• angiogenesis
• cancer stem cells
• cell cycle
• epithelial–mesenchymal transition
• flavonoid
• phytoestrogen
• programmed cell death

• Humans
• Genistein/pharmacology
• Genistein/therapeutic use
• Neoplasms/drug therapy
• Neoplasms/metabolism
• Neoplasms/pathology
• Animals
• Signal Transduction/drug effects
• Apoptosis/drug effects
• Epithelial-Mesenchymal Transition/drug effects
• Cell Proliferation/drug effects

• GPER
• coumestrol
• daidzein
• estrogen receptors
• estrogens
• genistein
• phytoestrogens
• prostate cancer
• quercetin
• resveratrol

• 007491 Fundação para a Ciência e Tecnologia
• 029114 Fundação para a Ciência e Tecnologia

• Humans
• Neoplasms/drug therapy
• Neoplasms/pathology
• Neoplastic Stem Cells

• R15 GM146188 NIGMS NIH HHS
• R35 GM134910 NIGMS NIH HHS

• Aging
• Amyloid-beta
• Anti-inflammatory
• Anticancer
• Antioxidant
• Autophagy
• Genistein
• Geroprotection
• Multimodal action
• Senescence

• Aging
• Alzheimer Disease/drug therapy
• Amyloid beta-Peptides/metabolism
• Cell Cycle Checkpoints
• Genistein/pharmacology
• Genistein/therapeutic use
• Humans

Bone metastasis is a serious and often lethal complication of particularly frequent carcinomas, such as breast and prostate cancers, which not only reduces survival but also worsens the patients’ quality of life. Therefore, it is important to find new and/or additional therapeutic possibilities that can counteract the colonization of bone tissue. High adherence to the Mediterranean diet (MD) is effective in the prevention of cancer and improves cancer patients’ health, thus, here, we considered its impact on bone metastasis. We highlighted some molecular events relevant for the development of a metastatic phenotype in cancer cells and the alterations of physiological bone remodeling, which occur during skeleton colonization. We then considered those natural compounds present in MD foods with a recognized role to inhibit or reverse the metastatic process both in in vivo and in vitro systems, and we reported the identified mechanisms of action. The knowledge of this bioactivity by the dietary components of the MD, together with its wide access to all people, could help not only to maintain healthy status but also to improve the quality of life of patients with bone metastases.

• Mediterranean diet
• bone metastasis
• breast cancer
• epithelial-mesenchymal transition
• nutrients
• osteoblastic bone metastasis
• osteolytic bone metastasis
• prostate cancer

• EMT
• EPLIN
• PCa
• chemoresistance
• metastasis

Isoflavones are phytoestrogens of plant origin, mostly found in the members of the Fabaceae family, that exert beneficial effects in various degenerative disorders. Having high similarity to 17-β-estradiol, isoflavones can bind estrogen receptors, scavenge reactive oxygen species, activate various cellular signal transduction pathways and modulate growth and transcription factors, activities of enzymes, cytokines, and genes regulating cell proliferation and apoptosis. Due to their pleiotropic activities isoflavones might be considered as a natural alternative for the treatment of estrogen decrease-related conditions during menopause. This review will focus on the effects of isoflavones on inflammation and chronic degenerative diseases including cancer, metabolic, cardiovascular, neurodegenerative diseases, rheumatoid arthritis and adverse postmenopausal symptoms.

• cancer
• daidzein
• degenerative diseases
• genistein
• inflammation
• isoflavones

• Female
• Free Radical Scavengers/therapeutic use
• Humans
• Isoflavones/therapeutic use
• Male
• Metabolic Diseases/drug therapy
• Metabolic Diseases/metabolism
• Neoplasms/drug therapy
• Neoplasms/metabolism
• Neurodegenerative Diseases/drug therapy
• Neurodegenerative Diseases/metabolism
• Postmenopause

• chemo resistance
• chemotherapeutic
• mechanisms
• nano scale delivery
• quercetin

Prostate cancer (PCa) represents a major cause of cancer mortality among men in developed countries. Patients with recurrent disease initially respond to androgen-deprivation therapy, but the tumor eventually progresses into castration-resistant PCa; in this condition, tumor cells acquire the ability to escape cell death and develop resistance to current therapies. Thus, new therapeutic approaches for PCa management are urgently needed. In this setting, natural products have been extensively studied for their anti-PCa activities, such as tumor growth suppression, cell death induction, and inhibition of metastasis and angiogenesis. Additionally, numerous studies have shown that phytochemicals can specifically target the androgen receptor (AR) signaling, as well as the PCa stem cells (PCSCs). Interestingly, many clinical trials have been conducted to test the efficacy of nutraceuticals in human subjects, and they have partially confirmed the promising results obtained in vitro and in preclinical models. This article summarizes the anti-cancer mechanisms and therapeutic potentials of different natural compounds in the context of PCa prevention and treatment.

