curcumin and sulforaphane

The blockade of the progression or onset of pathological events is essential for the homeostasis of an organism. Some common pathological mechanisms involving a wide range of diseases are the uncontrolled inflammatory reactions that promote fibrosis, oxidative reactions, and other alterations. Natural plant compounds (NPCs) are bioactive elements obtained from natural sources that can regulate physiological processes. Inflammation is recognized as an important factor in the development and evolution of chronic renal damage. Consequently, any compound able to modulate inflammation or inflammation-related processes can be thought of as a renal protective agent and/or a potential treatment tool for controlling renal damage. The objective of this research was to review the beneficial effects of bioactive natural compounds on kidney damage to reveal their efficacy as demonstrated in clinical studies.. This systematic review is based on relevant studies focused on the impact of NPCs with therapeutic potential for kidney disease treatment in humans.. Clinical studies have evaluated NPCs as a different way to treat or prevent renal damage and appear to show some benefits in improving OS, inflammation, and antioxidant capacity, therefore making them promising therapeutic tools to reduce or prevent the onset and progression of KD pathogenesis.. This review shows the promising clinical properties of NPC in KD therapy. However, more robust clinical trials are needed to establish their safety and therapeutic effects in the area of renal damage.

Topics: Antioxidants; Berberine; Beta vulgaris; Betalains; Biological Products; Catechin; Curcumin; Disulfides; Flavonoids; Humans; Isothiocyanates; Kidney; Kidney Diseases; Plant Extracts; Pomegranate; Protective Agents; Resveratrol; Sulfinic Acids; Sulfoxides; Xanthophylls

Cancer stem cells (CSCs) constitute a subpopulation of tumor cells that possess self-renewal and tumor initiation capacity, and the ability to give rise to the heterogeneous lineages of cancer cells that comprise the tumor. CSCs exhibit intrinsic mechanisms of resistance to virtually all conventional cancer therapeutics, allowing them to survive current cancer therapies and to initiate tumor recurrence and metastasis. Different pathways and mechanisms that confer resistance and survival of CSCs, including activation of the Wnt/β- catenin, Sonic Hedgehog, Notch, PI3K/Akt/mTOR and STAT3 signaling pathways, expression of aldehyde dehydrogenase 1 (ALDH1) and oncogenic microRNAs, and acquisition of epithelial-mesenchymal transition (EMT), have been identified recently. Certain phytochemicals, in particular curcumin, epigallocatechin-3-gallate (EGCG), sulforaphane, resveratrol and genistein have been shown to interfere with these intrinsic CSC pathways in vitro and in human xenograft mice, leading to elimination of CSCs. Moreover, recent clinical trials have demonstrated the therapeutic efficacy of five phytochemicals, alone or in combination with modern cancer therapeutics, and in various types of cancer. Since current cancer therapies fail to eradicate CSCs, leading to cancer recurrence and progression, targeting of CSCs with phytochemicals such as curcumin, EGCG, sulforaphane, resveratrol and genistein, combined with each other and/or in combination with conventional cytotoxic drugs and novel cancer therapeutics, may offer a novel therapeutic strategy against cancer.

Topics: Animals; Catechin; Curcumin; Genistein; Hedgehog Proteins; Humans; Isothiocyanates; Mice; Neoplasm Recurrence, Local; Neoplastic Stem Cells; Phosphatidylinositol 3-Kinases; Phytochemicals; Resveratrol; Sulfoxides

We conducted a systematic review of human trials examining the effects of dietary phytochemicals on Nrf2 activation. In accordance with the PRISMA guidelines, Medline, Embase and CAB abstracts were searched for articles from inception until March 2020. Studies in adult humans that measured Nrf2 activation (gene or protein expression changes) following ingestion of a phytochemical, either alone or in combination were included. The study was pre-registered on the Prospero database (Registration Number: CRD42020176121). Twenty-nine full-texts were retrieved and reviewed for analysis; of these, eighteen were included in the systematic review. Most of the included participants were healthy, obese or type 2 diabetics. Study quality was assessed using the Cochrane Collaboration Risk of Bias Assessment tool. Twelve different compounds were examined in the included studies: curcumin, resveratrol and sulforaphane were the most common (n = 3 each). Approximately half of the studies reported increases in Nrf2 activation (n = 10); however, many were of poor quality and had an unclear or high risk of bias. There is currently limited evidence that phytochemicals activate Nrf2 in humans. Well controlled human intervention trials are needed to corroborate the findings from in vitro and animal studies.

Topics: Adult; Aged; Antioxidants; Bias; Curcumin; Diabetes Mellitus, Type 2; Humans; Isothiocyanates; Middle Aged; NF-E2-Related Factor 2; Obesity; Oxidative Stress; Phytochemicals; Polyphenols; Resveratrol; Sulfoxides

The NLRP3 inflammasome formation and following cytokine secretion is a crucial step in innate immune responses. Internal and external factors may trigger inflammasome activation and result in inflammatory cytokine secretion. Inflammasome formation and activity play critical roles in several disease pathologies such as cardiovascular, metabolic, renal, digestive, and CNS diseases. Underlying pathways are not yet clear, but phytochemicals as alternative therapies have been extensively used for suppression of inflammatory responses.. In this review, we aimed to summarize in vivo and in vitro effects on NLRP3 inflammasome activation of selected phytochemicals.. Three phytochemicals; Sulforaphane, Curcumin, and Resveratrol were selected, and studies were reviewed to clarify their intracellular signaling mechanism in NLRP3 inflammasome activity. PubMed and Scopus databases are used for the search. For sulforaphane, 8 articles, for curcumin, 25 articles, and for resveratrol, 41 articles were included in the review.. In vitro and in vivo studies pointed out that the selected phytochemicals have inhibitory properties on NLRP3 inflammasome activity. However, neither the mechanism is clear, nor the study designs and doses are standardized.

Topics: Animals; Cardiovascular Diseases; Central Nervous System Diseases; Curcumin; Humans; Inflammasomes; Inflammation; Isothiocyanates; NLR Family, Pyrin Domain-Containing 3 Protein; Phytochemicals; Resveratrol; Signal Transduction; Sulfoxides

Drugs used in clinical oncology have narrow therapeutic indices with adverse toxicity often involving oxidative damage. Chemoresistance to these conventional antineoplastics is usually mediated by oxidative stress-upregulated pathways such as those of nuclear factor-kappa B (NF-κB) and hypoxia-inducible factor-1 alpha (HIF-1α). Accordingly, the use of antioxidants in combinational approaches has begun to be considered for fighting cancer because of both the protective role against adverse effects and the ability to sensitize chemoresistant cancer cells. Nuclear factor erythroid 2-related factor 2 (Nrf2) has been identified as a mediator of the cytoprotection but it is not regularly associated with tumor chemosensitization. However, some Nrf2 inducers could be exerting cytoprotective and chemosensitizing roles through a simple integrated mechanism in which the cellular level of reactive oxygen species is controlled, thus inhibiting the oxidative damage in non-target tissues and the tumor chemoresistance mediated by NF-κB or HIF-1α. As examples to show the general idea of this antioxidant combination chemotherapy, this review explores the preclinical information available for four combinations, each composed by a paradigmatic oncological drug (cisplatin or doxorubicin) and a recognized antioxidant (sulforaphane or curcumin). The issues for translating these outcomes to clinical trials are briefly discussed.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Cisplatin; Curcumin; Doxorubicin; Humans; Isothiocyanates; Sulfoxides

Diabetic nephropathy (DN) is manifested as increased urinary protein level, decreased glomerular filtration rate, and final renal dysfunction. DN is the leading cause of end-stage renal disease worldwide and causes a huge societal healthcare burden. Since satisfied treatments are still limited, exploring new strategies for the treatment of this disease is urgently needed. Oxidative stress takes part in the initiation and development of DN. In addition, nuclear factor erythroid 2-related factor 2 (Nrf2) plays a key role in the cellular response to oxidative stress. Thus, activation of Nrf2 seems to be a new choice for the treatment of DN. In current review, we discussed and summarized the therapeutic effects of Nrf2 activation on DN from both basic and clinical studies.

