stilbenes and Carcinoma

stilbenes has been researched along with Carcinoma* in 49 studies

Trials

2 trial(s) available for stilbenes and Carcinoma

ArticleYear
A phase II trial of fosbretabulin in advanced anaplastic thyroid carcinoma and correlation of baseline serum-soluble intracellular adhesion molecule-1 with outcome.
    Thyroid : official journal of the American Thyroid Association, 2009, Volume: 19, Issue:3

    Fosbretabulin is a novel vascular-disrupting agent that has antitumor activity against anaplastic thyroid cancer (ATC) cell lines, xenografts, and demonstrable efficacy in a phase I trial. This phase II study determined the efficacy and safety of fosbretabulin in patients with advanced ATC and whether fosbretabulin altered the natural history of ATC by virtue of doubling the median survival. A secondary aim evaluated the prognostic value of serum soluble intracellular adhesion molecule-1 (sICAM).. Twenty-six patients received fosbretabulin 45 mg/m(2) as a 10-minute intravenous infusion on days 1, 8, and 15 of a 28-day cycle. sICAM levels were obtained at baseline, over the first two cycles, and end of therapy. Treatment was continued until disease progression.. Fosbretabulin was well tolerated; grade 3 toxicity was observed in nine patients (35%), and grade 4 toxicity in one (4%). QTc prolongation delayed treatment in four causing one to stop treatment. Median survival was 4.7 months with 34% and 23% alive at 6 and 12 months, respectively. Median duration of stable disease in seven patients was 12.3 months (range, 4.4-37.9 months). Baseline serum sICAM levels were measured in 24 patients with a median 253.5 ng/mL. There was a significant difference in event-free survival among tertiles of baseline sICAM levels (p < 0.009).. There were no objective responses seen with single-agent fosbretabulin as administered in this trial, and we did not observe a doubling of survival as our primary endpoint. This is among the largest prospective trials ever conducted for ATC. Fosbretabulin has an acceptable safety profile in patients with advanced ATC, and one-third survived more than 6 months. Despite a small sample size, low baseline sICAM levels were predictive of event-free survival. Further prospective validation of sICAM as a therapeutic biomarker and exploring combination regimens with fosbretabulin are warranted.

    Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Bibenzyls; Carboplatin; Carcinoma; CD56 Antigen; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Metastasis; Neural Cell Adhesion Molecules; Organophosphorus Compounds; Paclitaxel; Stilbenes; Survivors; Thyroid Neoplasms; Treatment Outcome; Young Adult

2009
Antiestrogen tamoxifen in the treatment of advanced breast cancer: a series of 31 patients.
    Cancer treatment reports, 1977, Volume: 61, Issue:5

    Topics: Adult; Aged; Breast Neoplasms; Carcinoma; Clinical Trials as Topic; Female; Humans; Middle Aged; Neoplasm Metastasis; Remission, Spontaneous; Stilbenes; Tamoxifen; Time Factors

1977

Other Studies

47 other study(ies) available for stilbenes and Carcinoma

ArticleYear
Combretastatin A4 Regulates Proliferation, Migration, Invasion, and Apoptosis of Thyroid Cancer Cells via PI3K/Akt Signaling Pathway.
    Medical science monitor : international medical journal of experimental and clinical research, 2016, Dec-14, Volume: 22

    BACKGROUND Combretastatin A4 (CA4) is a potential therapeutic candidate for a variety of human cancer treatments. However, the inhibitive effects of CA4 on thyroid cancer cells are still not well-clarified. This study aimed to investigate the potential effect of CA4 on thyroid cancer cells, as well as underlying mechanism. MATERIAL AND METHODS Human thyroid papillary carcinoma cell line TPC1 was pre-treated with 5 concentrations of CA4 (0, 1, 2, 5, or 10 μM) for 2 h. Cell proliferation was determined by 3-(4, 5-dimethyl-2- thiazolyl)-2, 5-diphenyl -2-H-tetrazolium bromide (MTT) assay. Cell migration and invasion were detected by a modified Boyden chamber assay. Moreover, cell apoptosis was detected by terminal deoxynucleotidyl (TUNEL) staining assay and flow cytometry method. Western blot analysis was performed to determine the expression changes of epithelial-mesenchymal transition (EMT)-related proteins and phosphatidylinositol-3-kinase/serine/threonine kinase (PI3K/Akt) signaling pathway proteins. RESULTS CA4 significantly inhibited the cell proliferation, migration, and invasion, and significantly promoted cell apoptosis in a dose-dependent manner compared with the control group. The EMT-related protein levels of N-Cadherin, Vimentin, Snail1, Slug, Twist1, and ZEB1 were significantly decreased by CA4, while E-cadherin had no significant difference compared with the control group. Moreover, PI3K/Akt signaling pathway protein levels of p-PI3K and p-Akt were significantly decreased, whereas PI3K and Akt had no significant differences compared with the control group. CONCLUSIONS CA4 can inhibit proliferation, migration, and invasion and promote apoptosis of TPC1 cells. These effects might be through the PI3K/Akt signaling pathway. CA4 may be a potential therapeutic target for the treatment of thyroid cancer.

    Topics: Antineoplastic Agents; Apoptosis; Carcinoma; Carcinoma, Papillary; Cell Line, Tumor; Cell Movement; Cell Proliferation; Epithelial-Mesenchymal Transition; Humans; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction; Stilbenes; Thyroid Cancer, Papillary; Thyroid Neoplasms

2016
Modification of Antitumor Immunity and Tumor Microenvironment by Resveratrol in Mouse Renal Tumor Model.
    Cell biochemistry and biophysics, 2015, Volume: 72, Issue:2

    Renal cell carcinoma (RCC) microenvironment plays critical roles in antitumor immune response. Resveratrol exhibits a direct antitumor effect in various tumor models. However, the immunomodulatory effect of resveratrol on RCC microenvironment is unknown. In this study, we found that administration of low dose of resveratrol inhibits Renca tumor growth and its inhibition effect depends on CD8(+) T cells. Moreover, the proportion of regulatory T cells is decreased, while the proportion of myeloid-derived suppressor cells does not alter after resveratrol treatment. More importantly, massive amount of activated CD8(+) T cells accumulates in tumor microenvironment in the resveratrol-treated group and shows increased cytotoxicity, as indicated by a higher expression of Fas ligand. We also found that resveratrol switches the expression of T-helper (Th) 2 cytokines such as interleukin (IL)-6 and IL-10 to Th 1 cytokines with dominance of interferon (IFN)-γ, which increases the expression of Fas in Renca cells. Furthermore, we found resveratrol down-regulates angiogenesis along with decreased level of vascular endothelial growth factor in tumor microenvironment. Our results strongly suggest that resveratrol might be used for RCC immunotherapy through modulating tumor microenvironment.

    Topics: Animals; Carcinoma; Cell Line, Tumor; Fas Ligand Protein; Humans; Immunologic Factors; Immunotherapy; Interferon-gamma; Interleukin-10; Interleukin-6; Kidney Neoplasms; Lymphocyte Activation; Mice; Mice, Inbred BALB C; Resveratrol; Stilbenes; T-Lymphocytes, Regulatory; Tumor Microenvironment; Vascular Endothelial Growth Factor A

2015
Resveratrol analogue (E)-8-acetoxy-2-[2-(3,4-diacetoxyphenyl)ethenyl]-quinazoline induces G₂/M cell cycle arrest through the activation of ATM/ATR in human cervical carcinoma HeLa cells.
    Oncology reports, 2015, Volume: 33, Issue:5

    Styrylquinazolines are synthetic analogues of resveratrol and have been suggested to cause anti-inflammatory activity by modulating prostaglandin E₂ (PGE₂) production. In the present study, we evaluated cytotoxic effects of various styrylquinazoline derivatives and found that (E)-8-acetoxy-2-[2-(3,4-diacetoxyphenyl)ethenyl]-quinazoline (8-ADEQ) most potently inhibited the proliferation of the human cervical carcinoma HeLa cells. Exploring the growth-inhibitory mechanisms of 8-ADEQ, we found that it causes a cell cycle arrest at the G₂/M phase by DNA flow cytometric analysis, which was accompanied by upregulation of cyclin B1 expression and cyclin-dependent protein kinase 1 (Cdk1) phosphorylation. In addition, we observed that 8-ADEQ causes phosphorylation of the cell division cycle 25C (Cdc25C) protein through the activation of checkpoint kinases 1 (Chk1) and Chk2, which in turn were activated via ataxia telangiectasia mutated (ATM)/ataxia telangiectasia-Rad3-related (ATR) kinases in response to the DNA damage. Furthermore, ATM/ATR inhibitor caffeine, p53- or ATM/ATR-specific siRNA significantly attenuated 8-ADEQ-induced G₂/M arrest. These results suggest that the 8-ADEQ inhibits the proliferation of human cervical cancer HeLa cells by DNA damage-mediated G₂/M cell cycle arrest. 8-ADEQ‑induced G₂/M arrest is mediated by the activation of both Chk1/2-Cdc25 and p53-p21CIP1/WAF1 via ATM/ATR pathway, and indicates that 8-ADEQ appears to have potential in the treatment of cervical cancer.

