stilbenes and Lymphoma

Resveratrol (RSV) is a well known chemopreventive molecule featuring anti-cancer properties. Our paper describes the main molecular targets of RSV linked to its antiproliferative activity on lymphoma and leukemia experimental models. It discusses further the most recent and most promising among these molecular targets for a translational application.

Topics: Anticarcinogenic Agents; Humans; Leukemia; Lymphoma; Resveratrol; Stilbenes

Natural products have always been sought as a dependable source for the cure of many fatal diseases including cancer. Resveratrol (RSV), a naturally occurring plant polyphenol, has been of recent research interest and is being investigated for its beneficial biological properties that include antioxidant, anti-inflammatory, proapoptotic, and growth inhibitory activities. These effects are mainly mediated by cell cycle arrest, upregulation of proapoptotic proteins, loss of mitochondrial potential, and generation of reactive oxygen species. Among the beneficial properties of RSV, the anticancer property has been of the prime focus and extensively explored during the last few years. Although reports exist on the chemopreventive role of RSV in many solid tumors, limited information is available on the antiproliferative activity of RSV in human lymphoma cells and experimental models. Potential mechanisms for its antiproliferative effect include induction of cell differentiation, apoptosis, and inhibition of DNA synthesis. In this review, the different kinds of lymphoid malignancies and the main mechanisms of cell death induced by resveratrol are discussed. The challenges are limiting in vivo experimental studies involving resveratrol. An attempt for the translation of this compound into a clinical drug also forms a part of this review.

Topics: Anticarcinogenic Agents; Antineoplastic Agents, Phytogenic; Humans; Lymphoma; Multiple Myeloma; Resveratrol; Stilbenes

Lymphoma and leukemia represent a serious threat to human health and life expectancy. Resveratrol is, among the natural-derived chemopreventive molecules, one of the most effective and better studied. In this paper the main mechanisms of cell death triggered by- or linked to- resveratrol are reviewed and discussed. The main focus is on lymphoma and leukemia experimental models where resveratrol has been tested and investigated at the cellular, molecular or physiological levels. The most relevant in vivo challenges involving resveratrol are also reported and analyzed in order to define the key features of this polyphenol and the potential for the treatment of hematologic tumors.

Topics: Angiogenesis Inhibitors; Animals; Apoptosis; Biomarkers, Tumor; Cell Line, Tumor; Humans; Leukemia; Lymphoma; Models, Biological; Resveratrol; Stilbenes

Plant-derived polyphenolic compounds, such as the stilbene resveratrol (trans-3,4',5-trihydroxystilbene), have been identified as potent anti-cancer agents. Extensive in vitro studies revealed multiple intracellular targets of resveratrol, which affect cell growth, inflammation, apoptosis, angiogenesis, and invasion and metastasis. These include tumor suppressors p53 and Rb; cell cycle regulators, cyclins, CDKs, p21WAF1, p27KIP and INK and the checkpoint kinases ATM/ATR; transcription factors NF-kappaB, AP-1, c-Jun, and c-Fos; angiogenic and metastatic factors, VEGF and matrix metalloprotease 2/9; cyclooxygenases for inflammation; and apoptotic and survival regulators, Bax, Bak, PUMA, Noxa, TRAIL, APAF, survivin, Akt, Bcl2 and Bcl-X(L). In addition to its well-documented anti-oxidant properties, there is increasing evidence that resveratrol exhibits pro-oxidant activity under certain experimental conditions, causing oxidative DNA damage that may lead to cell cycle arrest or apoptosis. This review summarizes in vitro mechanistic data available for resveratrol and discusses new potential anti-cancer targets and the antiproliferative mechanisms of resveratrol.

Topics: Anticarcinogenic Agents; Breast Neoplasms; Cathepsins; Cell Cycle; Cell Division; Female; Humans; Inflammation; Leukemia; Lymphoma; Male; Neoplasms; Prostatic Neoplasms; Resveratrol; Safety; Stilbenes; Transcription Factors

Obstetrical complications affect more than a third of women globally, but are underrepresented in clinical research. Little is known about the comprehensive obstetrical clinical trial landscape, how it compares with other fields, or factors associated with the successful completion of obstetrical trials.. This study aimed to characterize obstetrical clinical trials registered on ClinicalTrials.gov with the primary objective of identifying features associated with early discontinuation and results reporting.. This is a cross-sectional study with descriptive, logistic regression and Cox regression analyses of clinical trials registered on ClinicalTrials.gov. Our primary exposure variables were trial focus (obstetrical or nonobstetrical) and trial funding (industry, United States government, or academic). We conducted additional exploratory analyses of other trial features including design, enrollment, and therapeutic focus. We examined the associations of exposure variables and other trial features with 2 primary outcomes: early discontinuation and results reporting.. Obstetrical trials represent only 1.9% of all clinical trials in ClinicalTrials.gov and have comparatively poor completion. All stakeholders should commit to increasing the number of obstetrical trials and improving their completion and dissemination to ensure clinical research reflects the obstetrical burden of disease and advances maternal health.

