Genistein-induced mir-23b expression inhibits the growth of breast cancer cells

Aim of the study: Genistein, an isoflavonoid, plays roles in the inhibition of protein tyrosine kinase phosphorylation, induction of apoptosis, and cell differentiation in breast cancer. This study aims to induce cellular stress by exposing genistein to determine alterations of miRNA expression profiles in MCF-7 cells. Material and methods: XTT assay and trypan blue dye exclusion assays were performed to examine the cytotoxic effects of genistein treatment. Expressions of miRNAs were quantified using Real-Time Online RT-PCR. Results: The IC50 dose of genistein was 175 μM in MCF-7 cell, line and the cytotoxic effect of genistein was detected after 48 hours. miR-23b was found to be up-regulated 56.69 fold following the treatment of genistein. It was found that miR-23b was up-regulated for MCF-7 breast cancer cells after genistein treatment. Conclusions: Up-regulated ex-expression of miR-23b might be a putative biomarker for use in the therapy of breast cancer patients. miR-23b up-regulation might be important in terms of response to genistein. © 2015, Termedia Publishing House Ltd. All rights reserved

Effect of oral genistein administration in early and late phases of allergic encephalomyelitis

Objective(s): Experimental allergic encephalomyelitis (EAE) is an autoimmune disease validated as animal model of multiple sclerosis (MS). Administration of genistein, a phytoestrogenic component of soy, to mice at the onset of EAE is known to attenuate the clinical signs of the disease. The potential effects of genistein on established EAE is less studied. In the current study, we aimed to compare the effects of genistein administration on EAE severity in early and late phases of the disease. Materials and Methods: The C57BL/6 mice were induced with EAE, using MOG 35-55 and gavaged with genistein (300 mg/kg) either after the appearance of the first clinical sign or 30 days post disease induction for ten days. 24 hr after the last gavage, mice were sacrificed. Brains and spleens were removed for assessing lymphocyte proliferation, cell cytotoxicity, and cytokine profile. Spinal cords were dissected to assess the amount of demyelination using Luxol fast blue/cresyl violet staining. Results: Administering mice with genistein, after the establishment of EAE, did not reverse the clinical signs of disease. However, treating with genistein at the onset of disease alleviated the clinical signs by reducing neuronal demyelination. Genistein suppressed the production of IFN-γ and enhanced IL-10 secretion in splenocyte and brain. Genistein also reduced IL-12 and TNF-α secretion in splenocytes, suppressed the proliferation of T-cells, and reduced the cell cytotoxicity. Conclusion: Genistein oral therapy might only reduce EAE severity if started in early phases of the disease

Synthesizing efficacious genistein in conjugation with superparamagnetic Fe₃O₄ decorated with bio-compatible carboxymethylated chitosan against acute leukemia lymphoma

Abstract Background Genistein (C15H10O5) is a soy isoflavone with anti-cancer properties such as inhibition of cell growth, proliferation and tumor invasion, but effective dosage against hematopoietic malignant cells was not in non-toxic range. This property cause to impede its usage as chemotherapeutic agent. Therefore, this hypothesis raised that synthesizing biocompatible nanoparticle could assist to prevail this struggle. Methods Genistein covalently attached on Fe3O4 nanoparticles decorated with carboxymethylated chitosan to fabricate Fe3O4-CMC-genistein in alkaline circumstance. This obtained nanoparticles were evaluated by TEM, DLS, FTIR, XRD and VSM and its anti-cancer effect by growth rate and MTT assays as well as flow cytometer on ALL cancer cell lines. Results Different evaluations indicated that the drug delivery vehicle had a mean diameter size around 12ƞm with well bounded components. This system presented high degree of magnetization and superparamagnetic properties as well as good water solubility. In comparison with pure genistein, significant growth inhibition on hematopoietic cancer cells in lower dose of genistein nano-conjugated onto Fe3O4-CMC. It increased long lasting effect of genistein in cancer cells also. Conclusion This delivery system for genistein could be remarkably promised and futuristic as biocompatible chemotherapeutic agent against hematopoietic malignant cells

Genistein increases epidermal growth factor receptor signaling and promotes tumor progression in advanced human prostate cancer.

Genistein is an isoflavone found in soy, and its chemo-preventive and -therapeutic effects have been well established from in vitro studies. Recently, however, its therapeutic actions in vivo have been questioned due to contradictory reports from animal studies, which rely on rodent models or implantation of cell lines into animals. To clarify in vivo effects of genistein in advanced prostate cancer patients, we developed a patient-derived prostate cancer xenograft model, in which a clinical prostatectomy sample was grafted into immune deficient mice. Our results showed an increased lymph node (LN) and secondary organ metastases in genistein-treated mice compared to untreated controls. Interestingly, invasive malignant cells aggregated to form islands/micrometastasis only in the secondary organs of the genistein-treated groups, not in the untreated control group. To understand the underlying mechanism for metastatic progression, we examined cell proliferation and apoptosis on paraffin-sections. Immunohistological data show that tumors of genistein-treated groups have more proliferating and fewer apoptotic cancer cells than those of the untreated group. Our immunoblotting data suggest that increased proliferation and metastasis are linked to enhanced activities of tyrosine kinases, EGFR and its downstream Src, in genistein-treated groups. Despite the chemopreventive effects proposed by earlier in vitro studies, the cancer promoting effect of genistein observed here suggests the need for careful selection of patients and safer planning of clinical trials

Genistein induces a protective immunomodulatory effect in a mouse model of cervical cancer