Topics: Animals; Anticarcinogenic Agents; Antioxidant Response Elements; Antioxidants; Curcumin; Cysteine Proteinase Inhibitors; Diabetic Nephropathies; Enzyme Inhibitors; Humans; Isothiocyanates; Leupeptins; Molecular Targeted Therapy; NF-E2-Related Factor 2; Oxidative Stress; Resveratrol; Rutin; Signal Transduction; Stilbenes; Sulfoxides; Trace Elements; Zinc

Non-alcoholic fatty liver disease (NAFLD) is a common clinicopathological condition, encompassing a range of conditions caused by lipid deposition within liver cells. To date, no approved drugs are available for the treatment of NAFLD, despite the fact that it represents a serious and growing clinical problem in the Western world. Identification of the molecular mechanisms leading to NAFLD-related fat accumulation, mitochondrial dysfunction and oxidative balance impairment facilitates the development of specific interventions aimed at preventing the progression of hepatic steatosis. In this review, we focus our attention on the role of dysfunctions in mitochondrial bioenergetics in the pathogenesis of fatty liver. Major data from the literature about the mitochondrial targeting of some antioxidant molecules as a potential treatment for hepatic steatosis are described and critically analysed. There is ample evidence of the positive effects of several classes of antioxidants, such as polyphenols (

Topics: Animals; Anthocyanins; Antioxidants; Carotenoids; Catechin; Coumestrol; Curcumin; Energy Metabolism; Fatty Liver; Glucosinolates; Humans; Imidoesters; Isothiocyanates; Lipogenesis; Mitochondria; Non-alcoholic Fatty Liver Disease; Nutritional Sciences; Oxidative Stress; Oximes; Polyphenols; Quercetin; Resveratrol; Stilbenes; Sulfoxides; Xanthophylls

Much of the recent research in neoplasia has been focusing on the epigenetics of cancer cells, particularly as regards the search for potential molecular biomarkers that could be used for early diagnosis, effective treatment, and prognosis of several types of cancer. Carcinogenesis often starts with mutations in oncogenes and tumor suppressor genes, and it leads to anomalies in cellular processes as vital as cell cycle regulation and apoptosis. Because malignant changes arise as a result of genetic as well as epigenetic mechanisms, one possible means of intervention involves reprogramming gene expression, so as to-at least in part-revert the molecular alterations. DNA methylation and demethylation, acetylation and deacetylation of histones, and microRNAs are a few examples of the epigenetic mechanisms responsible for tumor development and progression. Many biologically active compounds present in food-including sulforaphane, curcumin, and epigallocatechin-have been found to modulate those processes. We here systematically review information on the effects of such bioactive dietary compounds on human breast cancer cell lines, and explore the mechanisms underlying those effects with a view to their potential therapeutic application.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Breast Neoplasms; Catechin; Cell Cycle; Cell Line, Tumor; Curcumin; Epigenesis, Genetic; Female; Humans; Isothiocyanates; Sulfoxides; Telomerase

The recognition that food-derived nonnutrient molecules can modulate gene expression to influence intracellular molecular mechanisms has seen the emergence of the fields of nutrigenomics and nutrigenetics. The aim of this review is to describe the properties of nutrigenomic activators of transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2), comparing the potential for sulforaphane and other phytochemicals to demonstrate clinical efficacy as complementary medicines. Broccoli-derived sulforaphane emerges as a phytochemical with this capability, with oral doses capable of favourably modifying genes associated with chemoprevention. Compared with widely used phytochemical-based supplements like curcumin, silymarin, and resveratrol, sulforaphane more potently activates Nrf2 to induce the expression of a battery of cytoprotective genes. By virtue of its lipophilic nature and low molecular weight, sulforaphane displays significantly higher bioavailability than the polyphenol-based dietary supplements that also activate Nrf2. Nrf2 activation induces cytoprotective genes such as those playing key roles in cellular defense mechanisms including redox status and detoxification. Both its high bioavailability and significant Nrf2 inducer capacity contribute to the therapeutic potential of sulforaphane-yielding supplements.

Topics: Animals; Anticarcinogenic Agents; Area Under Curve; Brassica; Chemoprevention; Curcumin; Disease Models, Animal; Exercise; Gene Expression Profiling; Glucosinolates; Glycoside Hydrolases; Humans; Isothiocyanates; NAD(P)H Dehydrogenase (Quinone); NF-E2-Related Factor 2; Nitriles; Nutrigenomics; Nutritional Sciences; Oxidation-Reduction; Phytochemicals; Resveratrol; Signal Transduction; Silymarin; Stilbenes; Sulfoxides

Diet has been linked to an overwhelming proportion of cancers. Current chemotherapy and targeted therapies are limited by toxicity and the development of resistance against these treatments results in cancer recurrence or progression. In vitro evidence indicates that a number of dietary-derived agents have activity against a highly tumorigenic, chemoradiotherapy resistant population of cells within a tumour. This population is associated with cancer recurrence and is therefore clinically significant. Targeting this subpopulation, termed cancer stem-like cells with dietary-derived agents provides a potentially low toxicity strategy to enhance current treatment regimens. In addition, dietary-derived compounds also provide a novel approach to cancer prevention strategies. This review focusses on selected diet-derived agents that have been shown to specifically target cancer stem-like cells using in vivo models, or in clinical trials. Furthermore, the potential limitations of these studies are discussed, and areas of research that need to be addressed to allow successful translation of dietary-derived agents to the clinical arena are highlighted.

Topics: Animals; Anticarcinogenic Agents; Catechin; Cell Line, Tumor; Curcumin; Diet; Disease Models, Animal; Flavonoids; Humans; Isothiocyanates; Neoplasms; Neoplastic Stem Cells; Randomized Controlled Trials as Topic; Resveratrol; Stilbenes; Sulfoxides; Vitamin A

Hepatocellular carcinoma (HCC) is an aggressive and life-threatening disease often diagnosed at intermediate or advanced stages, which substantially limits therapeutic approaches to its successful treatment. This indicates that the prevention of HCC may be the most promising strategy in reducing its incidence and mortality. Emerging evidence indicates that numerous nutrients and nonnutrient dietary bioactive components can reduce the occurrence and/or delay the development of HCC through modifications of deregulated epigenetic mechanisms. This review examines the existing knowledge on the epigenetic mechanism-based studies in in vitro and in vivo models of HCC on the chemopreventive potential of epigenetic food components, including dietary methyl-group donors, epigallocatechin-3-gallate, sodium butyrate, resveratrol, curcumin, and sulforaphane, on liver carcinogenesis. Future direction and potential challenges in the effective use of bioactive food constituents in the prevention of HCC are highlighted and discussed.

Topics: Animals; Butyric Acid; Carcinoma, Hepatocellular; Catechin; Cell Line, Tumor; Curcumin; Disease Models, Animal; DNA Methylation; Epigenesis, Genetic; Food; Humans; Isothiocyanates; Phytochemicals; Resveratrol; Stilbenes; Sulfoxides

To evaluate the evidence from randomised trials for the efficacy and safety of phytotherapeutic interventions in the management of biochemically recurrent (BCR) prostate cancer, indicated by prostate-specific antigen (PSA) progression, numbers progressing to/time to initiation of androgen-deprivation therapy or salvage therapy.. MEDLINE (Ovid), EMBASE (Ovid), AMED (Ovid), CINAHL (EBSCO) and the Cochrane Library databases were searched. Clinical trials investigating phytotherapeutic interventions as dietary supplements or dietary components, including multi-component herbal formulations, in men with BCR prostate cancer were located. Eight of nine authors contacted for further information responded. Methodological quality was assessed using the Cochrane Collaboration's risk of bias assessment tool. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement for reporting systematic reviews was followed.. Of 23 full-text articles assessed for eligibility, five met the criteria for inclusion. Two studies were placebo controlled; two were active control trials; and one a high-/low-dose trial. The interventions were administered as isolated phytochemicals (sulphoraphane), phytotherapeutic extracts [Pomi-T (pomegranate, turmeric, green tea and broccoli sprout extract), soy, lycopene, and POMx (pomegranate extract)], or plant-derived dietary items (soy and lycopene). All studies found serum PSA levels to stabilise, decrease or rise more slowly in a significant number of men, and three studies reported stabilising or lengthening of PSA-doubling time. Studies were generally of good quality, but sample sizes were predominantly small, and durations short.. High-quality studies in this area are lacking. Sulphoraphane, lycopene, soy isoflavones, POMx, and Pomi-T are safe and well tolerated. There is limited evidence that they can affect PSA dynamics. No recommendation can be made for the use of these agents in managing prostate cancer morbidity and mortality until high-quality, fully powered studies are available. Recommendations are made for improving reproducibility and translation of findings with regard to study population, study endpoints, design, and the reporting of phytotherapeutic interventions.