Topics: Adipose Tissue, White; Adult; Aged; Air Pollutants; Animals; Anti-Inflammatory Agents; Arginine; bcl-2-Associated X Protein; Biofuels; Biological Products; Blood Glucose; Breast Neoplasms; Caspases; CD36 Antigens; Cell Communication; Cell Proliferation; Cell Survival; Cooking; Cross-Sectional Studies; Databases, Factual; Diabetes Mellitus, Type 2; Diphtheria Toxin; Double-Blind Method; Exenatide; Extracellular Polymeric Substance Matrix; Feasibility Studies; Female; Filgrastim; Fruit; Galactose; Gene Deletion; Gene Knockdown Techniques; Glucagon; Glucagon-Like Peptide-1 Receptor; Glucagon-Secreting Cells; Glucose; Glycated Hemoglobin; Hematopoietic Stem Cell Mobilization; Household Articles; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Islets of Langerhans; Lung; Lymphoma; Male; Metals, Heavy; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Nanoparticles; Neoplasms; Obesity; Obstetrics; Odds Ratio; Oxygen; Peripheral Blood Stem Cell Transplantation; Photochemotherapy; Plant Extracts; Polyethylene Glycols; Polyglutamic Acid; Porosity; Postprandial Period; Prospective Studies; Quality of Life; Receptors, Glucagon; Receptors, LDL; Receptors, Somatostatin; Registries; Rhodophyta; Rhodotorula; Risk Factors; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Signal Transduction; Somatostatin; Stilbenes; Terminalia; Treatment Outcome; United States; Venoms

The acquisition of ever increasing volumes of high resolution magnetic resonance imaging (MRI) data has created an urgent need to develop automated and objective image analysis algorithms that can assist in determining tumor margins, diagnosing tumor stage, and detecting treatment response.. We have shown previously that Minkowski functionals, which are precise morphological and structural descriptors of image heterogeneity, can be used to enhance the detection, in T1 -weighted images, of a targeted Gd(3+) -chelate-based contrast agent for detecting tumor cell death. We have used Minkowski functionals here to characterize heterogeneity in T2 -weighted images acquired before and after drug treatment, and obtained without contrast agent administration.. We show that Minkowski functionals can be used to characterize the changes in image heterogeneity that accompany treatment of tumors with a vascular disrupting agent, combretastatin A4-phosphate, and with a cytotoxic drug, etoposide.. Parameterizing changes in the heterogeneity of T2 -weighted images can be used to detect early responses of tumors to drug treatment, even when there is no change in tumor size. The approach provides a quantitative and therefore objective assessment of treatment response that could be used with other types of MR image and also with other imaging modalities.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Etoposide; Female; Image Interpretation, Computer-Assisted; Lymphoma; Magnetic Resonance Imaging; Mice; Mice, Inbred C57BL; Neoplasm Staging; Prognosis; Reproducibility of Results; Sensitivity and Specificity; Stilbenes; Treatment Outcome

Quantitative characterization of the in vivo effects of vascular-targeted therapies on tumor vessels is hampered by the absence of useful 3D vascular network descriptors aside from microvessel density. In this study, we extended the quantification of planar vessel distribution to the analysis of vascular volumes by studying the effects of antiangiogenic (sorafenib and sunitinib) or antivascular (combretastatin A4 phosphate) treatments on the quantity and spatial distributions of thin microvessels. These observations were restricted to perinecrotic areas of treated human multiple myeloma tumors xenografted in immunodeficient mice and to microvessels with an approximate cross-sectional area lower than 75 µm(2). Finally, vessel skeletonization minimized artifacts due to possible differential wall staining and allowed a comparison of the various treatment effects. Antiangiogenic drug treatment reduced the number of vessels of every caliber (at least 2-fold fewer vessels vs. controls; p<0.001, n = 8) and caused a heterogeneous distribution of the remaining vessels. In contrast, the effects of combretastatin A4 phosphate mainly appeared to be restricted to a homogeneous reduction in the number of thin microvessels (not more than 2-fold less vs. controls; p<0.001, n = 8) with marginal effects on spatial distribution. Unexpectedly, these results also highlighted a strict relationship between microvessel quantity, distribution and cross-sectional area. Treatment-specific changes in the curves describing this relationship were consistent with the effects ascribed to the different drugs. This finding suggests that our results can highlight differences among vascular-targeted therapies, providing hints on the processes underlying sample vascularization together with the detailed characterization of a pathological vascular tree.