• chemoprevention
• natural compounds
• novel therapeutic strategies
• phytochemicals
• prostate cancer

• Biological Products/pharmacology
• Biological Products/therapeutic use
• Chemoprevention/methods
• Humans
• Male
• Molecular Targeted Therapy/methods
• Prostatic Neoplasms/drug therapy
• Prostatic Neoplasms/pathology
• Prostatic Neoplasms/prevention & control

• FTO gene
• cancer
• dietary carbohydrate

• bioavailability
• dietary polyphenols
• molecular mechanisms
• prostate cancer

• bones
• metastasis
• prostate cancer
• soy isoflavones

• androgen receptor
• daidzein
• genistein
• glycitein
• prostate cancer
• soy isoflavones
• steroids

• Bone
• Cáncer
• MMP-9
• Metalloproteinases
• Metástasis
• Prostate
• Therapeutic targets

Prostate cancer (PCa) is the most frequently diagnosed cancer in men. Current research on tumour-related extracellular vesicles (EVs) suggests that exosomes play a significant role in paracrine signaling pathways, thus potentially influencing cancer progression via multiple mechanisms. In fact, during the last decade numerous studies have revealed the role of EVs in the progression of various pathological conditions including cancer. Moreover, differences in the proteomic, lipidomic, and cholesterol content of exosomes derived from PCa cell lines versus benign prostate cell lines confirm that exosomes could be excellent biomarker candidates. As such, as part of an extensive proteomic analysis using LCMS we previously described a potential role of exosomes as biomarkers for PCa. Current evidence suggests that uptake of EV's into the local tumour microenvironment encouraging us to further examine the role of these vesicles in distinct mechanisms involved in the progression of PCa and castration resistant PCa. For the purpose of this study, we hypothesized that exosomes play a pivotal role in cell-cell communication in the local tumour microenvironment, conferring activation of numerous survival mechanisms during PCa progression and development of therapeutic resistance. Our in vitro results demonstrate that PCa derived exosomes significantly reduce apoptosis, increase cancer cell proliferation and induce cell migration in LNCaP and RWPE-1 cells. In conjunction with our in vitro findings, we have also demonstrated that exosomes increased tumor volume and serum PSA levels in vivo when xenograft bearing mice were administered DU145 cell derived exosomes intravenously. This research suggests that, regardless of androgen receptor phenotype, exosomes derived from PCa cells significantly enhance multiple mechanisms that contribute to PCa progression.

• cancer development
• cancer progression
• exosomes

Epidemiological studies have shown that dietary compounds have significant effects on prostate carcinogenesis. Among dietary agents, genistein, the major isoflavone in soybean, is of particular interest because high consumption of soy products has been associated with a low incidence of prostate cancer, suggesting a preventive role of genistein in prostate cancer. In spite of numerous studies to understand the effects of genistein on prostate cancer, the mechanisms of action have not been fully elucidated. We investigated the differences in methylation and gene expression levels of prostate specimens from a clinical trial of genistein supplementation prior to prostatectomy using Illumina HumanMethylation450 and Illumina HumanHT-12 v4 Expression BeadChip Microarrays. The present study was a randomized, placebo-controlled, double-blind clinical trial on Norwegian patients who received 30 mg genistein or placebo capsules daily for 3–6 weeks before prostatectomy. Gene expression changes were validated by quantitative PCR (qPCR). Whole genome methylation and expression profiling identified differentially methylated sites and expressed genes between placebo and genistein groups. Differentially regulated genes were involved in developmental processes, stem cell markers, proliferation and transcriptional regulation. Enrichment analysis suggested overall reduction in MYC activity and increased PTEN activity in genistein-treated patients. These findings highlight the effects of genistein on global changes in gene expression in prostate cancer and its effects on molecular pathways involved in prostate tumorigenesis.

