stilbenes and Adenocarcinoma

stilbenes has been researched along with Adenocarcinoma* in 96 studies

Reviews

5 review(s) available for stilbenes and Adenocarcinoma

ArticleYear
Apoptosis by dietary agents for prevention and treatment of prostate cancer.
    Endocrine-related cancer, 2010, Volume: 17, Issue:1

    Accumulating data clearly indicate that induction of apoptosis is an important event for chemoprevention of cancer by naturally occurring dietary agents. In mammalian cells, apoptosis has been divided into two major pathways: the extrinsic pathway, activated by pro-apoptotic receptor signals at the cellular surface; and the intrinsic pathway, which involves the disruption of mitochondrial membrane integrity. This process is strictly controlled in response to integrity of pro-death signaling and plays critical roles in development, maintenance of homeostasis, and host defense in multicellular organisms. For chemoprevention studies, prostate cancer (PCa) represents an ideal disease due to its long latency, its high incidence, tumor marker availability, and identifiable preneoplastic lesions and risk groups. In this article, we highlight the studies of various apoptosis-inducing dietary compounds for prevention of PCa in vitro in cell culture, in preclinical studies in animals, and in human clinical trials.

    Topics: Adenocarcinoma; Aged; Animals; Apoptosis; Carotenoids; Catechin; Clinical Trials as Topic; Curcumin; Drug Screening Assays, Antitumor; Flavonoids; Flavonols; Genistein; Humans; Lycopene; Lythraceae; Male; Mice; Mice, Nude; Mice, Transgenic; Middle Aged; Neoplasm Proteins; Pentacyclic Triterpenes; Phytotherapy; Plant Extracts; Prostatic Neoplasms; Resveratrol; Stilbenes; Tumor Cells, Cultured

2010
Wine, spirits and the lung: good, bad or indifferent?
    Transactions of the American Clinical and Climatological Association, 2006, Volume: 117

    The putative cardiovascular risks and benefits of the ingestion of wine and alcohol-containing spirits have been well publicized; however, less attention has been focused upon the health effects of wine and spirits consumption on the respiratory system. This paper will highlight epidemiologic, clinical and experimental data on the effects of wine and distilled spirits [and the chemical components thereof] on lung function, chronic obstructive pulmonary disease progression, lung cancer risk, risk of developing acute respiratory distress syndrome, high altitude pulmonary edema and wine [sulfite] associated asthma. Several studies have demonstrated a positive [beneficial] effect of light-to-moderate wine consumption on pulmonary function, while chronic ingestion of distilled spirits may have either no effect, or a negative effect. Studies in Scandinavia, Europe and South America have suggested a possible protective effect of wine ingestion against lung cancer, especially adenocarcinoma. Resveratrol [3,5,4'-trihydroxystilbene] a polyphenolic compound found in red wine, has anti-oxidant, anti-inflammatory and estrogen agonist effects and may be responsible for some of the health benefits of wine. The spectrum of potentially beneficial clinical effects of resveratrol and other wine-derived compounds is discussed.

    Topics: Adenocarcinoma; Alcohol Drinking; Alcoholic Beverages; Alcoholism; Altitude Sickness; Antioxidants; Asthma; Female; Humans; Lung; Lung Neoplasms; Male; Pulmonary Disease, Chronic Obstructive; Pulmonary Edema; Respiratory Distress Syndrome; Resveratrol; Stilbenes; Sulfites; Wine

2006
Genistein and resveratrol: mammary cancer chemoprevention and mechanisms of action in the rat.
    Expert review of anticancer therapy, 2006, Volume: 6, Issue:12

    The environment, including diet, plays a critical role in a woman's subsequent risk of breast cancer. Two dietary polyphenols that have received attention from the health and research communities for their ability to protect against breast cancer are: genistein, a component of soy; and resveratrol, a phytoalexin found in red grapes and red wine. We and others have shown that both genistein and resveratrol can protect against mammary cancer in rodents. The timing of exposure to genistein appears critical for its mammary protective effects. It has been reported that genistein early in life causes enhanced mammary gland differentiation, alterations in cell proliferation and apoptosis, and upregulation of tumor-suppressor genes. With resveratrol in the diet, changes in cell proliferation and apoptosis in terminal ductal structures of the mammary gland might help to explain its protective effects. We conclude that genistein and resveratrol can protect against breast cancer by regulating important mammary growth and differentiation pathways.

    Topics: 9,10-Dimethyl-1,2-benzanthracene; Adenocarcinoma; Administration, Oral; Adolescent; Age Factors; Animals; Antioxidants; Carcinogens; Cell Differentiation; Chemoprevention; Diet; Drug Administration Schedule; Drug Synergism; Estradiol; Female; Gene Expression Regulation; Genistein; Humans; Mammary Glands, Animal; Mammary Neoplasms, Experimental; Molecular Structure; Pregnancy; Protein Kinase Inhibitors; Rats; Rats, Sprague-Dawley; Resveratrol; Sexual Maturation; Soy Foods; Stilbenes; Wine

2006
Resveratrol regulates cellular PKC alpha and delta to inhibit growth and induce apoptosis in gastric cancer cells.
    Investigational new drugs, 2005, Volume: 23, Issue:2

    Resveratrol, a dietary phytoalexin, has emerged as a promising chemopreventive agent due to its antiproliferative and pro-apoptotic action toward cancer cells and its ability to inhibit tumor growth in animals. Gastric adenocarcinoma cells respond to resveratrol treatment with suppression of DNA synthesis, activation of nitric oxide synthase, induction of apoptosis and inhibition of total PKC and PKC alpha activity. Here we demonstrate that treatment of gastric adenocarcinoma SNU-1 cells with resveratrol results in time and concentration dependent accumulation of tumor suppressors p21(cip1/WAF-1) and p53 and is preceded by loss of membrane-associated PKC delta protein and a concomitant increase in cytosolic PKC alpha. Arrest of the cell cycle at transition of S to G(2)/M phases correlates with the profile of (3)H-thymidine incorporation and accumulation of p21(cip1/WAF-1) and was temporally dependent on increase of p53. SNU-1 cells respond to resveratrol treatment with up-regulation of both Fas and Fas-L proteins, whereas in KATO-III cells, with deleted p53, only Fas-L is increased after resveratrol treatment. Although Fas and Fas-L proteins in SNU-1 cells and Fas-L in KATO-III cells were elevated within 24 h of cell treatment with low concentrations of resveratrol, significant apoptotic response at these concentrations was observed only after 48 h. Altogether, our findings indicate that resveratrol engages PKC alpha and delta signals in gastric adenocarcinoma SNU-1 cells prior to up-regulation of antiproliferative and pro-apoptotic signals. The specific cell death signals engaged by resveratrol appear to be cell type dependent and suggest that resveratrol has chemopreventive potential even after mutational changes have occurred.

    Topics: Adenocarcinoma; Anticarcinogenic Agents; Apoptosis; Cell Cycle; Cell Line, Tumor; Enzyme Activation; Fas Ligand Protein; Humans; Membrane Glycoproteins; Nitric Oxide Synthase; Protein Kinase C; Resveratrol; Stilbenes; Stomach Neoplasms

2005
The role of the estrogen receptor in diethylstilbestrol toxicity.
    Archives of toxicology. Supplement. = Archiv fur Toxikologie. Supplement, 1985, Volume: 8

    The site and specificity of the tissue response to a toxicant are of central importance; it is in this area of diethylstilbestrol (DES) toxicity that the estrogen receptor would appear to play its primary role. Compilation of the various sites of DES toxicity in humans and experimental animals indicates that lesions appear predominantly in estrogen responsive target tissues suggesting that the presence of the estrogen receptor in such target tissues may help govern the tissue specificity of the toxic insult. DES and many of its oxidative metabolites interact with high affinity with the estrogen receptor. Such an interaction may be responsible for localizing DES to target tissues. Autoradiographic and biochemical studies have supported the localization of radiolabeled DES in susceptible tissues. The intracellular mechanism of receptor binding of DES and certain metabolites could then result in mobilization of these compounds to the nucleus. Experimental evidence has shown that DES and a number of its metabolites are able to translocate receptor to the nucleus of uterine cells. Such an action by the receptor results in an increased probability of potential chemical interactions with the genome. The actual induction of a chemical lesion in the target cell may, at this point, proceed by non-receptor mediated mechanisms. For example, studies using in vitro cell culture systems which contain no estrogen receptors have shown that DES can induce neoplastic cell transformation, mutagenesis, irreversible binding to DNA and protein and unscheduled DNA synthesis. These results raise the possibility that a part of DES toxicity may follow pharmacologic principles established for chemical carcinogens. Following induction of the molecular lesion, the role of the receptor continues in this process by mediating increased protein synthesis and mitogenesis in responsive target tissues which ultimately permits a more extensive expression of the toxic effects. It has been demonstrated that DES is a potent mitogen in vivo in both uterine and pituitary tissues, subsequently, the lesion will perpetuate itself through this receptor mediated biological response. This is particularly important since a number of DES induced reproductive tract tumors are expressed only after additional estrogen exposure. While other tumors have been shown to be estrogen sensitive and will regress without continued estrogen stimulation. Therefore, it should be considered that the presence of the estrog

    Topics: Adenocarcinoma; Animals; Biological Transport; Cell Nucleus; Cricetinae; Dienestrol; Diethylstilbestrol; DNA; Female; Gene Expression Regulation; Genital Neoplasms, Female; Humans; Male; Mice; Neoplasms, Experimental; Oxidation-Reduction; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Receptors, Estrogen; Stilbenes; Structure-Activity Relationship

1985

Trials

3 trial(s) available for stilbenes and Adenocarcinoma

ArticleYear
Phase Ib trial of radiotherapy in combination with combretastatin-A4-phosphate in patients with non-small-cell lung cancer, prostate adenocarcinoma, and squamous cell carcinoma of the head and neck.
    Annals of oncology : official journal of the European Society for Medical Oncology, 2012, Volume: 23, Issue:1

    The vascular disrupting agent combretastatin-A4-phosphate (CA4P) demonstrated antitumour activity in preclinical studies when combined with radiation.. Patients with non-small-cell lung cancer (NSCLC), prostate adenocarcinoma, and squamous cell carcinoma of the head and neck (SCCHN) received 27 Gy in 6 fractions treating twice weekly over 3 weeks, 55 Gy in 20 fractions over 4 weeks, and 66 Gy in 33 fractions over 6 weeks respectively. CA4P was escalated from 50 mg/m2 to 63 mg/m2. CA4P exposure was further increased from one to three to six doses. Patients with SCCHN received cetuximab in addition.. Thirty-nine patients received 121 doses of CA4P. Dose-limiting toxic effects (DLTs) of reversible ataxia and oculomotor nerve palsy occurred in two patients with prostate cancer receiving weekly CA4P at 63 mg/m2. DLT of cardiac ischaemia occurred in two patients with SCCHN at a weekly dose of 50 mg/m2 in combination with cetuximab. Three patients developed grade 3 hypertension. Responses were seen in 7 of 18 patients with NSCLC. At 3 years, 3 of 18 patients with prostate cancer had prostate-specific antigen relapse.. Radiotherapy with CA4P appears well tolerated in most patients. The combination of CA4P, cetuximab, and radiotherapy needs further scrutiny before it can be recommended for clinical studies.

    Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Agents, Phytogenic; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Chemoradiotherapy; Dose-Response Relationship, Drug; Female; Head and Neck Neoplasms; Humans; Lung Neoplasms; Male; Middle Aged; Prostatic Neoplasms; Squamous Cell Carcinoma of Head and Neck; Stilbenes

2012
Clinical pharmacology of resveratrol and its metabolites in colorectal cancer patients.
    Cancer research, 2010, Oct-01, Volume: 70, Issue:19

    Resveratrol is a phytochemical with chemopreventive activity in preclinical rodent models of colorectal carcinogenesis. Antiproliferation is one of the many chemopreventive modes of action it has been shown to engage in. Concentrations of resveratrol, which can be achieved in human tissues after p.o. administration, have not yet been defined. The purpose of this study was to measure concentrations of resveratrol and its metabolites in the colorectal tissue of humans who ingested resveratrol. Twenty patients with histologically confirmed colorectal cancer consumed eight daily doses of resveratrol at 0.5 or 1.0 g before surgical resection. Resveratrol was found to be well tolerated. Normal and malignant biopsy tissue samples were obtained before dosing. Parent compound plus its metabolites resveratrol-3-O-glucuronide, resveratrol-4'-O-glucuronide, resveratrol-3-O-sulfate, resveratrol-4'-O-sulfate, resveratrol sulfate glucuronide, and resveratrol disulfate were identified by high-performance liquid chromatography (HPLC) with UV or mass spectrometric detection in colorectal resection tissue. Quantitation was achieved by HPLC/UV. Cell proliferation, as reflected by Ki-67 staining, was compared in preintervention and postintervention tissue samples. Resveratrol and resveratrol-3-O-glucuronide were recovered from tissues at maximal mean concentrations of 674 and 86.0 nmol/g, respectively. Levels of resveratrol and its metabolites were consistently higher in tissues originating in the right side of the colon compared with the left. Consumption of resveratrol reduced tumor cell proliferation by 5% (P = 0.05). The results suggest that daily p.o. doses of resveratrol at 0.5 or 1.0 g produce levels in the human gastrointestinal tract of an order of magnitude sufficient to elicit anticarcinogenic effects. Resveratrol merits further clinical evaluation as a potential colorectal cancer chemopreventive agent.

    Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Agents, Phytogenic; Cell Growth Processes; Colorectal Neoplasms; Combined Modality Therapy; Female; Humans; Immunohistochemistry; Ki-67 Antigen; Male; Middle Aged; Resveratrol; Stilbenes

2010
Phase II study of tamoxifen: report of 74 patients with stage IV breast cancer.
    Cancer treatment reports, 1976, Volume: 60, Issue:10

    Tamoxifen (NSC-180973), a synthetic antiestrogen, was studied for efficacy and toxicity in patients with metastatic breast adenocarcinoma. Two dose levels were used, 10 mg bid and 15 mg/m2 bid, in separate groups. In the 10-mg bid dosage group, 30 of the 31 patients were considered evaluable for efficacy. Five complete and 11 partial responses were recorded, for an overall response rate of 53%. In the 15-mg/m2 bid dosage group, 44 of the 45 patients were considered evaluable for efficacy. Three complete and 16 partial responses were recorded, for an overall response rate of 43%. All 76 patients were evaluated for toxicity. Side effects were generally mild, consisting mostly of hot flushes, transient leukopenia, transient thrombocytopenia, nausea, and fluid retention. A high degree of correlation between response and positive estrogen-receptor assay suggests the value of the test as a means to select patients for tamoxifen treatment. The conclusion from this study is that tamoxifen used as a single agent is an effective drug with minimal toxicity for treatment of metastatic breast adenocarcinoma.

    Topics: Adenocarcinoma; Adult; Aged; Breast Neoplasms; Clinical Trials as Topic; Dose-Response Relationship, Drug; Female; Humans; Liver Neoplasms; Lung Neoplasms; Middle Aged; Neoplasm Metastasis; Stilbenes; Tamoxifen

1976

Other Studies

88 other study(ies) available for stilbenes and Adenocarcinoma

ArticleYear
Resveratrol derivatives: Synthesis and their biological activities.
    European journal of medicinal chemistry, 2023, Jan-15, Volume: 246

    Resveratrol, a natural compound known especially for its antioxidant properties and protective action, opens the door for both it and its structural derivatives to be considered not only as chemopreventive but also as cancer chemotherapeutic agents. Due to the pharmacokinetic problems of resveratrol that demonstrate its poor bioavailability, the study of new derivatives is of interest. Thus, in this work (E)-stilbenes derived directly from resveratrol and other cyclic analogues containing the benzofuran or indole nucleus have been synthesized. The synthesized compounds have been evaluated for their ability to affect tumor growth in vitro. Compounds 2, 3, 4 and 5 have shown cytotoxicity in human colon cancer (HT-29) and human pancreatic adenocarcinoma cells (MIA PaCa-2) higher than those of (E)-resveratrol. The indolic derivative 13, a cyclic analog of resveratrol, has shown in vitro cytotoxic activity 8 times higher than resveratrol against HT-29 cancer cells. The cyclic derivatives 8, 9 and 12 showed a high inhibition of cell growth in HCT-116 (KRas mutant) at 20 μM, while 13 shows moderate antiangiogenesis activity at 10 μM.

    Topics: Adenocarcinoma; Antineoplastic Agents; Antioxidants; Humans; Pancreatic Neoplasms; Resveratrol; Stilbenes

2023
Studies on the Anticancer and Antioxidant Activities of Resveratrol and Long-Chain Fatty Acid Esters.
    International journal of molecular sciences, 2023, Apr-12, Volume: 24, Issue:8

    Resveratrol (RES) is gaining recognition as a natural bioactive compound. To expand the possible applications of RES with its enhanced bioactivity as well as to increase the health benefits of long-chain fatty acids, a lipophilization process of RES was performed using three fatty acids: palmitic acid (PA), oleic acid (OA), and conjugated linoleic acid (CLA). The obtained mono-, di-, and tri-esters of RES were evaluated for their anticancer and antioxidant properties against lung carcinoma (A549), colorectal adenocarcinoma (HT29), and pancreatic ductal adenocarcinoma (BxPC3) cell lines. Human fibroblast (BJ) cells were used as a control. Several parameters were investigated: cell viability and apoptosis, including the expression of major pro- and anti-apoptotic markers, as well as the expression of superoxide dismutase, a key enzyme of the body's antioxidant barrier. Three of the obtained esters: mono-RES-OA, mono-RES-CLA, and tri-RES-PA, which significantly reduced the tumor cell viability up to 23%, at concentrations 25, 10, 50 μg/mL, respectively, turned out to be particularly interesting. The above-mentioned resveratrol derivatives similarly increased the tumor cells' apoptosis by modifying their caspase activity of pro-apoptotic pathways (p21, p53, and Bax). Moreover, among the mentioned esters, mono-RES-OA induced apoptosis of the analyzed cell lines most strongly, reducing the number of viable cells up to 48% for HT29 cells versus 36% for pure RES. Furthermore, the selected esters exhibited antioxidant properties towards the normal BJ cell line by regulating the expression of major pro-antioxidant genes (superoxide dismutases-

    Topics: Adenocarcinoma; Antioxidants; Apoptosis; Esters; Fatty Acids; Humans; Resveratrol; Stilbenes; Superoxide Dismutase

2023
Pterostilbene Enhances Cytotoxicity and Chemosensitivity in Human Pancreatic Cancer Cells.
    Biomolecules, 2020, 05-04, Volume: 10, Issue:5

    Topics: Adenocarcinoma; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B; Cell Line, Tumor; Deoxycytidine; Drug Resistance, Neoplasm; Gemcitabine; Humans; Pancreatic Neoplasms; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Receptor for Advanced Glycation End Products; Signal Transduction; Stilbenes

2020
Pterostilbene enhances sorafenib's anticancer effects on gastric adenocarcinoma.
    Journal of cellular and molecular medicine, 2020, Volume: 24, Issue:21

    Sorafenib has been approved for the treatment of certain cancers in clinic. However, the effects of sorafenib on gastric adenocarcinoma (GAC) were still limited. This study aimed to evaluate both in vitro and in vivo efficacy of sorafenib in combination with pterostilbene (PTE) on the treatment of GAC. Here, the morphological changes and cell viability were recorded in both N87 and MKN45 cells. The cell cycle profile and apoptosis were assessed by flow cytometry. Subcutaneous tumour xenografts were constructed in nude mice, and IHC staining of the dissected tumour tissues was conducted. Our results showed that PTE enhanced sorafenib's inhibitory effects on cell viability. The obvious down-regulation of cyclin D1, Cdk-2, Cdk-4, Cdk-6 and p62 and the up-regulation of LC3II, caspase-9, caspase-3 and PARP cleavages were observed for the combination treatment with PTE and sorafenib than monotherapy. The combination treatment resulted in a higher level of cell cycle arrest at G1 phase and apoptosis than either drug. Besides, drug combination significantly enhanced the inhibition of tumour growth than sorafenib or PET alone in nude mice. The percentage of Ki-67- and PCNA-positive cells was distinctly reduced, and the apoptotic cells was obviously increased when compared with single drug therapy. Altogether, PET obviously enhanced sorafenib's antitumour effects against GAC through inhibiting cell proliferation, inducing autophagy and promoting apoptosis. The combination therapy with PET and sorafenib may serve as a novel therapeutic strategy for treating GAC and deserve further clinical trials.

    Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Apoptosis; Autophagy; Cell Death; Cell Line, Tumor; Cell Shape; Cell Survival; Drug Synergism; G1 Phase Cell Cycle Checkpoints; Male; Mice, Inbred BALB C; Mice, Nude; Sorafenib; Stilbenes; Stomach Neoplasms; Xenograft Model Antitumor Assays

2020
Combretastatin A4 Nanodrug-Induced MMP9 Amplification Boosts Tumor-Selective Release of Doxorubicin Prodrug.
    Advanced materials (Deerfield Beach, Fla.), 2019, Volume: 31, Issue:44

    Tumor-associated enzyme-activated prodrugs can potentially improve the selectivity of chemotherapeutics. However, the paucity of tumor-associated enzymes which are essential for prodrug activation usually limits the antitumor potency. A cooperative strategy that utilizes combretastatin A4 nanodrug (CA4-NPs) and matrix metalloproteinase 9 (MMP9)-activated doxorubicin prodrug (MMP9-DOX-NPs) is developed. CA4 is a typical vascular disrupting agent that can selectively disrupt immature tumor blood vessels and exacerbate the tumor hypoxia state. After treatment with CA4-NPs, MMP9 expression can be significantly enhanced by 5.6-fold in treated tumors, which further boosts tumor-selective active drug release of MMP9-DOX-NPs by 3.7-fold in an orthotopic 4T1 mammary adenocarcinoma mouse model. The sequential delivery of CA4-NPs and MMP9-DOX-NPs exhibits enhanced antitumor efficacy with reduced systemic toxicity compared with the noncooperative controls.