Topics: Animals; Antineoplastic Agents; Artifacts; Cell Line, Tumor; Cell Transformation, Neoplastic; Female; Humans; Imaging, Three-Dimensional; Lymphoma; Mice; Mice, Inbred NOD; Mice, SCID; Microvessels; Molecular Targeted Therapy; Neovascularization, Pathologic; Stilbenes

We explored the activity of SIRT1 activators (SRT501 and SRT2183) alone and in combination with panobinostat in a panel of malignant lymphoid cell lines in terms of biological and gene expression responses. SRT501 and SRT2183 induced growth arrest and apoptosis, concomitant with deacetylation of STAT3 and NF-κB, and reduction of c-Myc protein levels. PCR arrays revealed that SRT2183 leads to increased mRNA levels of pro-apoptosis and DNA-damage-response genes, accompanied by accumulation of phospho-H2A.X levels. Next, ChIP assays revealed that SRT2183 reduces the DNA-binding activity of both NF-κB and STAT3 to the promoter of GADD45G, which is one of the most upregulated genes following SRT2183 treatment. Combination of SRT2183 with panobinostat enhanced the anti-growth and anti-survival effects mediated by either compound alone. Quantitative-PCR confirmed that the panobinostat in combination with SRT2183, SRT501 or resveratrol leads to greater upregulation of GADD45G than any of the single agents. Panobinostat plus SRT2183 in combination showed greater inhibition of c-Myc protein levels and phosphorylation of H2A.X, and increased acetylation of p53. Furthermore, EMSA revealed that NF-κB binds directly to the GADD45G promoter, while STAT3 binds indirectly in complexes with NF-κB. In addition, the binding of NF-κB/STAT3 complexes to the GADD45G promoter is inhibited following panobinostat, SRT501 or resveratrol treatment. Moreover, the combination of panobinostat with SRT2183, SRT501 or resveratrol induces a greater binding repression than either agent alone. These data suggest that STAT3 is a corepressor with NF-κB of the GADD45G gene and provides in vitro proof-of-concept for the combination of HDACi with SIRT1 activators as a potential new therapeutic strategy in lymphoid malignancies.

Topics: Acetylation; Apoptosis; Cell Line, Tumor; Enzyme Inhibitors; GADD45 Proteins; Heterocyclic Compounds, 4 or More Rings; Histone Deacetylase Inhibitors; Histone Deacetylases; Histones; Humans; Hydroxamic Acids; Indoles; Intracellular Signaling Peptides and Proteins; Lymphoma; NF-kappa B; Panobinostat; Phosphorylation; Promoter Regions, Genetic; Protein Binding; Proto-Oncogene Proteins c-myc; Resveratrol; RNA Interference; RNA, Small Interfering; Sirtuin 1; STAT3 Transcription Factor; Stilbenes; Up-Regulation

Understanding the molecular mechanisms through which natural products and dietary supplements exhibit anticancer properties is crucial and can lead to drug discovery and chemoprevention. The current study sheds new light on the mode of action of resveratrol (RES), a plant-derived polyphenolic compound, against EL-4 lymphoma growth.. Immuno-compromised NOD/SCID mice injected with EL-4 tumor cells and treated with RES (100 mg/kg body weight) showed delayed development and progression of tumor growth and increased mean survival time. RES caused apoptosis in EL4 cells through activation of aryl hydrocarbon receptor (AhR) and upregulation of Fas and FasL expression in vitro. Blocking of RES-induced apoptosis in EL4 cells by FasL mAb, cleavage of caspases and PARP, and release of cytochorme c, demonstrated the participation of both extrinsic and intrinsic pathways of apoptosis. RES also induced upregulation of silent mating type information regulation 2 homolog, 1 (SIRT1) and downregulation of nuclear factor kappa B (NF-κB) in EL4 cells. siRNA-mediated downregulation of SIRT1 in EL4 cells increased the activation of NF-κB but decreased RES-mediated apoptosis, indicating the critical role of SIRT1 in apoptosis via blocking activation of NF-κB.. These data suggest that RES-induced SIRT1 upregulation promotes tumor cell apoptosis through negative regulation of NF-κB, leading to suppression of tumor growth.