Glycosylation of small biologically active molecules, either of natural or synthetic origin, has a profound impact on their solubility, stability, and bioactivity, making glycoconjugates attractive compounds as therapeutic agents or nutraceuticals. A large proportion of secondary metabolites, including flavonoids, occur in plants as glycosides, which adds to the molecular diversity that is much valued in medicinal chemistry studies. The subsequent growing market demand for glycosidic natural products has fueled the development of various chemical and biotechnological methods of glycosides preparation. The review gives an extensive overview of the processes of the synthesis of isoflavones and discusses recently developed major routes towards isoflavone-sugar formation processes. Special attention is given to the derivatives of genistein, the main isoflavone recognized as a useful lead in several therapeutic categories, with particular focus on anticancer drug design. The utility of chemical glycosylations as well as glycoconjugates preparation is discussed in some theoretical as well as practical aspects. Since novel approaches to chemical glycosylations and glycoconjugations are abundant and many of them proved suitable for derivatization of polyphenols a new body of evidence has emerged, indicating that sugar moiety can play a much more significant role, when attached to a pharmacophore, then being a mere “solubilizer”. In many cases, it has been demonstrated that semisynthetic glycoconjugates are much more potent cytostatic and cytotoxic agents than reference isoflavones. Moreover, the newly designed glycosides or glycoside mimics can act through different mechanisms than the parent active molecule.

• Chemical glycosylations
• isoflavone glycoconjugates
• isoflavones

Chemoprevention is one of the cancer prevention approaches wherein natural/synthetic agent(s) are prescribed with the aim to delay or disrupt multiple pathways and processes involved at multiple steps, i.e., initiation, promotion, and progression of cancer. Amongst environmental chemopreventive compounds, diet/beverage-derived components are under evaluation, because of their long history of exposure to humans, high tolerability, low toxicity, and reported biological activities. This compilation briefly covers and compares the available evidence on chemopreventive efficacy and probable mechanism of chemoprevention by selected dietary phytochemicals (capsaicin, curcumin, diallyl sulphide, genistein, green/black tea polyphenols, indoles, lycopene, phenethyl isocyanate, resveratrol, retinoids and tocopherols) in experimental systems and clinical trials. All the dietary phytochemicals covered in this review have demonstrated chemopreventive efficacy against spontaneous or carcinogen-induced experimental tumors and/or associated biomarkers and processes in rodents at several organ sites. The observed anti-initiating, anti-promoting and anti-progression activity of dietary phytochemicals in carcinogen-induced experimental models involve phytochemical-mediated redox changes, modulation of enzymes and signaling kinases resulting to effects on multiple genes and cell signaling pathways. Results from clinical trials using these compounds have not shown them to be chemopreventive. This may be due to our: (1) inability to reproduce the exposure conditions, i.e., levels, complexity, other host and lifestyle factors; and (2) lack of understanding about the mechanisms of action and agent-mediated toxicity in several organs and physiological processes in the host. Current research efforts in addressing the issues of exposure conditions, bioavailability, toxicity and the mode of action of dietary phytochemicals may help address the reason for observed mismatch that may ultimately lead to identification of new chemopreventive agents for protection against broad spectrum of exposures.

• Cancer prevention
• Dietary phytochemicals
• Chemoprevention
• Experimental efficacy
• Mechanisms of action
• Clinical trials
• Bioavailability
• Toxicity

• Ishikawa cells
• gene expression profiling
• genistein
• human uterus.
• in vitro
• microarrays

• Epigenetics
• Genistein
• Isoflavones
• Prostate cancer
• Soy phytoestrogens

• Amino Acid Substitution
• Androgens/chemistry
• Androgens/pharmacology
• Anticarcinogenic Agents/chemistry
• Anticarcinogenic Agents/pharmacology
• Cell Line, Tumor
• Cell Nucleus/genetics
• Cell Nucleus/metabolism
• Cell Nucleus/pathology
• Cell Proliferation/drug effects
• Gene Expression Regulation, Neoplastic/drug effects
• Genistein/chemistry
• Genistein/pharmacology
• Humans
• Male
• Mutation, Missense
• Neoplasm Proteins/agonists
• Neoplasm Proteins/biosynthesis
• Neoplasm Proteins/chemistry
• Phytosterols/chemistry
• Phytosterols/pharmacology
• Prostatic Neoplasms/drug therapy
• Prostatic Neoplasms/genetics
• Prostatic Neoplasms/metabolism
• Receptors, Androgen/biosynthesis
• Receptors, Androgen/genetics
• Glycine max/chemistry