    Topics: Adenocarcinoma; Animals; Antibiotics, Antineoplastic; Cell Line, Tumor; Cell Survival; Delayed-Action Preparations; Doxorubicin; Drug Liberation; Female; Glutamic Acid; Mammary Neoplasms, Experimental; Matrix Metalloproteinase 9; Mice; Mice, Inbred BALB C; Nanoparticles; Phenylalanine; Polyethylene Glycols; Prodrugs; Stilbenes; Tissue Distribution

2019
α9- and α7-containing receptors mediate the pro-proliferative effects of nicotine in the A549 adenocarcinoma cell line.
    British journal of pharmacology, 2018, Volume: 175, Issue:11

    Tobacco smoke contains many classes of carcinogens and although nicotine is unable to initiate tumourigenesis in humans and rodents, it promotes tumour growth and metastasis in lung tumours by acting on neuronal nicotinic ACh receptors (nAChRs). The aim of this study was to identify molecularly, biochemically and pharmacologically which nAChR subtypes are expressed and functionally activated by nicotine in lung cancer cell lines.. We used A549 and H1975 adenocarcinoma cell lines derived from lung tumours to test the in vitro effects of nicotine, and nAChR subtype-specific peptides and compounds.. The two adenocarcinoma cell lines express distinctive nAChR subtypes, and this affects their nicotine-induced proliferation. In A549 cells, nAChRs containing the α7 or α9 subunits not only regulate nicotine-induced cell proliferation but also the activation of the Akt and ERK pathways. Blocking these nAChRs by means of subtype-specific peptides, or silencing their expression by means of subunit-specific siRNAs, abolishes nicotine-induced proliferation and signalling. Moreover, we found that the α7 antagonist MG624 also acts on α9-α10 nAChRs, blocks the effects of nicotine on A549 cells and has dose-dependent cytotoxic activity.. These results highlight the pathophysiological role of α7- and α9-containing receptors in promoting non-small cell lung carcinoma cell growth and intracellular signalling and provide a framework for the development of new drugs that specifically target the receptors expressed in lung tumours.. This article is part of a themed section on Nicotinic Acetylcholine Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.11/issuetoc.

    Topics: A549 Cells; Adenocarcinoma; alpha7 Nicotinic Acetylcholine Receptor; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Humans; Lung Neoplasms; Nicotine; Quaternary Ammonium Compounds; Receptors, Nicotinic; Stilbenes; Structure-Activity Relationship

2018
ROS-mediated endoplasmic reticulum stress and mitochondrial dysfunction underlie apoptosis induced by resveratrol and arsenic trioxide in A549 cells.
    Chemico-biological interactions, 2016, Feb-05, Volume: 245

    Although it is well documented that endoplasmic reticulum (ER) stress and mitochondrial dysfunction are associated with apoptosis, little is known about whether they are involved in the apoptotic cell death induced by resveratrol and arsenic trioxide (ATO) combination. In this study, we identified a series of sensitization effects of resveratrol on human lung adenocarcinoma A549 cells to ATO treatment, with the combination index (CI) of resveratrol and ATO less than 1. Then, we demonstrated that ER stress was contributed to this synergistic effect, which was manifested by increased the expression levels of ER stress hallmarks, including 78-kDa glucose-regulated protein (GRP 78), caspase 12 and C/EBP-homologous protein (CHOP), In addition, mitochondrial dysfunction was observed after exposure of A549 cells to resveratrol or/and ATO, which was displayed by some alterations of mitochondria-related events, such as loss of mitochondrial membrane potential, cytochrome c release and changes of Bax and Bcl-2 expressions. Our results further demonstrated that resveratrol and ATO-induced ER stress and mitochondrial dysfunction were mediated by reactive oxygen species (ROS), showing that pre-treatment of N-acetyl-l-cysteine, a potent ROS scavenger, restored the ER stress and mitochondrial dysfunction in cells co-treated with resveratrol and ATO, thereby leading to the reduction of the apoptosis. Collectively, these results clearly suggest that ROS-mediated ER stress and mitochondrial dysfunction were involved in the apoptosis induced by resveratrol and ATO in A549 cells, which provides a novel insight into the molecular mechanisms of resveratrol-mediated ATO-sensitization.

    Topics: Adenocarcinoma; Adenocarcinoma of Lung; Antineoplastic Agents; Apoptosis; Arsenic Trioxide; Arsenicals; Cell Line, Tumor; Drug Synergism; Endoplasmic Reticulum Stress; Humans; Lung; Lung Neoplasms; Mitochondria; Oxides; Reactive Oxygen Species; Resveratrol; Stilbenes

2016
[Study on the resveratrol and arsenic trioxide combination induced apoptosis and its mechanism on lung adenocarcinoma cells].
    Wei sheng yan jiu = Journal of hygiene research, 2016, Volume: 45, Issue:1

    To explore the synergistically effects and mechanisms of resveratrol (RES) enhanced the oxidative stress and apoptotic cell death induced by As2O3 (arsenic trioxide).. According to the result of MTT assay, human lung adenocarcinoma A549 cells were divided into four treatment groups as follow: control group, single RES or As2O3 treated group and the group treated with RES and As2O3. Then the differences of cell viability, colony formation, level of ROS, GSH content, mitochondrial membrane potential and apoptosis rate were compared with single or combined treatment. In addition, pre-treatment with L-buthionine sulfoximine (L-BSO), the inhibitory of GSH synthesis, was used to identify the role of GSH in synergistically apoptosis induced by RES and As2O3.. The detected results demonstrated that RES could effectively inhibited the growth of A549 cells when its concentration above 20 μmol/L, and inhibition effects was concentration dependent manner. The rate of colony formation, GSH content, mitochondrial membrane potential and apoptosis rate in combination group were significantly lower than that of single RES or As2O3 treatment group (P < 0.05), whereas, RES markedly increased the level of ROS, the expression of cytochrome c and caspase 3 induced by As2O3. When pre-treatment with BSO before RES and As2O3 combination incubation, beside the apoptosis rate was increased from 30.0% to 77.7%, the GSH content was sharply depleted while ROS massively accumulated in intracellular.. RES could significantly intensified the effects of As2O3 in inhibiting the proliferation, depleting GSH content, ROS accumulation, mitochondrial membrane potential decline and cytochrome c releasing, thus leading to cells apoptosis via Cas-3 activation in a mitochondria-dependent pathway.

    Topics: Adenocarcinoma; Adenocarcinoma of Lung; Anticarcinogenic Agents; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Arsenic Trioxide; Arsenicals; Buthionine Sulfoximine; Caspase 3; Drug Synergism; Glutathione; Humans; Lung Neoplasms; Membrane Potential, Mitochondrial; Mitochondria; Oxidation-Reduction; Oxides; Resveratrol; Stilbenes; Tumor Cells, Cultured

2016
Resveratrol synergistically triggers apoptotic cell death with arsenic trioxide via oxidative stress in human lung adenocarcinoma A549 cells.
    Biological trace element research, 2015, Volume: 163, Issue:1-2

    Arsenic trioxide (As2O3) is a potent anticancer drug for the treatment of acute promyelocytic leukemia. However, the clinical applications of the agent to treat solid tumors are largely compromised by the drug resistance. Our previous study demonstrated that resveratrol, a plant-derived natural product, could potentiate the toxicity of arsenite in lung adenocarcinoma A549 cells at relatively high concentration, indicating that combination of resveratrol and As2O3 may be a helpful strategy to solve the drug resistance of As2O3 in tumor cells. To test this possibility, in the present study, we determined the combined effects of resveratrol and As2O3 in cultured A549 cells. Our results showed that co-treatment of resveratrol with As2O3 resulted in a synergistic augmentation of cytotoxicity and apoptosis in cells at the tested concentration. To further reveal the detailed mechanism of this synergistic effect on cytotoxicity and apoptosis, apoptosis-related proteins, DNA and chromosomal damage, and the level of oxidative stress were also evaluated. Our data revealed that co-treatment with resveratrol and As2O3 caused more genotoxicity and serious oxidative stress in A549 cells than that of single agent treatment. Moreover, resveratrol and As2O3 could also corporately enhance the release of cytochrome c and the expressions of death receptor Fas and FasL. Together, our results suggest that resveratrol and As2O3 synergistically increase the apoptotic cell death in A549 cells through induction of oxidative stress, indicating that the combination of resveratrol with As2O3 may be a promising strategy to increase the clinical efficacy of As2O3 in the treatment of lung tumor.

    Topics: Adenocarcinoma; Anticarcinogenic Agents; Apoptosis; Arsenic Trioxide; Arsenicals; Cell Line, Tumor; Drug Synergism; Humans; Lung Neoplasms; Oxidative Stress; Oxides; Resveratrol; Stilbenes

2015
Synthesis and cytotoxic activities of E-resveratrol derivatives.
    Chinese journal of natural medicines, 2015, Volume: 13, Issue:5

    The present study was designed to synthesize derivatives of E-resveratrol and evaluate their cytotoxic activity in vitro. Different functional groups were conjugated with the phenolic hydroxyl group of E-resveratrol, and the double bond of E-resveratrol was reduced. The in vitro cytotoxicity of the synthetic derivatives was evaluated against three tumor cell lines (A549, LAC, and HeLa) using the MTT assay. Twenty-six E-resveratrol derivatives were synthesized and their structures were confirmed by (1)H NMR, MS, IR, and elemental analyses. Compounds 1-6, 12, 15-21, and 23-26 were reported for the first time. Among them, Compounds 1, 2, 4, 5, and 9-11, showed significant cytotoxicity against tumor cells; especially, Compound 1 showed an IC50 value of 4.38 μmol · L(-1) in the A549 cells which was 15-fold more active than E-resveratrol; Compound 9 showed an IC50 value of 1.41 μmol · L(-1) in the HeLa cell line which was 90-fold more active than E-resveratrol, and close to adriamycin. The structure-activity relationships were also investigated. Compounds 1, 2 and 9-11 may serve as potential lead compounds for the discovery of new anticancer drugs.

    Topics: Adenocarcinoma; Antineoplastic Agents; Cell Line, Tumor; Female; HeLa Cells; Humans; Inhibitory Concentration 50; Lung Neoplasms; Resveratrol; Stilbenes; Structure-Activity Relationship; Uterine Cervical Neoplasms

2015
Trans-Resveratrol Induces Apoptosis through ROS-Triggered Mitochondria-Dependent Pathways in A549 Human Lung Adenocarcinoma Epithelial Cells.
    Planta medica, 2015, Volume: 81, Issue:12-13

    Resveratrol has been shown to be a potential chemopreventive and anticancer agent, inducing apoptosis in a variety of cancer cells. The present study was performed to evaluate the effect of resveratrol on A549 human lung adenocarcinoma epithelial cells. 3-(4,5-Dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide evaluation demonstrated that the exposure of cells to increasing concentrations of resveratrol (0-175 µM) for 24 h resulted in a decrease in cell viability (IC50 85.5 µM). Annexin V/propidium iodide double stain verified apoptosis in A549 cells, while negligible cell cytotoxity (≥ 0.5 %) was observed in all untreated incubations. Using colorimetric assay kits, induction of caspase-3, but not of caspase-8, activity was detected in response to resveratrol (> 130 µM). Confirmatory evidence of this finding was provided by Western blotting, indicating expression of cleaved caspase-3 levels in a concentration-dependent manner with a minimum resveratrol concentration of 65 µM required for activation of this protease, while that of caspase-8 remained unaffected. The apoptotic process was associated with reactive oxygen species production in a concentration-dependent manner, evidenced by microscopic examination and fluorescence-activated cell sorting analysis using the 2',7'-dichlorofluorescein diacetate assay. In the presence of the mitochondrial electron transport chain inhibitor rotenone, reactive oxygen species production and the concomitant apoptotic cell population were significantly reduced. This finding suggested that the resveratrol-induced apoptosis was mediated via a mitochondrial pathway alignment in human A549 cells. Although effective levels were observed at high concentrations, the outcome may well differ under in vivo conditions. Finally, experiments reaffirmed the chemical instability of trans-resveratrol, suggesting the need for protection of the solutions from extended exposure to light.

    Topics: Adenocarcinoma; Adenocarcinoma of Lung; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Caspase 3; Caspase 8; Cell Line, Tumor; Cell Survival; Epithelial Cells; Fluoresceins; Humans; Lung Neoplasms; Mitochondria; Reactive Oxygen Species; Resveratrol; Stilbenes; Tetrazolium Salts; Thiazoles

2015
PIAS3, SHP2 and SOCS3 Expression patterns in Cervical Cancers: Relevance with activation and resveratrol-caused inactivation of STAT3 signaling.
    Gynecologic oncology, 2015, Volume: 139, Issue:3

    Resveratrol inhibits cervical cancer (CC) cells by blocking STAT3 signaling. However, the mechanism of resveratrol-induced STAT3 inactivation remains largely unknown. SHP2, PIAS3, and SOCS3 are STAT3 negative regulators; therefore, their statuses in cervical adenocarcinoma (HeLa) and squamous cell carcinoma (SiHa and C33A) cell lines without and with resveratrol treatment and their correlation with STAT3 activation in CC specimens were investigated.. MTT and TUNEL assays were used to check the resveratrol sensitivity of CC cells, and immunocytochemical staining, Western blotting, and RT-PCR were used to analyze SHP2, PIAS3, and SOCS3 expression and the intracellular distribution of STAT3. Tissue microarray based immunohistochemical staining was performed to investigate potential correlations between SHP2, PIAS3, and SOCS3 expression and STAT3 activation.. PIAS3 and SOCS3 were found to be weakly expressed in CC cells and upregulated by resveratrol; this was accompanied by inhibition of STAT3 signaling. The SHP2 level remained unchanged in all three cell lines after resveratrol treatment. STAT3 nuclear translocation was more frequent in adenocarcinomas and squamous cell carcinomas than that of their noncancerous counterparts. The SOCS3 level and detection rate were higher in noncancerous squamous cells (but not in glandular epithelia) compared with their cancerous counterparts. The phospho-SHP2 detection rate was similar in noncancerous and tumor tissues of squamous and glandular origins; however, PIAS3 levels were distinct.. Of the three STAT3 negative regulators, PIAS3 correlated most negatively with STAT3 nuclear translocation and may inhibit STAT3 signaling in both histological CC subtypes. PIAS3 responsiveness may reflect greater resveratrol sensitivity and improved therapeutic outcome in CCs.

    Topics: Adenocarcinoma; Antineoplastic Agents, Phytogenic; Carcinoma, Squamous Cell; Cell Proliferation; Cell Survival; Cyclin D1; Female; Gene Expression; HeLa Cells; Humans; Inhibitor of Apoptosis Proteins; Molecular Chaperones; Phosphorylation; Protein Inhibitors of Activated STAT; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Proto-Oncogene Proteins c-myc; Resveratrol; RNA, Neoplasm; Signal Transduction; STAT3 Transcription Factor; Stilbenes; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Survivin; Uterine Cervical Neoplasms; Vascular Endothelial Growth Factor A

2015
Chemopreventive effect of resveratrol and apocynin on pancreatic carcinogenesis via modulation of nuclear phosphorylated GSK3β and ERK1/2.
    Oncotarget, 2015, Dec-15, Volume: 6, Issue:40

    Despite progress in clinical cancer medicine in multiple fields, the prognosis of pancreatic cancer has remained dismal. Recently, chemopreventive strategies using phytochemicals have gained considerable attention as an alternative in the management of cancer. The present study aimed to evaluate the chemopreventive effects of resveratrol (RV) and apocynin (AC) in N-Nitrosobis(2-oxopropyl)amine-induced pancreatic carcinogenesis in hamster. RV- and AC-treated hamsters showed significant reduction in the incidence of pancreatic cancer with a decrease in Ki-67 labeling index in dysplastic lesions. RV and AC suppressed cell proliferation of human and hamster pancreatic cancer cells by inhibiting the G1 phase of the cell cycle with cyclin D1 downregulation and inactivation of AKT-GSK3β and ERK1/2 signaling. Further, decreased levels of GSK3β(Ser9) and ERK1/2 phosphorylation and cyclin D1 expression in the nuclear fraction were observed in cells treated with RV or AC. Nuclear expression of phosphorylated GSK3β(Ser9) was also decreased in dysplastic lesions and adenocarcinomas of hamsters treated with RV or AC in vivo. These results suggest that RV and AC reduce phosphorylated GSK3β(Ser9) and ERK1/2 in the nucleus, resulting in inhibition of the AKT-GSK3β and ERK1/2 signaling pathways and cell cycle arrest in vitro and in vivo. Taken together, the present study indicates that RV and AC have potential as chemopreventive agents for pancreatic cancer.

    Topics: Acetophenones; Adenocarcinoma; Animals; Anticarcinogenic Agents; Antioxidants; Blotting, Western; Carcinogenesis; Cell Line, Tumor; Cell Nucleus; Cell Survival; Chemoprevention; Cricetinae; Disease Models, Animal; Female; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Humans; Immunohistochemistry; MAP Kinase Signaling System; Mesocricetus; Pancreatic Neoplasms; Phosphorylation; Resveratrol; Stilbenes

2015
Effect and Mechanism of Resveratrol on the Apoptosis of Lung Adenocarcinoma Cell Line A549.
    Cell biochemistry and biophysics, 2015, Volume: 73, Issue:2

    Lung adenocarcinoma is the most common subtype of non-small cell lung cancer and the leading cause of cancer death worldwide. In this study, we investigated the effect of resveratrol (Res) on lung adenocarcinoma A549 cells and its potential mechanism. We found after Res treatment, the interspace of A549 cells decreased and granular material increased in the cell nucleus. These changes were remarkably correlated with the increased concentration of Res. Res induces apoptosis in A549 cells and inhibits cell proliferation in a dose-dependent manner. We further showed that after Res treatment, expression of p53, Bax, and cleaved caspase-3 protein was dramatically up-regulated, while expression of Bcl-2 and the ratio of Bcl-2/Bax were down-regulated. Our study demonstrates that Res inhibits proliferation and induces apoptosis of A549 cells through regulation of p53, Bax, Bcl-2, and cleaved caspase-3 expression.

    Topics: A549 Cells; Adenocarcinoma; Adenocarcinoma of Lung; Antineoplastic Agents, Phytogenic; Apoptosis; bcl-2-Associated X Protein; Blotting, Western; Caspase 3; Cell Proliferation; Humans; Lung Neoplasms; Proto-Oncogene Proteins c-bcl-2; Resveratrol; Stilbenes; Tumor Suppressor Protein p53

2015
In-situ detection of resveratrol inhibition effect on epidermal growth factor receptor of living MCF-7 cells by Atomic Force Microscopy.
    Biosensors & bioelectronics, 2014, Jun-15, Volume: 56

    A new method based on Atomic Force Microscopy (AFM) was developed to real-time and in-situ detect epidermal growth factor receptor (EGFR) expression levels on living MCF-7 cells for evaluating the anticancer activity of resveratrol. Here, the inhibition effect of resveratrol on EGFR expression levels on MCF-7 cells was probed by epidermal growth factor (EGF)-functionalized tips for the first time. Changes in morphology and stiffness of single cell stimulated by resveratrol at different concentrations were detected by AFM. The consequences showed that resveratrol influenced the cellular state and reduced expression of EGFR on the cell surface, which were also interpreted by MTT assay and confocal microscopy assay. AFM, which was used to investigate potential targets for anti-tumor drug on living cells and realize a better understanding of drug action mechanism, was expected to be developed into a promising tool for screening of drugs.

    Topics: Adenocarcinoma; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Cell Survival; Epidermal Growth Factor; ErbB Receptors; Female; Humans; Immobilized Proteins; MCF-7 Cells; Microscopy, Atomic Force; Optical Imaging; Resveratrol; Stilbenes

2014
Resveratrol inhibits oesophageal adenocarcinoma cell proliferation via AMP-activated protein kinase signaling.
    Asian Pacific journal of cancer prevention : APJCP, 2014, Volume: 15, Issue:2

    Resveratrol has been examined in several model systems for potential effects against cancer. Adenosine monophosphate-activated protein kinase (AMPK) is reported to suppress proliferation in most eukaryocyte cells. Whether resveratrol via AMPK inhibits proliferation of oesophageal adenocarcinoma cells (OAC) is unknown. The aim of this study was to determine the roles of AMPK in the protective effects of resveratrol in OAC proliferation and to elucidate the underlying mechanisms. Treatment of cultured OAC derived from human subjects or cell lines with resveratrol resulted in decreased cell proliferation. Further, inhibition of AMPK by pharmacological reagent or genetical approach abolished resveratrol-suppressed OAC proliferation, reduced the level of p27Kip1, a cyclin-dependent kinase inhibitor, and increased the levels of S-phase kinase-associated protein 2 (Skp2) of p27Kip1-E3 ubiquitin ligase and 26S proteasome activity reduced by resveratrol. Furthermore, gene silencing of p27Kip1 reversed resveratrol-suppressed OAC proliferation. In conclusion, these findings indicate that resveratrol inhibits Skp2-mediated ubiquitylation and 26S proteasome-dependent degradation of p27Kip1 via AMPK activation to suppress OAC proliferation.