Background: Genistein (GEN), a naturally occurring flavonoid present in soy bean, has attracted scientific interest for its possible benefits in cancer. Objective: The potential immunomodulatory effects of genistein on the immune system and against TC-1 tumor cell line were evaluated in adult female C57BL/6 mice. Methods: Mice were treated with GEN 10 days before to 10 days after the tumor induction. Thirty days after the last GEN treatment, lymphocyte proliferation, Lactase Dehydrogenase (LDH) cytolytic activity and cytokine secretion were analyzed in GEN and control groups. Results: The results showed that ingestion of genistein significantly increased lymphocyte proliferation and LDH release. Furthermore, the treatment with genistein also caused a significant increment in interferon gamma (IFN-γ). In addition, the treatment achieved significant therapeutic effect in tumor models compared to the control group. These results indicated that the effect of GEN on tumor growth may be attributed to its effect on lymphocyte proliferation, cytolytic activity and IFN-γ production. Conclusion: These results demonstrate that GEN exerts an immunomodulatory effect in a mouse model of Human Papillomavirus (HPV) associated-cervical cancer

Cellular uptake of soy-derived phytoestrogens in vitro and in human whole blood

Epidemiological studies comparing typical Western and traditional Eastern lifestyles indicate that dietary intake of soyderived phytoestrogens, including genistein, daidzein, and equol, may have significant health protective effects on hormone-dependent cancers, osteoporosis and cardiovascular diseases. Phytoestrogens have been demonstrated to exert varying effects depending on tissue, endogenous hormone concentrations, and receptor types. Thus, a detailed understanding of the biodistribution and bioavailability of specific phytoestrogens is required in order to predict the subsequent biologic activities. In this study we aimed to investigate the cellular uptake of these soy-derived phytoestrogens in different cell types, including the mammary MCF-7/6 and MDAB-MB 231 cell lines, the ovarian Ishikawa Var-I cell lines and in murine adipocyte clusters. Furthermore, the biodistribution between serum and cell fraction was also investigated in human whole blood. Equol generally shows a higher cellular uptake when compared with genistein and daidzein. Therefore, equol may be more potent with respect to its relative bioactivity, which is corroborated by the observations of specific health effects associated with the equol-producer phenotype

Modulation of CXCR4, CXCL12, and Tumor Cell Invasion Potential In Vitro by Phytochemicals.

CXCR4 is a chemokine receptor frequently overexpressed on primary tumor cells. Organs to which these cancers metastasize secrete CXCL12, the unique ligand for CXCR4, which stimulates invasion and metastasis to these sites. Similar to our previous work with the chemoprotective phytochemical, 3,3'-diindolylmethane (DIM), we show here that genistein also downregulates CXCR4 and CXCL12 and subsequently lowers the migratory and invasive potentials of breast and ovarian cancer cells. Moreover, genistein and DIM elicit a significantly greater cumulative effect in lowering CXCR4 and CXCL12 levels than either compound alone. Our data suggest a novel mechanism for the protective effects of phytochemicals against cancer progression and indicate that in combination, these compounds may prove even more efficacious

Codelivery of Genistein and miRNA-29b to A549 Cells Using Aptamer-Hybrid Nanoparticle Bioconjugates.

This study aimed to evaluate the anti-cancer effect of a combination therapy of miRNA-29b and genistein loaded in mucin-1 (MUC 1)-aptamer functionalized hybrid nanoparticles in non-small cell lung cancer (NSCLC) A549 cell line. Genistein-miRNA-29b-loaded hybrid nanoparticles (GMLHN) was prepared and characterized. Particle size and zeta potential were measured using photon correlation spectroscopy (PCS). Encapsulation efficiency and loading efficiency were determined using HPLC. Preferential internalization of MUC 1-aptamer functionalized GMLHN by A549 cells was evaluated and compared to normal MRC-5 cells. The ability of GMLHN to downregulate targeted oncoproteins Phosphorylated protein kinase, strain AK, Thymoma (Phosphorylated protein kinase B) (pAKT), Phosphorylated phosphoinositide 3-kinase (p-PI3K), DNA (cytosine-5-)-methyltransferase 3 beta (DNMT3B) and Myeloid Cell Leukemia Sequence 1 (MCL 1) was evaluated using western blot, while antiproliferative effect and ability to initiate apoptosis was also assessed in A549 cells. MUC 1-aptamer functionalized GMLHN nanoparticles were prepared. These nanoparticles were preferentially internalized by A549 cells but less so, in MRC-5 cells. pAKT, p-PI3K, DNMT3B and MCL 1 were efficiently downregulated by these nanoparticles without affecting the levels of AKT and PI3K in A549 cells. GMLHN demonstrated a superior antiproliferative effect compared to individual genistein and miRNA-29b-loaded nanoparticles. Results generated were able to demonstrate that genistein-miRNA-29b-loaded hybrid nanoparticles (GMLHN) could be a potential treatment modality for NSCLC because of the ability of the payloads to attack multiple targets

Phytoestrogens

Collectively, plants contain several different families of natural products among which are compounds with weak estrogenic or antiestrogenic activity toward mammals. These compounds, termed phytoestrogens, include certain isoflavonoids, flavonoids, stilbenes, and lignans. The best-studied dietary phytoestrogens are the soy isoflavones and the flaxseed lignans. Their perceived health beneficial properties extend beyond hormone-dependent breast and prostate cancers and osteoporosis to include cognitive function, cardiovascular disease, immunity and inflammation, and reproduction and fertility. In the future, metabolic engineering of plants could generate novel and exquisitely controlled dietary sources with which to better assess the potential health beneficial effects of phytoestrogens