Molecular Mechanisms Of Genistein Research Articles

Genistein, a Potential Phytochemical against Breast Cancer Treatment-Insight into the Molecular Mechanisms

Breast cancer (BC) is one of the most common malignancies in women. Although widespread successful synthetic drugs are available, natural compounds can also be considered as significant anticancer agents for treating BC. Some natural compounds have similar effects as synthetic drugs with fewer side effects on normal cells. Therefore, we aimed to unravel and analyze several molecular mechanisms of genistein (GNT) against BC. GNT is a type of dietary phytoestrogen included in the flavonoid group with a similar structure to estrogen that might provide a strong alternative and complementary medicine to existing chemotherapeutic drugs. Previous research reported that GNT could target the estrogen receptor (ER) human epidermal growth factor receptor-2 (HER2) and several signaling molecules against multiple BC cell lines and sensitize cancer cell lines to this compound when used at an optimal inhibitory concentration. More specifically, GNT mediates the anticancer mechanism through apoptosis induction, arresting the cell cycle, inhibiting angiogenesis and metastasis, mammosphere formation, and targeting and suppressing tumor growth factors. Furthermore, it acts via upregulating tumor suppressor genes and downregulating oncogenes in vitro and animal model studies. In addition, this phytochemical synergistically reverses the resistance mechanism of standard chemotherapeutic drugs, increasing their efficacy against BC. Overall, in this review, we discuss several molecular interactions of GNT with numerous cellular targets in the BC model and show its anticancer activities alone and synergistically. We conclude that GNT can have favorable therapeutic advantages when standard drugs are not available in the pharma markets.

Cellular and molecular mechanisms of genistein in prevention and treatment of diseases: An overview.

Genistein is the simplest secondary metabolite in soybeans and belongs to a group of compounds called isoflavones. It is a phytoestrogen and it makes up more than 60% of soy isoflavones. Studies have shown the anti-inflammatory, anti-apoptotic, and anti-angiogenic effects of genistein in addition to its modulatory effects on steroidal hormone receptors. In this review, we discuss the pharmacologic and therapeutic effects of genistein on various diseases. PRACTICAL APPLICATIONS: In this review, we have discussed the therapeutic effects of genistein as the main constituent of soybeans on health conditions. Its antioxidant, anti-inflammatory, anti-apoptotic and, anti-angiogenic effects need more attention. The pharmacological properties of genistein make this natural isoflavone a potential treatment for various diseases such as postmenopausal symptoms, cancer, bone, brain, and heart diseases. Special emphasis should be given to it, resulting in using it in clinical as a safe, potent, and bioactive molecule.

Molecular Mechanisms of Action of Genistein in Cancer: Recent Advances.

Background: Genistein is one among the several other known isoflavones that is found in different soybeans and soy products. The chemical name of genistein is 4′,5,7-trihydroxyisoflavone. Genistein has drawn attention of scientific community because of its potential beneficial effects on human grave diseases, such as cancer. Mechanistic insight of genistein reveals its potential for apoptotic induction, cell cycle arrest, as well as antiangiogenic, antimetastatic, and anti-inflammatory effects.Objective: The purpose of this review is to unravel and analyze various molecular mechanisms of genistein in diverse cancer models.Data sources: English language literature was searched using various databases, such as PubMed, ScienceDirect, EBOSCOhost, Scopus, Web of Science, and Cochrane Library. Key words used in various combinations included genistein, cancer, anticancer, molecular mechanisms prevention, treatment, in vivo, in vitro, and clinical studies.Study selection: Study selection was carried out strictly in accordance with the statement of Preferred Reporting Items for Systematic Reviews and Meta-analyses.Data extraction: Four authors independently carried out the extraction of articles.Data synthesis: One hundred one papers were found suitable for use in this review.Conclusion: This review covers various molecular interactions of genistein with various cellular targets in cancer models. It will help the scientific community understand genistein and cancer biology and will provoke them to design novel therapeutic strategies.

The effect of geniste on Aβ25-35-induced PC12 cell apoptosis through the JNK-dependent Fas pathway.

The β-amyloid protein (Aβ) is considered to be the key factor for inducing Alzheimer's disease (AD). In recent years, the neuroprotective effects of genistein have drawn increasing attention. However, the molecular mechanisms of GEN (genistein) against Aβ are unclear. In the present study, we investigated the inhibitory effects of GEN on Aβ25-35-induced apoptosis in cultured PC12 cells and the related signaling pathway. Our data show that GEN significantly inhibited Aβ25-35-induced apoptosis of PC12 cells. GEN suppressed Aβ25-35-induced JNK activation and the JNK-dependent upregulation of Fas/FasL at the mRNA and protein levels induced by Aβ25-35 were significantly decreased by GEN. Additionally, GEN inhibited mRNA expression and activity of caspase-3 and caspase-8 induced by Aβ25-35. Together, these findings showed that Aβ-induced apoptosis of PC12 cells proceeds through the Fas/FasL pathway. The JNK signaling plays a critical role in regulating the anti-apoptotic effects of genistein. Thus, our results suggest that genistein can inhibit Aβ-induced apoptosis of PC12 cells through blockage of the JNK activation and subsequent suppression of the JNK-dependent Fas/FasL pathway.