    Topics: Adenocarcinoma; AMP-Activated Protein Kinases; Anticarcinogenic Agents; Apoptosis; Blotting, Western; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p57; Esophageal Neoplasms; Humans; Proteasome Endopeptidase Complex; Real-Time Polymerase Chain Reaction; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Small Interfering; S-Phase Kinase-Associated Proteins; Signal Transduction; Stilbenes; Tumor Cells, Cultured; Ubiquitination

2014
Involvement of the Nrf2 pathway in the regulation of pterostilbene-induced apoptosis in HeLa cells via ER stress.
    Journal of pharmacological sciences, 2014, Volume: 126, Issue:3

    Among the various cancer cell lines, HeLa cells were found to be sensitive to pterostilbene (Pte), a compound that is enriched in small fruits such as grapes and berries. However, the mechanism involved in the cytotoxicity of Pte has not been fully characterized. Using biochemical and free radical biological experiments in vitro, we identified the pro-apoptotic profiles of Pte and evaluated the level of redox stress-triggered ER stress during HeLa cell apoptosis. The data showed a strong dose-response relationship between Pte exposure and the characteristics of HeLa apoptosis in terms of changes in apoptotic morphology, DNA fragmentation, and activated caspases in the intrinsic apoptotic pathway. During drug exposure, alterations in the intracellular redox homeostasis that favor oxidation were necessary to cause ER stress-related apoptosis, as demonstrated by enzymatic and non-enzymatic redox modulators. A statistically significant and dose-dependent increase (P < 0.05) was found with regard to the unique expression levels of Nrf2/ARE downstream target genes in HeLa cells undergoing late apoptosis, levels that were restored with anti-oxidant application with the Pte treatment. Our research demonstrated that Pte trigged ER stress by redox homeostasis imbalance, which was negatively regulated by a following activation of Nrf2.

    Topics: Adenocarcinoma; Antineoplastic Agents, Phytogenic; Antioxidants; Apoptosis; Cell Proliferation; Dose-Response Relationship, Drug; Endoplasmic Reticulum Stress; Female; HeLa Cells; Humans; NF-E2-Related Factor 2; Oxidation-Reduction; Oxidative Stress; Signal Transduction; Stilbenes; Uterine Cervical Neoplasms

2014
A dietary pattern rich in lignans, quercetin and resveratrol decreases the risk of oesophageal cancer.
    The British journal of nutrition, 2014, Dec-28, Volume: 112, Issue:12

    Dietary lignans, quercetin and resveratrol have oestrogenic properties, and animal studies suggest that they synergistically decrease cancer risk. A protective effect of lignans on the development of oesophageal cancer in humans has recently been demonstrated, and the present study aimed to test whether these three phytochemicals synergistically decrease the risk of oesophageal cancer. Data from a Swedish nationwide population-based case-control study that recruited 181 cases of oesophageal adenocarcinoma (OAC), 158 cases of oesophageal squamous-cell carcinoma (OSCC), 255 cases of gastro-oesophageal junctional adenocarcinoma (JAC) and 806 controls were analysed. Exposure data were collected through face-to-face interviews and questionnaires. The intake of lignans, quercetin and resveratrol was assessed using a sixty-three-item FFQ. Reduced-rank regression was used to assess a dietary pattern, and a simplified dietary pattern score was categorised into quintiles on the basis of the distribution among the control subjects. Unconditional multivariable logistic regression provided OR with 95% CI, adjusted for all the potential risk factors. A dietary pattern rich in lignans, quercetin and resveratrol was mainly characterised by a high intake of tea, wine, lettuce, mixed vegetables, tomatoes, and whole-grain bread and a low intake of milk. There were dose-dependent associations between simplified dietary pattern scores and all types of oesophageal cancer (all P for trend < 0.05). On comparing the highest quintiles with the lowest, the adjusted OR were found to be 0.24 (95% CI 0.12, 0.49) for OAC, 0.31 (95% CI 0.15, 0.65) for OSCC, and 0.49 (95% CI 0.28, 0.84) for JAC. The results of the present study indicate that a dietary pattern characterised by the intake of lignans, quercetin and resveratrol may play a protective role in the development of oesophageal cancer in the Swedish population.

    Topics: Adenocarcinoma; Aged; Anticarcinogenic Agents; Antineoplastic Agents, Phytogenic; Carcinoma, Squamous Cell; Case-Control Studies; Diet; Esophageal Neoplasms; Esophagus; Feeding Behavior; Female; Humans; Lignans; Logistic Models; Male; Middle Aged; Odds Ratio; Plant Extracts; Quercetin; Resveratrol; Stilbenes

2014
Anti-estrogenic activity of a human resveratrol metabolite.
    Nutrition, metabolism, and cardiovascular diseases : NMCD, 2013, Volume: 23, Issue:11

    Resveratrol, the most investigated dietary compound in studies aimed at linking wine consumption to human health, is an extremely minor component of this beverage and it is generally studied in vitro as the unconjugated aglycone at concentrations largely exceeding those found in the human circulatory system after dietary intake. Moreover, following intestinal absorption, trans-resveratrol and its glucoside, which are naturally present in wine and other food sources, are converted to sulphate and glucuronide metabolites. An estrogenic activity has previously been documented for resveratrol, yet nothing is known about the activity of its blood-circulating metabolic derivatives.. Using a yeast two-hybrid detection system relying on the interaction between the ligand-binding domain of the human oestrogen receptors α and β and the human coactivator Tif2, we have systematically examined the oestrogen agonist and antagonist activities of the two main resveratrol forms present in planta (trans-resveratrol and trans-resveratrol-3-O-glucoside) and of the three main metabolites found in human plasma (trans-resveratrol-3-O-sulphate, trans-resveratrol-3-O-glucuronide and trans-resveratrol-4'-O-glucuronide). Only resveratrol-3-O-sulphate was found to display a fairly strong and oestrogen receptor α-preferential antagonistic activity, which was confirmed in a human breast adenocarcinoma cell line containing a luciferase reporter gene under the control of an oestrogen-responsive promoter.. We show, for the first time, that resveratrol-3-O-sulphate, but neither of its metabolites, is endowed with anti-estrogenic activity and how human metabolism of phenolic substances plays a pivotal role in modulating their biological effect.

    Topics: Adenocarcinoma; Antineoplastic Agents, Phytogenic; Binding Sites; Breast Neoplasms; Cell Line, Tumor; Clone Cells; Estrogen Antagonists; Estrogen Receptor alpha; Estrogen Receptor beta; Female; Glucosides; Glucuronides; Humans; MCF-7 Cells; Neoplasm Proteins; Nuclear Receptor Coactivator 2; Peptide Fragments; Phytoestrogens; Recombinant Proteins; Resveratrol; Stereoisomerism; Stilbenes; Sulfates

2013
Pterostilbene exerts antitumor activity via the Notch1 signaling pathway in human lung adenocarcinoma cells.
    PloS one, 2013, Volume: 8, Issue:5

    Although pterostilbene (PTE) has been shown to have potent antitumor activities against various cancer types, the molecular mechanisms of these activities remain unclear. In this study, we investigated the antitumor activity of PTE against human lung adenocarcinoma in vitro and in vivo and explored the role of the Notch1 signaling pathway in this process. PTE treatment resulted in a dose- and time-dependent decrease in the viability of A549 cells. Additionally, PTE exhibited strong antitumor activity, as evidenced not only by a reduced mitochondrial membrane potential (MMP) and a decreased intracellular glutathione content but also by increases in the apoptotic index and the level of reactive oxygen species (ROS). Furthermore, PTE treatment induced the activation of the Notch1 Intracellular Domain (NICD) protein and activated Hes1. DAPT (a gamma secretase inhibitor) and Notch1 siRNA prevented the induction of NICD and Hes1 activation by PTE treatment and sensitized the cells to PTE treatment. The down-regulation of Notch signaling also prevented the activation of pro-survival pathways (most notably the PI3K/Akt pathway) after PTE treatment. In summary, lung adenocarcinoma cells may enhance Notch1 activation as a protective mechanism in response to PTE treatment. Combining a gamma secretase inhibitor with PTE treatment may represent a novel approach for treating lung adenocarcinoma by inhibiting the survival pathways of cancer cells.

    Topics: Adenocarcinoma; Adenocarcinoma of Lung; Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Shape; Cell Survival; Dipeptides; Drug Resistance, Neoplasm; Drug Synergism; Glutathione; Humans; Lung Neoplasms; Male; Membrane Potential, Mitochondrial; Mice; Mice, Nude; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Receptor, Notch1; Signal Transduction; Stilbenes; Tumor Burden; Xenograft Model Antitumor Assays

2013
Dual role of resveratrol in modulation of genotoxicity induced by sodium arsenite via oxidative stress and apoptosis.
    Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association, 2013, Volume: 59

    The potential benefits of resveratrol as an anticancer (proapoptosis) and antioxidant (pro-survival) compound have been studied extensively. However, the role of resveratrol in modulation of the toxicity induced by sodium arsenite (NaAsO₂) is still unclear. In the present study, we examined the effects of resveratrol on NaAsO₂-induced cytotoxicity, DNA and chromosomal damage, cell cycle progression, apoptosis and oxidative stress in human lung adenocarcinoma epithelial (A549) cell line at concentrations from 1 to 20 μM after 24h exposure. Our results revealed that at 1 and 5 μM, resveratrol was found to exert benefit effects, promoting cell viability and proliferation over 24h NaAsO₂ exposure, whereas, resveratrol was showed to inhibit cell survival under the same condition at 20 μM. Corresponding to the opposing effect of resveratrol at low vs. high concentrations, DNA and chromosomal damage, cell apoptotic rate and level of oxidative stress were also alleviated by lower concentrations (1, 5 μM) of resveratrol, but exacerbated by higher concentration (20 μM) resveratrol. Our study implicates that resveratrol is the most beneficial to cells at 1 and 5 μM and caution should be taken in applying resveratrol as an anticancer therapeutic agent or nutraceutical supplement due to its concentration dependent effect.

    Topics: Adenocarcinoma; Adenocarcinoma of Lung; Antineoplastic Agents, Phytogenic; Antioxidants; Apoptosis; Arsenites; Cell Line, Tumor; Cell Proliferation; Cell Survival; Chromosome Breakage; Comet Assay; DNA Damage; Glutathione; Humans; Lung Neoplasms; Micronuclei, Chromosome-Defective; Mutagens; Neoplastic Stem Cells; Osmolar Concentration; Oxidation-Reduction; Oxidative Stress; Resveratrol; Sodium Compounds; Stilbenes

2013
Chemoprevention of benzo(a)pyrene-induced colon polyps in ApcMin mice by resveratrol.
    The Journal of nutritional biochemistry, 2013, Volume: 24, Issue:4

    Human dietary exposure to benzo(a)pyrene (BaP) has generated interest with regard to the association of BaP with gastrointestinal carcinogenesis. Since colon cancer ranks third among cancer-related mortalities, it is necessary to evaluate the effect of phytochemicals on colon cancer initiation and progression. In this study, we investigated the preventive effects of resveratrol (RVT) on BaP-induced colon carcinogenesis in Apc(Min) mouse model. For the first group of mice, 100 μg BaP/kg body weight was administered to mice in peanut oil via oral gavage over a 60-day period. For the second group, RVT was coadministered with BaP at a dose of 45 μg/kg. For the third group, RVT was administered for 1 week prior to BaP exposure for 60 days. Jejunum, colon and liver were collected at 60 days post BaP and RVT exposure; adenomas in jejunum and colon were counted and subjected to histopathology. RVT reduced the number of colon adenomas in BaP+RVT-treated mice significantly compared to that in mice that received BaP alone. While dysplasia of varying degrees was noted in colon of BaP-treated mice, the dysplasias were of limited occurrence in RVT-treated mice. To ascertain whether the tumor inhibition is a result of altered BaP-induced toxicity of tumor cells, growth, apoptosis and proliferation of adenocarcinoma cells were assessed posttreatment with RVT and BaP. Cotreatment with RVT increased apoptosis and decreased cell proliferation to a greater extent than with BaP alone. Overall, our observations reveal that RVT inhibits colon tumorigenesis when given together with BaP and holds promise as a therapeutic agent.

    Topics: Adenocarcinoma; Animals; Apoptosis; Benzo(a)pyrene; Cell Cycle; Colonic Neoplasms; Colonic Polyps; Male; Mice; Resveratrol; Stilbenes

2013
Resveratrol metabolites have an antiproliferative effect on intestinal epithelial cancer cells.
    Food chemistry, 2012, Oct-01, Volume: 134, Issue:3

    Trans-resveratrol (RV) is an active polyphenol with numerous physiological properties including antitumour activity, especially in colon cancer. RV is metabolized in the intestine and then in the liver to sulphated and glucuronidated forms that are exported to target organs. After exerting their effects, they are eliminated in the urine and stools. There are few and contradictory findings on the biological effects of RV metabolites. On the basis of RV metabolism, we selected three metabolites RV 3-O-sulphate, RV 3-O-glucuronide and RV 4'-O-glucuronide, and studied their effects on cell growth inhibition, the cell cycle and apoptosis using human adenocarcinoma cell line (Caco-2 cell) cultures. Our results show that RV metabolites have an antioxidant activity similar to that RV. Moreover, all metabolites inhibited cell growth in a concentration-dependent manner as well as [(3)H] thymidine incorporation. Furthermore, we observed an increase in the percentage of cell in G0/G1 phase induced by RV metabolite treatments, as well as the induction of apoptosis. On the basis of our results we propose, for the first time, that RV metabolites remain active after their biosynthesis, contributing to the health benefits attributed previously only to RV. These metabolites are a potential target for more research into the prevention and treatment of colon cancer.

    Topics: Adenocarcinoma; Antioxidants; Apoptosis; Cell Cycle; Cell Proliferation; Humans; Intestinal Neoplasms; Resveratrol; Stilbenes; Tumor Cells, Cultured

2012
Comparative effects of retinoic acid, vitamin D and resveratrol alone and in combination with adenosine analogues on methylation and expression of phosphatase and tensin homologue tumour suppressor gene in breast cancer cells.
    The British journal of nutrition, 2012, Volume: 107, Issue:6

    Aberrations in DNA methylation patterns have been reported to be involved in driving changes in the expression of numerous genes during carcinogenesis and have become promising targets for chemopreventive action of natural compounds. In the present study, we investigated the effects of all-trans retinoic acid (ATRA), vitamin D₃ and resveratrol alone and in combination with adenosine analogues, 2-chloro-2'-deoxyadenosine (2CdA) and 9-β-d-arabinosyl-2-fluoroadenine (F-ara-A), on the methylation and expression of phosphatase and tensin homologue (PTEN) tumour suppressor gene in MCF-7 and MDA-MB-231 breast cancer cells. The present results showed that in non-invasive MCF-7 cells, ATRA, vitamin D₃ and resveratrol possess high efficacy in the reduction of PTEN promoter methylation. It was associated with PTEN induction as well as DNA methyltransferase down-regulation and p21 up-regulation after treatments with vitamin D₃ and resveratrol, suggesting a complex regulation of the DNA methylation machinery. Vitamin D₃ and resveratrol improved the inhibitory effects of 2CdA and F-ara-A on PTEN methylation in MCF-7 cells; however, only the combined action of vitamin D₃ and 2CdA boosted the induction of PTEN expression, suggesting a cooperation of these compounds in additional processes driving changes in PTEN expression. In contrast, in highly invasive MDA-MB-231 cells, only vitamin D₃ reduced PTEN methylation and induced its expression without notable effects in combined treatments. The present results suggest that natural compounds can find application in epigenetic anticancer therapy aimed at inhibition of promoter methylation of tumour suppressor genes and induction of their expression at early stages of carcinogenesis.

    Topics: Adenocarcinoma; Adenosine; Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Antioxidants; Breast Neoplasms; Cell Line, Tumor; Cell Survival; Cholecalciferol; Cyclin-Dependent Kinase Inhibitor p21; DNA (Cytosine-5-)-Methyltransferase 1; DNA (Cytosine-5-)-Methyltransferases; DNA Methylation; Female; Gene Expression Regulation, Neoplastic; Humans; Inhibitory Concentration 50; Neoplasm Proteins; Promoter Regions, Genetic; PTEN Phosphohydrolase; Resveratrol; RNA, Messenger; Stilbenes; Tretinoin; Vitamins

2012
Adrenomedullin interacts with VEGF in endometrial cancer and has varied modulation in tumours of different grades.
    Gynecologic oncology, 2012, Volume: 125, Issue:1

    Endometrial cancer, in developed countries, is the most common malignancy of the female genital tract. Surgery and radiotherapy are successful in many patients but systemic and recurrent diseases have no consistently effective treatments, and for high grade advanced disease the prognosis is poor. The study investigated characteristics of adrenomedullin in endometrial cancer to assist in identifying targets for developing treatments.. Endometrial samples of women with and without cancer, and the Ishikawa cell line were used to investigate adrenomedullin mRNA regulation, peptide expression, adrenomedullin secretion and effects of adrenomedullin on VEGF secretion.. Expression of adrenomedullin mRNA was upregulated compared to that in healthy post-menopausal endometria. Adrenomedullin secretion was increased by cobalt chloride in this study. Secretion was reduced by the naturally-occurring compounds, (-)-epigallocatechin gallate (EGCG) and 3,4',5-trihydroxystilbene (resveratrol), which we have previously demonstrated to also suppress VEGF secretion in endometrial tumour tissue. We noted, for the first time, that adrenomedullin enhanced VEGF secretion from tumour cells.. Increased adrenomedullin expression may result in amplifying both tumorigenic and angiogenic activities. A substantial impact on growth of tumours may result in vivo as a consequence of the synergism between adrenomedullin and VEGF. Adrenomedullin, which has altered cellular characteristics in tumour compared to healthy tissue, offers an understudied target with potential to modify endometrial cancer behaviour, complementing other treatments.

    Topics: Adenocarcinoma; Adrenomedullin; Biomarkers, Tumor; Case-Control Studies; Catechin; Cell Line, Tumor; Cobalt; Endometrial Neoplasms; Female; Gene Expression Regulation, Neoplastic; Humans; Neoplasm Grading; Resveratrol; RNA, Messenger; Stilbenes; Up-Regulation; Vascular Endothelial Growth Factor A

2012
Resveratrol induces apoptosis via a Bak-mediated intrinsic pathway in human lung adenocarcinoma cells.
    Cellular signalling, 2012, Volume: 24, Issue:5

    Our recent study have shown that resveratrol (RV), a natural plant polyphenol found in red grape skins as well as other food product, induced apoptosis via the downstream factors, caspase-independent AIF and to lesser extent caspase-9, of intrinsic apoptosis pathway in human lung adenocarcinoma (ASTC-a-1) cells. This report is designed to explore the roles of the upstream mediators of the intrinsic pathway, such as Bak/Bax, Bim, Puma and Noxa, during RV-induced apoptosis in human lung adenocarcinoma (ASTC-a-1 and A549) cell lines. RV treatment remarkably induced the activation of Bak but not Bax, and silencing Bak but not Bax by shRNA almost completely prevented RV-induced cell death, mitochondrial dysfunction and also largely prevented RV-induced AIF release, demonstrating the preferential engagement of Bak but not Bax during RV-induced apoptosis. In addition, although RV treatment induced a significant degradation of Mcl-1, knockdown of Mcl-1 by shRNA only modestly increased RV-induced Bak activation. Interestingly, silencing Bim but not Puma and Noxa remarkably attenuated RV-induced cell death, loss of mitochondrial membrane potential, and Bak activation, suggesting the important roles of Bim. Collectively, our findings for the first time demonstrate that RV induces apoptosis dominantly via a Bak- but not Bax-mediated AIF-dependent mitochondrial apoptotic signaling pathway in which Bim but not Puma and Noxa may supply the force to trigger Bak activation and subsequent apoptosis in both ASTC-a-1 and A549 cell lines.

    Topics: Adenocarcinoma; Antineoplastic Agents, Phytogenic; Apoptosis; Apoptosis Inducing Factor; Apoptosis Regulatory Proteins; bcl-2 Homologous Antagonist-Killer Protein; bcl-2-Associated X Protein; Bcl-2-Like Protein 11; Caspase 9; Cell Line, Tumor; Cell Survival; Enzyme Activation; Humans; Lung Neoplasms; Membrane Proteins; Mitochondria; Proto-Oncogene Proteins; Resveratrol; Signal Transduction; Stilbenes

2012
p38 inhibitor SB203580 sensitizes the resveratrol-induced apoptosis in human lung adenocarcinoma (A549) cells.
    Journal of biochemical and molecular toxicology, 2012, Volume: 26, Issue:7

    Based on our recent findings that resveratrol, a natural plant polyphenol found in red grape skins as well as other food products, induces apoptosis via a caspase-independent intrinsic pathway in human lung adenocarcinoma cells, this study is designed to explore whether SB203580, a p38 inhibitor, potentiates the resveratrol-induced apoptosis of human lung adenocarcinoma (A549) cells. We found that pretreatment with SB203580 enhanced the resveratrol-induced apoptosis by accelerating the intrinsic apoptotic pathway including Bax activation, loss of mitochondrial membrane potential, and activation of both caspase-9 and -3. Although treatment with resveratrol alone did not induce caspase-8 activation, cotreatment with both SB203580 and resveratrol not only enhanced FasL cleavage but also activated caspase-8, indicating that the extrinsic apoptotic pathway may be involved in the synergistic effect. Collectively, we for the first time demonstrate that SB203580 synergistically enhances the resveratrol-induced apoptosis by accelerating Bax-mediated intrinsic pathway and initiating extrinsic pathway, suggesting a possible alternative therapeutic strategy for human lung cancer.