Topics: Antineoplastic Agents, Phytogenic; Brassica; Carotenoids; Curcuma; Glycine max; Humans; Isothiocyanates; Lycopene; Lythraceae; Male; Phytotherapy; Plant Extracts; Prostate-Specific Antigen; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Sulfoxides; Tea

Defects in initiating or executing cell death programs are responsible for cancer chemoresistance. The growing understanding of apoptotic programs suggests that compounds simultaneously inhibiting multiple signaling pathways might provide a better therapeutic outcome than that of individual inhibitors.. Natural compounds can modulate different survival pathways, thus enhancing the therapeutic effects of anticancer treatments. This review provides an overview of the preclinical and clinical relevance of chemosensitization, giving special reference to curcumin (CUR) and sulforaphane (SFN) as agents to overcome apoptosis resistance against chemotherapy.. Even if CUR and SFN are common dietary constituents, they are characterized by several problems still unresolved and hampering their development as anticancer drugs. For a drug to be safe, it must be devoid of toxicity, and some studies conducted to date raises concern about CUR and SFN safety. Moreover, the efficacy of a drug, alone or in association, is usually determined by randomized, placebo-controlled, double-blind clinical trials. No such trials have shown CUR and SFN to be effective so far. Thus, caution should be exercised when suggesting the use of CUR or SFN for cancer-related therapeutic purpose, especially for very early stage of malignancy, or in patients who are undergoing chemotherapy.

Topics: Animals; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Apoptosis; Curcumin; Drug Resistance, Neoplasm; Fluorouracil; Humans; Isothiocyanates; Neoplasms; Platinum Compounds; Signal Transduction; Sulfoxides

The pronounced effects of the epigenetic diet (ED) and caloric restriction (CR) have on epigenetic gene regulation have been documented in many pre-clinical and clinical studies. Understanding epigenetics is of high importance because of the concept that external factors such as nutrition and diet may possess the ability to alter gene expression without modifying the DNA sequence. The ED introduces bioactive medicinal chemistry compounds such as sulforaphane (SFN), curcumin (CCM), epigallocatechin gallate (EGCG) and resveratrol (RSV) that are thought to aid in extending the human lifespan. CR, although similar to ED in the target of longevity, mildly reduces the total daily calorie intake while concurrently providing all beneficial nutrients. Both CR and ED may act as epigenetic modifiers to slow the aging process through histone modification, DNA methylation, and by modulating microRNA expression. CR and ED have been proposed as two important mechanisms that modulate and potentially slow the progression of age-related diseases such as cardiovascular disease (CVD), cancer, obesity, Alzheimer's and osteoporosis to name a few. While many investigators have examined CR and ED as separate entities, this review will primarily focus on both as they relate to age-related diseases, their epigenetic effects and their medicinal chemistry.

Topics: Aging; Anticarcinogenic Agents; Caloric Restriction; Catechin; Chemistry, Pharmaceutical; Curcumin; Epigenesis, Genetic; Humans; Isothiocyanates; Resveratrol; Stilbenes; Sulfoxides

Cancer stem cells often have phenotypic and functional characteristics similar to normal stem cells including the properties of self-renewal and differentiation. Recent findings suggest that uncontrolled self-renewal may explain cancer relapses and may represent a critical target for cancer prevention. It is conceivable that the loss of regulatory molecules resulting from inappropriate consumption of specific foods and their constituents may foster the aberrant self-renewal of cancer stem cells. In fact, increasing evidence points to the network delivering signals for self-renewal from extracellular compartments to the nucleus including changes in stem cell environments, inducible expression of microRNAs, hyperplastic nuclear chromatin structures, and the on/off of differentiation process as possible sites of action for bioactive food components. Diverse dietary constituents such as vitamins A and D, genistein, (-)-epigallocatechin-3-gallate (EGCG), sulforaphane, curcumin, piperine, theanine and choline have been shown to modify self-renewal properties of cancer stem cells. The ability of these bioactive food components to influence the balance between proliferative and quiescent cells by regulating critical feedback molecules in the network including dickkopf 1 (DKK-1), secreted frizzled-related protein 2 (sFRP2), B cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1) and cyclin-dependent kinase 6 (CDK6) may account for their biological response. Overall, the response to food components does not appear to be tissue or organ specific, suggesting there may be common cellular mechanisms. Unquestionably, additional studies are needed to clarify the physiological role of these dietary components in preventing the resistance of tumor cells to traditional drugs and cancer recurrence.

Topics: Alkaloids; Benzodioxoles; Catechin; Cell Differentiation; Cell Proliferation; Choline; Curcumin; Cyclin-Dependent Kinase 6; Diet; Epigenesis, Genetic; Gene Expression Regulation; Genistein; Glutamates; Humans; Intercellular Signaling Peptides and Proteins; Isothiocyanates; Membrane Proteins; Mesenchymal Stem Cells; Neoplastic Stem Cells; Nuclear Proteins; Piperidines; Plant Extracts; Polycomb Repressive Complex 1; Polyunsaturated Alkamides; Proto-Oncogene Proteins; Repressor Proteins; STAT1 Transcription Factor; Sulfoxides; Thiocyanates; Vitamin A; Vitamin D; Wnt Proteins

The emergence of cancer stem cell theory has profound implications for cancer chemoprevention and therapy. Cancer stem cells give rise to the tumor bulk through continuous self-renewal and differentiation. Understanding the mechanisms that regulate self-renewal is of greatest importance for discovery of anticancer drugs targeting cancer stem cells. Naturally occurring dietary compounds have received increasing attention in cancer chemoprevention. The anticancer effects of many dietary components have been reported for both in vitro and in vivo studies. Recently, a number of studies have found that several dietary compounds can directly or indirectly affect cancer stem cell self-renewal pathways. Herein we review the current knowledge of most common natural dietary compounds for their impact on self-renewal pathways and potential effect against cancer stem cells. Three pathways (Wnt/β-catenin, Hedgehog and Notch) are summarized for their functions in self-renewal of cancer stem cells. The dietary compounds, including curcumin, sulforaphane, soy isoflavone, epigallocatechin-3-gallate, resveratrol, lycopene, piperine and vitamin D(3), are discussed for their direct or indirect effect on these self-renewal pathways. Curcumin and piperine have been demonstrated to target breast cancer stem cells. Sulforaphane has been reported to inhibit pancreatic tumor-initiating cells and breast cancer stem cells. These studies provide a basis for preclinical and clinical evaluation of dietary compounds for chemoprevention of cancer stem cells. This may enable us to discover more preventive strategies for cancer management by reducing cancer resistance and recurrence and improving patient survival.