Topics: Animals; Anticarcinogenic Agents; Antineoplastic Agents, Phytogenic; Apoptosis; Cell Line, Tumor; Fas Ligand Protein; fas Receptor; Gene Expression Regulation, Neoplastic; Lymphoma; Mice; Mice, Inbred NOD; Mice, SCID; NF-kappa B; Receptors, Aryl Hydrocarbon; Resveratrol; Sirtuin 1; Stilbenes

Adhesion of leukemic cells to vascular cells may confer resistance to chemotherapeutic agents. We hypothesized that disruption of leukemic cell cytoskeletal stability and interference with vascular cell interactions would promote leukemic cell death. We demonstrate that low and nontoxic doses of microtubule-destabilizing agent combretastatin-A4-phosphate (CA4P) inhibit leukemic cell proliferation in vitro and induce mitotic arrest and cell death. Treatment of acute myeloid leukemias (AMLs) with CA4P leads to disruption of mitochondrial membrane potential, release of proapoptotic mitochondrial membrane proteins, and DNA fragmentation, resulting in cell death in part through a caspase-dependent manner. Furthermore, CA4P increases intracellular reactive oxygen species (ROS), and antioxidant treatment imparts partial protection from cell death, suggesting that ROS accumulation contributes to CA4P-induced cytotoxicity in AML. In vivo, CA4P inhibited proliferation and circulation of leukemic cells and diminished the extent of perivascular leukemic infiltrates, prolonging survival of mice that underwent xenotransplantation without inducing hematologic toxicity. CA4P decreases the interaction of leukemic cells with neovessels by down-regulating the expression of the adhesion molecule VCAM-1 thereby augmenting leukemic cell death. These data suggest that CA4P targets both circulating and vascular-adherent leukemic cells through mitochondrial damage and down-regulation of VCAM-1 without incurring hematologic toxicities. As such, CA4P provides for an effective means to treat refractory organ-infiltrating leukemias.

Topics: Annexin A5; Antineoplastic Agents, Phytogenic; Apoptosis; Cell Death; Cell Division; DNA Damage; Humans; Leukemia, Myeloid, Acute; Lymphoma; Mitochondria; Reactive Oxygen Species; Stilbenes; Transplantation, Heterologous; Tumor Cells, Cultured

Resveratrol (RES) is a natural polyphenol present in red wines and various human food items. The estrogenic activity of RES was demonstrated in two in vitro assay systems, i.e. binding to human estrogen receptor alpha and stimulation of MCF-7 cell proliferation. To investigate the inhibition of cell proliferation observed at high concentrations of RES, we analyzed the compound for genotoxic potential. RES induced cellular toxicity, micronuclei, and metaphase chromosome displacement in L5178Y mouse lymphoma cells. Likewise, the induction of micronuclei was observed in Chinese hamster V79 cells. Determination of kinetochore signals in micronuclei and cell cycle analysis suggested that RES did not cause a direct disturbance of mitosis. In support of this notion, cell-free tubulin polymerization studies indicated no direct effect of RES on microtubule assembly. According to an estimation of daily intake and bioavailability, concentrations that were found genotoxic in vitro might be reached in human exposure. On the other side, the estrogenic acitivity might be beneficial. Therefore, further investigations of mechanisms, possibly including animal models, would be desirable to clarifiy a potential risk for humans.

Topics: Animals; Breast Neoplasms; Cell Cycle; Cell Division; Cell Survival; CHO Cells; Cricetinae; Dose-Response Relationship, Drug; Estrogen Receptor alpha; Fluorescein-5-isothiocyanate; Humans; Kinetochores; Lymphoma; Metaphase; Mice; Micronucleus Tests; Molecular Structure; Protein Binding; Receptors, Estrogen; Resveratrol; Stilbenes; Time Factors; Tubulin; Tumor Cells, Cultured

Topics: Animals; Contraceptive Agents, Female; Estradiol Congeners; Estrogens; Female; Humans; Lymphoma; Mice; Stilbenes