    Topics: Adenocarcinoma; Adenocarcinoma of Lung; Antineoplastic Agents, Phytogenic; Apoptosis; Caspase 3; Caspase 8; Caspase 9; Cell Line, Tumor; Cell Survival; Drug Synergism; Enzyme Inhibitors; Gene Expression Regulation, Neoplastic; Humans; Imidazoles; Lung Neoplasms; Membrane Potential, Mitochondrial; p38 Mitogen-Activated Protein Kinases; Pyridines; Resveratrol; Stilbenes

2012
The vascular targeting agent Combretastatin-A4 directly induces autophagy in adenocarcinoma-derived colon cancer cells.
    Biochemical pharmacology, 2012, Sep-01, Volume: 84, Issue:5

    Recent clinical data demonstrated that the vascular targeting agent Combretastatin-A4 phosphate (CA-4P) prolonged survival of patients with advanced anaplastic thyroid cancer without any adverse side effects. However, as a single agent CA-4 failed to reduce tumour growth in the murine CT-26 adenocarcinoma colon cancer model. Furthermore, the molecular mechanism of the innate resistance of HT-29 human adenocarcinoma cells to CA-4 is largely unknown. In this report, we demonstrate for the first time that prolonged exposure to CA-4 and an azetidinone cis-restricted analogue, CA-432 (chemical name; 4-(3-Hydroxy-4-methoxyphenyl)-3-phenyl-1-(3,4,5-trimethoxyphenyl)-azetidin-2-one) induced autophagy in adenocarcinoma-derived CT-26, Caco-2 and HT-29 cells but not in fibrosarcoma-derived HT-1080 cells. Autophagy is a fundamental self-catabolic process which can facilitate a prolonged cell survival in spite of adverse stress by generating energy via lysosomal degradation of cytoplasmic constituents. Autophagy was confirmed by acridine orange staining of vesicle formation, electron microscopy and increased expression of LC3-II. Combretastatin-induced autophagy was associated with a loss of mitochondrial membrane potential and elongation of the mitochondria. Furthermore, inhibition of autophagy by the vacuolar H(+)ATPase inhibitor Bafilomycin-A1 (BAF-A1) significantly enhanced CA-432 induced HT-29 cell death. Both CA-4 and its synthetic derivative, CA-432 induced the formation of large hyperdiploid cells in Caco-2 and CT-26 cells. The formation of these polyploid cells was significantly inhibited by autophagy inhibitor, BAF-A1. Results presented within demonstrate that autophagy is a novel response to combretastatin exposure and may be manipulated to enhance the therapeutic efficacy of this class of vascular targeting agents.

    Topics: Adenocarcinoma; Autophagy; Blotting, Western; Caspase 3; Caspase 7; Cell Line, Tumor; Colonic Neoplasms; Flow Cytometry; Humans; Membrane Potentials; Microscopy, Electron; Mitochondria; Stilbenes

2012
The resveratrol analog 4,4'-dihydroxy-trans-stilbene suppresses transformation in normal mouse fibroblasts and inhibits proliferation and invasion of human breast cancer cells.
    Carcinogenesis, 2012, Volume: 33, Issue:11

    4,4'-dihydroxy-trans-stilbene (DHS) is a synthetic analog of resveratrol, a phytoalexin known for its biological activities. We previously demonstrated that DHS exerts an antiproliferative effect on normal human fibroblasts that is higher than that of the natural parent molecule. No evidence regarding its role in human cancer cell lines has been found thus far. In this study, we investigated the effects of DHS both on chemical-induced transformation of BALB/c 3T3 mouse fibroblasts and on the proliferation and invasion of human breast cancer MCF-7 cells. The results showed that DHS markedly suppresses the two-stage (3-methylcholanthrene plus 12-O-tetradecanoylphorbol-13-acetate) cell transformation. Compared with resveratrol, DHS inhibited both anchorage-dependent and -independent MCF-7 growth more efficiently. In addition, a reduction in the number of cells in S-phase, characterized by a concomitant increase in the levels of p21 and p53 proteins, together with a strong inhibition of pRb protein phosphorylation, was observed in DHS-treated cells. Furthermore, DHS effected a strong reduction in matrix metalloproteinase-2 and -9 activities, concomitantly with a marked inhibition of cell adhesion to the extracellular matrix components as well as inhibition of cell migration and invasion. Importantly, modulation of the adhesion molecule E-cadherin was also found in DHS-treated cells. Taken together, these results demonstrate that the two 4,4'-hydroxyl groups on the stilbenic backbone make DHS a more active molecule than resveratrol in inhibiting neoplastic transformation, cancer cell proliferation and invasion. In conclusion, this study suggests that DHS could be a promising anticancer agent.

    Topics: Adenocarcinoma; Animals; Apoptosis; Blotting, Western; Breast Neoplasms; Cell Adhesion; Cell Cycle; Cell Movement; Cell Proliferation; Cell Transformation, Neoplastic; Cells, Cultured; Collagen Type I; Female; Fibroblasts; Humans; Mice; Mice, Inbred BALB C; Neoplasm Invasiveness; Stilbenes; Tumor Stem Cell Assay; Wound Healing

2012
Effects of various agents on DNA fragmentation and telomerase enzyme activities in adenocarcinoma cell lines.
    Molecular biology reports, 2011, Volume: 38, Issue:4

    Natural compounds such as resveratrol, tannic acid, and quercetin may help to treat cancer. Tamoxifen is a non-steroidal anti-estrogen drug widely used in the treatment of patients with estrogen receptor-positive breast cancer. The aim of the study was to compare the effects of these natural compounds and tamoxifen in colon adenocarcinoma (CaCo-2) and breast adenocarcinoma (MCF-7) cell lines, on telomerase enzyme activity, cell viability, number of cells and DNA fragmentation. In this study to determine telomerase enzyme activity was used PCR-ELISA kit. To determine cell viability and number of cells were used tripan blue stain. DNA fragmentation was determined by DNA ladder isolation kit. Tannic acid was more effective than resveratrol, with respect to reduction in telomerase activity, cell viability and cell count in breast adenocarcinoma. Tannic acid and tamoxifen was more effective than resveratrol and quercetin telomerase activity, cell viability and cell count in colon adenocarcinoma. Flavonoids such as resveratrol, tannic acid and quercetin which was studied on, has benefical effects on cancer therapy. These effects such as decreasing telomerase enzyme activity, cell viability and number of cells and inducing DNA fragmentation (apoptosis) must be studied for assist to develop new therapeutic pathways. There should be much more sudies in order to discover resveratrol, tannic acid and quercetin and other potential medicines.

    Topics: Adenocarcinoma; Analysis of Variance; Cell Line, Tumor; DNA Fragmentation; Enzyme-Linked Immunosorbent Assay; Humans; Quercetin; Resveratrol; Stilbenes; Tamoxifen; Tannins; Telomerase

2011
Effect of dietary supplementation on the prognostic value of urinary and serum 8-isoprostaglandin F2α in chemically-induced mammary carcinogenesis in the rat.
    Lipids in health and disease, 2011, Mar-03, Volume: 10

    The aim of the present study was to assess the effects of zinc or copper and polyphenolic compounds on the 8-isoprostaglandin F2α concentration in the serum and urine of rats with mammary cancer (adenocarcinoma) induced with 7,12-dimethylbenz[a]antracene. The research focused on the kinetics of alterations in urinary 8-isoPGF2α at the early stage of carcinogenesis as well as the influence of dietary factors on the process. The impact of selected compounds on the intensity of DMBA--induced carcinogenesis was also assessed.. Administration of DMBA, a compound that inducers mammary tumors in experimental animals, increased the serum and urinary 8-isoPGF2α levels in study rats. In the rat model, diet supplementation with zinc, combined with selected polyphenolic compounds (resveratrol or genistein) yielded a statistically significant decrease in the rat serum and urinary biomarker concentration with a simultaneously significant stimulation of carcinogenesis.The results indicate that there is an inverse correlation between the intensity of DMBA-induced carcinogenicity and the level of 8-isoPGF2α in urine and serum of rats.

    Topics: 9,10-Dimethyl-1,2-benzanthracene; Adenocarcinoma; Animals; Biomarkers, Tumor; Carcinogens; Copper; Dietary Supplements; Dinoprost; Female; Genistein; Mammary Neoplasms, Experimental; Prognosis; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes; Zinc

2011
Resveratrol induces mitochondria-mediated AIF and to a lesser extent caspase-9-dependent apoptosis in human lung adenocarcinoma ASTC-a-1 cells.
    Molecular and cellular biochemistry, 2011, Volume: 354, Issue:1-2

    Resveratrol (RV), a natural plant polyphenol widely present in foods such as grapes, wine, and peanuts, has an ability to inhibit various stages of carcinogenesis in vitro and in vivo. In this report, we explored the roles of intrinsic and extrinsic apoptotic pathways during RV-induced apoptosis in human lung adenocarcinoma (ASTC-a-1) cells. After exposure of cells to different concentrations of RV, we found that RV induced concentration-dependent apoptosis. Fluorometric substrates assay and western blotting (WB) analysis showed that caspase-8 was not activated, which was further verified by monitoring the cleavage of Bid to tBid using fluorescence resonance energy transfer (FRET) microscopy imaging inside single living cells, indicating that extrinsic apoptotic pathway was not involved in RV-induced apoptosis. In addition, inhibition of caspases-3 or -9 but not caspase-8 using the specific inhibitors of caspases modestly but significantly attenuated RV-induced apoptosis. Moreover, flow cytometry (FCM) analysis showed that RV treatment induced time-dependent loss of mitochondrial membrane potential (∆ψ(m)), in combination with the activation of caspases-3 and -9; we therefore concluded that RV-induced apoptosis involved the intrinsic apoptotic pathway. It is noteworthy that RV treatment induced translocation of AIF from mitochondria to nucleus in a time dependent manner, and that knockdown of AIF remarkably attenuated RV-induced apoptosis. Collectively, our findings demonstrate that RV induces caspase-8-independent apoptosis via AIF and to a lesser extent caspase-9-dependent mitochondrial pathway in ASTC-a-1 cells.

    Topics: Adenocarcinoma; Adenocarcinoma of Lung; Apoptosis; Apoptosis Inducing Factor; Caspase 3; Caspase 8; Caspase 9; Cell Line, Tumor; Cell Nucleus; Cell Survival; Enzyme Activation; Humans; Lung Neoplasms; Membrane Potential, Mitochondrial; Mitochondria; Protein Transport; Resveratrol; RNA Interference; Stilbenes

2011
Oral resveratrol therapy inhibits cancer-induced skeletal muscle and cardiac atrophy in vivo.
    Nutrition and cancer, 2011, Volume: 63, Issue:5

    The mechanism by which cancer mediates muscle atrophy has been delineated in the past 3 decades and includes a prominent role of tumor-derived cytokines, such as IL-6, TNFα, and IL-1. These cytokines interact with their cognate receptors on muscle to activate the downstream transcription factor NF-κB and induce sarcomere proteolysis. Experimentally, inhibiting NF-κB signaling largely prevents cancer-induced muscle wasting, indicating its prominent role in muscle atrophy. Resveratrol, a natural phytoalexin found in the skin of grapes, has recently been shown to inhibit NF-κB in cancer cells, which led us to hypothesize that it might have a protective role in cancer cachexia. Therefore, we investigated whether daily oral resveratrol could protect against skeletal muscle loss and cardiac atrophy in an established mouse model. We demonstrate resveratrol inhibits skeletal muscle and cardiac atrophy induced by C26 adenocarcinoma tumors through its inhibition of NF-κB (p65) activity in skeletal muscle and heart. These studies demonstrate for the first time the utility of oral resveratrol therapy to provide clinical benefit in cancer-induced atrophy through the inhibition of NF-κB in muscle. These findings may have application in the treatment of diseases with parallel pathophysiologies such as muscular dystrophy and heart failure.

    Topics: Adenocarcinoma; Administration, Oral; Animals; Body Composition; Cachexia; Cell Line, Tumor; Dose-Response Relationship, Drug; Echocardiography; Female; Gene Expression Regulation, Enzymologic; Heart; Mice; Muscle Proteins; Muscle, Skeletal; Muscular Atrophy; Myocardium; Neoplasm Transplantation; Random Allocation; Resveratrol; RNA, Messenger; Stilbenes; Transcription Factor RelA; Tripartite Motif Proteins; Ubiquitin-Protein Ligases; Weight Loss

2011
Inhibition of proliferation and induction of apoptosis by trimethoxyl stilbene (TMS) in a lung cancer cell line.
    Asian Pacific journal of cancer prevention : APJCP, 2011, Volume: 12, Issue:9

    Trimethoxyl stilbene (TMS) is a derivative of resveratrol, a compound shown to inhibit development of a variety of tumor types. We aimed to evaluate the effect of TMS on cell proliferation and apoptosis in the A549 non-small cell lung cancer cell line. Growth inhibition rate and colony formation was measured and apoptosis was determined with Hoechst 33258 staining. Protein expression levels of caspase-3, STAT3, STAT5b, JAK2, NF-κB, and IκB were examined by Western blotting. Furthermore, localization of NF-κB protein was also explored. TMS inhibited proliferation (IC50 8.6 μmol/L) and induced apoptosis of the cells in a concentration-dependent manner., also inducing apoptosis accompanied by up-regulated expression and cleavage activation of caspase-3, up-regulation of IκB and down-regulation of NFκB, STAT3, STAT5b, and JAK2 signal transduction. TMS has potential as a new drug for treatment of non-small cell lung cancer patients with anti-proliferation and apoptosis inducing effect of TMS to A549 cells apparently related to its inhibitory effect on STATs and NF-κB signal transduction. Up-regulation of caspase-3 further supports the potential clinical use of TMS for the treatment of non-small cell lung adenocarcinoma.

    Topics: Adenocarcinoma; Apoptosis; Carcinoma, Non-Small-Cell Lung; Caspase 3; Cell Line, Tumor; Cell Proliferation; Down-Regulation; Humans; I-kappa B Proteins; Janus Kinase 2; Lung Neoplasms; NF-kappa B; Signal Transduction; STAT3 Transcription Factor; STAT5 Transcription Factor; Stilbenes; Up-Regulation

2011
Resveratrol inhibits proliferation and induces apoptosis through the hedgehog signaling pathway in pancreatic cancer cell.
    Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.], 2011, Volume: 11, Issue:6

    To investigate the effect and possible mechanisms of resveratrol on pancreatic cancer cells in vitro.. After being treated with resveratrol, cell viability, cell cycle phase distribution and apoptosis rate of pancreatic cancer cells were measured by CCK-8 assay and flow cytometer, respectively. The effects of resveratrol on the Hedgehog pathway were studied by real-time RT-PCR and Western blotting. By interfering Gli1 expression in PANC-1 cells and overexpressing Gli1 in BxPC-3 cells, we detected the expressions of Gli1-targeted genes, such as Ptc1, CCND1 and BCL-2, compared with resveratrol experimental group. We further used the luciferase reporter assay to explore the correlation between resveratrol and Gli1.. Resveratrol inhibited the growth of pancreatic cancer cells in a dose- and time-dependent manner. Compared with control group, the cells in the G0/G1 phase and the apoptosis rate were significantly increased. Low concentration of resveratrol decreased the expression of the Hedgehog pathway members including Gli1, Ptc1 and Smo. The expression of downstream target genes of the Hedgehog pathway such as Gli1, Ptc1, CCND1 and BCL-2 were significantly decreased after 12.5 μM resveratrol treatment, which demonstrated a similar change of gene expression when Gli1 was knocked down by the RNAi technique in PANC-1 cells. Resveratrol also downregulated the expression of Gli1, Ptc1, CCND1 and BCL-2 in Gli1-overexpressed BxPC-3 cells. Results of the luciferase assay showed that resveratrol did not act on the Gli1 promoter directly.. Resveratrol can inhibit pancreatic cancer cell survival and its mechanisms might be partly via the Hedgehog signaling pathway. and IAP.

    Topics: Adenocarcinoma; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Hedgehog Proteins; Humans; Pancreatic Neoplasms; Resveratrol; Stilbenes

2011
Oral administration of resveratrol in suppression of pulmonary metastasis of BALB/c mice challenged with CT26 colorectal adenocarcinoma cells.
    Molecular nutrition & food research, 2010, Volume: 54, Issue:2

    Anti-cancer activities of resveratrol (3,4',5-trihydroxylstilbene) have attracted extensive research attention. Suppression of pulmonary metastasis of BALB/c mice challenged with CT26 colorectal adenocarcinoma cells achieved by oral administration of resveratrol was assessed in three separate experiments. Each mouse was challenged by tail vein injection with CT26 cells. Prior to challenge, 8-wk-old mice were fed with a basal diet and orally administered with resveratrol (30 mg/kg/2 days) eight or twelve times. After challenge, oral administration of resveratrol was continued until mice were sacrificed on day 20. As integrated from three experiments, 3.7% of the control mice (n=27) and 68.7% of the resveratrol-treated mice (n=26) exhibited free of metastasis. In a second study, 8-wk-old BALB/c mice were orally administered with resveratrol 12 times and challenged with CT26 cells for 100 days. All control mice died but 50% of the resveratrol-treated mice survived. The surviving mice were challenged with CT26 cells by hypodermic injection, fed with a basal diet for an additional 30 days, and sacrificed. Tumor lumps or nodules were not detected at the injection sites or in the lungs. This reveals that intrinsic vaccination-like defense has resulted from administration of resveratrol and challenge of tumor cells.

    Topics: Adenocarcinoma; Administration, Oral; Animals; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Immunologic Factors; Lung Neoplasms; Mice; Mice, Inbred BALB C; Neoplasm Recurrence, Local; Neoplasm Transplantation; Random Allocation; Resveratrol; Stilbenes; Survival Analysis; Tumor Burden

2010
Resveratrol, a multitargeted agent, can enhance antitumor activity of gemcitabine in vitro and in orthotopic mouse model of human pancreatic cancer.
    International journal of cancer, 2010, Jul-15, Volume: 127, Issue:2

    Gemcitabine, while a standard treatment of advanced pancreatic cancer (PaCa), alone is not very effective. New agents that are safe and effective are highly needed. Resveratrol is one such agent which is safe and multitargeted; and has been linked with suppression of survival, proliferation, invasion and angiogenesis of cancer. Whether resveratrol can sensitize PaCa to gemcitabine in vitro and in vivo was investigated. We established PaCa xenografts in nude mice, randomized into 4 groups, and treated with vehicle, gemcitabine, resveratrol and with combination. Modulation of NF-kappaB and markers of proliferation, angiogenesis and invasion were ascertained using electrophoretic mobility shift assay (EMSA), immunohistochemistry and western blot analysis. Resveratrol inhibited the proliferation of 4 different human PaCa cell lines, synergized the apoptotic effects of gemcitabine, inhibited the constitutive activation of NF-kappaB and expression of bcl-2, bcl-xL, COX-2, cyclin D1 MMP-9 and VEGF. In an orthotopic model of human PaCa, we found that resveratrol significantly suppressed the growth of the tumor (p < 0.001) and this effect was further enhanced by gemcitabine (p < 0.001). Both the markers of proliferation index Ki-67 and the micro vessel density CD31 were significantly downregulated in tumor tissue by the combination of gemcitabine and resveratrol (p < 0.001 vs. control; p < 0.01 vs. gemcitabine). As compared to vehicle control, resveratrol also suppressed the NF-kappaB activation and expression of cyclin D1, COX-2, ICAM-1, MMP-9 and survivin. Overall our results demonstrate that resveratrol can potentiate the effects of gemcitabine through suppression of markers of proliferation, invasion, angiogenesis and metastasis.

    Topics: Adenocarcinoma; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Blotting, Western; Carcinoma, Pancreatic Ductal; Cell Cycle; Cell Proliferation; Cyclooxygenase 2; Deoxycytidine; Gemcitabine; Humans; Immunoenzyme Techniques; In Vitro Techniques; Male; Mice; Mice, Nude; NF-kappa B; Pancreatic Neoplasms; Resveratrol; Stilbenes; Tumor Cells, Cultured; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays

2010
4'-Chloro-3,5-dihydroxystilbene, a resveratrol derivative, induces lung cancer cell death.
    Acta pharmacologica Sinica, 2010, Volume: 31, Issue:1

    To examine the antitumor effect of 4'-chloro-3,5-dihydroxystilbene, a resveratrol derivative, on lung adenocarcinoma A549 cells.. The cytotoxic IC(50) was determined by direct cell counting. Flow cytometry, monodansylcadaverine (MDC) staining, transfection, Western blot and a proteasome activity assay were used to study the cellular mechanism of 4'-chloro-3,5-dihydroxystilbene. A xenograft nude mouse model was used to analyze the antitumor effect in vivo.. 4'-Chloro-3,5-dihydroxystilbene induced a rapid and persistent increase in the intracellular reactive oxygen species in the cells, but the cell death could not be inhibited by two antioxidant agents. The derivative caused sub-G(1) formation, a decrease in the mitochondria membrane potential and poly (ADP-ribose) polymerase degradation, and the caspase inhibitor Z-VAD-FMK could partially prevent cell death. It also induced a significant increase in intracellular acidic vacuoles, LC3-II formation and intracellular GFP-LC3 aggregation. An autophagic inhibitor partially reversed cell death. Additionally, 4'-chloro-3,5-dihydroxystilbene induced the accumulation of ubiquitinated conjugates and inhibited proteasome activity in cells. In an in vivo study, 4'-chloro-3,5-dihydroxystilbene retarded tumor growth in nude mice.. These data suggest that the resveratrol derivative 4'-chloro-3,5-dihydroxystilbene could be developed as an anti-tumor compound.