Topics: Alkaloids; Animals; Anticarcinogenic Agents; Benzodioxoles; beta Catenin; Carotenoids; Catechin; Cell Differentiation; Cell Proliferation; Cholecalciferol; Curcumin; Diet; Humans; Isoflavones; Isothiocyanates; Lycopene; Neoplasms; Neoplastic Stem Cells; Piperidines; Polyunsaturated Alkamides; Resveratrol; Signal Transduction; Stilbenes; Sulfoxides; Thiocyanates; Wnt Proteins

Certain dietary chemicals influenced the expression of chemopreventive genes through the Nrf2-Keap1 pathway. However, the difference in Nrf2 activation potency of these chemicals is not well studied. This study is aimed at determining the difference in the potency of liver Nrf2 nuclear translocation induced by the administration of equal doses of selected dietary chemicals in mice. Male ICR white mice were administered 50 mg/kg of sulforaphane, quercetin, curcumin, butylated hydroxyanisole, and indole-3-carbinol for 14 days. On day 15, the animals were sacrificed, and their livers were isolated. Liver nuclear extracts were prepared, and Nrf2 nuclear translocation was detected through Western blotting. To determine the implication of the Nrf2 nuclear translocation on the expression levels of several Nrf2-regulated genes, liver RNA was extracted for qPCR assay. Equal doses of sulforaphane, quercetin, curcumin, butylated hydroxyanisole, and indole-3-carbinol significantly induced the nuclear translocation of Nrf2 with different intensities and subsequently increased the expression of Nrf2-regulated genes with an almost similar pattern as the Nrf2 nuclear translocation intensities (sulforaphane > butylated hydroxyanisole = indole-3-carbinol > curcumin > quercetin). In conclusion, sulforaphane is the most potent dietary chemical that induces the Nrf2 translocation into the nuclear fraction in the mouse liver.

Topics: Animals; Butylated Hydroxyanisole; Curcumin; Kelch-Like ECH-Associated Protein 1; Liver; Male; Mice; Mice, Inbred ICR; NF-E2-Related Factor 2; Quercetin

Doxorubicin (DOX) chemotherapy is associated with the release of inflammatory cytokines from macrophages. This has been suggested to be, in part, due to DOX-mediated leakage of endotoxins from gut microflora, which activate Toll-like receptor 4 (TLR4) signaling in macrophages, causing severe inflammation. However, the direct function of DOX on macrophages is still unknown. In the present study, we tested the hypothesis that DOX alone is incapable of stimulating inflammatory response in macrophages. Then, we compared the anti-inflammatory effects of curcumin (CUR), resveratrol (RES) and sulforaphane (SFN) against lipopolysaccharide/interferon-gamma (LPS/IFN-γ)-mediated inflammation in the absence or presence of DOX. For this purpose, RAW 264.7 cells were stimulated with LPS/IFN-γ (10 ng/mL/10 U/mL) in the absence or presence of DOX (0.1 µM). Our results showed that DOX alone is incapable of stimulating an inflammatory response in RAW 264.7 macrophages. Furthermore, after 24 h of incubation with LPS/IFN-γ, a significant increase in tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and inducible nitric oxide synthase (iNOS) mRNA levels was observed. Similarly, nitric oxide (NO) production and TNF-α and IL-6 protein levels were significantly upregulated. Moreover, in LPS/IFN-γ-treated macrophages, the microRNAs (miRNAs) miR-146a, miR-155, and miR-21 were significantly overexpressed. Interestingly, upon testing CUR, RES, and SFN against LPS/IFN-γ-mediated inflammation, only SFN was able to significantly reverse the LPS/IFN-γ-mediated induction of iNOS, TNF-α and IL-6 and attenuate miR-146a and miR-155 levels. In conclusion, SFN, at the transcriptional and posttranscriptional levels, exhibits potent immunomodulatory action against LPS/IFN-γ-stimulated macrophages, which may indicate SFN as a potential treatment for DOX-associated inflammation.

Topics: Animals; Antibiotics, Antineoplastic; Curcumin; Doxorubicin; Immunologic Factors; Inflammation; Inflammation Mediators; Interferon-gamma; Interleukin-6; Isothiocyanates; Lipopolysaccharides; Macrophages; Mice; Molecular Targeted Therapy; Nitric Oxide Synthase Type II; RAW 264.7 Cells; Resveratrol; RNA, Messenger; Sulfoxides; Tumor Necrosis Factor-alpha

Topics: Caco-2 Cells; Caffeic Acids; Cell Line; Cell Proliferation; Cell Survival; Colonic Neoplasms; Curcumin; Dietary Supplements; Dose-Response Relationship, Drug; Drug Synergism; HT29 Cells; Humans; Isothiocyanates; Sulfoxides

c-Myb regulates tumorigenesis in multiple cancers. Here we show, for the first time, the mechanism of c-Myb-mediated proliferation, invasion, and drug resistance in ovarian cancer (OC), the most lethal gynecological cancer, and a comparative analyses of dietary agents, curcumin, epigallocatechin-3-gallate (EGCG), and sulforaphane in inhibiting c-Myb activity. We evaluated myb expression in patients with OC and found its increased expression in patients with cancer, compared with normal controls and in higher grade tumors, compared with low-grade tumors. Using ES2 and OVCAR3 cell line models, along with the silencing or overexpression of c-Myb, we establish a role of c-Myb in determining resistance to cisplatin. c-Myb overexpression activated NF-κB and STAT3 signaling leading to enhanced proliferation, invasion, and cisplatin resistance. Contrary to this, silencing of c-Myb inhibited proliferation, invasion, and sensitized OC cells to cisplatin. Further, among the dietary agents tested, EGCG almost completely inhibited the c-Myb-induced proliferation and invasion whereas sulforaphane also had significant inhibitory effect. Both compounds significantly sensitized OC cells to cisplatin, reversing the c-Myb effects. Higher c-Myb levels in patients with ovarian cancer lead to poor survival and our results indicate a possible effect of dietary factors EGCG and sulforaphane against c-Myb-mediated ovarian cancer progression and chemoresistance.

Topics: Antineoplastic Agents; Catechin; Cell Proliferation; Cisplatin; Curcumin; Drug Resistance, Neoplasm; Female; Humans; Isothiocyanates; NF-kappa B; Ovarian Neoplasms; Proto-Oncogene Proteins c-myb; Signal Transduction; STAT3 Transcription Factor; Sulfoxides

Lycopene, sulforaphane, quercetin, and curcumin, ingredients of daily diet, show significant anticancer and chemopreventive potential; however, no data are available showing thorough evaluation of jointly used phytochemicals on cancer cell proliferation. Here, we compare anticancer potential of mentioned substances applied separately or in combination (as MIX) by measuring mitochondrial activity (MTT test), DNA synthesis (BrdU test) and lactate dehydrogenase release (LDH test) in colon epithelial (CCD841 CoTr), and colon cancer (HT-29, LS174T) cells. Additive inhibitory effect of simultaneously used phytochemicals on cancer cells proliferation has been shown. In epithelial cells, tested combination effectively inhibited mitochondrial activity, but not DNA synthesis. LDH test revealed cytotoxicity of tested mixture against cancer cells without negative effect on normal cells. Furthermore, we demonstrated that MIX enhances antiproliferative effect of common cytostatics: 5-fluorouracil and cisplatin. Presented data suggest chemopreventive potential of the proposed combination of natural substances and their usefulness as adjuvant strategy during chemotherapy. PRACTICAL APPLICATIONS: Colorectal cancer is one of the most common causes of cancer death worldwide. Since its development and progression is strongly correlated with dietary habits, healthy diet as well as supplementation with proved anticancer agents seems to be reasonable strategy of colon cancer prevention and treatment. In the present study, we have focused on four natural compounds abundantly found in daily diet i.e., lycopene, sulforaphane, quercetin, and curcumin, with well established anticancer potential. Their individual and collective impact both on normal colon epithelium cells and colon cancer cells viability, growth, and proliferation was examined. Furthermore, activity of the substances combined as MIX to influence antiproliferative potential of commonly used in colon cancer treatment cytostatics, 5-fluorouracil, and cisplatin was verified. Proposed in the study combination of phytochemicals with experimentally proven antiproliferative activity may propose an effective strategy for prevention and treatment of colon cancer.