    Topics: Ataxia Telangiectasia Mutated Proteins; Carcinoma; CDC2 Protein Kinase; cdc25 Phosphatases; Cell Cycle Checkpoints; Cell Division; Checkpoint Kinase 1; Checkpoint Kinase 2; Cyclin B1; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinases; DNA Damage; Female; G2 Phase; HeLa Cells; Humans; Phosphorylation; Protein Kinases; Quinazolines; Resveratrol; Signal Transduction; Stilbenes; Tumor Suppressor Protein p53; Up-Regulation; Uterine Cervical Neoplasms

2015
A cluster of noncoding RNAs activates the ESR1 locus during breast cancer adaptation.
    Nature communications, 2015, Apr-29, Volume: 6

    Estrogen receptor-α (ER)-positive breast cancer cells undergo hormone-independent proliferation after deprivation of oestrogen, leading to endocrine therapy resistance. Up-regulation of the ER gene (ESR1) is critical for this process, but the underlying mechanisms remain unclear. Here we show that the combination of transcriptome and fluorescence in situ hybridization analyses revealed that oestrogen deprivation induced a cluster of noncoding RNAs that defined a large chromatin domain containing the ESR1 locus. We termed these RNAs as Eleanors (ESR1 locus enhancing and activating noncoding RNAs). Eleanors were present in ER-positive breast cancer tissues and localized at the transcriptionally active ESR1 locus to form RNA foci. Depletion of one Eleanor, upstream (u)-Eleanor, impaired cell growth and transcription of intragenic Eleanors and ESR1 mRNA, indicating that Eleanors cis-activate the ESR1 gene. Eleanor-mediated gene activation represents a new type of locus control mechanism and plays an essential role in the adaptation of breast cancer cells.

    Topics: Adaptation, Physiological; Base Sequence; Breast Neoplasms; Carcinoma; Estrogen Receptor alpha; Estrogens; Female; Gene Expression Profiling; Gene Expression Regulation; Humans; In Situ Hybridization, Fluorescence; MCF-7 Cells; Molecular Sequence Data; Resveratrol; RNA, Untranslated; Stilbenes

2015
Co-Encapsulation of Combretastatin-A4 Phosphate and Doxorubicin in Polymersomes for Synergistic Therapy of Nasopharyngeal Epidermal Carcinoma.
    Journal of biomedical nanotechnology, 2015, Volume: 11, Issue:6

    In this study, we designed biodegradable polymersomes for co-delivery of an antiangiogenic drug combretastatin-A4 phosphate (CA4P) and doxorubicin (DOX) to collapse tumor neovasculature and inhibit cancer cell proliferation with the aim to achieve synergistic antitumor effects. The polymersomes co-encapsulating DOX and CA4P (Ps-DOX-CA4P) were prepared by solvent evaporation method using methoxy poly(ethylene glycol)-b-polylactide (mPEG-PLA) block copolymers as drug carriers. The resulting Ps-DOX-CA4P has vesicles shape with uniform sizes of about 50 nm and controlled co-encapsulation ratios of DOX to CA4P. More importantly, Ps-DOX-CA4P (1:10) showed strong synergistic cytotoxicity (combination index CI = 0.31) against human nasopharyngeal epidermal carcinoma (KB) cells. Furthermore, Ps-DOX-CA4P accumulated remarkably in KB tissues xenografts in nude mice. Consistent with these observations, Ps-DOX-CA4P (1:10) achieved significant antitumor potency because of fast tumor vasculature disruption and sustained tumor cells proliferation inhibition in vivo. The overall findings indicate that co-delivery of an antiangiogenic drug and a chemotherapeutic agent in polymersomes is a potentially promising strategy for cancer therapy.

    Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Doxorubicin; Drug Carriers; Drug Combinations; Drug Compounding; Drug Synergism; Female; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Nanocapsules; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Polymers; Stilbenes; Tissue Distribution; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

2015
Treatment with a vascular disrupting agent does not increase recruitment of indium labelled human endothelial outgrowth cells in an experimental tumour model.
    BMC cancer, 2014, Dec-02, Volume: 14

    The effect of vascular disrupting agents in tumour therapy depends on both the immediate vascular shutdown, and on the following re-vascularization of the tumour. The aim of this study was to use a tumour model to investigate whether endothelial outgrowth cells (EOCs) influenced the short term treatment efficiency of combretastatin A-4 disodium phosphate (CA4P) and 5,6-dimethylxanthenone-4-acetic acid (DMXAA) by increasing EOC tumour recruitment.. In order to visualize the recruitment of EOCs to the tumours, umbilical cord blood derived human EOCs were labelled with 111Indium-tropolone in a dose of 0.37 MBq pr 3×106 cells and were injected intravenously into mice carrying a C3H mammary carcinoma on their right rear foot. DMXAA and CA4P in different concentrations and at different exposure times were used to create a hypoxic environment in the C3H mammary carcinoma in the mice. Three different mice strains with various degrees of functional immune system were used to study the homing capability of EOCs.. Our data showed that approximately 4% of the total injected radioactive dose per gram of tissue was found in the tumour after treatment with CA4P and DMXAA. Regardless of the concentration and the treatment duration, CA4P did not increase EOC recruitment to the tumour in comparison to EOC recruitment in control tumours in any of the 3 mice strains studied.. Our data showed that regardless of the grade of the immune system, ranging from a fully working to a fully compromised immune system, treatment with CA4P did not increase recruitment of xenotransplanted EOCs to tumour tissue.

    Topics: Angiogenesis Inhibitors; Animals; Breast Neoplasms; Carcinoma; Cell Movement; Cell Survival; Cell Tracking; Cells, Cultured; Disease Models, Animal; Endothelial Cells; Female; Fetal Blood; Humans; Indium Radioisotopes; Mice; Mice, Nude; Stilbenes; Xanthones

2014
Resveratrol inhibits human nasopharyngeal carcinoma cell growth via blocking pAkt/p70S6K signaling pathways.
    International journal of molecular medicine, 2013, Volume: 31, Issue:3

    Resveratrol (trans-3,4',5-trihydroxystilbene) has been shown to exert potent anticancer effects on various types of cancer through its anti-proliferative, anti-angiogenic, antioxidant and pro-apoptotic functions. There is still a lack of experimental evidence regarding whether resveratrol has potential anticancer activity in human nasopharyngeal carcinoma (NPC) cells. The purpose of this study was to explore the anticancer activity of resveratrol in human NPC cells both in vitro and in vivo. Our results indicated that treatment with resveratrol led to a time- and dose-dependent decrease in cell proliferation in NPC cells. A dose-dependent increase in apoptosis in response to resveratrol treatment was also observed in NPC cells. Flow cytometric analysis showed that treatment of NPC cells with resveratrol led to cell cycle arrest at the S and G2/M phases. Mechanistically, resveratrol treatment downregulated the expression of Bcl-2 and hypoxia-inducible factor-1α (HIF-1α) proteins and upregulated the expression of caspase-3 protein. In addition, resveratrol treatment also significantly decreased the phosphorylation levels of Akt1, p70S6K and p-4E-BP-1 and the protein expression of several cyclins involved in cell cycle regulation. In vivo studies further showed that resveratrol was able to significantly inhibit the growth of NPC tumor xenografts in nude mice. Collectively, our findings suggest that resveratrol exerts potent anti-prolife-rative and pro-apoptotic effects on human NPC cells possibly through interfering with the pAkt1/p70S6K signaling pathways, thus it may potentially be developed as an effective agent for chemoprevention and chemotherapy of human NPC.

    Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Carcinoma; Caspase 3; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cyclins; Female; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Mice; Mice, Inbred BALB C; Mice, Nude; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Neoplasm Transplantation; Phosphorylation; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Resveratrol; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Stilbenes; Xenograft Model Antitumor Assays

2013
The effect of sulfated (1→3)-α-l-fucan from the brown alga Saccharina cichorioides Miyabe on resveratrol-induced apoptosis in colon carcinoma Cells.
    Marine drugs, 2013, Jan-21, Volume: 11, Issue:1

    Accumulating data clearly indicate that the induction of apoptosis by nontoxic natural compounds is a potent defense against the development and progression of many malignancies, including colon cancer. Resveratrol and the fucoidans have been shown to possess potent anti-tumor activity in vitro and in vivo. The aim of the present study was to examine whether the combination of a fucoidan from the brown alga Saccharina cichorioides Miyabe and resveratrol would be an effective preventive and/or therapeutic strategy against colon cancer. Based on NMR spectroscopy and MALDI-TOF analysis, the fucoidan isolated and purified from Saccharina cichorioides Miyabe was (1→3)-α-l-fucan with sulfate groups at C2 and C4 of the α-l-fucopyranose residues. The fucoidan enhanced the antiproliferative activity of resveratrol at nontoxic doses and facilitated resveratrol-induced apoptosis in the HCT 116 human colon cancer cell line. Apoptosis was realized by the activation of initiator caspase-9 and effector caspase-7 and -3, followed by the cleavage of PARP. Furthermore, significant inhibition of HCT 116 colony formation was associated with the sensitization of cells to resveratrol by the fucoidan. Taken together, these results demonstrate that the combination of the algal fucoidan with resveratrol may provide a potential therapy against human colon cancer.

    Topics: Antineoplastic Agents; Apoptosis; Carcinoma; Caspases; Cell Line, Tumor; Cell Proliferation; Colonic Neoplasms; HCT116 Cells; Humans; Magnetic Resonance Spectroscopy; Phaeophyceae; Polysaccharides; Resveratrol; Stilbenes; Sulfuric Acid Esters

2013
A combination of resveratrol and melatonin exerts chemopreventive effects in N-methyl-N-nitrosourea-induced rat mammary carcinogenesis.
    European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation (ECP), 2012, Volume: 21, Issue:2

    The neurohormone melatonin is primarily involved in the regulation of circadian rhythms, but also acts as an antioxidant and anticarcinogenic agent, especially in breast cancer. Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a widely known polyphenolic agent from red wine, which has been shown to exert antioxidant, anti-inflammatory and anticarcinogenic effects. The objective of this study was therefore to investigate the effects of melatonin in combination with resveratrol in a rat model of experimental mammary carcinogenesis. Female Sprague-Dawley rats aged 31 days were used in the experiment. Mammary carcinogenesis was induced by N-methyl-N-nitrosourea (NMU), which was administered in two intraperitoneal doses (50 mg/kg of body weight). Chemoprevention with resveratrol and melatonin started 2 weeks before the first dose of NMU and lasted until the end of the experiment. The basic parameters evaluated were: tumour incidence, latency period, tumour frequency per group and tumour volume. In addition, oestrogen receptors ERα and ERß, melatonin receptor MT1, proliferating cell nuclear antigen and vascular endothelial growth factor were determined by immunohistochemical staining. The combination of resveratrol and melatonin reduced tumour incidence by approximately 17% and significantly decreased the quantity of invasive and in-situ carcinomas. Food intake declined in the second and seventh weeks after the administration of carcinogen. Resveratrol in combination with melatonin returned food intake to the level of intact controls. Resveratrol in combination with melatonin has some protective effects on NMU-induced rodent breast cancer. Further studies are necessary to confirm these effects of this promising combination.

    Topics: Algorithms; Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinogens; Carcinoma; Chemoprevention; Drug Evaluation, Preclinical; Estrogen Receptor alpha; Female; Mammary Neoplasms, Experimental; Melatonin; Methylnitrosourea; Proliferating Cell Nuclear Antigen; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes; Vascular Endothelial Growth Factor A

2012
Inhibitory effects of (-)-epigallocatechin-3-gallate and pterostilbene on pancreatic cancer growth in vitro.
    The Journal of surgical research, 2012, Volume: 177, Issue:2

    It has been previously shown that the naturally occurring antioxidant (-)-epigallocatechin-3-gallate (EGCG), found in green tea, and pterostilbene, a stilbenoid derived from blueberries, inhibit pancreatic cancer in vitro when used individually. We hypothesized that the combination of EGCG and pterostilbene would reveal additive effects in vitro.. Using the pancreatic cancer cell lines MIA PaCa-2 and PANC-1, efficacy and synergism were evaluated for cell proliferation and viability (3-(4,5-dimethyltiazol-2-y1)-2,5-diphenltetrazolium bromide assays, cell cycle analysis) and mitochondrial apoptosis (mitochondrial depolarization, cytochrome C release, caspase-3/7 activity, cell death detection using enzyme-linked immunosorbent assay).. Cell proliferation assays revealed significant additive antiproliferative effects with pterostilbene and EGCG in both cell lines at the later, 72-h, point (P < 0.05). MIA underwent S-phase arrest with the combination (10-12% increase); however, cell cycle arrest was not observed in PANC. The combination induced mitochondrial depolarization and upregulated cytochrome C (P < 0.05) in MIA, but these effects were not observed in PANC. EGCG increased caspase-3/7 in MIA; however, the combination did not significantly increase the activity in either cell line (P < 0.05). Apoptosis was only observed in PANC (P < 0.05). The reduction in proliferation in MIA in the 3-(4,5-dimethyltiazol-2-y1)-2,5-diphenltetrazolium bromide assays with the combination indicated that cell death occurs, possibly through another mechanism.. Our results are encouraging regarding the future use of EGCG and pterostilbene to improve traditional pancreatic cancer therapies. In conclusion, EGCG and pterostilbene have additive, antiproliferative effects in vitro and alter the apoptotic mechanisms in both cell lines by modulation at different points in the mechanism.

    Topics: Anticarcinogenic Agents; Carcinoma; Caspases; Catechin; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cytochromes c; DNA Fragmentation; Drug Evaluation, Preclinical; Humans; Pancreatic Neoplasms; Stilbenes

2012
Resveratrol induces apoptosis associated with mitochondrial dysfunction in bladder carcinoma cells.
    International journal of urology : official journal of the Japanese Urological Association, 2012, Volume: 19, Issue:8

    Resveratrol shows chemopreventive activity in a variety of human cancers by targeting mitochondria and triggering apoptosis. The purpose of this study was to investigate the antitumor action of resveratrol in bladder cancer and its underlying mechanism.. Using two different bladder cell lines, BTT739 and T24, the cytotoxicity of resveratrol were determined by MTT assay. The apoptosis induced by resveratrol was assayed by transferase dUTP nick end labeling staining. To show whether the mitochondrial dysfunction involved in the effects of resveratrol, mitochondrial function was detected by mitochondrial membrane potential, reactive oxygen species production and adenosine 5'-triphosphate content. In addition, the markers of apoptosis in the intrinsic mitochondrial-dependent pathway were analyzed by the release of cytochrome c and the activities of caspase-9 and caspase-3.. Resveratrol effectively decreased cell viability and induced apoptosis in a concentration- and time-dependent manner. In addition, resveratrol significantly disrupted the mitochondrial membrane potential in both intact cells and isolated mitochondria. Resveratrol also increased reactive oxygen species production and reduced adenosine 5'-triphosphate concentrations. Western blot analysis showed that resveratrol provoked the release of cytochrome c from mitochondria to the cytosol. Furthermore, resveratrol significantly promoted the activation of caspase-9 and caspase-3.. These findings suggest that resveratrol efficiently triggers apoptosis in bladder cancer cells through the intrinsic mitochondrial-dependent pathway, which is associated with mitochondrial dysfunction. Resveratrol might have great pharmacological promise in the treatment of bladder cancer.

