Mechanism of action of genistein on breast cancer and differential effects of different age stages

Javed L., Khakwani A., Khan U., Humphrey M.B.

Medication-induced osteoporosis leads to substantial fracture morbidity. With polypharmacy and the aging population in the United States, significant increases in medication-associated fractures are predicted. The most common medication to cause osteoporosis and increase fractures is glucocorticoids. Many other therapies, including loop diuretics, SGLT2 inhibitors, thiazolidinediones, proton pump inhibitors, selective serotonin reuptake inhibitors, heparin, warfarin, antiepileptics, aromatase inhibitors, anti-androgen therapies, gonadotropin-releasing hormone antagonists, and calcineurin inhibitors are associated with increased fracture risks. Here, we review the latest evidence for fracture risk for these medications and discuss fracture risk screening and management strategies.

Guelfi G., Pasquariello R., Anipchenko P., Capaccia C., Pennarossa G., Brevini T.A., Gandolfi F., Zerani M., Maranesi M.

Genistein is a natural compound belonging to flavonoids, having antioxidant, anti-inflammatory, and anti-neoplastic properties. Genistein is considered a phytoestrogen. As such, genistein can bind estrogen receptors (ERα and ERβ), although with a lower affinity than that of estradiol. Despite considerable work, the effects of genistein are not well established yet. This review aims to clarify the role of genistein on female and male reproductive functions in mammals. In females, at a high dose, genistein diminishes the ovarian activity regulating several pathway molecules, such as topoisomerase isoform I and II, protein tyrosine kinases (v-src, Mek-4, ABL, PKC, Syk, EGFR, FGFR), ABC, CFTR, Glut1, Glut4, 5α-reductase, PPAR-γ, mitogen-activated protein kinase A, protein histidine kinase, and recently circulating RNA-miRNA. The effect of genistein on pregnancy is still controversial. In males, genistein exerts an estrogenic effect by inducing testosterone biosynthesis. The interaction of genistein with both natural and synthetic endocrine disruptors has a negative effect on testis function. The positive effect of genistein on sperm quality is still in debate. In conclusion, genistein has a potentially beneficial effect on the mechanisms regulating the reproduction of females and males. However, this is dependent on the dose, the species, the route, and the time of administration.

Patra A., Satpathy S., Naik P.K., Kazi M., Hussain M.D.

Moghtaderi M., Sedaghatnia K., Bourbour M., Fatemizadeh M., Salehi Moghaddam Z., Hejabi F., Heidari F., Quazi S., Farasati Far B.

Recently, nanotechnology is involved in various fields of science, of which medicine is one of the most obvious. The use of nanoparticles in the process of treating and diagnosing diseases has created a novel way of therapeutic strategies with effective mechanisms of action. Also, due to the remarkable progress of personalized medicine, the effort is to reduce the side effects of treatment paths as much as possible and to provide targeted treatments. Therefore, the targeted delivery of drugs is important in different diseases, especially in patients who receive combined drugs, because the delivery of different drug structures requires different systems so that there is no change in the drug and its effectiveness. Niosomes are polymeric nanoparticles that show favorable characteristics in drug delivery. In addition to biocompatibility and high absorption, these nanoparticles also provide the possibility of reducing the drug dosage and targeting the release of drugs, as well as the delivery of both hydrophilic and lipophilic drugs by Niosome vesicles. Since various factors such as components, preparation, and optimization methods are effective in the size and formation of niosomal structures, in this review, the characteristics related to niosome vesicles were first examined and then the in silico tools for designing, prediction, and optimization were explained. Finally, anticancer drugs delivered by niosomes were compared and discussed to be a suitable model for designing therapeutic strategies. In this research, it has been tried to examine all the aspects required for drug delivery engineering using niosomes and finally, by presenting clinical examples of the use of these nanocarriers in cancer, its clinical characteristics were also expressed.

Jain R., Bolch C., Al-Nakkash L., Sweazea K.L.

Diabetes is the eighth leading cause of death in the world and the prevalence is rising in low-income countries. Cardiovascular diseases are the leading cause of death worldwide, especially for individuals with diabetes. Although medications exist to treat symptoms of diabetes, lack of availability and high costs may deter their use by individuals with low incomes as well as those in low-income nations. Therefore, this systematic review was performed to determine whether genistein, a phytoestrogen found in soy products, could provide therapeutic benefits for individuals with diabetes. We searched PubMed and SCOPUS using the terms “genistein,” “diabetes,” and “glucose” and identified 33 peer-reviewed articles that met our inclusion criteria. In general, preclinical studies demonstrated that genistein decreases body weight and circulating glucose and triglycerides concentrations, whereas increasing insulin levels and insulin sensitivity. Genistein also delayed the onset of type 1 and type 2 diabetes. In contrast, clinical studies utilizing genistein generally reported no significant relationship between genistein and body mass, circulating glucose, glycated hemoglobin (A1C) concentrations, or onset of type 1 diabetes. However, genistein was found to improve insulin sensitivity and serum triglyceride concentrations and delayed the onset of type 2 diabetes. In summary, preclinical and clinical studies suggest that genistein may help delay the onset of type 2 diabetes and improve several symptoms associated with the disease. Although additional research is required to confirm these findings, the results highlighted in this review provide some evidence that genistein may offer a natural approach to mitigating some of the complications associated with diabetes.