• R01 CA116195 NCI NIH HHS
• CA 116195 NCI NIH HHS

• 3' Untranslated Regions
• Aged
• Aged, 80 and over
• Animals
• Antineoplastic Agents/pharmacology
• Apoptosis/drug effects
• Apoptosis/genetics
• Base Pairing
• Base Sequence
• Binding Sites
• Cell Movement/drug effects
• Cell Movement/genetics
• Cell Proliferation
• Gene Expression Regulation, Neoplastic/drug effects
• Genes, Tumor Suppressor
• Genistein/pharmacology
• Humans
• Male
• Mice
• MicroRNAs/genetics
• Middle Aged
• Neoplasm Grading
• Neoplasm Invasiveness
• Neoplasm Staging
• Prostatic Neoplasms/genetics
• Prostatic Neoplasms/pathology
• RNA Interference

• R01CA160079 NCI NIH HHS
• R01 CA160079 NCI NIH HHS
• R01CA138642 NCI NIH HHS
• T32 DK007790 NIDDK NIH HHS
• T32DK007790 NIDDK NIH HHS
• R01 CA138642 NCI NIH HHS

• Angiogenesis Inhibitors/therapeutic use
• Animals
• Antioxidants/therapeutic use
• Antirheumatic Agents/chemistry
• Antirheumatic Agents/pharmacokinetics
• Antirheumatic Agents/therapeutic use
• Arthritis, Rheumatoid/drug therapy
• Clinical Trials as Topic
• Genistein/chemistry
• Genistein/pharmacokinetics
• Genistein/therapeutic use
• Humans
• Mice
• Molecular Structure

Survivin is expressed in prostate cancer (PCa), and its downregulation sensitizes PCa cells to chemotherapeutic agents in vitro and in vivo. Small membrane-bound vesicles called exosomes, secreted from the endosomal membrane compartment, contain RNA and protein that they readily transport via exosome internalization into recipient cells. Recent progress has shown that tumor-derived exosomes play multiple roles in tumor growth and metastasis and may produce these functions via immune escape, tumor invasion and angiogenesis. Furthermore, exosome analysis may provide novel biomarkers to diagnose or monitor PCa treatment.

Exosomes were purified from the plasma and serum from 39 PCa patients, 20 BPH patients, 8 prostate cancer recurrent and 16 healthy controls using ultracentrifugation and their quantities and qualities were quantified and visualized from both the plasma and the purified exosomes using ELISA and Western blotting, respectively.

Survivin was significantly increased in the tumor-derived samples, compared to those from BPH and controls with virtually no difference in the quantity of Survivin detected in exosomes collected from newly diagnosed patients exhibiting low (six) or high (nine) Gleason scores. Exosome Survivin levels were also higher in patients that had relapsed on chemotherapy compared to controls.

These studies demonstrate that Survivin exists in plasma exosomes from both normal, BPH and PCa subjects. The relative amounts of exosomal Survivin in PCa plasma was significantly higher than in those with pre-inflammatory BPH and control plasma. This differential expression of exosomal Survivin was seen with both newly diagnosed and advanced PCa subjects with high or low-grade cancers. Analysis of plasma exosomal Survivin levels may offer a convenient tool for diagnosing or monitoring PCa and may, as it is elevated in low as well as high Gleason scored samples, be used for early detection.