    Topics: Adenosine Triphosphate; Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Carcinoma; Caspase 3; Caspase 9; Cell Line, Tumor; Cytochromes c; Drug Screening Assays, Antitumor; Enzyme Activation; Humans; Membrane Potential, Mitochondrial; Mice; Reactive Oxygen Species; Resveratrol; Stilbenes; Urinary Bladder Neoplasms

2012
Resveratrol induces apoptosis of human nasopharyngeal carcinoma cells via activation of multiple apoptotic pathways.
    Journal of cellular physiology, 2011, Volume: 226, Issue:3

    Resveratrol, a naturally occurring dietary compound with chemopreventive properties has been reported to trigger a variety of cancer cell types to apoptosis. Whether resveratrol shows any activity on human nasopharyngeal carcinoma (NPC) cells remained to be determined. The aim of this study was to investigate the effect and mechanism of resveratrol on human NPC cells. Treatment of resveratrol resulted in significant decrease in cell viability of NPC cell lines in a dose- and time-dependent manner. A dose-dependent apoptotic cell death was also measured by flow cytometery analysis. Molecular mechanistic studies of apoptosis unraveled resveratrol treatment resulted in a significant loss of mitochondrial transmembrane potential, release of cytochrome c, enhanced expression of Fas ligand (FasL), and suppression of glucose-regulated protein 78 kDa (GRP78). These were followed by activation of caspases-9, -8, -4, and -3, subsequently leading to DNA fragmentation and cell apoptosis. Furthermore, up-regulation of proapoptotic Bax and down-regulation of antiapoptotic Bcl-2 protein were also observed. Taken together, resveratrol induces apoptosis in human NPC cells through regulation of multiple apoptotic pathways, including death receptor, mitochondria, and endoplasmic reticulum (ER) stress. Resveratrol can be developed as an effective compound for human NPC treatment.

    Topics: Apoptosis; Carcinoma; Caspases; Cell Line, Tumor; Cell Survival; DNA Fragmentation; Drug Screening Assays, Antitumor; Endoplasmic Reticulum Chaperone BiP; Fas Ligand Protein; Gene Expression Regulation, Neoplastic; Heat-Shock Proteins; Humans; Membrane Potential, Mitochondrial; Models, Biological; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Proto-Oncogene Proteins c-bcl-2; Resveratrol; Signal Transduction; Stilbenes; Transcription Factor CHOP

2011
Resveratrol and N-acetylcysteine block the cancer-initiating step in MCF-10F cells.
    Free radical biology & medicine, 2011, Jan-01, Volume: 50, Issue:1

    Substantial evidence suggests that catechol estrogen-3,4-quinones react with DNA to form predominantly the depurinating adducts 4-hydroxyestrone (estradiol)-1-N3Ade [4-OHE(1)(E(2))-1-N3Ade] and 4-OHE(1)(E(2))-1-N7Gua. Apurinic sites resulting from these adducts generate critical mutations that can initiate cancer. The paradigm of cancer initiation is based on an imbalance in estrogen metabolism between activating pathways that lead to estrogen-DNA adducts and deactivating pathways that lead to estrogen metabolites and conjugates. This imbalance can be improved to minimize formation of adducts by using antioxidants, such as resveratrol (Resv) and N-acetylcysteine (NAcCys). To compare the ability of Resv and NAcCys to block formation of estrogen-DNA adducts, we used the human breast epithelial cell line MCF-10F treated with 4-OHE(2). Resv and NAcCys directed the metabolism of 4-OHE(2) toward protective pathways. NAcCys reacted with the quinones and reduced the semiquinones to catechols. This pathway was also carried out by Resv. In addition, Resv induced the protective enzyme quinone reductase, which reduces E(1)(E(2))-3,4-quinones to 4-OHE(1)(E(2)). Resv was more effective at increasing the amount of 4-OCH(3)E(1)(E(2)) than NAcCys. Inhibition of estrogen-DNA adduct formation was similar at lower doses, but at higher doses Resv was about 50% more effective than NAcCys. Their combined effects were additive. Therefore, these two antioxidants provide an excellent combination to protect catechol estrogens from oxidation to catechol quinones.

    Topics: Acetylcysteine; Anticarcinogenic Agents; Breast Neoplasms; Carcinoma; Cell Line; Cell Transformation, Neoplastic; Drug Combinations; Drug Evaluation, Preclinical; Drug Synergism; Female; Humans; Mammary Glands, Human; Models, Biological; Resveratrol; Stilbenes

2011
Rhapontigenin inhibited hypoxia inducible factor 1 alpha accumulation and angiogenesis in hypoxic PC-3 prostate cancer cells.
    Biological & pharmaceutical bulletin, 2011, Volume: 34, Issue:6

    Hypoxia inducible factor 1 alpha (HIF-1α) is frequently over-expressed in the numerous types of cancer and plays an important role in angiogenesis. In the present study, the inhibitory mechanism of rhapontigenin isolated from Vitis coignetiae was investigated on HIF-1α stability and angiogenesis in human prostate cancer PC-3 cells. Rhapontigenin significantly suppressed HIF-1α accumulation at protein level but not at mRNA level in PC-3 cells under hypoxia. Also, rhapontigenin suppressed hypoxia-induced HIF-1α activation in various cancer cells, such as colorectal adenocarcinoma (SW620), breast adenocarcinoma (MCF-7), fibrosarcoma (HT-1080) and prostate carcinoma (LNCaP). Interestingly, rhapontigenin had more potency in inhibition of hypoxia-induced HIF-1α expression than that of resveratrol, a known HIF-1α inhibitor. In addition, rhapontigenin promoted hypoxia-induced HIF-1α degradation and cycloheximide (CHX) blocked protein synthesis. A prolyl hydroxylase (PHD) inhibitor dimethyloxalylglycine (DMOG) is usually utilized to examine whether prolyl hydroxylation is involved in inhibition of HIF-1α accumulation. Here, DMOG recovered HIF-1α accumulation inhibited by rhapontigenin. Immunoprecipitation assay also revealed that rhapotigenin enhanced the binding of hydroxylated HIF-1α to von Hippel-Lindau (VHL) tumor suppressor protein. Furthermore, rhapontigenin reduced vascular endothelial growth factor (VEGF) secretion in hypoxic PC-3 cells as well as suppressed tube formation in human umbilical vein endothelial cells (HUVECs) treated by the conditioned media of hypoxic PC-3 cells. However, anti-angiogenic effect of rhapontigenin in hypoxic PC-3 cells was reversed by DMOG. Taken together, these findings suggest that rhapontigenin inhibits HIF-1α accumulation and angiogenesis in PC-3 prostate cancer cells.

    Topics: Amino Acids, Dicarboxylic; Angiogenesis Inhibitors; Carcinoma; Cell Hypoxia; Cell Line; Cell Line, Tumor; Culture Media, Conditioned; Endothelium, Vascular; Enzyme Inhibitors; Female; Humans; Hydroxylation; Hypoxia-Inducible Factor 1, alpha Subunit; Male; Neoplasms; Neovascularization, Pathologic; Procollagen-Proline Dioxygenase; Prostatic Neoplasms; Protein Processing, Post-Translational; Stilbenes; Vascular Endothelial Growth Factor A; Von Hippel-Lindau Tumor Suppressor Protein

2011
Interleukin-1beta-induced iNOS expression in human lung carcinoma A549 cells: involvement of STAT and MAPK pathways.
    Indian journal of experimental biology, 2011, Volume: 49, Issue:11

    For understanding of signaling molecules important in lung cancer growth and progression, IL-1beta effect was analyzed on iNOS expression and key signaling molecules in human lung carcinoma A549 cells and established the role of specific signaling molecules by using specific chemical inhibitors. IL-1beta exposure (10 ng/ml) induced strong iNOS expression in serum starved A549 cells. Detailed molecular analyses showed that IL-1beta increased expression of phosphorylated STAT1 (Tyr701 and Ser727) and STAT3 (Tyr705 and Ser727) both in total cell lysates and nuclear lysates. Further, IL-1beta exposure strongly activated MAPKs (ERK1/2, JNK1/2 and p38) and Akt as well as increased nuclear levels of NF-kappaB and HIF-1alpha in A549 cells. Use of specific chemical inhibitors for JAK1 kinase (piceatannol), JAK2 kinase (AG-490), MEK1/2 (PD98059) and JNK1/2 (SP600125) revealed that IL-1beta-induced iNOS expression involved signaling pathways in addition to JAK-STAT and ERK1/2-JNK1/2 activation. Overall, these results suggested that instead of specific pharmacological inhibitors, use of chemopreventive agents with broad spectrum efficacy to inhibit IL-1beta-induced signaling cascades and iNOS expression would be a better strategy towards lung cancer prevention and/or treatment.