Ferreira M., Costa D., Sousa Â.

Cancer is the second leading cause of death worldwide. Cervical cancer, for instance, is considered a major scourge in low-income countries. Its development is mostly associated with the human papillomavirus persistent infection and despite the availability of preventive vaccines, they are only widely administered in more developed countries, thus leaving a large percentage of unvaccinated women highly susceptible to this type of cancer. Current treatments are based on invasive techniques, being far from effective. Therefore, the search for novel, advanced and personalized therapeutic approaches is imperative. Flavonoids belong to a group of natural polyphenolic compounds, well recognized for their great anticancer capacity, thus promising to be incorporated in cancer therapy protocols. However, their use is limited due to their low solubility, stability and bioavailability. To surpass these limitations, the encapsulation of flavonoids into delivery systems emerged as a valuable strategy to improve their stability and bioavailability. In this context, the aim of this review is to present the most reliable flavonoids-based delivery systems developed for anticancer therapies and the progress accomplished, with a special focus on cervical cancer therapy. The gathered information revealed the high therapeutic potential of flavonoids and highlights the relevance of delivery systems application, allowing a better understanding for future studies on effective cancer therapy.

BOUTAS I., KONTOGEORGI A., DIMITRAKAKIS C., KALANTARIDOU S.N.

Chen M., Li S., Srinivasasainagendra V., Sharma M., Li Z., Tiwari H., Tollefsbol T.O., Li Y.

Abstract Breast cancer has strong developmental origins and maternal nutrition composition may influence later-life breast cancer risk in the offspring. Our study focused on a bioactive dietary component, genistein (GE) enriched in soybean products, to investigate specific timing of maternal GE exposure that may influence preventive efficacy of GE on offspring breast cancer later in life, and to explore the potential epigenetic mechanisms. Our results indicate a time-dependent effect of maternal GE exposure on early-life breast cancer development in offspring mice. Through integrated transcriptome and methylome analyses, we identified several candidate genes showing significantly differential gene expression and DNA methylation changes. We further found maternal long-term GE treatment can induce inherited epigenetic landmark changes in a candidate tumor suppressor gene, Trp63, resulting in transcriptional activation of Trp63 and induction of the downstream target genes. Our results suggest that maternal long-term exposure to soybean GE may influence early-life epigenetic reprogramming processes, which may contribute to its temporal preventive effects on breast cancer in the offspring. This study provides important mechanistic insights into an appropriate maternal administration of soybean products on prevention of breast cancer later in offspring life.

Akbarzadeh I., Farid M., Javidfar M., Zabet N., Shokoohian B., Arki M.K., Shpichka A., Noorbazargan H., Aghdaei H.A., Hossein-khannazer N., Timashev P., Makvandi P., Vosough M.

The aim, as proof of concept, was to optimize niosomal formulations of tamoxifen in terms of size, morphology, encapsulation efficiency, and release kinetics for further treatment of the breast cancer (BC). Different assays were carried out to evaluate the pro-apoptotic and cytotoxicity impact of tamoxifen-loaded niosomes in two BC cells, MDA-MB-231 and SKBR3. In this study, tamoxifen was loaded in niosomes after optimization in the formulation. The formulation of niosomes supported maximized drug entrapment and minimized their size. The novel formulation showed improvement in storage stability, and after 60 days only, small changes in size, polydispersity index, and drug entrapment were observed. Besides, a pH-dependent release pattern of formulated niosomes displayed slow release at physiological pH (7.4) and a considerable increase of release at acidic pH (5.4), making them a promising candidate for drug delivery in the BC treatment. The cytotoxicity study exhibited high biocompatibility with MCF10A healthy cells, while remarkable inhibitory effects were observed after treatment of cancerous lines, MDA-MB-231, and SKBR3 cells. The IC50 values for the tamoxifen-loaded niosomes were significantly less than other groups. Moreover, treatment with drug-loaded niosomes significantly changed the gene expression pattern of BC cells. Statistically significant down-regulation of cyclin D , cyclin E , VEGFR-1 , MMP-2 , and MMP-9 genes and up-regulation of caspase-3 and caspase-9 were observed. These results were in correlation with cell cycle arrest, lessoned migration capacity, and increased caspase activity and apoptosis induction in cancerous cells. Optimization in the formulation of tamoxifen-loaded niosomes can make them a novel candidate for drug delivery in BC treatment.