Topics: Antineoplastic Agents; Cell Proliferation; Cell Survival; Colonic Neoplasms; Curcumin; Drug Synergism; HT29 Cells; Humans; Isothiocyanates; Lycopene; Mitochondria; Quercetin; Sulfoxides

Self-emulsifying drug delivery systems (SEDDS) have been used as a formulation strategy to overcome the challenges in formulating poorly water soluble drugs. The objective of the present study was to report on the solubilizing capacity of sulforaphane (SFN) and its utilization to formulate SEDDS of poorly water soluble drugs. A set of 24 drugs was tested for their solubility in SFN of which Cyclosporine A, Celecoxib, Paclitaxel, Docetaxel, and Curcumin were selected for subsequent SEDDS formulation development utilizing SFN as common solubilizer. SFN-SEDDS formulations were developed utilizing a step-wise screening method that enabled the selection of the most efficient surfactants and co-surfactants to yield transparent microemulsions by microscopic analysis and absorbance data. The optimized SEDDS formulation for curcumin was selected for further investigation by DSC and FTIR, and was subjected to a dissolution study where more than 95% of the drug was found to dissolve within 10 min in both simulated gastric and intestinal fluids. The physical stability of the SEDDS was also confirmed in both media when monitored at three different temperatures (4, 25 and 37 °C) up to 30 days. This study introduced a new approach to formulating SEDDS by utilizing the solubilizing capacity of SFN and introduced high throughput screening approach to formulation development and stability study.

Topics: Calorimetry, Differential Scanning; Curcumin; Drug Delivery Systems; Drug Liberation; Drug Stability; Emulsions; High-Throughput Screening Assays; Isothiocyanates; Solubility; Spectroscopy, Fourier Transform Infrared; Sulfoxides; Surface-Active Agents

Natural products have been used for the treatment of various diseases such as cancer. Curcumin (CUR) and sulforaphane (SF) have anti-cancer effects, but their application is restricted because of their low water solubility and poor oral bioavailability. To improve the bioavailability and solubility of SF and CUR, we performed an advanced delivery of SF and CUR with PEGylated gold coated Fe

Topics: Apoptosis; Biological Availability; Cell Line, Tumor; Cell Migration Assays; Curcumin; Drug Delivery Systems; Drug Stability; Ferric Compounds; Gold; Humans; Isothiocyanates; Metal Nanoparticles; Necrosis; Particle Size; Polyethylene Glycols; Solubility; Sulfoxides

Fucoxanthin (Fx), one of the major xanthophylls in brown algae, is known to be effective for colorectal cancer (CRC) chemoprevention through inhibiting cell growth, cell cycle and caspase activation. Recently, we observed fucoxanthinol (FuOH), an anti-cancer active metabolite of Fx, treatment of human CRC cells resulted in plenty of living floating cells several hours after exposure, and induced apoptosis. In the present study, we investigated whether FuOH induced anchorage-dependent apoptosis, that is "anoikis", along with integrin signal suppression in human CRC cells. We found that cells exposed to 2.5 μM FuOH clearly showed anti-proliferative and apoptotic effects to DLD-1 cells, human CRC cells. FuOH treatment of DLD-1 cells led to an increase in anoikis-like changes represented by Calcein AM negative/ethidium homodimer-1 positive cell and living floating cells. Moreover, FuOH decreased FAK activation, and altered integrin β1 expression and distribution after 6 h treatment. After 24 h, the cells decreased PPARγ expression and Akt activation and increased integrin β1 expression. Our findings suggested that FuOH can induce anoikis in CRC cells through suppression of integrin signals in human CRC cells.

Topics: Allyl Compounds; Anoikis; Antineoplastic Agents, Phytogenic; beta Carotene; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Curcumin; Dietary Supplements; Focal Adhesion Kinase 1; Gene Expression Regulation, Neoplastic; Humans; Integrin beta1; Isothiocyanates; Lipids; PPAR gamma; Sulfides; Sulfoxides

According to the National Center of Health Statistics, cancer was the culprit of nearly 600,000 deaths in 2016 in the USA. It is by far one of the most heterogeneous diseases to treat. Treatment for metastasized cancers remains a challenge despite modern diagnostics and treatment regimens. For this reason, alternative approaches are needed. Chemoprevention using dietary phytochemicals such as triterpenoids, isothiocyanates, and curcumin in the prevention of initiation and/or progression of cancer poses a promising alternative strategy. However, significant challenges exist in the extrapolation of in vitro cell culture data to in vivo efficacy in animal models and to humans. In this review, the dose at which these phytochemicals elicit a response in vitro and in vivo of a multitude of cellular signaling pathways will be reviewed highlighting Nrf2-mediated antioxidative stress, anti-inflammation, epigenetics, cytoprotection, differentiation, and growth inhibition. The in vitro-in vivo dose response of phytochemicals can vary due, in part, to the cell line/animal model used, the assay system of the biomarker used for the readout, chemical structure of the functional analog of the phytochemical, and the source of compounds used for the treatment study. While the dose response varies across different experimental designs, the chemopreventive efficacy appears to remain and demonstrate the therapeutic potential of triterpenoids, isothiocyanates, and curcumin in cancer prevention and in health in general.

Topics: Animals; Anticarcinogenic Agents; Cell Line, Tumor; Chemoprevention; Curcumin; Dose-Response Relationship, Drug; Humans; Isothiocyanates; NF-E2-Related Factor 2; Sulfoxides; Triterpenes; Ursolic Acid

Our previous studies have established the efficacy of chemopreventive regimens of aspirin and curcumin (CUR) encapsulated within solid lipid nanoparticles (SLNs) in combination with free sulforaphane (ACS combination) to prevent or delay the initiation and progression of pancreatic cancer, classified as one of the deadliest diseases with very low chances of survival upon diagnosis. Although toxicity of individual drugs and SLN has been studied previously, there are no studies in current literature that evaluate the potential toxicity of a combined regimen of ACS, especially when encapsulated within chitosan-SLNs (c-SLNs). Hence, objective of the current study was to investigate the potential toxic effects of ACS c-SLN combined chemopreventive regimens following acute (3 days), subacute (28 days), and subchronic (90 days) administrations by oral gavage in BALB/c mice. Mice were administered the following regimens: saline, blank c-SLN, low-dose ACS c-SLN (2+4.5+0.16 mg/kg), medium-dose ACS c-SLN (20+45+1.6 mg/kg), and high-dose ACS c-SLN (60+135+4.8 mg/kg). The potential toxicity was evaluated based on animal survival, body weight, hematology, blood chemistry, and organ histopathology. During 3-day, 28-day, and 90-day study periods, no animal deaths were observed. Treatment with ACS c-SLNs did not cause alteration in complete blood counts and blood chemistry data. Histopathological examination of various organ sections (pancreas, heart, liver, kidney, and brain) appeared normal. Based on the results of this study, no signs of toxicity in acute, subacute, and subchronic studies following oral administration of ACS c-SLNs were found indicating that the oral dosing regimens were safe at the levels tested for long-term administration to prevent the onset of pancreatic cancer.

Topics: Administration, Oral; Animals; Aspirin; Body Weight; Chitosan; Curcumin; Drug Liberation; Female; Isothiocyanates; Lipids; Mice, Inbred BALB C; Nanoparticles; Particle Size; Static Electricity; Sulfoxides; Toxicity Tests

Parkinson's disease (PD) is the second most common neurodegenerative disease, with the prevalence increasing as the population ages. Many mechanisms have been implicated in the pathogenesis of PD including oxidative stress, mitochondrial dysfunction, protein aggregation, and inflammation. Current treatment strategies focus on symptomatic improvement. However, therapies to modify disease progression are lacking. A whole food, plant-based diet contains many compounds that fight oxidative stress and inflammation. Evidence from animal models show that various phytochemicals may alter the mechanisms contributing to PD pathophysiology. Epidemiological studies show a relationship between reduced risk of PD and diet. We hypothesize that phytochemicals in plant-based foods may contribute to neuroprotection in PD and that adopting a plant-based diet may provide symptomatic improvement and alter disease progression in PD.