    Topics: Carcinoma; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Humans; Janus Kinase 1; Lung Neoplasms; MAP Kinase Signaling System; Nitric Oxide Synthase Type II; Signal Transduction; STAT1 Transcription Factor; STAT3 Transcription Factor; Stilbenes

2011
3,5,3',4',5'-pentamethoxystilbene (MR-5), a synthetically methoxylated analogue of resveratrol, inhibits growth and induces G1 cell cycle arrest of human breast carcinoma MCF-7 cells.
    Journal of agricultural and food chemistry, 2010, Jan-13, Volume: 58, Issue:1

    3,5,3',4',5'-pentamethoxystilbene (MR-5) is a synthetically methoxylated analogue of resveratrol and has been suggested to have antitumor activity because of structural similarity to resveratrol. Herein, we investigate the antiproliferative effect of MR-5 in human breast cancer MCF-7 cells and demonstrate that MR-5 had a more potent inhibition on cell growth compared with resveratrol and other methoxylated derivatives. Exploring the growth-inhibitory mechanisms of MR-5, we found that it is accompanied by G1 cell cycle arrest, which coincides with a marked inhibition of G1 cell cycle regulatory proteins, including decreased cyclins (D1/D3/E) and cyclin-dependent kinases (CDK2/4/6) and increased CDK inhibitors (CKIs) such as p15, p16, p21, and p27. Furthermore, the increase in CKI levels by MR-5 resulted in a concomitant increase in their interactions of CDK4 and CDK2, along with a strong inhibition in CDK4 kinase activity and the accumulation of hypophosphorylated Rb. MR-5 also modulated some critical kinase activities related to cell cycle regulation, including Akt, mitogen-activated protein kinase (ERK1/2), p38 mitogen-activated protein kinase (p38 MAPK), and focal adhesion kinase (FAK) in MCF-7 cells. In total, our results demonstrate that MR-5 affects multiple cellular targets that contribute to its antiproliferative activity in MCF-7 cells and provide novel information for synthetic chemists to design new antitumor agents with introduction of methoxylated group(s) in the basic compound.

    Topics: Breast Neoplasms; Carcinoma; Cell Cycle; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Female; Gene Expression Regulation, Neoplastic; Growth Inhibitors; Humans; Stilbenes

2010
Pterostilbene inhibits lung cancer through induction of apoptosis.
    The Journal of surgical research, 2010, Jun-01, Volume: 161, Issue:1

    Lung cancer remains the leading cause of cancer mortality in the United States. Resveratrol is a potent antioxidant found in grapes that inhibits several types of cancer, including lung cancer. Herein, we investigated the effects of pterostilbene, an analog of resveratrol found in blueberries, on lung cancer, in vitro. We hypothesized that pterostilbene would inhibit lung cancer cell growth in vitro by a pro-apoptotic mechanism.. Two lung cancer cell lines (NCI-H460 and SK-MES-1) were cultured using standard techniques. Cells were treated with increasing doses of pterostilbene (10-100 microM). Cell viability was measured at 24, 48, and 72h using a MTT assay. Apo-ONE Caspase-3/7 assay was used to evaluate caspase activity. T-test and two-way ANOVA were used for statistical analysis.. Pterostilbene significantly decreased cell viability in lung cancer cells in a concentration- and time-dependent manner (P<0.001). Concentrations greater than 20 microM of pterostilbene produced significant growth inhibition by 72h (P<0.001). Apoptosis and caspase-3/7 activity were significantly increased by pterostilbene treatment (P<0.05).. Pterostilbene inhibits growth via apoptosis induction in vitro. Further in vitro mechanistic studies and in vivo experiments are warranted to determine the potential role for pterostilbene in lung cancer treatment or prevention.

    Topics: Apoptosis; Carcinoma; Caspases, Effector; Cell Line, Tumor; Drug Evaluation, Preclinical; Humans; Lung Neoplasms; Stilbenes; Up-Regulation

2010
Resveratrol-induced p53-independent apoptosis of human nasopharyngeal carcinoma cells is correlated with the downregulation of ΔNp63.
    Cancer gene therapy, 2010, Volume: 17, Issue:12

    ΔNp63, the N-terminal truncated isoform of p63, has been found to be overexpressed in several human epithelial cancers, including nasopharyngeal carcinomas (NPCs), suggesting a function in carcinogenesis. Trans-resveratrol (RSV) has been shown to exert proapoptotic activities through a p53-dependent or p53-independent pathway in various cancer cells. However, the effects of RSV on NPC are still unexplored. In this study, we investigated the apoptotic effects of RSV on ΔNp63-overexpressing NPC cell lines. We showed that RSV (12-100 μ) induced dose-dependent growth suppression, cell-cycle arrest in the S phase and caspase-dependent apoptosis in NPC-TW076 and NPC-TW039 cells. The RSV effect was accompanied by the downregulation of ΔNp63 and the upregulation of p53 protein in a dose-dependent manner. By using small-interfering RNA (siRNA) technology, we found that the targeted silencing of ΔNp63 induced apoptosis and sensitized the NPC cells to RSV-induced apoptosis through caspase-3 activation, whereas suppression of p53 by siRNA did not inhibit RSV-induced apoptosis. Furthermore, transfection with p53 siRNA or pretreatment with caspase inhibitors (Z-VAD-fmk or Z-DEVD-fmk) had no influence on the RSV downregulation of ΔNp63. Interestingly, ecoptic expression of ΔNp63 did not significantly block RSV-induced cell death and was also downregulated after RSV treatment. Downregulation of ΔNp63 by RSV was shown to occur at the mRNA transcript and post-translational levels. Importantly, RSV enhanced chemotheraptic drug-induced apoptosis in NPC and two human carcinoma cell lines, HT1376 and Hep3B cells. These results suggested that ΔNp63, but not p53, is a molecular target of RSV-induced apoptosis and the regulation of ΔNp63 expression by RSV may provide a therapeutic effect of RSV in human NPC.

    Topics: Anticarcinogenic Agents; Apoptosis; Carcinoma; Cell Line, Tumor; Cell Proliferation; Down-Regulation; Humans; Nasopharyngeal Neoplasms; Resveratrol; RNA, Small Interfering; Stilbenes; Trans-Activators; Transcription Factors; Tumor Suppressor Protein p53; Tumor Suppressor Proteins

2010
Non-invasive imaging of combretastatin activity in two tumor models: Association with invasive estimates.
    Acta oncologica (Stockholm, Sweden), 2010, Volume: 49, Issue:7

    The efficacy of the vascular disrupting agent combretastatin A-4 phosphate (CA4P) depends on several factors including tumor size, nitric oxide level, interstitial fluid pressure, and vascular permeability. These factors vary among tumor types. The aim of this study was to investigate all these factors in two tumor models that respond differently to CA4P.. Mice bearing C3H mammary carcinomas or KHT sarcomas (200 to 800 mm(3)) were intraperitoneally injected with CA4P (100 mg/kg). Tumor size and the effect of a nitric oxide inhibitor nitro-L-arginine (NLA) administered intravenously were evaluated by necrotic fraction histologically assessed at 24 hours. Interstitial fluid pressure (IFP) was measured using the wick-in-needle technique, and vascular characteristics were assessed with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI).. Initial necrotic fraction was about 10% in both tumor models at 200 mm(3), but only increased significantly with tumor size in the C3H mammary carcinoma. In this tumor, CA4P significantly induced further necrosis by about 15% at all sizes, but in the KHT tumor, the induced necrotic fraction depended on tumor size. For both tumor types, NLA with CA4P significantly increased necrotic fraction above that for each drug alone. CA4P significantly decreased IFP in all tumors except in the 800 mm(3) C3H tumor, which had an initially non-significant lower value. Interstitial volume estimated by DCE-MRI increased in all groups, except the 800 mm(3) C3H tumors. DCE-MRI vascular parameters showed different initial characteristics and general significant reductions following CA4P treatment.. Both tumor models showed differences in all factors before treatment, and in their response to CA4P. Perfusion and permeability as estimated by DCE-MRI play a central role in the CA4P response, and interstitial volume and IFP seemed related. These factors may be of clinical value in the planning of CA4P treatments.