• Biomarkers, Tumor/blood
• Case-Control Studies
• Disease Progression
• Early Detection of Cancer
• Exosomes/metabolism
• Humans
• Inhibitor of Apoptosis Proteins/blood
• Male
• Neoplasm Grading
• Neoplasm Proteins/blood
• Prognosis
• Prostate-Specific Antigen/blood
• Prostatic Hyperplasia/blood
• Prostatic Neoplasms/blood
• Prostatic Neoplasms/diagnosis
• Prostatic Neoplasms/pathology
• Survivin

• P20 MD001632 NIMHD NIH HHS
• P30 CA062203 NCI NIH HHS

• Antineoplastic Agents/pharmacology
• Apoptosis/drug effects
• Cell Movement/drug effects
• Cell Survival/drug effects
• Female
• Gene Expression Regulation, Neoplastic/drug effects
• Genistein/pharmacology
• HeLa Cells
• Humans
• Matrix Metalloproteinase 9/genetics
• Matrix Metalloproteinase 9/metabolism
• Matrix Metalloproteinase Inhibitors/pharmacology
• Tissue Inhibitor of Metalloproteinase-1/antagonists & inhibitors
• Tissue Inhibitor of Metalloproteinase-1/biosynthesis
• Uterine Cervical Neoplasms/drug therapy
• Uterine Cervical Neoplasms/enzymology
• Uterine Cervical Neoplasms/genetics
• Uterine Cervical Neoplasms/pathology

Prostate cancer (PCa) bone metastases have long been believed to be osteoblastic because of bone remodeling leading to the formation of new bone. However, recent studies have shown increased osteolytic activity in the beginning stages of PCa bone metastases, suggesting that targeting both osteolytic and osteoblastic mediators would likely inhibit bone remodeling and PCa bone metastasis. In this study, we found that PCa cells could stimulate differentiation of osteoclasts and osteoblasts through the up-regulation of RANKL, RUNX2 and osteopontin, promoting bone remodeling. Interestingly, we found that formulated isoflavone and 3,3′-diindolylmethane (BR-DIM) were able to inhibit the differentiation of osteoclasts and osteoblasts through the inhibition of cell signal transduction in RANKL, osteoblastic, and PCa cell signaling. Moreover, we found that isoflavone and BR-DIM down-regulated the expression of miR-92a, which is known to be associated with RANKL signaling, EMT and cancer progression. By pathway and network analysis, we also observed the regulatory effects of isoflavone and BR-DIM on multiple signaling pathways such as AR/PSA, NKX3-1/Akt/p27, MITF, etc. Therefore, isoflavone and BR-DIM with their multi-targeted effects could be useful for the prevention of PCa progression, especially by attenuating bone metastasis mechanisms.

• Bone Neoplasms/metabolism
• Bone Neoplasms/secondary
• Bone Remodeling/drug effects
• Cadherins/genetics
• Cadherins/metabolism
• Cell Differentiation/drug effects
• Cell Line, Tumor
• Coculture Techniques
• Epithelial-Mesenchymal Transition/drug effects
• Epithelial-Mesenchymal Transition/genetics
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Humans
• Indoles/pharmacology
• Isoflavones/pharmacology
• Male
• MicroRNAs/genetics
• Models, Biological
• Osteoblasts/cytology
• Osteoblasts/drug effects
• Osteoclasts/cytology
• Osteoclasts/drug effects
• Prostatic Neoplasms/metabolism
• Prostatic Neoplasms/pathology
• RANK Ligand/metabolism
• Signal Transduction/drug effects
• Transforming Growth Factor beta/pharmacology
• Vimentin/genetics
• Vimentin/metabolism

• R01 CA131151 NCI NIH HHS
• 5R01CA131151 NCI NIH HHS
• 5R01CA108535 NCI NIH HHS
• 5R01CA132794 NCI NIH HHS
• R01 CA108535 NCI NIH HHS
• 5R01CA083695 NCI NIH HHS
• R01 CA132794 NCI NIH HHS
• R01 CA083695 NCI NIH HHS

• carcinogenesis
• chemoprevention
• current status
• herbal antioxidant
• screening assays

• Animals
• Anticarcinogenic Agents/administration & dosage
• Anticarcinogenic Agents/adverse effects
• Anticarcinogenic Agents/pharmacokinetics
• Biological Availability
• Carcinogenicity Tests
• Carcinogens/analysis
• Cardiovascular Diseases/chemically induced
• Cardiovascular Diseases/prevention & control
• Diet
• Disease Models, Animal
• Drug Combinations
• Female
• Hormone Replacement Therapy
• Humans
• Isoflavones/adverse effects
• Isoflavones/metabolism
• Isoflavones/pharmacokinetics
• Male
• Neoplasms/chemically induced
• Neoplasms/prevention & control
• Osteoporosis, Postmenopausal/chemically induced
• Osteoporosis, Postmenopausal/prevention & control
• Phytoestrogens/administration & dosage
• Phytoestrogens/adverse effects
• Phytotherapy
• Plant Extracts/administration & dosage
• Plant Extracts/adverse effects
• Plant Extracts/pharmacokinetics
• Risk Assessment
• Glycine max/chemistry