Topics: Animals; Antioxidants; Curcumin; Diet; Ergothioneine; Fragaria; Humans; Inflammation; Isothiocyanates; Mitochondria; Nervous System; Neurons; Oxidative Stress; Parkinson Disease; Phytochemicals; Plants; Quercetin; Sulfoxides

Novel iminothiazinylbutadienols and divinylpyrimidinethiones were designed and synthesized as analogues of curcumin with its diketone moiety masked as a heterocyclic adduct with thiourea. The chemical stability of these novel heterocyclic compounds was improved as compared to curcumin. They exhibit longer half-lives and do not react with nucleophilic thiols under physiological conditions. In an ARE-luciferase reporter assay, some of these new curcumin analogues are more effective ARE activators than curcumin and isothiocyanates.

Topics: Antioxidant Response Elements; Curcumin; Drug Design; Isothiocyanates; Molecular Structure; Pyrimidines; Structure-Activity Relationship; Sulfoxides; Thiadiazines; Thiones; Thiourea

Pancreatic cancer ranks as the fourth most deadly form of cancer in the United States with ~37,000 deaths each year. The present study evaluated the chemopreventive potential of a combination of aspirin (ASP), curcumin (CUR) and sulforaphane (SFN) in low doses to human pancreatic cancer cells, MIA PaCa-2 and Panc-1. Results demonstrated that low doses of ASP (1 mM), CUR (10 µM) and SFN (5 µM) (ACS) combination reduced cell viability by ~70% (P<0.001), and also induced cell apoptosis by ~51% (P<0.001) accompanied by activation of caspase-3 and Poly(ADP-ribose) polymerase (PARP) proteins. The NF-κB DNA binding activity was inhi-bited by ~45% (P<0.01) and ~75% (P<0.001) in MIA PaCa-2 and Panc-1 cells, respectively. Mechanistic studies revealed that ACS promoted increase expression of phospho extracellular signal-regulated kinase 1/2 (P-ERK1/2), c-Jun, p38 MAPK and p53 proteins. Furthermore, the cells pretreated with U0126 (ERK1/2 inhibitor) partially abolished the effect of ACS on cell viability. Data from this study demonstrate that a low-dose ACS combination inhibits cell growth by inducing cell apoptosis, and proposes sustained activation of the ERK1/2 signaling pathway as one of the possible mechanisms.

Topics: Antineoplastic Combined Chemotherapy Protocols; Aspirin; Cell Line, Tumor; Cell Survival; Curcumin; DNA-Binding Proteins; Gene Expression Regulation, Neoplastic; Humans; Isothiocyanates; MAP Kinase Signaling System; NF-kappa B; Pancreatic Neoplasms; Sulfoxides; Thiocyanates

Pancreatic cancer is a deadly disease killing 37,000 Americans each year. Despite two decades of research on treatment options, the chances of survival are still less than 5% upon diagnosis. Recently, chemopreventive strategies have gained considerable attention as an alternative to treatment. We have previously shown significant in vitro chemopreventive effects with low-dose combinations of aspirin, curcumin, and sulforaphane (ACS) on pancreatic cancer cell lines. Here, we report the results of 24-week chemopreventive study with the oral administration of ACS combinations on the N-nitrosobis (2-oxopropyl) amine (BOP)-treated Syrian golden hamster model to suppress the progression of pancreatic intraepithelial neoplasms (PanIN) using unmodified (free drug) combinations of ACS, and nanoencapsulated (solid lipid nanoparticles; SLN) combinations of aspirin, curcumin, and free sulforaphane. The use of three different doses (low, medium, and high) of unmodified ACS combinations exhibited reduction in tumor incidence by 18%, 50%, and 68.7% respectively; whereas the modified nanoencapsulated ACS regimens reduced tumor incidence by 33%, 67%, and 75%, respectively, at 10 times lower dose compared with the free drug combinations. Similarly, although the unmodified free ACS showed a notable reduction in cell proliferation, the SLN encapsulated ACS regimens showed significant reduction in cell proliferation at 6.3%, 58.6%, and 72.8% as evidenced by proliferating cell nuclear antigen expression. Cell apoptotic indices were also upregulated by 1.5, 2.8, and 3.2 times, respectively, compared with BOP control. These studies provide a proof-of-concept for the use of an oral, low-dose, nanotechnology-based combinatorial regimen for the long-term chemoprevention of pancreatic cancer.

Topics: Adenocarcinoma; Administration, Oral; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Aspirin; Carcinogens; Cell Line, Tumor; Cricetinae; Curcumin; Disease Models, Animal; Disease Progression; Drug Delivery Systems; Immunohistochemistry; In Situ Nick-End Labeling; Isothiocyanates; Lipids; Male; Mesocricetus; Nanoparticles; Nitrosamines; Pancreatic Neoplasms; Proliferating Cell Nuclear Antigen; Sulfoxides

The ability to adapt to acute oxidative stress (e.g. H(2)O(2), peroxynitrite, menadione, and paraquat) through transient alterations in gene expression is an important component of cellular defense mechanisms. We show that such adaptation includes Nrf2-dependent increases in cellular capacity to degrade oxidized proteins that are attributable to increased expression of the 20 S proteasome and the Pa28αβ (11 S) proteasome regulator. Increased cellular levels of Nrf2, translocation of Nrf2 from the cytoplasm to the nucleus, and increased binding of Nrf2 to antioxidant response elements (AREs) or electrophile response elements (EpREs) in the 5'-untranslated region of the proteasome β5 subunit gene (demonstrated by chromatin immunoprecipitation (or ChIP) assay) are shown to be necessary requirements for increased proteasome/Pa28αβ levels, and for maximal increases in proteolytic capacity and stress resistance; Nrf2 siRNA and the Nrf2 inhibitor retinoic acid both block these adaptive changes and the Nrf2 inducers DL-sulforaphane, lipoic acid, and curcumin all replicate them without oxidant exposure. The immunoproteasome is also induced during oxidative stress adaptation, contributing to overall capacity to degrade oxidized proteins and stress resistance. Two of the three immunoproteasome subunit genes, however, contain no ARE/EpRE elements, and Nrf2 inducers, inhibitors, and siRNA all have minimal effects on immunoproteasome expression during adaptation to oxidative stress. Thus, immunoproteasome appears to be (at most) minimally regulated by the Nrf2 signal transduction pathway.

Topics: Active Transport, Cell Nucleus; Adaptation, Physiological; Animals; Anticarcinogenic Agents; Antineoplastic Agents; Antioxidants; Cell Nucleus; Cells, Cultured; Curcumin; Cytoplasm; Enzyme Induction; Isothiocyanates; Mice; NF-E2-Related Factor 2; Oxidative Stress; Proteasome Endopeptidase Complex; Response Elements; Sulfoxides; Thioctic Acid; Thiocyanates; Tretinoin

Organophosphate insecticides (OPIs) are widely used in agriculture and horticulture for controlling insects in crops, ornamentals, lawns, fruits, and vegetables. But, there have not yet any study about effects of sulforophane (SFN) and curcumin (CUR) on the oxidative stress created by acute toxic effects of malathion (MAL) as an OPI often causing human and animal poisoning.. The aim of this study was to investigate the effects of SFN and CUR on the oxidative stress created in the lung, liver, and kidney tissues of rats by acute MAL toxicity.. Thirty-six mature Sprague Dawley rats weighing 200-250 g were used. The rats were randomly divided into six groups: unmedicated control, SFN, CUR, MAL control, MAL + SFN, and MAL + CUR. Tissue samples were analyzed for glutathione (GSH), malondialdehyde (MDA), and nitric oxide (NO) levels in the lung, liver, and kidney tissues. Biochemical parameters were measured colorimetrically by using a spectrophotometer.. No statistically significantly difference was found when comparing the unmedicated control, SFN, and CUR groups. MAL significantly increased MDA levels in the liver and kidney tissues, but SFN and CUR these levels. MAL did significantly reduce the GSH levels, but SFN and CUR increased these levels by blocking the MAL effect in the liver tissues. Also, MAL significantly increased the NO levels, depending on the severity of the tissue damage, and SFN and CUR attenuated to NO levels and remained under the effect of MAL.. SFN and CUR, which showed similar effects, could be used to protect against the oxidative stress caused by acute malathion intoxication.