    Topics: Animals; Antineoplastic Agents, Phytogenic; Carcinoma; Cell Line, Tumor; Contrast Media; Diagnostic Imaging; Disease Models, Animal; Female; Magnetic Resonance Imaging; Mammary Neoplasms, Experimental; Mice; Mice, Inbred C3H; Nitric Oxide; Sarcoma; Statistics as Topic; Stilbenes; Treatment Outcome; Tumor Burden

2010
Chemoprevention of ovarian cancer.
    Cancer treatment and research, 2009, Volume: 149

    Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Anticarcinogenic Agents; Apoptosis; Carcinoma; Chemoprevention; Chickens; Disease Models, Animal; Drug Delivery Systems; Fatty Acids, Omega-3; Female; Humans; Mice; Neoplasm Proteins; Ovarian Neoplasms; Phytoestrogens; Progestins; Resveratrol; Retinoids; Stilbenes; Vitamin D

2009
[Resveratrol increases sensitivity of CNE2 cells to chemotherapeutic drugs under hypoxia].
    Zhong xi yi jie he xue bao = Journal of Chinese integrative medicine, 2009, Volume: 7, Issue:10

    To explore the sensitization effects of resveratrol on CNE2 nasopharyngeal carcinoma cell line with hypoxia-induced chemotherapy resistance and the potential mechanism.. Human CNE2 nasopharyngeal carcinoma cell line was cultured under hypoxic conditions (37 degrees centigrade, 5% CO(2), 2% O(2)) in vitro. The cultured cells were treated with different concentrations of resveratrol for 48 h. Reversal fold (RF) of reseratrol to chemotherapeutic drugs in CNE2 cells was measured by methyl thiazolyl tetrazolium (MTT) assay. Apoptotic rate of CNE2 cells was observed by flow cytometry. Reverse transcription-polymerase chain reaction (RT-PCR) method and Western blotting were used to investigate the expressions of multidrug resistance gene 1 (mdr1), multidrug resistance-associated protein 1 (MRP1) and hypoxia inducible factor 1alpha (HIF-1alpha) in CNE2 cells.. Resveratrol combined with chemotherapeutics produced a synergistic effect. The RF of 200 micromol/L resveratrol to paclitaxel was 2.58. Combined with paclitaxel, 25, 50, 100 and 200 micromol/L of resveratrol increased the apoptotic rate of CNE2 cells from (22.14+/-1.09)% to (23.24+/-1.37)%, (27.57+/-2.01)%, and (30.36+/-2.31)%, respectively. Resveratrol could down-regulate the expressions of HIF-1alpha, mdr1 and MRP1 significantly. After being treated with resveratrol at different concentrations separately, the expressions of HIF-1alpha, mdr1 and MRP1 in CNE2 cells decreased significantly as compared with paclitaxel alone or paclitaxel plus verapamil (P<0.01).. Resveratrol can enhance the sensitivity of CNE2 cells to chemotherapeutic drugs under hypoxia. The potential mechanism is partly attributed to inhibiting the gene expressions of HIF-1alpha, mdr1 and MRP1.

    Topics: Antineoplastic Agents, Phytogenic; Carcinoma; Cell Hypoxia; Cell Line, Tumor; Down-Regulation; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Multidrug Resistance-Associated Proteins; Nasopharyngeal Neoplasms; Paclitaxel; Resveratrol; Stilbenes

2009
Overexpression of human papillomavirus type 16 oncoproteins enhances hypoxia-inducible factor 1 alpha protein accumulation and vascular endothelial growth factor expression in human cervical carcinoma cells.
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2007, May-01, Volume: 13, Issue:9

    Human papillomavirus (HPV)-16 oncoproteins, E6 and E7, are associated with enhanced tumor angiogenesis in human cervical cancers. The purpose of this study was (a) to investigate whether expression of HPV-16 E6 and E7 oncoproteins induces hypoxia-inducible factor 1 alpha (HIF-1 alpha) and vascular endothelial growth factor expression in cervical cancer cells; and (b) to assess the effect of resveratrol on 16 E6- and E7-induced HIF-1 alpha and VEGF gene expression.. Human cervical cancer cell lines C-33A and HeLa were transiently cotransfected with pSG5-HPV-16 E6 or 16 E7 constructs along with HIF-1 alpha small interfering RNA (siRNA) or nonspecific siRNA. The expression of HIF-1 alpha/VEGF was measured using real-time PCR, Western blot analysis, or ELISA. The in vitro angiogenic activity induced by 16 E6- and E7-transfected cells was examined. The effect of resveratrol on oncoprotein-induced HIF-1 alpha/VEGF expression and in vitro angiogenesis was investigated.. HPV-16 E6- and E7-transfected cervical cancer cells express increased HIF-1 alpha protein and VEGF expression. These stimulatory effects were abrogated by cotransfection with either HIF-1 alpha siRNA or treatment with resveratrol. Blocking extracellular signal-regulated kinase 1/2 (ERK 1/2) and phosphoinositide-3-kinase by PD98059 and LY294002, respectively, abolished 16 E6- and E7-induced HIF-1 alpha and VEGF expression. Functionally, we showed that HPV-16 E6- and E7-transfected cervical cancer cells stimulated in vitro capillary or tubule formation, and these angiogenic effects could be abolished either by cotransfection with HIF-1 alpha siRNA or by treatment with resveratrol.. HPV-16 oncoproteins contribute to enhanced angiogenesis in cervical cancer cells via HIF-1 alpha-dependent VEGF expression. Resveratrol suppresses 16 E6- and E7-induced HIF-1 alpha-mediated angiogenic activity and, thus, is a promising chemotherapeutic agent for human cervical cancer.

    Topics: Anticarcinogenic Agents; Carcinoma; Chromones; Female; Flavonoids; HeLa Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Morpholines; Neovascularization, Pathologic; Oncogene Proteins, Viral; Papillomavirus E7 Proteins; Phosphoinositide-3 Kinase Inhibitors; Repressor Proteins; Resveratrol; RNA, Small Interfering; Stilbenes; Transcriptional Activation; Transfection; Uterine Cervical Neoplasms; Vascular Endothelial Growth Factor A

2007
Combination chemotherapy including combretastatin A4 phosphate and paclitaxel is effective against anaplastic thyroid cancer in a nude mouse xenograft model.
    The Journal of clinical endocrinology and metabolism, 2007, Volume: 92, Issue:8

    Anaplastic thyroid cancer (ATC) is extremely aggressive, and no effective treatment is available. Combretastatin A4 phosphate (CA4P), a vascular disrupting agent, has limited activity against ATC in a clinical trial, and so does paclitaxel.. We hypothesized that a triple-drug combination including CA4P and paclitaxel would improve efficacy against ATC. Therefore, we evaluated two such combinations in vivo.. We used a nude mouse xenograft model with ARO and KAT-4 cells.. The first combination consisted of CA4P, paclitaxel, and manumycin A (a farnesyltransferase inhibitor), and the second, CA4P, paclitaxel, and carboplatin.. Main outcome measures included tumor growth curves and tumor weights.. Tumor growth curve analysis (linear mixed models, P < 0.05) and xenograft weight analysis (Kruskal-Wallis one-way ANOVA on ranks, post hoc pairwise comparison, Dunn's test, P < 0.05) demonstrated that both triple-drug combinations were significantly better than placebo for both cell lines. Anti-bromodeoxyuridine immunostaining of xenograft sections from animals injected with bromodeoxyuridine before being killed showed that CA4P alone did not inhibit DNA synthesis, but manumycin A and paclitaxel did. CA4P decreased the depth of the viable outer rim of tumor cells on xenograft sections. Using electron microscopy, we found blebbing/budding of endothelial cells into capillary lumens and autophagy of tumor cells in CA4P-treated xenografts.. Both triple-drug combinations demonstrated excellent antineoplastic activity against ATC. The correlative findings in xenografts were consistent with vascular disruption but not direct inhibition of cell proliferation as the primary antineoplastic mechanism contributed by CA4P. These regimens warrant further investigation in clinical trials for ATC.

    Topics: Animals; Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Bromodeoxyuridine; Carboplatin; Carcinoma; Cell Line, Tumor; Cell Shape; Endothelial Cells; Humans; Immunohistochemistry; Mice; Mice, Nude; Microscopy, Electron, Transmission; Neoplasm Transplantation; Paclitaxel; Polyenes; Polyunsaturated Alkamides; Stilbenes; Thyroid Neoplasms; Transplantation, Heterologous

2007
Molecular mechanisms of resveratrol action in lung cancer cells using dual protein and microarray analyses.
    Cancer research, 2007, Dec-15, Volume: 67, Issue:24

    Resveratrol, a natural phytoestrogen found in red wine and a variety of plants, is reported to have protective effects against lung cancer; however, there is little work directed toward the understanding of the mechanism of its action in this disease. In this study, we used a combination of experimental approaches to understand the biological activity and molecular mechanisms of resveratrol. Microarray gene expression profiling and high-throughput immunoblotting (PowerBlot) methodologies were employed to gain insights into the molecular mechanisms of resveratrol action in human lung cancer cells. In this report, we confirm the up-regulation of p53 and p21 and the induction of apoptosis by the activation of the caspases and the disruption of the mitochondrial membrane complex. We show the arrest of A549 cells in the G(1) phase of cell cycle in the presence of resveratrol and also report alterations in both gene and protein expressions of cyclin A, chk1, CDC27, and Eg5. Furthermore, the results indicated that resveratrol action is mediated via the transforming growth factor-beta pathway, particularly through the Smad proteins. Results showed the down-regulation of the Smad activators 2 and 4 and the up-regulation of the repressor Smad 7 as a result of resveratrol treatment. Resveratrol is a potent inhibitor of A549 lung cancer cell growth, and our results suggest that resveratrol may be a promising chemopreventive or chemotherapeutic agent for lung cancer.