Khan S., Suryavanshi M., Kaur J., Nayak D., Khurana A., Manchanda R.K., Tandon C., Tandon S.

As per the latest Globocan statistics, the high prevalence rate of breast cancer in low- and middle-income countries has led to it becoming the most common cancer to be diagnosed, hence posing a major public health challenge. As per this data, more than 11.7% of the estimated new cancer cases in 2020 were due to breast cancer. A small but significant subpopulation of cells with self- renewing ability are present in the tumor stroma and have been given the nomenclature of cancer stem cells (CSCs). These cells display a high degree of plasticity owing to their ability to transition from the slowly cycling quiescent phase to the actively proliferating phenotype. This attribute of CSCs allows them to differentiate into various cell types having diverse functions. Breast CSCs have a pivotal role in development, metastasis, treatment resistance and relapse of breast cancers. This review focuses on the pathways regulating breast CSC maintenance and the current strategies that are being explored for directing the development of novel, targeted, therapeutic approaches for limiting and eradicating this aberrant stem cell population.

Wan M.L., Co V.A., El-Nezami H.

Endocrine-disrupting compounds (EDCs) are ubiquitous substances that are found in our everyday lives, including pesticides, plasticizers, pharmaceutical agents, personal care products, and also in food products and food packaging. Increasing epidemiological evidence suggest that EDCs may affect the development or progression of breast cancer and consequently lead to lifelong harmful health consequences, especially when exposure occurs during early life in humans. Yet so far no appraisal of the available evidence has been conducted on this topic.To systematically review all the available epidemiological studies about the association of the levels of environmental exposures of EDCs with breast cancer risk.The search was performed in accordance with the PRISMA guidelines. We retrieved articles from PubMed (MEDLINE) until 10 March 2021. The key words used in this research were: "Endocrine disruptor(s)" OR "Endocrine disrupting chemical(s)" OR any of the EDCs mentioned below AND "Breast cancer" to locate all relevant articles published. We included only cohort studies and case-control studies. All relevant articles were accessed in full text and were evaluated and summarized in tables.We identified 131 studies that met the search criteria and were included in this systematic review. EDCs reviewed herein included pesticides (e.g. p,p'-dichlorodiphenyltrichloroethane (DDT), p,p'-dichlorodiphenyldichloroethylene (DDE), atrazine, 2,3,7,8-tetrachloridibenzo-p-dioxin (TCDD or dioxin)), synthetic chemicals (e.g. bisphenol A (BPA), phthalates, per- and polyfluoroalkyl substances (PFAS), parabens, polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), contraceptive pills), phytoestrogens (e.g. genistein, resveratrol), and certain mycotoxins (e.g. zearalenone). Most studies assessed environmental EDCs exposure via biomarker measurements.We identified certain EDC exposures could potentially elevate the risk of breast cancer. As majority of EDCs are highly persistent in the environment and bio-accumulative, it is essential to assess the long-term impacts of EDC exposures, especially multi-generational and transgenerational. Also, since food is often a major route of exposure to EDCs, well-designed exposure assessments of potential EDCs in food and food packing are necessary and their potential link to breast cancer development need to be carefully evaluated for subsequent EDC policy making and regulations.

Ghosh B., Biswas S.

In recent years, polymeric micelles have been extensively utilized in pre-clinical studies for delivering poorly soluble chemotherapeutic agents in cancer. Polymeric micelles are formed via self-assembly of amphiphilic polymers in facile manners. The wide availability of hydrophobic and, to some extent, hydrophilic polymeric blocks allow researchers to explore various polymeric combinations for optimum loading, stability, systemic circulation, and delivery to the target cancer tissues. Moreover, polymeric micelles could easily be tailor-made by increasing and decreasing the number of monomers in each polymeric chain. Some of the widely accepted hydrophobic polymers are poly(lactide) (PLA), poly(caprolactone) (PCL), poly(lactide- co -glycolide) (PLGA), polyesters, poly(amino acids), lipids. The hydrophilic polymers used to wrap the hydrophobic core are poly(ethylene glycol), poly(oxazolines), chitosan, dextran, and hyaluronic acids. Drugs could be conjugated to polymers at the distal ends to prepare pharmacologically active polymeric systems that impart enhanced solubility and stability of the conjugates and provide an opportunity for combination drug delivery. Their nano-size enables them to accumulate to the tumor microenvironment via the Enhanced Permeability and Retention (EPR) effect. Moreover, the stimuli-sensitive breakdown provides the micelles an effective means to deliver the therapeutic cargo effectively. The tumor micro-environmental stimuli are pH, hypoxia, and upregulated enzymes. Externally applied stimuli to destroy micellar disassembly to release the payload include light, ultrasound, and temperature. This article delineates the current trend in developing polymeric micelles combining various block polymeric scaffolds. The development of stimuli-sensitive micelles to achieve enhanced therapeutic activity are also discussed. • Polymeric micelles are self-assembled nano-aggregates of amphiphilic b- co -polymers. • Micelles load drugs physico-chemically, tumor-targeted by active/passive phenomena. • The review focusses on various lipophilic and hydrophilic micellar building blocks. • Micelles sensitive to stimuli, pH, hypoxia, temperature, and light are discussed.

