Trailblazing perspectives on targeting breast cancer stem cells.

Breast cancer (BCa) is one of the most prevalent malignant tumors affecting women's health worldwide. The recurrence and metastasis of BCa have made it a long-standing challenge to achieve remission-persistent or disease-undetectable clinical outcomes. Cancer stem cells (CSCs) possess the ability to self-renew and generate heterogeneous tumor bulk.

Elucidating the Inhibitory Effect of Resveratrol and Its Structural Analogs on Selected Nucleotide-Related Enzymes.

Resveratrol, the most widely studied natural phytochemical, has been shown to interact with different target proteins. Previous studies show that resveratrol binds and inhibits DNA polymerases and some other enzymes; however, the binding and functioning mechanisms remain unknown. The elucidated knowledge of inhibitory mechanisms of resveratrol will assist us in new drug discovery.

Resveratrol Suppresses Prostate Cancer Epithelial Cell Scatter/Invasion by Targeting Inhibition of Hepatocyte Growth Factor (HGF) Secretion by Prostate Stromal Cells and Upregulation of E-cadherin by Prostate Cancer Epithelial Cells.

Cancer mortality is primarily attributed to metastasis and the resulting compromise of organs secondary to the initial tumor site. Metastasis is a multi-step process in which the tumor cells must first acquire a migratory phenotype and invade through the surrounding tissue for spread to distant organs in the body. The ability of malignant cells to migrate and breach surrounding tissue/matrix barriers is among the most daunting challenges to disease management for men in the United States diagnosed with prostate cancer (CaP), especially since, at diagnosis, a high proportion of patients already have occult or clinically-detectable metastasis.

Control of DNA structure and function by phytochemicals/DNA interaction: Resveratrol/piceatannol induces Cu-independent, cleavage of supercoiled plasmid DNA.

Topoisomerases are enzymes that catalyze DNA unwinding and scissions to resolve topological entanglements possibly arising during DNA replication/transcription. Chemicals which disrupt or inhibit topoisomerase-mediated DNA unwinding can induce breaks that subsequently lead to programmed cell death. Herein we perform experiments guided by the following considerations.

Tumor PD-L1 Induction by Resveratrol/Piceatannol May Function as a Search, Enhance, and Engage ("SEE") Signal to Facilitate the Elimination of "Cold, Non-Responsive" Low PD-L1-Expressing Tumors by PD-L1 Blockade.

Programmed cell death ligand 1 (PD-L1) is an immune regulatory protein that facilitates tumor escape from host immune surveillance. In the clinic, tumors with high level of PD-L1 have been used to identify patients who might respond favorably to treatment by anti-PD-L1 antibodies (PD-L1 blockade, PLB). Typically, a progression-free response of 9-20% to PLB has been observed, the basis for the low success rate is largely unknown.

Nucleolin Is a Functional Binding Protein for Salinomycin in Neuroblastoma Stem Cells.

The aim of this study is to illuminate a novel therapeutic approach by identifying a functional binding target of salinomycin, an emerging anticancer stem cell (CSC) agent, and to help dissect the underlying action mechanisms. By utilizing integrated strategies, we identify that nucleolin (NCL) is likely a salinomycin-binding target and a critical regulator involved in human neuroblastoma (NB) CSC activity. Salinomycin markedly suppresses NB CD34 expression and reduces CD34+ cell population in an NCL-dependent manner via disruption of the interaction of NCL with CD34 promoter.

Upregulation of PD‑L1 expression by resveratrol and piceatannol in breast and colorectal cancer cells occurs via HDAC3/p300‑mediated NF‑κB signaling.

Programmed cell death ligand 1 (PD‑L1) expressed in cancer cells interacting with its receptor programmed cell death 1 (PD‑1) expressed in immune cells represents a regulatory axis linked to the suppression and evasion of host immune functions. The blockade of PD‑1/PD‑L1 interaction using monoclonal antibodies has emerged as an effective therapy for several solid tumors; however, durable response has been observed in a subset of patients with PD‑L1-positive tumors. Thus, the understanding of the mechanisms responsible for the expression of PD‑L1 in tumor cells may help to improve the response to PD‑L1 blockade therapies.

NRH:quinone oxidoreductase 2 (NQO2) and glutaminase (GLS) both play a role in large extracellular vesicles (LEV) formation in preclinical LNCaP-C4-2B prostate cancer model of progressive metastasis.