    Topics: Anticarcinogenic Agents; Carcinoma; Cell Cycle; Cell Division; Cell Line, Tumor; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Oligonucleotide Array Sequence Analysis; Resveratrol; Stilbenes; Tumor Suppressor Protein p53

2007
Resveratrol-caused apoptosis of human prostate carcinoma LNCaP cells is mediated via modulation of phosphatidylinositol 3'-kinase/Akt pathway and Bcl-2 family proteins.
    Molecular cancer therapeutics, 2006, Volume: 5, Issue:5

    Prostate cancer is a major health problem in the U.S. and the available treatment and surgical options have proven to be inadequate in controlling the mortality and morbidity associated with this disease. It is therefore necessary to intensify our efforts to better understand this disease and develop novel approaches for its prevention and treatment. This study was conducted to evaluate the chemopreventive/antiproliferative potential of resveratrol (trans-3,4',5,-trihydroxystilbene) against prostate cancer and its mechanism of action. Treatment with resveratrol (0-50 micromol/L for 24 hours) resulted in a significant (a) decrease in cell viability, (b) decrease of clonogenic cell survival, (c) inhibition of androgen (R1881)-stimulated growth, and (d) induction of apoptosis in androgen-responsive human prostate carcinoma (LNCaP) cells. Interestingly, at similar concentrations, resveratrol treatment did not affect the viability or rate of apoptosis in normal human prostate epithelial cells. Furthermore, our data showed that resveratrol-treatment resulted in significant dose-dependent inhibition in the constitutive expression of phosphatidylinositol 3'-kinase and phosphorylated (active) Akt in LNCaP cells. Resveratrol treatment for LNCaP cells was also found to result in a significant (a) loss of mitochondrial membrane potential, (b) inhibition in the protein level of antiapoptotic Bcl-2, and (c) increase in proapoptotic members of the Bcl-2 family, i.e., Bax, Bak, Bid, and Bad. Taken together, our data suggested that resveratrol causes an inhibition of phosphatidylinositol 3'-kinase/Akt activation that, in turn, results in modulations in Bcl-2 family proteins in such a way that the apoptosis of LNCaP cells is promoted. Based on these studies, we suggest that resveratrol could be developed as an agent for the management of prostate cancer.

    Topics: Androgens; Antineoplastic Agents, Phytogenic; Apoptosis; Carcinoma; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Down-Regulation; Humans; Male; Microscopy, Fluorescence; Phosphatidylinositol 3-Kinases; Prostatic Neoplasms; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Resveratrol; Signal Transduction; Stilbenes

2006
Low-dose combretastatin A4 phosphate enhances the immune response of tumor hosts to experimental colon carcinoma.
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2006, Aug-01, Volume: 12, Issue:15

    Although there is a need to enhance the therapeutic efficiency in cancer by combining immunotherapeutic procedures with other therapy, combination with chemotherapy is complicated due to immunosuppressive effects of most chemotherapeutic drugs. The purpose of this investigation was to study whether combining tumor cell immunization with the vascular targeting drug combretastatin A4 phosphate (CA4P) would enhance tumor retardation and/or affect the antitumor immune response.. Rats with intrahepatic colon carcinoma were immunized weekly with IL-18/IFNgamma-transfected tumor cells, starting day 9, and were treated with a low-dose CA4P (2 mg/kg, 5 days a week starting day 7). The effect of CA4P was studied on tumor growth and on immune reactivity in vitro.. Rats with preexisting tumor, immunized and treated with low-dose CA4P, had a significantly retarded tumor growth compared with rats receiving CA4P or immunization alone. Splenocytes from rats treated with this combination had a significantly enhanced antitumor immune response compared with splenocytes from control rats. Exposure of nonadherent splenocytes to CA4P in vitro did not enhance their proliferation. However, 3-hour pretreatment of adherent splenocytes with 0.3 microg/mL CA4P significantly enhanced proliferation and IFNgamma production of admixed nonadherent splenocytes, partly due to nitric oxide reduction. Combining the nitric oxide synthase inhibitor N-nitro-l-arginine methyl ester with CA4P and immunization further retarded tumor growth.. Concomitant treatment of rats with progressively growing tumor with immunization and low-dose CA4P significantly enhances the therapeutic effect as compared with either treatment alone and results in an enhanced antitumor immune reactivity.

    Topics: Administration, Oral; Animals; Carcinoma; Cell Proliferation; Colonic Neoplasms; Dose-Response Relationship, Drug; Dose-Response Relationship, Immunologic; Humans; Injections, Intraperitoneal; Interferon-gamma; NG-Nitroarginine Methyl Ester; Nitric Oxide; Rats; Rats, Inbred BN; Rats, Inbred WF; Stilbenes; Structure-Activity Relationship; Transplantation, Heterologous; Xenograft Model Antitumor Assays

2006
Resveratrol interferes with AKT activity and triggers apoptosis in human uterine cancer cells.
    Molecular cancer, 2006, Oct-17, Volume: 5

    Endometrial cancer is the fourth most prominent cancer among all feminine cancers in the Western world. Resveratrol, a natural anti-oxidant found in red wine emerging as a novel anticancer agent, exerts antiproliferative and pro-apoptotic activity in various cancer cell types, but its effect on uterine cancer cells is poorly understood. At the molecular level, resveratrol has been reported to inhibit cyclooxygenase (COX) expression and/or activity; in endometrial cancer cells, COX-2 is overexpressed and confers cellular resistance to apoptosis. The aim of the present study was to determine if resveratrol could exert anti-proliferative and pro-apoptotic activity over uterine cancer cells upon inhibition of COX-2 expression and/or activity. Six different human uterine cancer cell lines were used as a model (HeLa, Hec-1A, KLE, RL95-2, Ishikawa and EN-1078D).. High-dose of resveratrol triggered apoptosis in five out of six uterine cancer cell lines, as judged from Hoechst nuclear staining and effector caspase cleavage. In accordance, uterine cancer cell proliferation was decreased. Resveratrol also reduced cellular levels of the phosphorylated/active form of anti-apoptotic kinase AKT. Endogenous COX-2 protein levels were decreased, concomitant with a decrease in production of COX metabolites PGE2 and PGF2alpha, in each uterine cancer cell line expressing detectable levels of COX-1 and/or COX-2 in presence of resveratrol. Although COX expression was identified as a target of resveratrol in uterine cancer cells, inhibition of COX activity or exogenously added PGE2 did not modulate the effect of resveratrol on cellular proliferation.. High-dose of resveratrol exerts tumoricidal activity over uterine cancer cells and regulates COX expression. In these cells, resveratrol would not directly target COX activity, but possibly other enzymes involved in prostaglandin synthesis that act downstream of the COXs.