Sung H., Ferlay J., Siegel R.L., Laversanne M., Soerjomataram I., Jemal A., Bray F.

This article provides an update on the global cancer burden using the GLOBOCAN 2020 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer. Worldwide, an estimated 19.3 million new cancer cases (18.1 million excluding nonmelanoma skin cancer) and almost 10.0 million cancer deaths (9.9 million excluding nonmelanoma skin cancer) occurred in 2020. Female breast cancer has surpassed lung cancer as the most commonly diagnosed cancer, with an estimated 2.3 million new cases (11.7%), followed by lung (11.4%), colorectal (10.0 %), prostate (7.3%), and stomach (5.6%) cancers. Lung cancer remained the leading cause of cancer death, with an estimated 1.8 million deaths (18%), followed by colorectal (9.4%), liver (8.3%), stomach (7.7%), and female breast (6.9%) cancers. Overall incidence was from 2-fold to 3-fold higher in transitioned versus transitioning countries for both sexes, whereas mortality varied

Zhang X., Powell K., Li L.

Despite recent advances in diagnosis and treatment, breast cancer (BC) is still a major cause of cancer-related mortality in women. Breast cancer stem cells (BCSCs) are a small but significant subpopulation of heterogeneous breast cancer cells demonstrating strong self-renewal and proliferation properties. Accumulating evidence has proved that BCSCs are the driving force behind BC tumor initiation, progression, metastasis, drug resistance, and recurrence. As a heterogeneous disease, BC contains a full spectrum of different BC subtypes, and different subtypes of BC further exhibit distinct subtypes and proportions of BCSCs, which correspond to different treatment responses and disease-specific outcomes. This review summarized the current knowledge of BCSC biomarkers and their clinical relevance, the methods for the identification and isolation of BCSCs, and the mechanisms regulating BCSCs. We also discussed the cellular origin of BCSCs and the current advances in single-cell lineage tracing and transcriptomics and their potential in identifying the origin and lineage development of BCSCs.

Scioli Montoto S., Muraca G., Ruiz M.E.

In the golden age of pharmaceutical nanocarriers, we are witnessing a maturation stage of the original concepts and ideas. There is no doubt that nanoformulations are extremely valuable tools for drug delivery applications; the current challenge is how to optimize them to ensure that they are safe, effective and scalable, so that they can be manufactured at an industrial level and advance to clinical use. In this context, lipid nanoparticles have gained ground, since they are generally regarded as non-toxic, biocompatible and easy-to-produce formulations. Pharmaceutical applications of lipid nanocarriers are a burgeoning field for the transport and delivery of a diversity of therapeutic agents, from biotechnological products to small drug molecules. This review starts with a brief overview of the characteristics of solid lipid nanoparticles and discusses the relevancy of performing systematic preformulation studies. The main applications, as well as the advantages that this type of nanovehicles offers in certain therapeutic scenarios are discussed. Next, pharmacokinetic aspects are described, such as routes of administration, absorption after oral administration, distribution in the organism (including brain penetration) and elimination processes. Safety and toxicity issues are also addressed. Our work presents an original point of view, addressing the biopharmaceutical aspects of these nanovehicles by means of descriptive statistics of the state-of-the-art of solid lipid nanoparticles research. All the presented results, trends, graphs and discussions are based in a systematic (and reproducible) bibliographic search that considered only original papers in the subject, covering a 7 years range (2013-today), a period that accounts for more than 60% of the total number of publications in the topic in the main bibliographic databases and search engines. Focus was placed on the therapeutic fields of application, absorption and distribution processes and current efforts for the translation into the clinical practice of lipid-based nanoparticles. For this, the currently active clinical trials on lipid nanoparticles were reviewed, with a brief discussion on what achievements or milestones are still to be reached, as a way of understanding the reasons for the scarce number of solid lipid nanoparticles undergoing clinical trials.