Topics: Animals; Antioxidants; Colorimetry; Curcumin; Female; Insecticides; Isothiocyanates; Kidney; Liver; Lung; Malathion; Nitric Oxide; Oxidative Stress; Random Allocation; Rats; Rats, Sprague-Dawley; Severity of Illness Index; Spectrophotometry; Sulfoxides; Thiocyanates

Pancreatic cancer is the fourth largest cause of cancer deaths in the Unites States and the prognosis is grim with <5% survival chances upon diagnosis. The objective of this study was to assess the combined chemopreventive effect of solid lipid nanoparticle (SLN) encapsulated drugs aspirin (ASP), curcumin (CUR) and free sulforaphane (SFN) for the chemoprevention of pancreatic cancer. Experiments were carried out (1) to evaluate the feasibility of encapsulation of these chemopreventive agents within solid lipid systems and (2) to measure the synergistic effects of a combination of ASP with CUR in SLNs mixed with free SFN against cell proliferation and apoptosis in pancreatic cancer cells, MIA PaCa-2 and Panc-1. The SLNs were prepared using a modified solvent evaporation technique and were characterized for particle sizing, encapsulation efficiency and drug release. ASP and CUR SLNs were formulated within the particle size range of 150‑250 nm and were found to have an encapsulation efficiency of 85 and 69%, respectively. Sustained release of drugs over a 96 h period from SLNs was observed. The SLNs were stable over a 3-month storage period at room temperature. Cell viability studies demonstrated that combinations of low doses of ASP SLN (25 µM), CUR SLN (2.5 µM) and free SFN (5 µM) significantly reduced cell viability by 43.6 and 48.49% in MIAPaca-2 and Panc-1 cell lines, respectively. Furthermore, increased apoptosis of 61.3 and 60.37% was found in MIA Paca-2 and Panc-1 cell lines, respectively, in comparison to the individual doses administered. Synergistic effects were demonstrated using MTS and apoptosis assays. Thus, this study successfully demonstrated the feasibility of using a solid lipid nanoparticulate system for the first time to deliver this novel combination chemoprevention regimen, providing valuable evidence for the usability of nanotechnology-based drug regimens towards pancreatic cancer chemoprevention.

Topics: Apoptosis; Aspirin; Cell Line, Tumor; Cell Survival; Chemoprevention; Curcumin; Drug Combinations; Drug Stability; Drug Synergism; Humans; Inhibitory Concentration 50; Isothiocyanates; Lipids; Nanocapsules; Nanoconjugates; Pancreatic Neoplasms; Particle Size; Sulfoxides; Thiocyanates

Alpha-class glutathione transferases (α-GSTs) have been shown to protect cells from the harmful effects of reactive oxygen species (ROS) induced lipid peroxidation (LPO) during oxidative stress caused by various physico-chemical agents. While GSTA1-1/A2-2 isozymes exhibit high activity towards lipid and fatty acid hydroperoxides through their selenium independent glutathione peroxidase (GPx) activity, the GSTA4-4 isozyme efficiently metabolizes the LPO product 4-hydroxynonenal (4-HNE) by conjugating it with glutathione (GSH). Because of the fact that ROS generated by the chemopreventive agents, sulforaphane (SFN) and curcumin (Cur), are implicated in the mechanisms of cancer cell killing, the present studies were designed to investigate the contribution of ROS induced LPO in the cytotoxic effects of these agents and the role of α-class GSTs in modulating their toxicity. Human erythroleukemic (HL60) cells were stably transfected with the cDNA encoding the hGSTA1-1 and mGsta4-4 isozymes. After analysing the expression and activities of the respective GST isozymes, the effects of SFN and Cur on the extent of LPO, cytotoxicity and apoptosis were compared in empty vector (VT), hGSTA1-1 and mGsta4-4 expressing HL60 cells. These studies demonstrate that when compared with SFN, Cur was relatively more cytotoxic to HL60 cells. The ectopic expression of hGSTA1-1 and mGsta4-4 isozymes provided resistance to SFN and Cur induced cytotoxicity and apoptosis through a significant suppression of LPO in these cells. Overall, the results suggest that the expression of α-class GSTs in cancer cells can modulate the therapeutic efficacy of chemopreventive agents.

Topics: Blotting, Western; Curcumin; Glutathione Transferase; HL-60 Cells; Humans; Isothiocyanates; Leukemia; Oxidative Stress; Sulfoxides; Thiocyanates

Topics: Animals; Brassica; Breeding; Cooking; Curcumin; Diet; Fruit; Genetic Variation; Genistein; Genome, Human; Humans; Isothiocyanates; Metagenome; Mice; Neoplasms; Phytotherapy; Rats; Reproducibility of Results; Resveratrol; Risk Management; Stilbenes; Sulfoxides; Thiocyanates; Time Factors; Vegetables

Prostate cancer is a polyfactorial molecular anomaly that is offering refractoriness against a broad range of therapeutic drugs. Growth factor receptors are actively implicated in oncogenesis. PDGFR/EGFR mediated exacerbated signaling has a central participation and is contributory in fueling the signal transductions that gear up prostate cancer progression.. In this particular study, androgen sensitive, Prostate cancer cell line (LNCaP) was used. Pretreatment of cell line with PDGF resulted in an enhanced proliferation of cells which was evaluated by MTT assay. Treatment of cell line with either alone Curcumin, EGCG, sulforaphane or in combination was evaluated. PDGFR/EGFR activation (phosphorylation) was studied using western blot.. Results indicated that phosphorylation was gradually downregulated after treatment with individual compound. However there was a remarkable decrease in cellular proliferation after a combinatorial approach which is indicative of the fact that PDGFR phosphorylation was decreased outstandingly as evaluated by MTT assay. That also gave a prominent decline in the expression and subsequent decrease in proliferation pattern of cells.. Despite the fact that little is still known regarding the mechanistic insights by which phytonutrients act as barrier to cancer, and attempts to translate the studies from benchtop to bedside are in progress. A detailed analysis of nutraceuticals will help a lot in identifying the stumbling blocks in the standardization of therapeutic interventions.

Topics: Anticarcinogenic Agents; Antineoplastic Agents; Catechin; Cell Line, Tumor; Cell Proliferation; Curcumin; Drug Synergism; ErbB Receptors; Humans; Isothiocyanates; Male; Phosphorylation; Prostatic Neoplasms; Receptor, Platelet-Derived Growth Factor beta; Signal Transduction; Sulfoxides; Thiocyanates

Accumulating evidence from epidemiologic and clinical studies indicates that chronic inflammatory disorders harbor an increased risk of cancer development. Curcumin (CUR) has been strongly linked to the anti-inflammatory effect. On the other hand, isothiocyanates such as sulforaphane (SFN) and phenethyl isothiocyanate (PEITC) are strong phase-II detoxifying/antioxidant enzymes inducer. Therefore it is interesting to see if combination of these drugs can inhibit inflammation with higher combined efficacies.. We used nitric oxide (NO) assay to assess the synergism of the different combinations of CUR, SFN and PEITC. The inflammatory markers, e.g. iNOS, COX-2, prostaglandin E2 (PGE2), tumor necrosis factor (TNF) and interleukin-1 (IL-1) levels were determined using RT-PCR, Western blot and ELISA assays.. We report that combination of PEITC + SFN or CUR + SFN has a synergistic effect in down-regulating inflammation markers like TNF, IL-1, NO, PGE2. The synergism is probably due to the synergistic induction of phase II/antioxidant enzymes including heme-oxygenase1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO-1).. Our data suggest that CUR + SFN and PEITC + SFN combinations could be more effective than used alone in preventing inflammation and possibly its associated diseases including cancer.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Anticarcinogenic Agents; Biomarkers; Cell Line; Curcumin; Cyclooxygenase 2; Dinoprostone; Dose-Response Relationship, Drug; Down-Regulation; Drug Synergism; Interleukin-1; Isothiocyanates; Lipopolysaccharides; Macrophages; Nitric Oxide; Nitric Oxide Synthase Type II; Reverse Transcriptase Polymerase Chain Reaction; Sulfoxides; Thiocyanates; Tumor Necrosis Factor-alpha