In the course of studies aimed at the role of oxidative stress in the development of metastatic potential in the LNCaP-C4-2B prostate cancer progression model system, we found a relative decrease in the level of expression of the cytoplasmic nicotinamide riboside: quinone oxidoreductase (NQO2) and an increase in the oxidative stress in C4-2B cells compared to that in LNCaP or its derivatives C4 and C4-2. It was also found that C4-2B cells specifically shed large extracellular vesicles (LEVs) suggesting that these LEVs and their cargo could participate in the establishment of the osseous metastases. The level of expression of caveolin-1 increased as the system progresses from LNCaP to C4-2B.

Application of open-access databases to determine functional connectivity between resveratrol-binding protein QR2 and colorectal carcinoma.

Colorectal cancer (CRC) is a major cause of cancer-associated deaths worldwide. Recently, oral administration of resveratrol (trans-3,5,4'-trihydroxystilbene) has been reported to significantly reduce tumor proliferation in colorectal cancer patients, however, with little specific information on functional connections. The pathogenesis and development of colorectal cancer is a multistep process that can be categorized using three phenotypic pathways, respectively, chromosome instability (CIN), microsatellite instability (MSI), and CpG island methylator (CIMP).

Recent Advances and Challenges in Studies of Control of Cancer Stem Cells and the Gut Microbiome by the Trametes-Derived Polysaccharopeptide PSP (Review).

The medicinal mushroom Trametes versicolor has been well recognized for its activity in maintaining the general health of the population and in managing and treating human diseases in various cultures. Its use has been recently gaining acceptance and popularity in Western countries. The reported health benefits of T.

Functional/activity network (FAN) analysis of gene-phenotype connectivity liaised by grape polyphenol resveratrol.

Resveratrol is a polyphenol that has witnessed an unprecedented yearly growth in PubMed citations since the late 1990s. Based on the diversity of cellular processes and diseases resveratrol reportedly affects and benefits, it is likely that the interest in resveratrol will continue, although uncertainty regarding its mechanism in different biological systems remains.We hypothesize that insights on disease-modulatory activities of resveratrol might be gleaned by systematically dissecting the publicly available published data on chemicals and drugs.

Combined metformin and resveratrol confers protection against UVC-induced DNA damage in A549 lung cancer cells via modulation of cell cycle checkpoints and DNA repair.

Aging in humans is a multi-factorial cellular process that is associated with an increase in the risk of numerous diseases including diabetes, coronary heart disease and cancer. Aging is linked to DNA damage, and a persistent source of DNA damage is exposure to ultraviolet (UV) radiation. As such, identifying agents that confer protection against DNA damage is an approach that could reduce the public health burden of age-related disorders.

Repositioning of drugs using open-access data portal DTome: A test case with probenecid (Review).

The one gene-one enzyme hypothesis, first introduced by Beadle and Tatum in the 1940s and based on their genetic analysis and observation of phenotype changes in Neurospora crassa challenged by various experimental conditions, has witnessed significant advances in recent decades. Much of our understanding of the association between genes and their phenotype expression has benefited from the completion of the human genome project, and has shown continual transformation guided by the effort directed at the annotation and characterization of human genes. Similarly, the idea of one drug‑one primary disease indication that traditionally has been the benchmark for the labeling and usage of drugs has also undergone evident progressive refinements; in recent years the science and practice of pharmaceutical development has notable success in the strategy of drug repurposing.

A microRNA-1280/JAG2 network comprises a novel biological target in high-risk medulloblastoma.

Over-expression of PDGF receptors (PDGFRs) has been previously implicated in high-risk medulloblastoma (MB) pathogenesis. However, the exact biological functions of PDGFRα and PDGFRβ signaling in MB biology remain poorly understood. Here, we report the subgroup specific expression of PDGFRα and PDGFRβ and their associated biological pathways in MB tumors.

Activation of NQO1 in NQO1*2 polymorphic human leukemic HL-60 cells by diet-derived sulforaphane.

Background: The

Nad(p)h: quinone oxidoreductase (NQO1) confers protection against semiquinones and also elicits oxidative stress. The C609T polymorphism of the NQO1 gene, designated NQO1*2, significantly reduces its enzymatic activity due to rapid degradation of protein. Since down regulation of NQO1 mRNA expression correlates with increased susceptibility for developing different types of cancers, we investigated the link between leukemia and the NQO1*2 genotype by mining a web-based microarray dataset, ONCOMINE.

Biochemical and cellular evidence demonstrating AKT-1 as a binding partner for resveratrol targeting protein NQO2.

Background: AKT plays an important role in the control of cell proliferation and survival. Aberrant activation of AKT frequently occurs in human cancers making it an attractive drug targets and leading to the synthesis of numerous AKT inhibitors as therapeutic candidates. Less is known regarding proteins that control AKT.