    Topics: Adenocarcinoma; Animals; Antineoplastic Agents, Phytogenic; Cell Death; Cell Line, Tumor; Female; Green Fluorescent Proteins; Humans; Inhibitory Concentration 50; Lung Neoplasms; Membrane Potential, Mitochondrial; Mice; Mice, Nude; Microtubule-Associated Proteins; Poly(ADP-ribose) Polymerases; Reactive Oxygen Species; Stilbenes; Xenograft Model Antitumor Assays

2010
Resveratrol inhibits human lung adenocarcinoma cell metastasis by suppressing heme oxygenase 1-mediated nuclear factor-kappaB pathway and subsequently downregulating expression of matrix metalloproteinases.
    Molecular nutrition & food research, 2010, Volume: 54 Suppl 2

    Resveratrol exhibits potential anti-carcinogenic activities. Heme oxygenase-1 (HO-1) is involved in angiogenesis and tumor metastasis. Matrix metalloproteinases (MMPs) are key enzymes in the degradation of extracellular matrix, and their expression may be dysregulated in lung cancer metastasis. In this study, we investigated the anti-invasive mechanism of resveratrol in lung cancer cells. HO-1 was shown to be elevated (approximately 4.7-fold) in lung cancer tumor samples as compared with matched normal tissues. After treatment of lung adenocarcinoma cell line A549 cells with resveratrol (50 microM) for 24 h, the migratory and invasive abilities (38 and 30% inhibition, respectively) of A549 cells were significantly reduced. Resveratrol significantly inhibited HO-1-mediated MMP-9 (35% inhibition) and MMP-2 (28% inhibition) expression in lung cancer cells. Nuclear factor (NF)-kappaB inhibitor induced a marked reduction in MMP-9 and MMP-2 expression, suggesting NF-kappaB pathway could play an important role. Furthermore, HO-1 inhibition and silencing significantly suppressed MMPs and invasion of lung cancer cells. Our results suggest that resveratrol inhibited HO-1 and subsequently MMP-9 and MMP-2 expression in lung cancer cells. The inhibitory effects of resveratrol on MMP expression and invasion of lung cancer cells are, in part, associated with the HO-1-mediated NF-kappaB pathway.

    Topics: Adenocarcinoma; Antineoplastic Agents, Phytogenic; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Movement; Cell Survival; Down-Regulation; Gene Silencing; Heme Oxygenase-1; Humans; Lung Neoplasms; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Matrix Metalloproteinases; Neoplasm Invasiveness; NF-kappa B; Osmolar Concentration; Resveratrol; RNA, Small Interfering; Signal Transduction; Stilbenes

2010
Cytotoxic effect of wine polyphenolic extracts and resveratrol against human carcinoma cells and normal peripheral blood mononuclear cells.
    Journal of medicinal food, 2010, Volume: 13, Issue:4

    Red and white wine polyphenols have been reported to provide substantial health benefits. In this study, the cytotoxic activity of red and white wine polyphenolic extracts and of resveratrol was evaluated against different cancer cell lines--human cervix adenocarcinoma HeLa, human breast adenocarcinoma MDA-MB-361, and human breast carcinoma MDA-MB-453--and normal human peripheral blood mononuclear cells (PBMCs). Qualitative and quantitative compositions of wine polyphenolic extracts obtained by fractional vacuum distillation of corresponding wines were determined using spectrophotometric methods and high-performance liquid chromatography with diode array detection and liquid chromatography with electrospray ionization-time of flight mass spectrometry analysis. It was demonstrated that wine polyphenolic extracts and resveratrol exerted higher cytotoxic activity against HeLa and MDA-MB-453 cells in comparison to MDA-MB-361 cells and unstimulated and stimulated PBMCs. Furthermore, white wine polyphenolic extract exhibited a significantly higher antiproliferative action on cancer cell lines than red wine extract. The presence of condensed or fragmented nuclei in HeLa cells, pretreated with extract of white wine and stained with a mixture of acridine orange and ethidium bromide, pointed to the morphological signs of apoptosis. In addition, HeLa cells in late stages of apoptosis or secondary necrosis were also observed. Results from our study suggest that polyphenolic extracts from red and white wine may have anticarcinogenic potential.

    Topics: Adenocarcinoma; Cell Line, Tumor; Cell Survival; Cells, Cultured; Cytotoxins; Female; Flavonoids; Humans; Leukocytes, Mononuclear; Phenols; Polyphenols; Resveratrol; Stilbenes; Uterine Cervical Neoplasms; Wine

2010
2,3',4,4',5'-Pentamethoxy-trans-stilbene, a resveratrol derivative, inhibits colitis-associated colorectal carcinogenesis in mice.
    British journal of pharmacology, 2010, Volume: 160, Issue:6

    Resveratrol, a naturally occurring polyphenolic antioxidant, has been shown to exhibit chemoprophylactic effects on cancer development. Previously, we reported that 2,3',4,4',5'-pentamethoxy-trans-stilbene (PMS), a methoxylated resveratrol derivative, exerted a highly potent anti-proliferative effect on human colon cancer cells as compared with its parent compound. In the present study, the chemopreventive effect of PMS was evaluated in a mouse model of colitis-associated colon carcinogenesis.. Seven-week-old Balb/c mice were injected i.p. with 10 mg.kg(-1) azoxymethane (AOM). After 1 week, 3% dextran sodium sulphate (DSS) was administered in the drinking water for 7 days followed by 14 days of tap water for recovery, and this cycle was repeated twice.. Intragastric administration of PMS (25, 50 mg.kg(-1) body weight) for 16 weeks significantly reduced the multiplicity of colonic neoplasms by 15% and 35% (P < 0.01) respectively. Moreover, PMS at 50 mg.kg(-1) inhibited colon cancer cell proliferation and promoted apoptosis. Such changes were accompanied by reduction of Akt (protein kinase B) phosphorylation, inactivation of beta-catenin and down-regulation of inducible nitric oxide synthase. In parallel, in vitro studies also demonstrated that PMS inhibited proliferation and induced apoptosis in the murine colon adenocarcinoma cell line Colon26 with concomitant inhibition of Akt phosphorylation and inactivation of beta-catenin.. PMS effectively suppressed colon carcinogenesis in an AOM/DSS animal model and may merit further clinical investigation as a chemoprophylactic agent against colitis-associated colon cancer in humans.

    Topics: Adenocarcinoma; Animals; Apoptosis; Azoxymethane; Cell Line, Tumor; Cell Proliferation; Colitis; Colonic Neoplasms; Colorectal Neoplasms; Dextran Sulfate; Disease Models, Animal; Dose-Response Relationship, Drug; Male; Mice; Mice, Inbred BALB C; Stilbenes

2010
Anti-tumor effects of bakuchiol, an analogue of resveratrol, on human lung adenocarcinoma A549 cell line.
    European journal of pharmacology, 2010, Sep-25, Volume: 643, Issue:2-3

    Anti-tumor activity of bakuchiol, an analogue of resveratrol, was investigated on human lung adenocarcinoma A549 cell line. MTT assay revealed that IC(50) of bakuchiol at 72h was 9.58+/-1.12 micromol/l, much lower than that of resveratrol (33.02+/-2.35 micromol/l). Bakuchiol but not resveratrol elevated intracellular reactive oxygen species. Bakuchiol reduced mitochondrial membrane potential (Psim) of cells in a concentration- and time-dependent manner, showing a more potent effect than that of resveratrol. More apoptotic cells were induced by bakuchiol, compared with resveratrol. Subsequently, S phase arrest, caspase 9/3 activaton, p53 and Bax up-regulation, as well as Bcl-2 down-regulation were observed in bakuchiol-treated A549 cells. The results point toward that S phase-related cell cycle regulation, more importantly reactive oxygen species-related apoptosis might contribute to the anticancer properties of bakuchiol, which will strongly support the further development of bakuchiol against non-small-cell lung cancer.

    Topics: Adenocarcinoma; Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Apoptosis Regulatory Proteins; Cell Line; Cell Line, Tumor; Cell Survival; Cells, Cultured; Humans; Inhibitory Concentration 50; Lung Neoplasms; Membrane Potential, Mitochondrial; Mice; Osmolar Concentration; Phenols; Reactive Oxygen Species; Resveratrol; S Phase; Stilbenes; Time Factors; Tumor Suppressor Protein p53

2010
[Resveratrol inhibits EGF-induced invasion of human lung adenocarcinoma A549 cells].
    Zhongguo fei ai za zhi = Chinese journal of lung cancer, 2010, Volume: 13, Issue:4

    Invasion and metastasis are the primary causes of death in patients with pulmonary carcinoma. The epidermal growth factor (EGF) stimulates A549 cells invasion greatly through activating ERK and PI3K-Akt signaling pathway. The aim of this study is to elucidate the inhibitory effect of Resveratrol on EGF-induced invasive ability of A549 cells in vitro and explore the molecular mechanism.. The cytotoxicity of Resveratrol was evaluated by methyl thiazolyltetrazolium (MTT) assay. Then, the A549 cells were treated with EGF and non-cytotoxic concentration of Resveratrol. The cells' invasion were detected by Boyden chamber assay; MMP-2 activity was determined by gelatine zymography assay; the changes of the related proteins were detected by Western blot.. Resveratrol was not toxic to A549 cells at the concentration between 0 to 30 microM. The invasion ability of EGF-induced A549 cells was decreased after treatment with 20 microM resveratrol for 24 h, accompanied by the inhibition of MMP-2 secretion. And the levels of p-ERK1/2, PI3K (within 6 h) were suppressed too.. 20 microM Resveratrol inhibits A549 cells' invasion possibly through the suppression of the activation of ERK and PI3K-Akt signaling pathways, subsequently exerting inhibitory effect on MMP-2.

    Topics: Adenocarcinoma; Anticarcinogenic Agents; Blotting, Western; Cell Line, Tumor; Epidermal Growth Factor; Humans; Lung Neoplasms; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Phosphatidylinositol 3-Kinases; Resveratrol; Signal Transduction; Stilbenes

2010
Role of phenolic compounds in nitric oxide synthase activity in colon and breast adenocarcinoma.
    Cancer biotherapy & radiopharmaceuticals, 2010, Volume: 25, Issue:5

    Cancer chemopreventive agents are designed to reduce the incidence of tumorigenesis by intervening at one or more stages of carcinogenesis. This study aimed to determine the effects of resveratrol (RES) and tannic acid (TA), which are chemopreventive agents, on the nitric oxide synthase (NOS) levels that are effective for development of cancer in colon and breast cancer cell lines. The CaCo-2 (human colon carcinoma cell line) and MCF-7 (Michigan Cancer Foundation-7; human breast adenocarcinoma cell line) cells were grown in the laboratory. RES and TA were used to treat CaCo-2 and MCF-7 cells. Nitric Oxide Synthase Assay Kit was used to determine the NOS enzyme activity of CaCo-2 and MCF-7. Statistical differences between control and RES- and TA-treated cells were calculated using the Student's t-test for double comparison. It was observed that NO activity was generally decreased in CaCo-2 and MCF-7 cells, in which RES and TA were applied. Results suggest that the phenolic compounds RES and TA have different effects on NOS enzyme activity of the colon and breast cancer cells.

    Topics: Adenocarcinoma; Anticarcinogenic Agents; Breast Neoplasms; Caco-2 Cells; Cell Line, Tumor; Chemoprevention; Colonic Neoplasms; Female; Humans; Nitric Oxide Synthase; Phenols; Resveratrol; Stilbenes; Tannins

2010
Stilbenes as multidrug resistance modulators and apoptosis inducers in human adenocarcinoma cells.
    Anticancer research, 2010, Volume: 30, Issue:11

    The search for promising modulators of cancer multidrug resistance (MDR) that are able to reduce the activity of P-glycoprotein, thus restoring the cytotoxicity of anticancer drugs, is ongoing. The identification of compounds that overcome the apoptosis deficiency that frequently accompanies MDR is also of great therapeutic importance.. Four stilbenes, resveratrol, piceatannol and its two derivatives, were tested for their MDR-modulating and apoptosis-inducing activity in drug-sensitive (LoVo) and doxorubicin-resistant human adenocarcinoma cell line (LoVo/Dx) by means of flow cytometry and fluorescence microscopy.. Trans-3,5,3',4'-tetramethoxystilbene (PicMet) was identified as a promising modulator that efficiently increased accumulation of both rhodamine 123 and doxorubicin inside resistant cells. It also increased sensitivity of LoVo/Dx cells to doxorubicin. Resveratrol and trans-3,5,3',4'-tetracetoxystilbene (PicAcet) were identified as apoptosis inducers in LoVo/Dx cells.. The stilbene structure may constitute a promising chemical scaffold for the synthesis of potential MDR modulators.

    Topics: Adenocarcinoma; Apoptosis; Cell Line, Tumor; Colorectal Neoplasms; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Flow Cytometry; Humans; Stilbenes

2010
trans-Resveratrol inhibits H2O2-induced adenocarcinoma gastric cells proliferation via inactivation of MEK1/2-ERK1/2-c-Jun signalling axis.
    Biochemical pharmacology, 2009, Feb-01, Volume: 77, Issue:3

    In this report we investigate the signalling pathway activated by H(2)O(2) in human adenocarcinoma gastric cells (AGS) and we evaluate the anti-proliferative action of the natural stilbene trans-resveratrol. We demonstrate that H(2)O(2) accelerates cell growth and induces a prompt MEK1/2-ERK1/2 activation. Such events are also associated with the activation of c-Jun and its translocation into the nuclear compartment. A specific inhibitor of ERK1/2 phosphorylation by MEK1/2 (U0126) abrogates these phenomena. On the contrary, specific inhibition of JNK activity does not influence H(2)O(2)-mediated growth, suggesting that cell proliferation likely proceeds via MEK1/2-ERK1/2-Jun signalling axis. trans-Resveratrol is also able to completely suppress the increase in proliferation. We demonstrate that this property is not due to its antioxidant capacity but rather due to a specific inhibition of ERK1/2 phosphorylation by MEK1/2 and repression of c-Jun activation.

    Topics: Adenocarcinoma; Blotting, Western; Cell Proliferation; Enzyme Activation; Humans; Hydrogen Peroxide; MAP Kinase Signaling System; Mitogen-Activated Protein Kinases; Phosphorylation; Reactive Oxygen Species; Resveratrol; Stilbenes; Stomach Neoplasms

2009
Resveratrol analog-3,5,4'-trimethoxy-trans-stilbene inhibits invasion of human lung adenocarcinoma cells by suppressing the MAPK pathway and decreasing matrix metalloproteinase-2 expression.
    Molecular nutrition & food research, 2009, Volume: 53, Issue:3

    Resveratrol (3,5,4'-trihydroxystilbene) is a natural polyphenol that presents various physiological activities. It has been reported that the methylated derivatives of resveratrol show better potential antifungal and antiproliferative activities than resveratrol. In the present study, we investigated the inhibitory effect of 3,5,4'-trimethoxy-trans-stilbene (MR-3), a methylated derivative of resveratrol, on the invasion of A549 cells (a human lung adenocarcinoma cell line). We found that treatment with MR-3 at the concentration of 5 muM resulted in antiadhesive, antimigratory, and antiinvasive activities on A549 cells through the suppression of matrix metalloproteinase (MMP)-2 protein expression and transcriptional levels in a time-dependent manner. The suppression of MMP-2 expression by MR-3 led to an inhibition of A549 cell invasion by inactivating phosphorylation of SAPK/c-Jun N-terminal kinase (JNK) and p38 MAPK signaling pathways. A time-dependent inhibition of protein levels for p65, c-Jun, and c-Fos in the nucleus by MR-3 treatment was also observed. In conclusion, our data demonstrate that the antiinvasive effects of MR-3 on A549 cells are likely mediated through the inhibition of phosphorylation of JNK and p38, as well as a reduction in the protein levels of nuclear factor-kappa B (NF-kappaB) and activator protein-1 (AP-1) in the nucleus, ultimately leading to downregulation of MMP-2 expression.

    Topics: Adenocarcinoma; Cell Line, Tumor; Cell Nucleus; Enzyme Inhibitors; Gene Expression; Humans; JNK Mitogen-Activated Protein Kinases; Lung Neoplasms; Matrix Metalloproteinase 2; Matrix Metalloproteinase Inhibitors; Mitogen-Activated Protein Kinases; Neoplasm Invasiveness; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Phosphorylation; RNA, Messenger; Signal Transduction; Stilbenes; Transcription Factor AP-1

2009
The effects of resveratrol and tannic acid on apoptosis in colon adenocarcinoma cell line.
    Saudi medical journal, 2009, Volume: 30, Issue:2

    To investigate the effects of resveratrol and tannic acid on apoptosis, and Bcl-2 homologous antagonist/killer (Bak) and fas associated death domain (FADD) proteins in the CaCo-2 cell line.. In the present study, resveratrol and tannic acid were administrated in the CaCo-2 cell line at doses of 25, 50, and 100 microM. The CaCo-2 cells were grown and cultured in the Medical Biology Department, Eskisehir Osmangazi University, Eskisehir, Turkey in 2007. The effects of these agents on apoptotic index were determined by Apop Taq peroxidase kit and their effects on the ratios of Bak and FADD proteins by the immunohistochemical staining method at 24, 48, and 72 hours. Stained and non-stained cells in 30 separate areas of the 3 separate chamber slides, prepared for each group, were counted. The percentage of apoptosis, and Bak and FADD proteins was calculated with the control. Mean +/- standard error values were calculated for the 3 experiments.. Apoptotic index, Bak protein percentage ratio, and FADD protein percentage ratio values in all groups that received tannic acid and resveratrol increased when compared within the groups. This increase was found to be time and dose independent in all parameters.. Cells undergo apoptosis in 2 pathways (mitochondrial and death receptor) in resveratrol and tannic acid induced CaCo-2 cells.

    Topics: Adenocarcinoma; Antineoplastic Agents, Phytogenic; Apoptosis; bcl-2 Homologous Antagonist-Killer Protein; Cell Line, Tumor; Colonic Neoplasms; Fas-Associated Death Domain Protein; Humans; Resveratrol; Stilbenes; Tannins

2009
Selective cytotoxic activities of two novel synthetic drugs on human breast carcinoma MCF-7 cells.
    Anticancer research, 2009, Volume: 29, Issue:8

    Breast cancer is the second leading cause of cancer deaths in US women. We evaluated two novel compounds, piperidinyl-diethylstilbestrol (DES) and pyrrolidinyl-diethylstilbestrol (DES) for cytotoxicity against brine shrimp larvae, MCF-7 and rat normal liver cells.. In vivo cytotoxicity was evaluated against shrimp larvae for 24 h, while in vitro cell toxicity was evaluated by dye binding crystal-violet method after 48 h. The role of these compounds on different phases of the cell cycle was assessed by flow cytometry.. In shrimp assay, piperidinyl-DES and pyrrolidinyl-DES were potent with 50% effective dose (ED(50)) values of 7.9+/-0.38 and 15.6+/-1.3 microM, respectively. In MCF-7 and normal liver cells, the 50% lethal concentration (LC(50)) values were 19.7+/-0.95, 17.6+/-0.4 microM and 35.1 and >50 microM, respectively. Cell cycle analyses indicated that MCF-7 cells were arrested at the G(0)/G(1) stage with these compounds.. The results indicate that pyrrolidinyl-DES possesses highly selective, potent anticancer activity.

    Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Apoptosis; Artemia; Biological Assay; Breast Neoplasms; Cell Cycle; Female; Flow Cytometry; Humans; Larva; Liver; Piperidines; Pyrrolidines; Rats; Stilbenes

2009
Resveratrol protects against Cisplatin-induced cardiotoxicity by alleviating oxidative damage.
    Cancer biotherapy & radiopharmaceuticals, 2009, Volume: 24, Issue:6

    The clinical use of cisplatin, a potent antineoplastic agent, is limited by its severe adverse effects. The present study was designed to evaluate the effects of resveratrol on cisplatin-induced cardiac injury. Resveratrol is a potent free radical scavenger. In the present study, we tested whether resveratrol would prevent cisplatin-induced cardiotoxicity in rats. Plasma-enzyme activities and histologic myocardial changes were examined. The anticancer role of resveratrol and/or cisplatin were measured by MTT. Our data showed that cisplatin led to cardiac-function deterioration, myocardial injury, increased lactate dehydrogenase, creatine kinase, malondialdehyde activities, and decreased activities of superoxide dismutase, glutathione, glutathione peroxidase, and catalase. Treatment with resveratrol effectively hindered the adverse effects of cisplatin in a dose-dependent manner, such as myocardial injury and impaired heart function. An in vitro cytotoxic study showed that resveratrol could increase the antineoplastic activity of cisplatin to A549 adenocarcinoma cells. All the above lines of evidence suggest that resveratrol protects cardiomyocytes from cisplatin-induced cardiotoxicity via the suppression of oxidative stress.