• Adenocarcinoma/diet therapy
• Adenocarcinoma/pathology
• Adenocarcinoma/prevention & control
• Aged
• Animals
• Apoptosis
• Carotenoids/pharmacology
• Carotenoids/therapeutic use
• Catechin/analogs & derivatives
• Catechin/pharmacology
• Catechin/therapeutic use
• Clinical Trials as Topic
• Curcumin/pharmacology
• Curcumin/therapeutic use
• Drug Screening Assays, Antitumor
• Flavonoids/pharmacology
• Flavonoids/therapeutic use
• Flavonols
• Genistein/pharmacology
• Genistein/therapeutic use
• Humans
• Lycopene
• Lythraceae
• Male
• Mice
• Mice, Nude
• Mice, Transgenic
• Middle Aged
• Neoplasm Proteins/antagonists & inhibitors
• Neoplasm Proteins/metabolism
• Pentacyclic Triterpenes/pharmacology
• Pentacyclic Triterpenes/therapeutic use
• Phytotherapy
• Plant Extracts/administration & dosage
• Plant Extracts/therapeutic use
• Prostatic Neoplasms/diet therapy
• Prostatic Neoplasms/pathology
• Prostatic Neoplasms/prevention & control
• Resveratrol
• Stilbenes/pharmacology
• Stilbenes/therapeutic use
• Tumor Cells, Cultured/drug effects

• P50 DK065303 NIDDK NIH HHS
• R01 CA 101039 NCI NIH HHS
• R01 CA078809 NCI NIH HHS
• R01 CA 120451 NCI NIH HHS
• R01 CA078809-10 NCI NIH HHS
• R01 CA 78809 NCI NIH HHS
• R01 CA120451-05 NCI NIH HHS
• R01 CA101039 NCI NIH HHS
• R01 CA120451 NCI NIH HHS
• R01 CA101039-05 NCI NIH HHS

• Adult
• Combined Modality Therapy
• Double-Blind Method
• Humans
• Isoflavones/therapeutic use
• Male
• Middle Aged
• Prostate-Specific Antigen/blood
• Prostatic Neoplasms/therapy
• Radiotherapy Dosage
• Glycine max

• P30 CA022453 NCI NIH HHS
• R01 CA140314 NCI NIH HHS

Platinum-resistance (PR) continues to be a major problem in the management of epithelial ovarian cancer (EOC). Response to various chemotherapeutic agents is poor in patients deemed PR. Genistein, a soy isoflavone has been shown to enhance the effect of chemotherapy in prostate and pancreatic cancer cells in vitro and in vivo by reversing chemo-resistance phenotype. The goal of this study was to investigate the effects of combination therapy with genistein and cisplatin as well as other cytotoxic conventional chemotherapeutic agents in platinum-sensitive (PS) and resistant EOC cells.

The PS human ovarian cancer cell line A2780 and its PR clone C200 cells were pretreated with genistein, followed by the combination of genistein and either cisplatin, taxotere or gemcitabine. Cell survival and apoptosis was assessed by MTT and histone-DNA ELISA. Electrophoretic mobility shift assay (EMSA) was used to evaluate NF-κB DNA binding activity. Western blot analysis was performed with antibodies to Bcl-2, Bcl-xL, survivin, c-IAP and PARP.

Reduction in cell viability, and corresponding induction of apoptosis was observed with genistein pretreatment followed by combination treatment with each of the drugs in both cell lines. The PS cell line was pretreated for 24 hours; in contrast, the PR cell line required 48 hours pretreatment to achieve a response. The anti-apoptotic genes c-IAP1, Bcl-2, Bcl-xL, survivin and NF-κB DNA binding activity were all found to be down-regulated in the combination groups.

This study convincingly demonstrated that the current strategy can be translated in a pre-clinical animal model, and thus it should stimulate future clinical trial for the treatment of drug-resistant ovarian cancer.