.

CONCLUSIONSGenistein can improve the mandible bone metabolism as well as its effect on femur through the promotion of bone formation and the prevention of bone resorption with slight side effect. Genistein provides an additional viable way to therapy for osteoporosis in the jaw bones.

Alkaline Phosphatase ; blood ; Animals ; Bone Density ; drug effects ; Estradiol ; blood ; Female ; Genistein ; pharmacology ; therapeutic use ; Mandible ; drug effects ; metabolism ; Osteocalcin ; blood ; Osteoporosis ; prevention & control ; Ovariectomy ; Ovary ; drug effects ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo study the effect of genistein on the expression of heme oxygenase-1 (HO-1) in rats with pulmonary arterial hypertension (PAH) induced by monocrotaline (MCT).

METHODSSixty male Sprague-Dawley rats were randomly divided into 4 groups (n=15), namely the control group, model group, low-dose (20 µg/kg) genistein group and high-dose (80 µg/kg) genistein group. The hemodynamic parameters were measured and the remodeling of pulmonary small arteries was observed by electron microscope (EM). The expression of HO-1 in the lung tissues were detected by Western blotting.

RESULTSCompared with the model group, genistein treatment significantly reduced the elevated mean pulmonary arterial pressure, improved the right ventricular hypertrophy index, and increased the expression of HO-1 in a dose-dependent manner.

CONCLUSIONGenistein attentuates pulmonary arterial hypertension in MCT-treated rats possibly by up-regulation of HO-1 in the lung tissues.

Animals ; Genistein ; pharmacology ; therapeutic use ; Heme Oxygenase (Decyclizing) ; metabolism ; Hypertension, Pulmonary ; chemically induced ; drug therapy ; enzymology ; Lung ; enzymology ; pathology ; Male ; Monocrotaline ; Rats ; Rats, Sprague-Dawley ; Up-Regulation ; drug effects

Soy isoflavones exhibit various biological activities, such as antioxidant, anti-tumor, anti-inflammatory, and cardiovascular protective effects. The present study was designed to investigate the effects of sixteen synthesized 3-amino-2-hydroxypropoxy genistein derivatives on cell proliferation and activation of Nrf2 (Nuclear factor erythroid 2-related factor 2)/ARE (antioxidant response elements) pathway in human cancer cell lines. Most of the tested compounds exerted greater cytotoxic activity than genistein, as measured by MTT assay. Moreover, compound 8c showed the highest ARE-luciferase reporter activity among the test compounds. It strongly promoted Nrf2 nuclear translocation and up-regulated the expression of total Nrf2 and downstream targets NQO-1 and HO-1 at protein level. The present study may provide a basis for the application of isoflavone derivatives as Nrf2/ARE pathway inducers for cancer therapy and cancer prevention.
Antioxidant Response Elements ; Cell Line, Tumor ; Cell Proliferation ; Genistein ; chemical synthesis ; pharmacology ; therapeutic use ; Heme Oxygenase-1 ; metabolism ; Humans ; Isoflavones ; NF-E2-Related Factor 2 ; metabolism ; Neoplasms ; drug therapy ; metabolism ; Signal Transduction ; Soybeans ; chemistry ; Up-Regulation