Abstract A057: Therapeutic potential of genistein via targeting the microRNA miR-155 in breast cancer

Abstract We previously reported that dietary genistein significantly inhibits mammary tumor growth and metastasis of estrogen receptor (ER) (-) MDA-MB-435 metastatic cancer cells in immunocompromised mice. The purpose of the present study is to investigate the molecular mechanisms of genistein in ER (-) breast cancer cells. We report that at low physiologically relevant concentrations, genistein significantly inhibits cell growth and induces apoptosis in MDA-MB-435 and Hs578t breast cancer cells. To investigate the mechanism by which genistein regulates cancer cell viability, a panel of microRNAs (miRNAs) were tested for differential expression in response to genistein treatment. We found that miR-155, a designated oncomiR in breast cancer, is significantly downregulated by genistein in MDA-MB-435 and Hs578t cells. Concomitantly, pro-apoptotic and anti-cell proliferative miR-155 targets FOXO3, PTEN, casein kinase (CK1alpha), and p27 are upregulated by genistein. Moreover, the CK1alpha target beta catenin is downregulated in the MDA-MB-435 cells, thus further contributing to the anticancer effects of genistein by inhibiting wnt signaling. Stable ectopic expression of miR-155 in MDA-MB-435 and Hs578t cells decreases the inhibitory effect of genistein on cell viability, and abrogates the effect of genistein on apoptosis and expression of pro-apoptotic proteins. Therefore, genistein acts as a potential anti breast cancer therapeutic via downregulation of miR-155, a critical suppressor of apoptosis. This study was sponsored by United States Army/BCRP W81XWH-11-1-0199 (to CDP), NIH/NIGMS SC3GM084824 (to SD), NIH/NIGMS G12RR035051 (to UPR MSC), and NIH/NIGMS G12RR003035 and Title V PPOHA US Department of Education #P031M105050 (to UCC). Citation Format: Columba de la Parra, Linette Castillo-Pichardo, Luis A. Cubano, George A. Calin, Suranganie Dharmawardhane. Therapeutic potential of genistein via targeting the microRNA miR-155 in breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr A057.

Genistein induces G2/M cell cycle arrest and apoptosis via ATM/p53-dependent pathway in human colon cancer cells

Soybean isoflavones have been used as a potential preventive agent in anticancer research for many years. Genistein is one of the most active flavonoids in soybeans. Accumulating evidence suggests that genistein alters a variety of biological processes in estrogen-related malignancies, such as breast and prostate cancers. However, the molecular mechanism of genistein in the prevention of human colon cancer remains unclear. Here we attempted to elucidate the anticarcinogenic mechanism of genistein in human colon cancer cells. First we evaluated the growth inhibitory effect of genistein and two other isoflavones, daidzein and biochanin A, on HCT-116 and SW-480 human colon cancer cells. In addition, flow cytometry was performed to observe the morphological changes in HCT-116/SW-480 cells undergoing apoptosis or cell cycle arrest, which had been visualized using Annexin V-FITC and/or propidium iodide staining. Real-time PCR and western blot analyses were also employed to study the changes in expression of several important genes associated with cell cycle regulation. Our data showed that genistein, daidzein and biochanin A exhibited growth inhibitory effects on HCT-116/SW-480 colon cancer cells and promoted apoptosis. Genistein showed a significantly greater effect than the other two compounds, in a time- and dose-dependent manner. In addition, genistein caused cell cycle arrest in the G2/M phase, which was accompanied by activation of ATM/p53, p21waf1/cip1 and GADD45α as well as downregulation of cdc2 and cdc25A demonstrated by q-PCR and immunoblotting assay. Interestingly, genistein induced G2/M cell cycle arrest in a p53-dependent manner. These findings exemplify that isoflavones, especially genistein, could promote colon cancer cell growth inhibition and facilitate apoptosis and cell cycle arrest in the G2/M phase. The ATM/p53-p21 cross-regulatory network may play a crucial role in mediating the anticarcinogenic activities of genistein in colon cancer.

Activation of nuclear factor erythroid 2-related factor 2 and PPARγ plays a role in the genistein-mediated attenuation of oxidative stress-induced endothelial cell injury