In search of antiaging modalities: evaluation of mTOR- and ROS/DNA damage-signaling by cytometry.

This review presents the evidence in support of the IGF-1/mTOR/S6K1 signaling as the primary factor contributing to aging and cellular senescence. Reviewed are also specific interactions between mTOR/S6K1 and ROS-DNA damage signaling pathways. Outlined are critical sites along these pathways, including autophagy, as targets for potential antiaging (gero-suppressive) and/or chemopreventive agents.

In silico and biochemical analyses identify quinone reductase 2 as a target of piceatannol.

To obtain information on anti-prostate cancer (CaP) activities of piceatannol, a metabolite biotransformed from resveratrol by cytochrome P450 CYP1B, CWR22Rv1 cells were incubated with increasing dose of piceatannol. Proliferation and apoptosis assays in exposed cells showed that piceatannol produced inhibition comparable to resveratrol. To determine whether quinone reductase 2 (NQO2) plays a role in the observed effects, in silico analysis was performed.

Thalidomide-a notorious sedative to a wonder anticancer drug.

In the past 50 years, thalidomide has undergone a remarkable metamorphosis from a notorious drug inducing birth defects into a highly effective therapy for treating leprosy and multiple myeloma. Today, most notably, thalidomide and its analogs have shown efficacy against a wide variety of diseases, including inflammation and cancer. The mechanism underlying its teratogenicity as well as its anticancer activities has been intensively studied.

Salinomycin: a novel anti-cancer agent with known anti-coccidial activities.

Salinomycin, traditionally used as an anti-coccidial drug, has recently been shown to possess anti-cancer and anti-cancer stem cell (CSC) effects, as well as activities to overcome multi-drug resistance based on studies using human cancer cell lines, xenograft mice, and in case reports involving cancer patients in pilot clinical trials. Therefore, salinomycin may be considered as a promising novel anti-cancer agent despite its largely unknown mechanism of action. This review summarizes the pharmacologic effects of salinomycin and presents possible mechanisms by which salinomycin exerts its anti-tumorigenic activities.

Resveratrol and its metabolites modulate cytokine-mediated induction of eotaxin-1 in human pulmonary artery endothelial cells.

Coronary heart disease (CHD) is a leading cause of death in many developed countries. Evidence has long implicated endothelial injury and inflammation as apical events in the pathogenesis of atherosclerosis, the primary cause of CHD. Numerous risk factors contribute to a damaged, inflamed endothelium.

Regulation of cell cycle transition and induction of apoptosis in HL-60 leukemia cells by the combination of Coriolus versicolor and Ganoderma lucidum.

Medicinal mushrooms have served as the mainstay of treatment for a variety of human illnesses in Asian countries, mostly as supplements by cancer patients. Extracts prepared from Trametes versicolor under the trade name of I'm-Yunity exhibit anti-tumorigenic activities, as supported by inhibition of the proliferation and induction of apoptosis in malignant cells. Similar effects have also been observed for the Reishi mushroom Ganoderma lucidum.

Mechanisms of ceramide-induced COX-2-dependent apoptosis in human ovarian cancer OVCAR-3 cells partially overlapped with resveratrol.

Ceramide is a member of the sphingolipid family of bioactive molecules demonstrated to have profound, diverse biological activities. Ceramide is a potential chemotherapeutic agent via the induction of apoptosis. Exposure to ceramide activates extracellular-signal-regulated kinases (ERK)1/2- and p38 kinase-dependent apoptosis in human ovarian cancer OVCAR-3 cells, concomitant with an increase in the expression of COX-2 and p53 phosphorylation.

Potential anti-aging agents suppress the level of constitutive mTOR- and DNA damage- signaling.

Two different mechanisms are considered to be the primary cause of aging. Cumulative DNA damage caused by reactive oxygen species (ROS), the by-products of oxidative phosphorylation, is one of these mechanisms (ROS concept). Constitutive stimulation of mitogen- and nutrient-sensing mTOR/S6 signaling is the second mechanism (TOR concept).

AKT/mTOR as Novel Targets of Polyphenol Piceatannol Possibly Contributing to Inhibition of Proliferation of Cultured Prostate Cancer Cells.

The polyphenol piceatannol has shown inhibition against tyrosine and serine/threonine kinases. Whether piceatannol also exerts activity on the mammalian target of rapamycin (mTOR), a kinase involved in growth control of eukaryotic cells, is not known. In this study, we tested the effects of piceatannol on proliferation of androgen-dependent (AD) LNCaP and androgen-independent (AI) DU145 and PC-3 prostate cancer (CaP) cells.