We have considered a novel "rational" gene targeting approach for treating pathologies whose genetic bases are defined using select phytochemicals. We reason that one such potential application of this approach would be conditions requiring immunosuppression such as autoimmune disease and transplantation, where the genetic target is clearly defined; i.e., interleukin-2 and associated T-cell activation. Therefore, we hypothesized that select phytochemicals can suppress T-lymphocyte proliferation both in vitro and in vivo. The immunosuppressive effects of berry extract, curcumin, quercetin, sulforaphane, epigallocatechin gallate (EGCG), resveratrol, alpha-tocopherol, vitamin C and sucrose were tested on anti-CD3 plus anti-CD28-activated primary human T-lymphocytes in culture. Curcumin, sulforaphane, quercetin, berry extract and EGCG all significantly inhibited T-cell proliferation, and this effect was not due to toxicity. IL-2 production was also reduced by these agents, implicating this important T-cell cytokine in proliferation suppression. Except for berry extract, these same agents also inhibited mouse splenic T-cell proliferation and IL-2 production. Subsequent in vivo studies revealed that quercetin (but not sulforaphane) modestly suppressed mouse splenocyte proliferation following supplementation of BALB/c mice diets. This effect was especially prominent if corrected for the loss of supplement "recall" as observed in cultured T-cells. These results suggest the potential use of these select phytochemicals for treating autoimmune and transplant patients, and support our strategy of using select phytochemicals to treat genetically-defined pathologies, an approach that we believe is simple, healthy, and cost-effective.

Topics: Animals; Anthocyanins; Autoimmunity; Catechin; CD28 Antigens; CD3 Complex; Cell Line; Cell Proliferation; Curcumin; Female; Humans; Immunosuppressive Agents; Interleukin-2; Isothiocyanates; Magnoliopsida; Mice; Mice, Inbred BALB C; Organ Transplantation; Plant Extracts; Quercetin; Spleen; Sulfoxides; T-Lymphocytes; Thiocyanates

Prostate cancer is the most commonly diagnosed malignancy in men and is thought to arise as a result of endogenous oxidative stress in the face of compromised carcinogen defenses. We tested whether carcinogen defense (phase 2) enzymes could be induced in the prostate tissues of rats after oral feeding of candidate phase 2 enzyme inducing compounds.. Male F344 rats were gavage fed sulforaphane, beta-naphthoflavone, curcumin, dimethyl fumarate or vehicle control over five days, and on the sixth day, prostate, liver, kidney and bladder tissues were harvested. Cytosolic enzyme activities of nicotinamide quinone oxidoreductase (NQO1), total glutathione transferase (using DCNB) and mu-class glutathione transferase (using CDNB) were determined in the treated and control animals and compared.. In prostatic tissues, sulforaphane produced modest but significant increases in the enzymatic activities of NQO1, total GST and GST-mu compared to control animals. beta-naphthoflavone significantly increased NQO1 and GST-mu activities and curcumin increased total GST and GST-mu enzymatic activities. Dimethyl fumarate did not significantly increase prostatic phase 2 enzyme activity. Compared to control animals, sulforaphane also significantly induced NQO1 or total GST enzyme activity in the liver, kidney and, most significantly, in the bladder tissues. All compounds were well tolerated over the course of the gavage feedings.. Orally administered compounds will induce modestly phase 2 enzyme activity in the prostate although the significance of this degree of induction is unknown. The 4 different compounds also altered phase 2 enzyme activity to different degrees in different tissue types. Orally administered sulforaphane potently induces phase 2 enzymes in bladder tissues and should be investigated as a bladder cancer preventive agent.

Topics: Animals; Anticarcinogenic Agents; beta-Naphthoflavone; Curcumin; Dimethyl Fumarate; Fumarates; Glutathione Transferase; Isothiocyanates; Kidney; Liver; Male; NAD(P)H Dehydrogenase (Quinone); Prostate; Rats; Rats, Inbred F344; Sulfoxides; Thiocyanates; Urinary Bladder

The gastrointestinal glutathione peroxidase (GI-GPx, GPx2) is a selenoprotein that was suggested to act as barrier against hydroperoxide absorption but has also been implicated in the control of inflammation and malignant growth. In CaCo-2 cells, GI-GPx was induced by t-butyl hydroquinone (tBHQ) and sulforaphane (SFN), i.e., "antioxidants" known to activate the "antioxidant response element" (ARE) via electrophilic thiol modification of Keap1 in the Nrf2/Keap1 system. The functional significance of a putative ARE in the GI-GPx promoter was validated by transcriptional activation of reporter gene constructs upon exposure to electrophiles (tBHQ, SFN, and curcumin) or overexpression of Nrf2 and by reversal of these effects by mutation of the ARE in the promoter and by overexpressed Keap1. Binding of Nrf2 to the ARE sequence in authentic gpx2 was corroborated by chromatin immunoprecipitation. Thus, the presumed natural antioxidants sulforaphane and curcumin may exert their anti-inflammatory and anticarcinogenic effects not only by induction of phase 2 enzymes but also by the up-regulation of the selenoprotein GI-GPx.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Anticarcinogenic Agents; Antioxidants; Cell Line, Tumor; Curcumin; DNA-Binding Proteins; Gene Expression Regulation; Genes, Reporter; Glutathione Peroxidase; Humans; Hydroquinones; Intracellular Signaling Peptides and Proteins; Isothiocyanates; Kelch-Like ECH-Associated Protein 1; NF-E2-Related Factor 2; Promoter Regions, Genetic; Protein Binding; Proteins; Response Elements; Sulfoxides; Thiocyanates; Trans-Activators

1. The naturally occurring compounds curcumin (CUR), 3,3'-diindolylmethane (DIM), isoxanthohumol (IXN), 8-prenylnaringenin (8PN), phenethyl isothiocyanate (PEITC) and sulforaphane (SFN) protect animals against chemically induced tumours. Putative chemoprotective mechanisms include modulated expression of hepatic biotransformation enzymes. However, few, if any, studies have used human primary cells as test models. 2. The present study investigated the effects of these phytochemicals on the expression of four carcinogenesis-relevant enzymes--cytochrome P450 (CYP)1A1 and 1A2, NAD(P)H:quinone oxidoreductase (NQO1) and glutathione S-transferase A1 (GSTA1)--in primary cultures of freshly isolated human hepatocytes. 3. Quantitative RT-PCR analyses demonstrated that CYP1A1 was up-regulated by PEITC and DIM in a dose-dependent manner. CYP1A2 transcription was significantly activated following DIM, IXN, 8PN and PEITC treatments. DIM exhibited a remarkably effective induction response of CYP1A1 (474-, 239- and 87-fold at 50, 25 and 10 microM, respectively) and CYP1A2 (113-, 70- and 31-fold at 50, 25 and 10 microM, respectively), that was semiquantitatively reflected in protein levels. NQO1 expression responded to PEITC (11 x at 25 microM), DIM (4.5 x at 50 microM) and SFN (5 x at 10 microM) treatments. No significant effects on GSTA1 transcription were seen. 4. The findings show novel and unexpected effects of these phytochemicals on the expression of human hepatic biotransformation enzymes that play key roles in chemical-induced carcinogenesis.

Topics: Anticarcinogenic Agents; Carcinogens; Carrier Proteins; Curcumin; Cytochrome P-450 CYP1A1; Cytochrome P-450 CYP1A2; Enzymes; Flavanones; Gene Expression Regulation; Glutathione Transferase; Hepatocytes; Humans; Inactivation, Metabolic; Indoles; Isothiocyanates; NAD(P)H Dehydrogenase (Quinone); Plants; Sulfoxides; Thiocyanates