We investigate the cytoprotective effects and the molecular mechanism of genistein in oxidative stress-induced injury using an endothelial cell line (EA.hy926). An oxidative stress model was established by incubating endothelial cells with H₂O₂. According to the present results, genistein pretreatment protected endothelial cells against H₂O₂-induced decreases in cell viability and increases in apoptosis. Genistein also prevented the inhibition of B-cell lymphoma 2 and the activation of caspase-3 induced by H₂O₂. Genistein increased superoxide dismutase (SOD), catalase (CAT) and glutathione (GSH) levels and attenuated the decrease in these antioxidants during oxidative stress. We also found that genistein induced the promoter activity of both nuclear factor erythroid 2-related factor 2 (Nrf2) and PPARγ. Additionally, genistein induced the nuclear translocation of Nrf2 and PPARγ. While genistein caused the up-regulation of both Nrf2 and PPARγ, it also activated and up-regulated the protein expression and transcription of a downstream protein, haem oxygenase-1 (HO-1). Moreover, the use of Nrf2 small interfering RNA transfection and HO-1- or PPARγ-specific antagonists (Znpp and GW9662, respectively) blocked the protective effects of genistein on endothelial cell viability during oxidative stress. Therefore, we conclude that oxidative stress-induced endothelial cell injury can be attenuated by treatment with genistein, which functions via the regulation of the Nrf2 and PPARγ signalling pathway. Additionally, the endogenous antioxidants SOD, CAT and GSH appear to play a role in the antioxidant activity of genistein. The present findings suggest that the beneficial effects of genistein involving the activation of cytoprotective antioxidant genes may represent a novel strategy in the prevention and treatment of cardiovascular endothelial damage.

Genistein reverses free fatty acid-induced insulin resistance in HepG2 hepatocytes through targeting JNK

This study investigated the effects and molecular mechanisms of genistein in improving insulin resistance induced by free fatty acids (FFAs) in HepG2 hepatocytes. A model of insulin resistance in HepG2 cells was established by adding palmitic acid (0.5 mmol/L) to the culture medium and the cells were treated by genistein. Glucose consumption of HepG2 cells was determined by glucose oxidase method. The levels of c-jun N-terminal kinase (JNK) phosphorylation, insulin receptor substrate-1 (IRS-1) Ser307 phosphorylation, JNK, IRS-1, phosphatidylinositol-3-kinase p85 (PI-3K p85) and glucose transporter 1 (GLUT1) proteins were detected by Western blotting. The results showed that after the treatment with palmitic acid for 24 h, the insulin-stimulated glucose transport in HepG2 cells was inhibited, and the glucose consumption was substantially reduced. Meanwhile, the expressions of IRS-1, PI-3K p85 protein and GLUT1 were obviously reduced, while the levels of JNK phosphorylation and IRS-1 Ser307 phosphorylation and the expression of JNK protein were significantly increased, as compared with cells of normal control. However, the aforementioned indices, which indicated the existence of insulin resistance, were reversed by genistein at 1-4 μmol/L in a dose-dependent manner. It was concluded that insulin resistance induced by FFAs in HepG2 hepatocytes could be improved by genistein. Genistein might reverse FFAs-induced insulin resistance in HepG2 cells by targeting JNK.

Molecular Effects of the Isoflavonoid Genistein in Prostate Cancer

Differences in diet have been proposed to be at least partially responsible for the low rate of prostate cancer in Asian populations compared with men in Western countries. One of the compounds that occurs in a greater quantity in the Eastern diet is genistein, an isoflavonoid found in high concentrations in serum after ingestion of soy-rich foods. Extensive molecular studies have been performed to determine its potential health benefits. The mechanism of action of genistein is complex and includes several cellular pathways. In addition to its estrogenic and/or antiestrogenic activities, genistein has been reported to inhibit steroidogenesis and block several protein tyrosine kinases, including epidermal growth factor receptor and src tyrosine kinases. Moreover, it arrests the cell cycle, induces apoptosis, and has antiangiogenic and antimetastatic properties and antioxidant activity. Herein, we review the current literature on the molecular mechanisms of genistein in relation to its effects on prostate cancer cells.

Effects of Genistein, A Soybean-Derived Isoflavone, on Proliferation and Differentiation of B16-BL6 Mouse Melanoma Cells

Genistein, a soybean-derived isoflavone, may contribute to the lower cancer incidence in South Asian countries. In this study, the effects and molecular mechanisms of genistein on growth and differentiation of B16-BL6 mouse melanoma cells were investigated. Genistein suppressed the growth of these melanoma cells. The IC50 value is 15.5μM. On the other hand, genistein induced the changes of cell shape and cytoskeletal network. The cytoskeletal filaments were induced to form a bundle along the direction of elongation of the cells. Moreover, tyrosine phosphorylation levels of cytoskeleton-associated proteins decreased after the cells were exposed to 20 or 30 μM of genistein for 3 days. All these morphological and molecular changes were accompanied by appearance of the differentiated phenotypes. Genistein induced the increase of cellular melanin content, enhancement of tyrosinase activity, and decrease of colonization potentials in soft agar in a time-dependent and dose-dependent manner. The effective concentration was no more than 10 μM after 3 days' exposure. The tumorigenic potentials of B16-BL6 cells in C57BL/6 mouse also decreased after exposure to 20 or 30 μM of genistein for 3 days. When expressions of tumor-related genes were investigated in the differentiation-induced cells, the content of P53 dramatically increased while that of c-Myc protein decreased. Therefore, due to its ability to induce cellular and molecular changes, genistein suppressed the growth and induced differentiated phenotypes in B16-BL6 melanoma cells.