    Topics: Adenocarcinoma; Angiogenesis Inhibitors; Animals; Anticarcinogenic Agents; Antineoplastic Agents; Cisplatin; Creatine Kinase; Free Radical Scavengers; Heart; Humans; L-Lactate Dehydrogenase; Lipid Peroxidation; Lung Neoplasms; Male; Malondialdehyde; Myocardium; Rats; Rats, Wistar; Resveratrol; Stilbenes

2009
Growth inhibition of human colon cancer cells by plant compounds.
    Clinical laboratory science : journal of the American Society for Medical Technology, 2008,Summer, Volume: 21, Issue:3

    Evidence is accumulating that compounds of plant origin (phytochemicals) exert anti-cancer effects. The purpose of this study was to determine if resveratrol, cinnamaldehyde, and piperine (from red grapes, cinnamon, black pepper respectively) have anti-proliferative effects on colon cancer.. Quantitative effects of each phytochemical on concentration responses and time courses of proliferation of cultured human colon cancer cells (DLD-1) were assessed.. Research was performed at Saint Louis University.. Responses were measured by spectrophotometry of surviving cells stained by a dye method.. Phytochemicals displayed anti-proliferative effects on DLD-1 cells in concentration- and kinetic-dependent manners. Cinnamaldehyde offered statistically significant effects at 24 hours [200 microM], 48 hours [100 - 200 microM], and 72 hours [200 microM]. Piperine displayed a trend towards anti-proliferation at 24 hours and statistically significant inhibition at 48 and 72 hours [100 - 200 microM]. Resveratrol displayed significant anti-proliferative effects at 24 hours [50-200 microM], 48 hours [10-200 microM], and 72 hours [10-200 microM].. Cinnamaldehyde, piperine, and resveratrol offer significant in vitro anti-proliferative effects on cultured human colon cancer cells. While each phytochemical exhibited significant anti-proliferative effects, resveratrol results were most impressive in that lower concentrations administered at regular intervals were significantly effective. These results taken together with everyday dietary availability of concentrations used in this study strongly suggest that regular intake of low doses of these phytochemicals offer preventive effects against colon cancer.

    Topics: Acrolein; Adenocarcinoma; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Piperidines; Plant Extracts; Resveratrol; Stilbenes

2008
Antitumor activity of 3,5,4'-trimethoxystilbene in COLO 205 cells and xenografts in SCID mice.
    Molecular carcinogenesis, 2008, Volume: 47, Issue:3

    Resveratrol (R-3), a trihydroxy trans-stilbene from grape, inhibits multistage carcinogenesis in animal models. Here we report that 3,5,4'-trimethoxystilbene (MR-3), the permethylated derivative of R-3 was more potent against the growth of human cancer cells (HT-29, PC-3, COLO 205) with estimated IC(50) values of 81.31,42.71, and 6.25 microM, respectively. We further observed that MR-3 induced apoptosis in COLO 205 cells through modulation of mitochondrial functions regulated by reactive oxygen species (ROS). ROS generation occurs in the early stages of MR-3-induced apoptosis, preceding cytochrome-c release, caspase activation, and DNA fragmentation. Significant therapeutic effects were demonstrated in vivo by treating severe combined immune deficiency (SCID) mice bearing COLO 205 tumor xenografts with MR-3 (50 mg/kg ip). Assays on DNA fragmentation and caspase activation were performed and demonstrated that apoptosis occurred in tumor tissues treated with MR-3. The appearance of apoptotic cells, as shown by Hematoxylin and Eosin (H&E) staining, and an increase in p21 and decrease in proliferating cell nuclear antigen (PCNA) protein by immuno-histochemistry were observed in tumor tissues under MR-3 treatment. Our study identifies the novel mechanisms of the antitumor effects of MR-3 and indicates that these results may have significant applications for cancer chemotherapy.

    Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Apoptosis; Caspases; Cell Line, Tumor; Cell Proliferation; Colonic Neoplasms; DNA Fragmentation; Drug Evaluation, Preclinical; Enzyme Activation; Humans; Immunohistochemistry; Inhibitory Concentration 50; Membrane Potentials; Mice; Mice, SCID; Mitochondria; Molecular Structure; Proliferating Cell Nuclear Antigen; Reactive Oxygen Species; Stilbenes; Xenograft Model Antitumor Assays

2008
Resveratrol analog trans 3,4,5,4'-tetramethoxystilbene (DMU-212) mediates anti-tumor effects via mechanism different from that of resveratrol.
    Cancer chemotherapy and pharmacology, 2008, Volume: 63, Issue:1

    Resveratrol is a well-known chemopreventive and chemotherapeutic agent. Among all of the resveratrol analogs synthesized, 3,4,5,4'-tetramethoxystilbene (DMU-212) shows high activity and selectivity against various cancer cell types. The objective of this study is to investigate why DMU-212 has higher anti-tumor activity than resveratrol.. The effects of DMU-212 and resveratrol on cell viability, cell cycle, Stat3 activation, and microtubule dynamic were investigated and compared using MTT assay, cell cycle analysis, Western blot, tubulin polymerization assay, respectively, in MDA-MB-435 and MCF-7 human breast cancer cells.. Compared to resveratrol, DMU-212 exerted a significantly higher growth inhibition in both cell lines. Further studies demonstrated that DMU-212 acted via different mechanisms from resveratrol. First, DMU-212 induced predominantly G2/M arrest whereas resveratrol induced G0/G1 arrest in both cell lines. Correlating with these findings, resveratrol induced more dramatic changes in the expression of Cyclin D1 compared to DMU-212. Second, DMU-212 induced apoptosis and reduced the expression of multiple anti-apoptotic proteins more appreciably than resveratrol. Third, while both agents inhibited Stat3 phosphorylation, treatments of DMU-212 but not resveratrol led to a significant increase in tubulin polymerization. The higher sensitivity to DMU-122 in MDA-MB-435 correlated with the more prominent effects seen in these parameters in this cell line, as compared to MCF7.. Compared to resveratrol, the novel stilbene derivative, DMU-212, had higher anti-tumor effects, which are likely owing to its modulation of multiple cellular targets.

    Topics: Adenocarcinoma; Antineoplastic Agents; Apoptosis; Apoptosis Regulatory Proteins; Biopolymers; Breast Neoplasms; Cell Cycle; Cell Line, Tumor; Estrogens; Female; Humans; Neoplasm Proteins; Neoplasms, Hormone-Dependent; Resveratrol; STAT3 Transcription Factor; Stilbenes; Tubulin

2008
Estrogen and resveratrol regulate Rac and Cdc42 signaling to the actin cytoskeleton of metastatic breast cancer cells.
    Neoplasia (New York, N.Y.), 2007, Volume: 9, Issue:2

    Estrogen and structurally related molecules play critical roles in breast cancer. We reported that resveratrol (50 microM), an estrogen-like phytosterol from grapes, acts in an antiestrogenic manner in breast cancer cells to reduce cell migration and to induce a global and sustained extension of actin structures called filopodia. Herein, we report that resveratrol-induced filopodia formation is time-dependent and concentration-dependent. In contrast to resveratrol at 50 microM, resveratrol at 5 microM acts in a manner similar to estrogen by increasing lamellipodia, as well as cell migration and invasion. Because Rho GTPases regulate the extension of actin structures, we investigated a role for Rac and Cdc42 in estrogen and resveratrol signaling. Our results demonstrate that 50 microM resveratrol decreases Rac and Cdc42 activity, whereas estrogen and 5 microM resveratrol increase Rac activity in breast cancer cells. MDA-MB-231 cells expressing dominant-negative Cdc42 or dominant-negative Rac retain filopodia response to 50 microM resveratrol. Lamellipodia response to 5 microM resveratrol, estrogen, or epidermal growth factor is inhibited in cells expressing dominant-negative Rac, indicating that Rac regulates estrogen and resveratrol (5 microM) signaling to the actin cytoskeleton. These results indicate that signaling to the actin cytoskeleton by low and high concentrations of resveratrol may be differentially regulated by Rac and Cdc42.

    Topics: Actins; Adenocarcinoma; Breast Neoplasms; cdc42 GTP-Binding Protein; Cell Line, Tumor; Cell Movement; Cytoskeleton; Dose-Response Relationship, Drug; Epidermal Growth Factor; Estradiol; Estrogens; Female; Genes, Dominant; Humans; Neoplasm Invasiveness; Neoplasms, Hormone-Dependent; Pseudopodia; rac GTP-Binding Proteins; Recombinant Fusion Proteins; Resveratrol; Stilbenes; Transfection

2007
Quantitative determination of trans-polydatin, a natural strong anti-oxidative compound, in rat plasma and cellular environment of a human colon adenocarcinoma cell line for pharmacokinetic studies.
    Journal of chromatography. B, Analytical technologies in the biomedical and life sciences, 2007, Aug-15, Volume: 855, Issue:2

    A simple, accurate, precise, specific and reproducible high-performance liquid chromatography (HPLC) method was developed for determination of trans-polydatin, a natural strong anti-oxidative compound, in rat plasma and cell suspension. The assay procedure involved simple liquid-liquid extraction, the supernatant liquid was added an equal volume of water to avoid solvent effect. The detection of the analyte peak was achieved by monitoring the eluate using a UV detector set at 303 nm. The analysis used a Hypersil ODS2 C18 column (5 microm, 4.6 mm x 250 mm) and methanol/distilled water as the mobile phase (flow rate=1 mL/min). A total analytical run was achieved within 6.0 min and calibration curve was linear over a wide concentration range of 0.25-40 microg/mL for plasma sample and 1.0-500 microM for cell suspension, the coefficients of correlation were 0.9997 and 0.9999 or better, respectively. There was 80.7+/-7.86%, 96.8+/-3.20% and 102.7+/-9.72% recovery from 0.5, 10, and 40 microg/mL plasma samples, respectively. Intra- and inter-batch accuracy and precision were acceptable for the both matrices. The RSD of intra- and inter-day assay variations were all less than 10%. Both analyte and IS were stable in the battery of stability studies, freeze-thaw cycles. The described assay method was applied to pharmacokinetic studies in rats and a human colon adenocarcinoma cell line (Caco-2) successfully. The application of the assay to determine the pharmacokinetic is described.

    Topics: Adenocarcinoma; Animals; Antioxidants; Cell Line, Tumor; Chromatography, High Pressure Liquid; Colonic Neoplasms; Glucosides; Rats; Reproducibility of Results; Sensitivity and Specificity; Stilbenes; Time Factors

2007
Identifying the estrogen receptor coactivator PELP1 in autophagosomes.
    Cancer research, 2007, Sep-01, Volume: 67, Issue:17

    Resveratrol, a well-established phytoestrogen and chemopreventive agent, has gained much attention among oncologists because it can act as both estrogen receptor agonist and antagonist, depending on dosage and cell context. It is increasingly accepted that steroidal receptor coregulators may also function in the cytoplasmic compartment. Deregulation and altered localization of these coregulators could influence target gene expression and participate in the development of hormone-responsive cancers. Proline-, glutamic acid-, and leucine-rich protein-1 (PELP1), a novel estrogen receptor (ER) coactivator, plays an important role in the genomic and nongenomic actions of ER. Furthermore, recent studies have shown that differential compartmentalization of PELP1 could be crucial in modulating sensitivity to tamoxifen. In this study, we investigated the role of PELP1 in resveratrol-induced autophagy in lung cancer and salivary gland adenocarcinoma cell lines. Resveratrol reversibly inhibited the growth of these cancer cell lines and induced autophagy, as evidenced by microtubule-associated protein 1 light chain 3 (LC3) up-regulation in a time-dependent and 3-methyladenine-sensitive manner. Confocal microscopic analysis showed that resveratrol induced PELP1 accumulation in autophagosomes with green fluorescent protein-LC3. The intermediary molecule involved in PELP1 accumulation in resveratrol-induced autophagosomes is hepatocyte growth factor-regulated tyrosine kinase substrate (HRS), a trafficking molecule that binds to PELP1. These results identify PELP1 for the first time in autophagosomes, implying that both PELP1 and HRS reallocate to autophagosomes in response to resveratrol treatment, which might be important in the process of autophagy in the cancer cells.

    Topics: Adenocarcinoma; Antineoplastic Agents, Phytogenic; Autophagy; Cell Cycle; Cell Proliferation; Co-Repressor Proteins; Endosomal Sorting Complexes Required for Transport; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Lysosomes; Microtubule-Associated Proteins; Models, Biological; Phosphoproteins; Protein Transport; Receptors, Estrogen; Resveratrol; Salivary Gland Neoplasms; Stilbenes; Trans-Activators; Transcription Factors; Tumor Cells, Cultured

2007
Resveratrol induces apoptosis and inhibits angiogenesis in human breast cancer xenografts in vivo.
    Cancer letters, 2006, Jan-08, Volume: 231, Issue:1

    Resveratrol, a polyphenol found in grapes and wine, is considered a potential cancer chemopreventive agent. Resveratrol has been shown to induce transcription via both ERalpha and ERbeta. We observed significantly lower tumor growth, decreased angiogenesis, and increased apoptotic index in ERalpha- ERbeta+ MDA-MB-231 tumors in resveratrol-treated nude mice compared with controls. In vitro we found a significant increase in apoptosis in resveratrol-treated MDA-MB-231 cells in addition to significantly reduced extracellular levels of VEGF. This study supports the potential use of resveratrol as a chemotherapeutic agent in breast cancers.

    Topics: Adenocarcinoma; Animals; Anticarcinogenic Agents; Apoptosis; Breast Neoplasms; Estrogen Receptor alpha; Estrogen Receptor beta; Female; Humans; Mice; Mice, Nude; Neovascularization, Pathologic; Resveratrol; Stilbenes; Transplantation, Heterologous; Vascular Endothelial Growth Factor A

2006
Protective effects of benzyl isothiocyanate and sulforaphane but not resveratrol against initiation of pancreatic carcinogenesis in hamsters.
    Cancer letters, 2006, Sep-28, Volume: 241, Issue:2

    Potential chemopreventive effects of naturally occurring agents were investigated using a new 16-week medium-term pancreatic carcinogenesis models in hamsters. Male 6-week-old Syrian hamsters were subcutaneously injected with 10mg/kg body weight N-nitrosobis(2-oxopropyl)amine (BOP) four times within a week, and fed a diet supplemented with 80ppm benzyl isothiocyanate (BITC), 80ppm sulforaphane (SFN) or 10ppm resveratrol (RES) during the initiation or post-initiation stages. For the initiation stage, each chemical was given for 3 weeks including 1 week before and after the BOP injections. With post-initiation exposure, the groups were changed from basal diet 1 week after the last BOP injection, and then fed each chemical for 14 weeks. All the animals were sacrificed after 16 weeks. The multiplicities of combined pancreatic lesions including atypical hyperplasias and adenocarcinomas were significantly decreased by BITC and SFN given in the initiation but not the post-initiation stage. On the other hand, RES, a naturally occurring inhibitor of cyclooxygenase-2 (COX-2) reported chemopreventive effects, failed to show significant effects on pancreatic carcinogenesis in either the initiation or post-initiation stages. Our data suggest that the naturally occurring isothiocyanates BITC and SFN can block BOP-initiation of hamster pancreatic carcinogenesis.

    Topics: Adenocarcinoma; Animals; Antineoplastic Agents, Phytogenic; Carcinogenicity Tests; Carcinogens; Cell Transformation, Neoplastic; Cricetinae; Cyclooxygenase 2; Diet; Injections, Subcutaneous; Isothiocyanates; Male; Membrane Proteins; Mesocricetus; Neoplasms, Experimental; Nitrosamines; Pancreatic Neoplasms; Resveratrol; Stilbenes; Sulfoxides; Thiocyanates

2006
Resveratrol engages selective apoptotic signals in gastric adenocarcinoma cells.
    World journal of gastroenterology, 2006, Sep-21, Volume: 12, Issue:35

    To investigate the intracellular apoptotic signals engaged by resveratrol in three gastric adenocarcinoma cancer cell lines, two of which (AGS and SNU-1) express p53 and one (KATO-III) with deleted p53.. Nuclear fragmentation was used to quanti-tate apoptotic cells; caspase activity was determined by photometric detection of cleaved substrates; formation of oxidized cytochrome C was used to measure cytochrome C activity, and Western blot analysis was used to determine protein expression.. Gastric cancer cells, irrespective of their p53 status, responded to resveratrol with fragmentation of DNA and cleavage of nuclear lamins A and B and PARP. Resveratrol, however, has no effect on mitochondria-associated apoptotic proteins Bcl-2, Bcl-xl, Bax, Bid or Smac/Diablo, and did not promote sub-cellular redistribution of cytochrome C, indicating that resveratrol-induced apoptosis of gastric carcinoma cells does not require breakdown of mitochondrial membrane integrity. Resveratrol up-regulated p53 protein in SNU-1 and AGS cells but there was a difference in response of intracellular apoptotic signals between these cell lines. SNU-1 cells responded to resveratrol treatment with down-regulation of survivin, whereas in AGS and KATO-III cells resveratrol stimulated caspase 3 and cytochrome C oxidase activities.. These findings indicate that even within a specific cancer the intracellular apoptotic signals engaged by resveratrol are cell type dependent and suggest that such differences may be related to differentiation or lack of differentiation of these cells.

    Topics: Adenocarcinoma; Antineoplastic Agents, Phytogenic; Apoptosis; Caspases; Cell Line, Tumor; Electron Transport Complex IV; Fas-Associated Death Domain Protein; Gene Expression Regulation, Neoplastic; Humans; Inhibitor of Apoptosis Proteins; Microtubule-Associated Proteins; Neoplasm Proteins; Proto-Oncogene Proteins c-bcl-2; Resveratrol; Stilbenes; Stomach Neoplasms; Survivin; Tumor Suppressor Protein p53

2006
Resveratrol-induced modification of polyamine metabolism is accompanied by induction of c-Fos.
    Carcinogenesis, 2003, Volume: 24, Issue:3

    The objective of the current study was to investigate the effect of resveratrol, a naturally occurring polyphenol with cancer chemopreventive properties, on polyamine metabolism in the human colonic adenocarcinoma cell line Caco-2. We demonstrated that inhibition of ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine biosynthesis, was due to attenuated ODC protein and mRNA levels (50-200 microM). The naturally occurring resveratrol analog piceatannol (100 microM) also diminished ODC activity, protein and mRNA levels, whereas the green tea polyphenol (-)-epigallocatechin gallate (EGCG; 100 microM) exerted only weak effects on ODC. The transcription factor c-Myc, a positive regulator of the odc gene was attenuated by resveratrol treatment and to a lesser extent by piceatannol and EGCG. S-Adenosylmethionine decarboxylase, an enzyme that synthesizes higher polyamines, was concomitantly inhibited by resveratrol and piceatannol treatment, whereas EGCG did not affect its activity. In addition resveratrol, piceatannol and EGCG enhanced spermidine/spermine N(1)-acetyltransferase activity, an enzyme that degrades polyamines in cooperation with polyamine oxidase. Intracellular levels of spermine and spermidine were not affected, whereas putrescine and N(8)-acetylspermidine concentrations increased after incubation with resveratrol. These events were paralleled by an increase of the activator protein-1 constituents c-Fos and c-Jun. Whereas DNA-binding activity of c-Jun remained unchanged, DNA-binding activity of c-Fos was significantly enhanced by resveratrol and piceatannol, but inhibited by EGCG. The data suggest that growth arrest by resveratrol is accompanied by inhibition of polyamine synthesis and increased polyamine catabolism. C-Fos seems to play a role in this context. Effects of piceatannol on polyamine synthesis were similar, but not as potent as those exerted by resveratrol.

    Topics: Acetyltransferases; Adenocarcinoma; Adenosylmethionine Decarboxylase; Anticarcinogenic Agents; Base Sequence; Caco-2 Cells; Catechin; Colonic Neoplasms; DNA Primers; Gene Expression Regulation; Humans; Ornithine Decarboxylase; Polyamines; Proto-Oncogene Proteins c-fos; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; Stilbenes

2003
Resveratrol and red wine extracts inhibit the growth of CagA+ strains of Helicobacter pylori in vitro.
    The American journal of gastroenterology, 2003, Volume: 98, Issue:6

    Topics: Adenocarcinoma; Amoxicillin; Antigens, Bacterial; Antineoplastic Agents, Phytogenic; Bacterial Proteins; Chemoprevention; Gastrointestinal Neoplasms; Helicobacter pylori; Humans; Penicillins; Phenols; Plant Extracts; Resveratrol; Stilbenes; Wine

2003
Resveratrol analog (Z)-3,5,4'-trimethoxystilbene is a potent anti-mitotic drug inhibiting tubulin polymerization.
    International journal of cancer, 2003, Nov-01, Volume: 107, Issue:2

    Resveratrol (3,5,4'-trihydroxystilbene) a natural polyphenol present in medicinal plants, grapes and wines, has potent chemopreventive properties on intestinal carcinogenesis. A methylated derivative (Z-3,5,4'-trimethoxystilbene: R3) was synthesized. R3 at 0.3 microM exerted a 80% growth inhibition of human colon cancer Caco-2 cells and arrested growth completely at 0.4 microM (R3 was 100-fold more active than resveratrol). The cis conformation of R3 was also 100-fold more potent than the trans isomer. R3 (0.3 microM) caused cell cycle arrest at the G2/M phase transition. The drug inhibited tubulin polymerization in a dose-dependent manner (IC50=4 microM), and it reduced also by 2-fold ornithine decarboxylase and s-adenosylmethionine decarboxylase activities. This caused the depletion of the polyamines, putrescine and spermidine, which are growth factors for cancer cells. R3 inhibited partially colchicine binding to its binding site on tubulin, indicating that R3 either partially overlaps with colchicine binding or that R3 binds to a specific site of tubulin that is not identical with the colchicine binding site modifying colchicine binding by allosteric influences. The resveratrol derivative (Z)-3,5,4'-trimethoxystilbene (R3) is an interesting anti-mitotic drug that exerts cytotoxic effects by depleting the intracellular pool of polyamines and by altering microtubule polymerization. Such a drug may be useful for the treatment of neoplastic diseases.

    Topics: Adenocarcinoma; Antineoplastic Agents, Phytogenic; Apoptosis; Binding Sites; Caco-2 Cells; Cell Cycle; Cell Division; Colchicine; Colonic Neoplasms; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Gout Suppressants; Humans; Microtubules; Mitosis; Ornithine Decarboxylase; Ornithine Decarboxylase Inhibitors; Polyamines; Polymers; Resveratrol; Stilbenes; Tubulin; Tubulin Modulators; Vinblastine

2003
Resveratrol, a chemopreventive agent, disrupts the cell cycle control of human SW480 colorectal tumor cells.
    International journal of molecular medicine, 2002, Volume: 10, Issue:2

    Resveratrol is a natural polyphenolic compound produced by a number of plants and found in high amount in peanuts, seeds, grapes or berries as source of human nutrition. Epidemiological studies strongly suggest that resveratrol may act as a cancer chemopreventive compound. The mechanism by which resveratrol inhibits cell proliferation was studied in human colorectal tumor SW480 cell line. The results show that resveratrol strongly inhibits cell proliferation at the micromolar range in a time- and dose-dependent manner. Resveratrol appears to block the cell cycle at the transition --> G2/M since inhibition of [(3)H]-thymidine incorporation is not observed, while there is an increase of the cell number in S phase. During this inhibition process, resveratrol increases the content of cyclins A and B1 as well as cyclin-dependent kinases Cdk1 and Cdk2. Moreover, resveratrol promotes Cdk1 phosphorylation. In conclusion, resveratrol exerts a strong inhibition of SW480 human colorectal tumor cell proliferation at least by modulating cyclin and cyclin-dependent kinase activities.

    Topics: Adenocarcinoma; Anticarcinogenic Agents; CDC2 Protein Kinase; CDC2-CDC28 Kinases; Cell Cycle; Cell Division; Colorectal Neoplasms; Cyclin A; Cyclin B; Cyclin B1; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinases; DNA Replication; Enzyme Induction; Flow Cytometry; Gene Expression Regulation, Neoplastic; Growth Inhibitors; Humans; Neoplasm Proteins; Phosphorylation; Protein Processing, Post-Translational; Protein Serine-Threonine Kinases; Resveratrol; S Phase; Stilbenes; Tumor Cells, Cultured

2002
Suppression of 7,12-dimethylbenz(a)anthracene-induced mammary carcinogenesis in rats by resveratrol: role of nuclear factor-kappaB, cyclooxygenase 2, and matrix metalloprotease 9.
    Cancer research, 2002, Sep-01, Volume: 62, Issue:17

    We have reported recently that resveratrol (trans-3,4',5-trihydroxystilbene), a polyphenolic phytoalexin found in grapes, fruits, and root extracts of the weed Polygonum cuspidatum, is a potent inhibitor of nuclear factor (NF)-kappaB activation. Because NF-kappaB suppression has been linked with chemoprevention, this prompted us to investigate the chemopreventive potential of resveratrol by testing it against mammary carcinogenesis induced by 7,12-dimethylbenz(a)anthracene (DMBA) in female Sprague Dawley rats. Dietary administration of resveratrol (10 ppm) had no effect on body weight gain and tumor volume but produced striking reductions in the incidence (45%; P < 0.05), multiplicity (55%; P < 0.001), and extended latency period of tumor development relative to DMBA-treated animals. Histopathological analysis of the tumors revealed that DMBA induced ductal carcinomas and focal microinvasion in situ (7 of 7), whereas treatment with resveratrol suppressed DMBA-induced ductal carcinoma. Immunohistochemistry and Western blot analysis revealed that resveratrol suppressed the DMBA-induced cyclooxygenase-2 and matrix metalloprotease-9 expression in the breast tumor. Gel shift analysis showed suppression of DMBA-induced NF-kappaB activation by resveratrol. Treatment of human breast cancer MCF-7 cells with resveratrol also suppressed the NF-kappaB activation and inhibited proliferation at S-G(2)-M phase. Overall, our results suggest that resveratrol suppresses DMBA-induced mammary carcinogenesis, which correlates with down-regulation of NF-kappaB, cyclooxygenase-2, and matrix metalloprotease-9 expression.

    Topics: 9,10-Dimethyl-1,2-benzanthracene; Adenocarcinoma; Animals; Anticarcinogenic Agents; Antineoplastic Agents, Phytogenic; Blotting, Western; Breast Neoplasms; Carcinogens; Cell Division; Cyclooxygenase 2; Female; Humans; Immunohistochemistry; Isoenzymes; Mammary Neoplasms, Experimental; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Membrane Proteins; NF-kappa B; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha

2002
Schedule dependence of combretastatin A4 phosphate in transplanted and spontaneous tumour models.
    International journal of cancer, 2002, Nov-01, Volume: 102, Issue:1

    Tubulin depolymerizing drugs that selectively disrupt tumour-associated vasculature have recently been identified. The lead drug in this class, combretastatin A4 phosphate (CA4P), has just completed Phase I clinical trial. Previous studies have focussed on the effects of single drug doses and have demonstrated little or no retardation of tumour growth when CA4P is used alone, but significant benefit when it is combined with conventional treatment. We have investigated the effects of multiple daily or twice daily dosing with CA4P on the vascular function, cell survival and growth of syngeneic and spontaneous breast cancers in mice. In both transplanted and spontaneous tumours significant growth retardation is observed if CA4P is administered daily (10 doses x 50 mg/kg), whereas no significant effects are seen if the same total dose (500 mg/kg) is administered as a single bolus injection. This effect is attributed, at least in part, to anti-proliferative effects on the tumour and endothelial cells, which retard the revascularisation and repopulation of the tumour core that is initially necrosed by the drug treatment. Further investigation of dose scheduling showed that the initial anti-vascular effects of CA4P are enhanced by administering the drug in 2 equal doses separated between 2 and 6 hr. The twice daily dosing schedule (25 mg/kg twice a day) produced increased growth retardation compared to the 50 mg/kg once a day schedule in the transplanted CaNT tumour. It did not do so in the spontaneous T138 tumour model. These studies indicate that the potential anti-tumour activity of CA4P when used as a single agent in clinical trials may be enhanced when used in multiple dose schedules.

    Topics: Adenocarcinoma; Animals; Antineoplastic Agents, Phytogenic; Carcinoma, Adenosquamous; Cell Survival; Female; Mammary Neoplasms, Experimental; Mice; Mice, Inbred CBA; Neoplasm Transplantation; Stilbenes; Xenograft Model Antitumor Assays

2002
Differential sensitivity of two adenocarcinoma xenografts to the anti-vascular drugs combretastatin A4 phosphate and 5,6-dimethylxanthenone-4-acetic acid, assessed using MRI and MRS.
    NMR in biomedicine, 2002, Volume: 15, Issue:2

    The effects of two anti-vascular agents, combretastatin A4 phosphate (CA4P), and 5,6-dimethylxanthenone-4-acetic acid (DMXAA), on the perfusion of two human colon adenocarcinomas implanted in SCID mice, were assessed for up to 3 h using non-invasive magnetic resonance imaging (MRI) and spectroscopy techniques (MRS). MRI measurements of GdDTPA inflow showed that treatment with CA4P had little effect on the perfusion of HT29 tumours. Localized (31)P MRS measurements also showed that the drug had no significant effect on tumour cell energy status, as assessed from the ratio of the integrals of the signals from inorganic phosphate (P(i)) and nucleoside triphosphates. However, after treatment with DMXAA, perfusion was reduced and the P(i)/NTP ratio increased, indicating that the HT29 tumour is susceptible to the action of this drug. The LS174T tumour model was susceptible to both CA4P and DMXAA, using the criteria of changes in GdDTPA inflow and P(i)/NTP ratio.

    Topics: Adenocarcinoma; Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Contrast Media; Gadolinium DTPA; Humans; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Mice; Mice, SCID; Stilbenes; Transplantation, Heterologous; Xanthenes; Xanthones

2002
Inhibition of gastric cancer cell proliferation by resveratrol: role of nitric oxide.
    American journal of physiology. Gastrointestinal and liver physiology, 2002, Volume: 282, Issue:5

    Resveratrol is a dietary phytochemical that has been shown to inhibit proliferation of a number of cell lines, and it behaves as a chemopreventive agent in assays that measure the three stages of carcinogenesis. We tested for its chemopreventive potential against gastric cancer by determining its interaction with signaling mechanisms that contribute to the proliferation of transformed cells. Low levels of exogenous reactive oxygen (H(2)O(2)) stimulated [(3)H]thymidine uptake in human gastric adenocarcinoma SNU-1 cells, whereas resveratrol suppressed both synthesis of DNA and generation of endogenous O(2)(-) but stimulated nitric oxide (NO) synthase (NOS) activity. To address the role of NO in the antioxidant action of resveratrol, we measured the effect of sodium nitroprusside (SNP), an NO donor, on O(2)(-) generation and on [(3)H]thymidine incorporation. SNP inhibited DNA synthesis and suppressed ionomycin-stimulated O(2)(-) generation in a concentration-dependent manner. Our results revealed that the antioxidant action of resveratrol toward gastric adenocarcinoma SNU-1 cells may reside in its ability to stimulate NOS to produce low levels of NO, which, in turn, exert antioxidant action. Resveratrol-induced inhibition of SNU-1 proliferation may be partly dependent on NO formation, and we hypothesize that resveratrol exerts its antiproliferative action by interfering with the action of endogenously produced reactive oxygen. These data are supportive of the action of NO against reactive oxygen and suggest that a resveratrol-rich diet may be chemopreventive against gastric cancer.

    Topics: Adenocarcinoma; Antineoplastic Agents, Phytogenic; Apoptosis; Cell Division; DNA; Humans; Hydrogen Peroxide; Ionomycin; Ionophores; NADP; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Nitroprusside; Oxidants; Protein Kinase C; Reactive Oxygen Species; Resveratrol; Stilbenes; Stomach Neoplasms; Superoxides; Tumor Cells, Cultured

2002
Combretastatin A-4 prodrug inhibits growth of human non-small cell lung cancer in a murine xenotransplant model.
    The Annals of thoracic surgery, 2001, Volume: 71, Issue:5

    Combretastatin A-4 prodrug (CA-4PD) has been identified as a potent antivascular agent in various rodent tumor models. The aim of this study was to investigate the effect of CA-4PD on human non-small cell lung cancer (NSCLC).. Cytostatic and cytotoxic effects of CA-4PD on selected NSCLC cells, Colo-699 and KNS-62, were studied in vitro. After subcutaneous xenotransplantation the effect of systemically administrated CA-4PD on tumor growth was investigated in vivo. A newly established orthotopic xenotransplant model was employed to estimate prolongation of survival after intrapulmonary tumor induction with secondary metastatic disease.. In vitro, CA-4PD displayed a time and dose dependent antiproliferative effect on human lung cancer cells. In vivo, CA-4PD significantly delayed growth of subcutaneously induced lung cancer. This growth delay was translated into a prolongation of survival in the metastasizing orthotopic xenotransplant model.. In vitro CA-4PD inhibits proliferation of NSCLC cells, most likely by disruption of microtubule assembly. In vivo, systemic treatment inhibits growth of subcutaneously xenotransplanted tumors by an antivascular effect. In the case of metastasizing human lung cancer this translated into a prolongation of survival.

    Topics: Adenocarcinoma; Animals; Antineoplastic Agents, Phytogenic; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cell Division; Cell Survival; Dose-Response Relationship, Drug; Female; Humans; Lung Neoplasms; Mice; Mice, SCID; Neoplasm Transplantation; Prodrugs; Stilbenes; Tumor Cells, Cultured

2001
Eradication of colorectal xenografts by combined radioimmunotherapy and combretastatin a-4 3-O-phosphate.
    Cancer research, 2001, Jun-15, Volume: 61, Issue:12

    Solid tumors have a heterogeneous pathophysiology, which has a major impact on therapy. Using SW1222 colorectal xenografts grown in nude mice, we have shown that antibody-targeted radioimmunotherapy (RIT) effectively treated the well-perfused tumor rim, producing regressions for approximately 35 days, but was less effective at the more hypoxic center. By 72 h after RIT, the number of apoptotic cells rose from an overall value of 1% in untreated tumors to 35% at the tumor periphery and 10% at the center. The antivascular agent disodium combretastatin A-4 3-O-phosphate (CA4-P) rapidly reduced tumor blood flow to 62% of control values by 1 h, 23% by 3 h, and between 32-36% from 6 to 24 h after administration. This created central hemorrhagic necrosis, but a peripheral rim of cells continued to grow, and survival was unaffected. Changes in the pattern of perfusion across the tumor over time were zonal. Untreated mice showed perfusion throughout the tumor, with greatest activity at the rim. There was an overall reduction at 1 h, and total cessation of central perfusion from 3 h onward. A narrow peripheral rim of perfusion was always present, which increased in intensity and extent between 6 and 24 h, either through reperfusion or new vessel growth. Combining these two complementary therapies (7.4 MBq (131)I-labeled anti-carcinoembryonic antigen IgG i.v. plus a single 200 mg/kg dose of CA4-P i.p.) produced complete cures in five of six mice for >9 months. Allowing maximal tumor localization of antibody (48 h) before blood flow inhibition by CA4-P increased tumor retention by two to three times control levels by 96 h without altering normal tissue levels, as confirmed by gamma counting and phosphor image analysis. The success of this combined, synergistic therapy was probably the result of several factors: (a) the killing of tumor cells in the outer, radiosensitive region by targeted radiotherapy; (b) enhancement of RIT by entrapment of additional radioantibody after combretastatin-induced vessel collapse; and (c) destruction of the central, more hypoxic and radioresistant region by CA4-P. This work demonstrates the need to consider cancer treatment in a biologically heterogeneous setting, if results are to be effectively translated to the clinic.

    Topics: Adenocarcinoma; Animals; Antibodies, Monoclonal; Antineoplastic Agents, Phytogenic; Apoptosis; Cell Division; Colonic Neoplasms; Combined Modality Therapy; Female; Humans; Immunotoxins; Iodine Radioisotopes; Mice; Mice, Nude; Radioimmunotherapy; Stilbenes; Tissue Distribution; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

2001
p21 Waf1/Cip1 can protect human colon carcinoma cells against p53-dependent and p53-independent apoptosis induced by natural chemopreventive and therapeutic agents.
    Oncogene, 2001, Jun-07, Volume: 20, Issue:26

    The molecular basis for the sensitivity of tumor cells to chemopreventive natural food compounds and commonly used chemotherapeutic agents is not well understood, not least because studies are frequently confounded by the diversity among cell lines or rely on experimental protein overexpression. Here we investigated the effects of n-butyrate, a cancer-preventive short-chain fatty acid produced by anaerobic bacteria in the gastrointestinal tract, on the human wild-type p53 and p21 expressing HCT116 colon carcinoma cell line and on HCT116 cells with either p53 or p21 alleles inactivated by homologous recombination. The effects of n-butyrate were then compared with those elicited by cytotoxic drugs and the natural chemopreventive phytoalexin of wine and grapes, resveratrol. We document that physiological concentrations of n-butyrate stimulate p21 expression and induce apoptosis independently of p53, and that the absence of p21 increases apoptosis drastically. The apoptosis is mediated through the mitochondria and is accompanied by mitochondrial proliferation and membrane potential changes. Adriamycin, etoposide, cisplatinum, colcemid and resveratrol induce distinct cellular responses; however, absence of p21 favors apoptosis-induction by adriamycin, etoposide and colcemid. Thus, control of p21 expression may support chemoprevention and certain tumor therapies.

    Topics: Adenocarcinoma; Alleles; Amino Acid Chloromethyl Ketones; Anticarcinogenic Agents; Antineoplastic Agents; Apoptosis; Benzothiazoles; Butyrates; Cisplatin; Colonic Neoplasms; Cyclin-Dependent Kinase Inhibitor p21; Cyclins; Cysteine Proteinase Inhibitors; Demecolcine; Doxorubicin; Drug Resistance, Neoplasm; Etoposide; Fluorouracil; Gene Expression Regulation, Neoplastic; Genes, p53; Humans; Intracellular Membranes; Membrane Potentials; Mitochondria; Neoplasm Proteins; Recombination, Genetic; Resveratrol; Stilbenes; Thiazoles; Toluene; Tumor Cells, Cultured; Tumor Suppressor Protein p53

2001
Resveratrol exhibits cytostatic and antiestrogenic properties with human endometrial adenocarcinoma (Ishikawa) cells.
    Cancer research, 2001, Aug-15, Volume: 61, Issue:16

    Trans-3,4',5-trihydroxystilbene (resveratrol), a polyphenolic compound found in the human diet, was reported recently to serve as an estrogen agonist with cultured MCF-7 cells transfected with estrogen response element-luciferase reporter plasmids. As currently shown, treatment of cultured human endometrial adenocarcinoma (Ishikawa) cells with resveratrol (concentrations as high as 10 microM) did not significantly increase the levels of an estrogen-inducible marker enzyme, alkaline phosphatase. To the contrary, when alkaline phosphatase was induced by treatment with 1 nM of 17beta-estradiol (E(2)), resveratrol exhibited a dose-dependent decrease in activity (IC(50) = 2.3 microM). Furthermore, when Ishikawa cells were treated with resveratrol as a single agent, estrogen-inducible progesterone receptor (PR) was not enhanced, and PR expression induced by treatment with E(2) was inhibited by resveratrol in a dose-dependent fashion at both the mRNA and protein levels. In addition, resveratrol mediated suppression of a functional activity of PR as demonstrated by down-regulation of alpha(1)-integrin expression induced by E(2) plus progesterone. With transient transfection experiments conducted with Ishikawa cells, antiestrogenic effects were confirmed by dose-dependent inhibition of E(2)-induced estrogen response element-luciferase transcriptional activity. Because resveratrol antagonized estrogenic effects in Ishikawa cells, competitive binding analyses were performed to examine the potential of displacing [(3)H]E(2) from human estrogen receptor (ER). Resveratrol showed no discernable activity with ER-alpha, but with ER-beta, E(2) was displaced with an IC(50) of 125 microM. However, mRNA and protein expression of ER-alpha but not ER-beta were suppressed by resveratrol in Ishikawa cells, in the concentration range of 5-15 microM. In addition, in the presence or absence of E(2), resveratrol inhibited Ishikawa cell proliferation in a time-dependent manner with cells accumulating in the S phase of the cycle < or =48 h. This effect was reversible. Analysis of some critical cell cycle proteins revealed a specific increase in expression of cyclins A and E but a decrease in cyclin-dependent kinase 2. These data suggest resveratrol exerts an antiproliferative effect in Ishikawa cells, and the effect may be mediated by both estrogen-dependent and -independent mechanisms.

    Topics: Adenocarcinoma; Alkaline Phosphatase; Antigens, CD; Antineoplastic Agents, Phytogenic; CDC2-CDC28 Kinases; Cell Survival; Cyclin A; Cyclin E; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinases; Down-Regulation; Drug Interactions; Endometrial Neoplasms; Estradiol; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogen Receptor Modulators; Female; Gene Expression Regulation, Neoplastic; Humans; Integrin alpha1; Protein Serine-Threonine Kinases; Receptors, Estrogen; Receptors, Progesterone; Resveratrol; RNA, Messenger; S Phase; Stilbenes; Transcriptional Activation; Tumor Cells, Cultured

2001
Resveratrol-induced inactivation of human gastric adenocarcinoma cells through a protein kinase C-mediated mechanism.
    Biochemical pharmacology, 2001, Nov-15, Volume: 62, Issue:10

    Resveratrol, a polyphenolic phytochemical present in berries, grapes, and wine, has emerged as a promising chemopreventive candidate. Because there is scant information regarding natural agents that prevent, suppress, or reverse gastric carcinogenesis, the aim of the present study was to determine the chemopreventive potential of resveratrol against gastric cancer by investigating cellular and molecular events associated with resveratrol treatment of human gastric adenocarcinoma cells. We determined the action of resveratrol on cellular function and cellular integrity by measuring DNA synthesis, cellular proliferation, cell cycle distribution, cytolysis, apoptosis, and phosphotransferase activities of two key signaling enzymes, protein kinase C (PKC) and mitogen-activated protein kinases (ERK1/ERK2), in human gastric adenocarcinoma KATO-III and RF-1 cells. Resveratrol inhibited [3H]thymidine incorporation into cellular DNA of normally proliferating KATO-III cells and of RF-1 cells whose proliferation was stimulated with carcinogenic nitrosamines. Treatment with resveratrol arrested KATO-III cells in the G(0)/G(1) phase of the cell cycle and eventually induced apoptotic cell death, but had a minimal effect on cell lysis. Resveratrol treatment had no effect on ERK1/ERK2 activity but significantly inhibited PKC activity of KATO-III cells and of human recombinant PKCalpha. Results indicate that resveratrol has potential as a chemopreventive agent against gastric cancer because it exerts an overall deactivating effect on human gastric adenocarcinoma cells. Resveratrol-induced inhibition of PKC activity and of PKCalpha, without any change in ERK1/ERK2 activity, suggests that resveratrol utilizes a PKC-mediated mechanism to deactivate gastric adenocarcinoma cells.

    Topics: Adenocarcinoma; Anticarcinogenic Agents; Apoptosis; Cell Cycle; Cell Division; DNA, Neoplasm; Humans; Mitogen-Activated Protein Kinases; Protein Kinase C; Resveratrol; Stilbenes; Stomach Neoplasms; Tumor Cells, Cultured

2001
Structural determinants for activation and block of CFTR-mediated chloride currents by apigenin.
    American journal of physiology. Cell physiology, 2000, Volume: 279, Issue:6

    Apigenin (4',5,7-trihydroxyflavone) is an activator of cystic fibrosis transmembrane conductance regulator (CFTR)-mediated Cl(-) currents across epithelia at low concentrations and a blocker at high concentrations. We determined the roles of structural components of apigenin for both stimulation and block of Cl(-) currents across Calu-3 epithelia. The half-maximal binding affinity of apigenin for current stimulation (K(s)) was 9.1 +/- 1.3 microM, and the rank-order of molecular structures was 7-hydroxyl > pyrone = 4'-hydroxyl > 5-hydroxyl. Both the 7-hydroxyl and the 4'-hydroxyl served as H-bond acceptors, whereas the 5-hydroxyl was an H-bond donor. The half-maximal binding affinity of apigenin during current block was 74 +/- 11 microM. Blocked Cl(-) currents were structurally determined by 7-hydroxyl = 4'-hydroxyl > pyrone > 5-hydroxyl. Prestimulation of tissues with forskolin significantly affected activation kinetics and binding characteristics. After forskolin stimulation, K(s) was 4.1 +/- 0.9 microM, which was structurally determined by pyrone > all hydroxyls > single hydroxyls. In contrast, block of Cl(-) current by apigenin was not affected by forskolin stimulation. We conclude that apigenin binds to a stimulatory and an inhibitory binding site, which are distinguished by their affinities and the molecular interactions during binding.

    Topics: 4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid; Adenocarcinoma; Anesthetics, Local; Apigenin; Biological Transport; Calcium Channel Blockers; Chlorides; Colforsin; Cystic Fibrosis Transmembrane Conductance Regulator; Dose-Response Relationship, Drug; Enzyme Inhibitors; Epithelial Cells; Flavonoids; Humans; Lidocaine; Lung; Lung Neoplasms; ortho-Aminobenzoates; Quinidine; Resveratrol; Stilbenes; Structure-Activity Relationship; Tumor Cells, Cultured

2000
Differential effects on growth, cell cycle arrest, and induction of apoptosis by resveratrol in human prostate cancer cell lines.
    Experimental cell research, 1999, May-25, Volume: 249, Issue:1

    Epidemiologic studies have suggested that nutrition plays an important role in carcinogenesis and that 30% of cancer morbidity and mortality can potentially be prevented with proper adjustment of diets. Resveratrol, a polyphenol present in red wines and a variety of human foods, has recently been reported to exhibit chemopreventive properties when tested in a mouse skin cancer model system. In this study, we investigated the effects of resveratrol on growth, induction of apoptosis, and modulation of prostate-specific gene expression using cultured prostate cancer cells that mimic the initial (hormone-sensitive) and advanced (hormone-refractory) stages of prostate carcinoma. Androgen-responsive LNCaP and androgen-nonresponsive DU-145, PC-3, and JCA-1 human prostate cancer cells were cultured with different concentrations of resveratrol (2. 5 x 10(-5)-10(-7) M). Cell growth, cell cycle distribution, and apoptosis were determined. Addition of 2.5 x 10(-5) M resveratrol led to a substantial decrease in growth of LNCaP and in PC-3 and DU-145 cells, but only had a modest inhibitory effect on proliferation of JCA-1 cells. Flow cytometric analysis showed resveratrol to partially disrupt G1/S transition in all three androgen-nonresponsive cell lines, but had no effect in the androgen-responsive LNCaP cells. In difference to the androgen-nonresponsive prostate cancer cells however, resveratrol causes a significant percentage of LNCaP cells to undergo apoptosis and significantly lowers both intracellular and secreted prostate-specific antigen (PSA) levels without affecting the expression of the androgen receptor (AR). These results suggest that resveratrol negatively modulates prostate cancer cell growth, by affecting mitogenesis as well as inducing apoptosis, in a prostate cell-type-specific manner. Resveratrol also regulates PSA gene expression by an AR-independent mechanism.

    Topics: Adenocarcinoma; Apoptosis; Cell Cycle; Cell Division; Flow Cytometry; G1 Phase; Gene Expression Regulation; Growth Inhibitors; Humans; Male; Prostate-Specific Antigen; Prostatic Neoplasms; Receptors, Androgen; Resveratrol; S Phase; Stilbenes; Tumor Cells, Cultured

1999
Cell cycle effects and control of gene expression by resveratrol in human breast carcinoma cell lines with different metastatic potentials.
    International journal of oncology, 1999, Volume: 15, Issue:2

    Trans-resveratrol, a polyphenol present in red wines and various human foods, is an antioxidant also with reported chemopreventive properties. However, whether resveratrol may exert different effects in malignant cells with a common anatomical origin yet displaying different invasive characteristics is not known. Since invasiveness and metastasis are considered to be the most insidious and life-threatening aspects for all cancers, we compared the ability of resveratrol to control growth and cell cycle transition in the highly invasive MDA-MB-435 with the minimally invasive MCF-7 breast carcinoma cells. The data revealed that resveratrol exerted a greater inhibitory effect on the MDA-MB-435 cells. A diminution of percentage of cells in G1 phase and a corresponding accumulation of cells in S phase of the cell cycle was observed. We also studied the effect of resveratrol on a panel of MDA-MB-435 cells transfected with nm23-H1 and nm23-H2 genes, which have been suggested to play a role in controlling metastasis in breast cancer cells. These cells are designated as Vbeta, 1beta, 1Tbeta, 2beta, and 2Tbeta, respectively. The control Vbeta consists of MDA-MB-435 cells transfected with bacterial beta-glucuronidase. Cells labeled 1beta and 1Tbeta correspond to those carrying beta-glucuronidase and overexpressed wild-type (His118) or mutant (Tyr118, catalytically inactive) nm23-H1 genes. The 2beta and 2Tbeta refer to cells transfected with wild-type and mutant nm23-H2 genes. The responses of these cells to resveratrol were assessed by measuring proliferation, cell cycle phase distribution, and changes in expression of several genes. These studies have shown that resveratrol (25 microM, 3 days) reduced growth of all cell types by 60-80%. Overexpression of both wild-type and catalytically inactive nm23-H1 (1beta, 1Tbeta) but not nm23-H2 (2beta, 2Tbeta) reduced the proportion of cells in G1 phase, compared to the Vbeta control cells. Little changes in expression of PCNA, Rb, p53, and bcl-2 were observed in the five cell types treated with resveratrol, compared to untreated cells. Noted exceptions included reduced expression of Rb protein and increased expression of p53 in 2beta and 2Tbeta cells, and increased expression of bcl-2 in 2beta cells, treated with resveratrol. In contrast, resveratrol upregulated expression of cathepsin D by 50-100% in all cell lines except 1beta. These results suggest that the intrinsic metastatic potential of cancer cells may affect their r

    Topics: Adenocarcinoma; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Cell Cycle; Chemoprevention; Female; Gene Expression Regulation, Neoplastic; Humans; Neoplasm Metastasis; Resveratrol; Stilbenes; Transfection

1999
Novel combretastatin analogues effective against murine solid tumors: design and structure-activity relationships.
    Journal of medicinal chemistry, 1998, Jul-30, Volume: 41, Issue:16

    A series of combretastatin A-4 (CA-4) analogues were synthesized, and their cytotoxic effects against murine Colon 26 adenocarcinoma and inhibitory activity on tubulin polymerization were evaluated. Since CA-4 has limited aqueous solubility, the target compounds were designed to improve solubility by introduction of a nitrogen-containing group. Among the compounds synthesized, those with an amino moiety in place of the phenolic OH of CA-4 showed potent antitubulin activity and cytotoxicity against murine Colon 26 adenocarcinoma in vitro. Some of the compounds which were potent in vitro were evaluated in the murine tumor model Colon 26 in vivo. Among these, 13bHCl, 21aHCl, and 21bHCl showed significant antitumor activity in the animal model, while CA-4 was ineffective. 13bHCl and 21aHCl were further evaluated in two murine tumor models (Colon 38 and 3LL) and human xenografts HCT-15. These compounds showed potent antitumor activity comparable or superior to that of CDDP. The structure-activity relationships of this series of compounds are also discussed.

    Topics: Acrylonitrile; Adenocarcinoma; Aniline Compounds; Animals; Anisoles; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Biopolymers; Cell Survival; Colonic Neoplasms; Drug Screening Assays, Antitumor; Humans; Mice; Neoplasm Transplantation; Solubility; Stilbenes; Structure-Activity Relationship; Transplantation, Heterologous; Tubulin; Tumor Cells, Cultured

1998
Combretastatin A-4, an agent that displays potent and selective toxicity toward tumor vasculature.
    Cancer research, 1997, May-15, Volume: 57, Issue:10

    Selective induction of vascular damage within tumors represents an emerging approach to cancer treatment. Histological studies have shown that several tubulin-binding agents can induce vascular damage within tumors but only at doses approximating the maximum tolerated dose, which has limited their clinical applicability. In this study, we show that the combretastatin A-4 prodrug induces vascular shutdown within tumors at doses less than one-tenth of the maximum tolerated dose. In vitro studies indicate that a short drug exposure results in profound long-term antiproliferative/cytotoxic effects against proliferating endothelial cells but not cells that are quiescent prior to and during drug exposure. Vascular shutdown, within experimental and human breast cancer models in vivo following systemic drug administration, was demonstrated with a reduction in functional vascular volume of 93% at 6 h following drug administration and persisted over the next 12 h, with corresponding histology consistent with hemorrhagic necrosis resulting from vascular damage. These actions against tumor vasculature and the broad therapeutic window demonstrate the clinical potential of these drugs and warrant further study to elucidate the mechanisms responsible for the antivascular effects of combretastatin A-4.

    Topics: Adenocarcinoma; Animals; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Endothelium, Vascular; Hindlimb; Humans; Mice; Mice, Inbred CBA; Neoplasms; Neoplasms, Experimental; Neovascularization, Pathologic; Perfusion; Prodrugs; Rats; Stilbenes

1997
Inhibition of mucin secretion in a colonic adenocarcinoma cell line by DIDS and potassium channel blockers.
    Biochimica et biophysica acta, 1990, Apr-09, Volume: 1052, Issue:1

    The factors which influence the exocytosis of mucins are not well characterized. Since the physical properties of mucins may be affected significantly by the co-secretion of electrolytes and water, we studied the relationship between ion movement and mucin secretion in T84 cells, a human colonic adenocarcinoma cell line which has been well characterized with respect to apical chloride secretion. Secretion of mucin was assessed by immunoassay of mucin appearing in the medium within 30 min of stimulation. Cells were grown on plastic in DMEM/Ham's F12 medium and experiments were carried out at 70% confluence. Mucin secretion was stimulated by the calcium ionophore A23187, or A23187 plus vasoactive intestinal polypeptide. Stimulated mucin secretion was not affected by loop diuretics (furosemide (1 x 10(-3) M) or bumetanide (1 x 10(-4) M)), with or without the addition of ouabain (5 x 10(-5) M) and amiloride (1 x 10(-5) M), making it unlikely that transcellular chloride movements in necessary for mucin secretion. However, 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS; (1 x 10(-5) and 5 x 10(-5) M) and three potassium channel blockers BaCl2 (1 x 10(-3) and 5 x 10(-3) M), tetraethylammonium chloride (1 x 10(-2) M) and quinine (5 x 10(-4) M) inhibited mucin secretion. A DIDS-sensitive chloride channel or chloride/bicarbonate exchanger and a Ca2(+)-dependent potassium channel may play important roles in mucin secretion. Since plasma membranes are sparingly permeable to DIDS, the DIDS-sensitive site is likely to be on the apical plasma membrane, perhaps at an initiation locus for exocytosis.

    Topics: 4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic Acid; 4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid; Adenocarcinoma; Amiloride; Barium; Barium Compounds; Calcimycin; Cell Line; Chlorides; Colonic Neoplasms; Furosemide; Humans; Kinetics; Mucins; Ouabain; Potassium Channels; Quinine; Stilbenes; Tetraethylammonium; Tetraethylammonium Compounds; Tumor Cells, Cultured; Vasoactive Intestinal Peptide

1990
Inhibition of mammary carcinogenesis of dimethylbenzanthracene treated rats with a brominated triphenylethylene.
    Biomedicine / [publiee pour l'A.A.I.C.I.G.], 1979, Volume: 31, Issue:5

    Daily administration of a brominated triphenylethylene (TBP), to rats which received 20 mg of DMBA p. o. inhibits mammary carcinogenesis. The effect appears even with very small doses (i ppm in the diet) and seems to be dose related. With one exception (an adenofibroma) the tumours in control and treated animals were malignant. Administration of TBP prevents the appearance of corporea lutea in the ovaries but not the usual necrosis of the adrenal cortex.

    Topics: 9,10-Dimethyl-1,2-benzanthracene; Adenocarcinoma; Adenofibroma; Adrenal Cortex; Animals; Benz(a)Anthracenes; Corpus Luteum; Estradiol Congeners; Female; Mammary Neoplasms, Experimental; Necrosis; Organ Size; Ovary; Rats; Stilbenes

1979
The mass spectra of diethylstilbestrol and related compounds.
    Biomedical mass spectrometry, 1978, Volume: 5, Issue:10

    The low resolution mass spectra of E-3,4-bis-(p-hydroxyphenyl)-hex-3-ene (diethylstilbestrol), E-[1,1,1-3H3]3,4-bis-(p-hydroxyphenyl)-hex-3-ene, E-2,3-bis-(p-hydroxyphenyl)-but-2-ene (dimethylstilbestrol), E,E-3,4-bis-(p-hydroxyphenyl)hexa-2,4-diene (dienestrol) and 3,4-bis-(p-hydroxyphenyl)-hexane (hexestrol) were examined as the parent compounds, their diacetates, dimethyl ethers, and bis-trimethylsilyl ethers. In addition, the mass spectra of the diethyl ether and the hexadeuteriodimethyl ether of E-3,4-bis-(p-hydroxyphenyl)-hex-3-ene were studied. Each compound gives rise to several sets of characteristic fragment ions associated with loss of alkyl groups, loss of aryl groups and rearrangements. An ion of m/e 165 (C13H9) was found in the spectra of all the compounds studied. With the aid of high resolution mass spectrometry empirical formulae were assigned to major ions of the free diphenols.

    Topics: Adenocarcinoma; Animals; Dienestrol; Diethylstilbestrol; Female; Hexestrol; Humans; Ions; Mammals; Mass Spectrometry; Pregnancy; Stilbenes; Vaginal Neoplasms

1978
Antiestrogenic and antitumor properties of tamoxifen in laboratory animals.
    Cancer treatment reports, 1976, Volume: 60, Issue:10

    This paper reviews the antiestrogenic and antitumor properties of tamoxifen (NSC-180973; ICI-46474) in the rat. In classic tests for antiestrogenic activity, tamoxifen inhibits the actions of estradiol in the rat uterus and vagina. At the cellular level, tamoxifen inhibits estrogen binding to cytoplasmic estrogen receptors, but although estrogen-receptor units are translocated to the nucleus DNA synthesis does not occur. It is suggested that tamoxifen competes for estrogen receptors in the cytoplasm and the false messenger units block the nuclear acceptors which are normally activated by estradiol-estrogen receptor complexes thereby provoking DNA synthesis. Tamoxifen inhibits the growth of some 7.12-dimethylbenz(a)anthracene-induced rat mammary tumors whereas others continue to grow. Estrogen-stimulated rises in plasma prolactin are only partially inhibited by tamoxifen although at the tumor level, tamoxifen completely blocks estrogen binding. There is a linear correlation (P less than 0.01) between estrogen-receptor levels in tumor biopsies before therapy and tumor responses to 3 weeks of tamoxifen treatment (50 mug/day) i.e., tumors with low levels of estrogen receptors do not respond to therapy whereas tumors with higher levels of estrogen receptors regress. It is suggested that tamoxifen antagonizes the actions of estrogen at the tumor level by blocking the estrogen-receptor mechanism thereby producing tumor regression. Therefore, estrogen-receptor measurements in tumor biopsies before therapy may be a useful predictive test for the tumor response to tamoxifen treatment.

    Topics: 9,10-Dimethyl-1,2-benzanthracene; Adenocarcinoma; Animals; Antineoplastic Agents; Binding, Competitive; Estrogen Antagonists; Female; Mammary Neoplasms, Experimental; Rats; Receptors, Estrogen; Stilbenes; Tamoxifen

1976
The combined effect of nonsteroidal anti-oestrogens and sex steroids on the growth of rat uterine adenocarcinoma cells in tissue culture.
    British journal of obstetrics and gynaecology, 1976, Volume: 83, Issue:3

    Nonsteroidal anti-oestrogenic drugs, tamoxifen and clomiphene citrate, at concentrations higher than 0.001 mug/ml reduced the colony forming ability of cells derived from a rat uterine adenocarcinoma in vitro. The 50 per cent inhibitory dose of these drugs was about one-hundredth of that of sex steroids. When the cells were treated with combinations of these nonsteroidal anti-oestrogenic drugs and the 50 per cent inhibitory dose (8 mug/ml) of progesterone, a synergistic effect on the inhibition of colony formation was observed. In contrast to progesterone, oestradiol-17beta (the 50 per cent inhibitory dose of which was about 16 mug/ml) suppressed additively the colony formation only in combination with low doses of anti-oestrogenic drugs.

    Topics: Adenocarcinoma; Animals; Cell Division; Clomiphene; Estradiol; Female; Progesterone; Rats; Stilbenes; Tamoxifen; Uterine Neoplasms; Uterus

1976
Tamoxifen (ICI 46,474) and the human carcinoma 8S oestrogen receptor.
    European journal of cancer, 1975, Volume: 11, Issue:3

    Topics: Adenocarcinoma; Breast Neoplasms; Centrifugation, Density Gradient; Cytosol; Estradiol; Female; Humans; Protein Binding; Receptors, Cell Surface; Stilbenes; Tamoxifen; Uterine Neoplasms

1975
[Therapy and follow-up study of the prostatic neoplasm].
    Der Urologe. Ausg. A, 1972, Volume: 11, Issue:4

    Topics: Adenocarcinoma; Aged; Biopsy; Carcinoma; Cell Nucleus; Chlorotrianisene; Estradiol; Evaluation Studies as Topic; Follow-Up Studies; Humans; Inclusion Bodies; Male; Middle Aged; Prostatectomy; Prostatic Neoplasms; Radiotherapy, High-Energy; Stilbenes; Testis

1972
Specific estrogen binding by the cytoplasm fof human breast carcinoma.
    The Journal of clinical endocrinology and metabolism, 1970, Volume: 30, Issue:5

    Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Adult; Aged; Binding Sites; Breast Neoplasms; Carcinoma, Intraductal, Noninfiltrating; Clomiphene; Estradiol; Estriol; Estrogen Antagonists; Estrone; Female; Humans; Ketones; Mastectomy; Middle Aged; Protein Binding; Stilbenes; Tritium

1970
The nuclear sex of breast cancer.
    Surgery, gynecology & obstetrics, 1967, Volume: 125, Issue:4

    Topics: Adenocarcinoma; Adrenal Cortex Hormones; Adrenalectomy; Breast Neoplasms; Castration; Clomiphene; Cortisone; Estrogens; Female; Humans; Hypophysectomy; Neoplasm Metastasis; Sex Chromatin; Stilbenes; Testosterone

1967
FURTHER OBSERVATIONS ON THE EFFECTS OF CLOMIPHENE CITRATE IN ANOVULATORY FEMALES.
    American journal of obstetrics and gynecology, 1965, Jun-01, Volume: 92

    Topics: 17-Ketosteroids; Adenocarcinoma; Atrophy; Chorionic Gonadotropin; Clomiphene; Diagnosis; Drug Therapy; Endometriosis; Endometrium; Female; Follicle Stimulating Hormone; Genital Diseases, Female; Gonadotropins; Humans; Hyperplasia; Infertility; Infertility, Female; Ovulation; Pathology; Polycystic Ovary Syndrome; Stilbenes; Toxicology; Urine; Uterine Neoplasms

1965
REVERSAL OF BENIGN AND MALIGNANT ENDOMETRIAL CHANGES WITH CLOMIPHENE.
    American journal of obstetrics and gynecology, 1964, Apr-15, Volume: 88

    Topics: Adenocarcinoma; Amenorrhea; Clomiphene; Endometrial Hyperplasia; Endometriosis; Female; Humans; Menopause; Pathology; Stilbenes

1964