    Topics: Apoptosis; Carcinoma; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cyclooxygenase 1; Cyclooxygenase 2; Dinoprostone; Endometrial Neoplasms; Female; HeLa Cells; Humans; Proto-Oncogene Proteins c-akt; Resveratrol; Signal Transduction; Stilbenes; Uterine Neoplasms

2006
Anti-vascular agent Combretastatin A-4-P modulates hypoxia inducible factor-1 and gene expression.
    BMC cancer, 2006, Dec-07, Volume: 6

    A functional vascular network is essential for the survival, growth and spread of solid tumours, making blood vessels a key target for therapeutic strategies. Combretastatin A-4 phosphate (CA-4-P) is a tubulin-depolymerising agent in Phase II clinical trials as a vascular disrupting agent. Not much is known of the molecular effect of CA-4-P under tumour conditions. The tumour microenvironment differs markedly from that in normal tissue, specifically with respect to oxygenation (hypoxia). Gene regulation under tumour conditions is governed by hypoxia inducible factor 1 (HIF-1), controlling angiogenic and metastatic pathways.. We investigated the effect of CA-4-P on factors of the upstream and downstream signalling pathway of HIF-1 in vitro.. CA-4-P treatment under hypoxia tended to reduce HIF-1 accumulation in a concentration-dependent manner, an effect which was more prominent in endothelial cells than in cancer cell lines. Conversely, CA-4-P increased HIF-1 accumulation under aerobic conditions in vitro. At these concentrations of CA-4-P under aerobic conditions, nuclear factor kappaB was activated via the small GTPase RhoA, and expression of the HIF-1 downstream angiogenic effector gene, vascular endothelial growth factor (VEGF-A), was increased.. Our findings advance the understanding of signal transduction pathways involved in the actions of the anti-vascular agent CA-4-P.

    Topics: Antineoplastic Agents, Phytogenic; Carcinoma; Colonic Neoplasms; Dose-Response Relationship, Drug; Gene Expression Regulation, Neoplastic; Humans; Hypoxia-Inducible Factor 1; Signal Transduction; Stilbenes; Tumor Cells, Cultured; Urinary Bladder Neoplasms

2006
Redistribution of CD95, DR4 and DR5 in rafts accounts for the synergistic toxicity of resveratrol and death receptor ligands in colon carcinoma cells.
    Oncogene, 2004, Nov-25, Volume: 23, Issue:55

    The natural phytoalexin resveratrol (3, 5, 4'-trihydroxystilbene) exhibits both chemopreventive and antitumor activities through a variety of mechanisms. We have shown previously that resveratrol-induced apoptosis of a human colon cancer cell line involved the redistribution of CD95 (Fas/Apo-1) into lipid rafts. Here, we show that, in colon cancer cells that resist to resveratrol-induced apoptosis, the polyphenol also induces a redistribution of death receptors into lipid rafts. This effect sensitizes these tumor cells to death receptor-mediated apoptosis. In resveratrol-treated cells, tumor necrosis factor (TNF), anti-CD95 antibodies and TNF-related apoptosis-inducing ligand (TRAIL) activate a caspase-dependent death pathway that escapes Bcl-2-mediated inhibition. Resveratrol does not enhance the number of death receptors at the surface of tumor cells but induces their redistribution into lipid rafts and facilitates the caspase cascade activation in response to death receptor stimulation. The cholesterol sequestering agent nystatin prevents resveratrol-induced death receptor redistribution and cell sensitization to death receptor stimulation. Thus, whatever its ability to induce apoptosis in a tumor cell, resveratrol induces redistribution of death receptors into lipid rafts. This redistribution sensitizes the cells to death receptor stimulation. Such a sensitizing effect may be of therapeutic interest if TRAIL agonists are introduced in clinics.

    Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Apoptosis Regulatory Proteins; Blotting, Western; Carcinoma; Caspases; Cell Line, Tumor; Colonic Neoplasms; fas Receptor; Flow Cytometry; Humans; Ligands; Lipid Metabolism; Lipids; Membrane Glycoproteins; Membrane Microdomains; Mitochondria; Nystatin; Proto-Oncogene Proteins c-bcl-2; Receptors, TNF-Related Apoptosis-Inducing Ligand; Receptors, Tumor Necrosis Factor; Resveratrol; Signal Transduction; Stilbenes; Time Factors; TNF-Related Apoptosis-Inducing Ligand; Transfection; Tumor Necrosis Factor-alpha

2004
Resveratrol induces apoptosis in human esophageal carcinoma cells.
    World journal of gastroenterology, 2003, Volume: 9, Issue:3

    To investigate the apoptosis in esophageal cancer cells induced by resveratrol, and the relation between this apoptosis and expression of Bcl-2 and Bax.. In in vitro experiments, MTT assay was used to determine the cell growth inhibitory rate. Transmission electron microscope and TUNEL staining method were used to quantitatively and qualitively detect the apoptosis status of esophageal cancer cell line EC-9706 before and after the resveratrol treatment. Immunohistochemical staining was used to detect the expression of apoptosis-regulated gene Bcl-2 and Bax.. Resveratrol inhibited the growth of esophageal cancer cell line EC-9706 in a dose-and time-dependent manner. Resveratrol induced EC-9706 cells to undergo apoptosis with typically apoptotic characteristics, including morphological changes of chromatin condensation, chromatin crescent formation, nucleus fragmentation and apoptotic body formation. TUNEL assay showed that after the treatment of EC-9706 cells with resveratrol (10 mmol/L) for 24 to 96 hours, the AIs were apparently increased with treated time (P<0.05). Immunohistochemical staining showed that after the treatment of EC-9706 cells with resveratrol (10 mmol/L) for 24 to 96 hours, the PRs of Bcl-2 proteins were apparently reduced with treated time (P<0.05) and the PRs of Bax proteins were apparently increased with treated time (P<0.05).. Resveratrol is able to induce the apoptosis in esophageal cancer. This apoptosis may be mediated by down-regulating the apoptosis-regulated gene Bcl-2 and up-regulating the expression of apoptosis-regulated gene bax.

    Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Carcinoma; Esophageal Neoplasms; Humans; Resveratrol; Stilbenes; Tumor Cells, Cultured

2003
Comparative molecular field analysis study of stilbene derivatives active against A549 lung carcinoma.
    Chemical & pharmaceutical bulletin, 2003, Volume: 51, Issue:5

    A series of 43 stilbene derivatives that showed cytotoxicity against human lung carcinoma (A549) was analyzed using comparative molecular field analysis (CoMFA) for defining the hypothetic pharmacophore model. The polyoxylated stilbenes were found to be active inhibitors of tubulin polymerization. Several cis-stilbenes are structurally similar to combretastatins. However, the trans-stilbenes are assumed to be close to resveratrol found in grapes and have been reported to be potential cancer chemopreventive agents by modulating the initiation, promotion, and progression of the carcinogenic process. With several synthesized compounds that were evaluated for antitumor cytotoxicity against human lung tumor cells (A549), the stilbene derivatives were subjected to CoMFA. To perform systematic molecular modeling of these compounds, a conformational search was carried out based on the precise dihedral angle analysis of the lead compound (1p). The X-ray crystallographic structure of combretastatin A-1 was also used for defining the active conformers of the compounds. After determining the energy-minimized conformers of the lead compound (1p), CoMFA was performed using five different alignments. The three dimensional (3D)-quantitative structure-activity relationship study resulted in reasonable cross-validated, conventional r(2) values equal to 0.640 and 0.958, respectively.

    Topics: Algorithms; Antineoplastic Agents; Carcinoma; Cell Line, Tumor; Cell Survival; Computer Simulation; Crystallography, X-Ray; Heterocyclic Compounds; Humans; Lung Neoplasms; Models, Molecular; Molecular Conformation; Quantitative Structure-Activity Relationship; Stilbenes

2003
Antiproliferative effect of resveratrol in human prostate carcinoma cells.
    Journal of medicinal food, 2003,Winter, Volume: 6, Issue:4

    Resveratrol, a polyphenolic phytoalexin found in grapes, may have potential for the prevention and treatment of human cancer. We report here that resveratrol inhibits the growth of human prostate carcinoma DU145 cells and provide a molecular explanation of the effect. Resveratrol treatment in DU145 cells resulted in a dose-dependent inhibition of cell growth and induced apoptotic cell death. The antiproliferative effect of resveratrol was associated with the inhibition of D-type cyclins and cyclin-dependent kinase (Cdk) 4 expression, and the induction of tumor suppressor p53 and Cdk inhibitor p21. Moreover, the kinase activities of cyclin E and Cdk2 were inhibited by resveratrol without alteration of their protein levels. Resveratrol treatment also up-regulated the Bax protein and mRNA expression in a dose-dependent manner; however, Bcl-2 and Bcl-xL levels were not significantly affected. These effects were found to correlate with an activation of caspase-3 and caspase-9. Taken together, our study suggests that resveratrol has a strong potential for development as an agent for the prevention of human prostate cancer.

    Topics: Antineoplastic Agents, Phytogenic; Apoptosis; bcl-2-Associated X Protein; Carcinoma; Caspases; Cell Division; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinases; Cyclins; Dose-Response Relationship, Drug; Humans; Male; Prostatic Neoplasms; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Resveratrol; Stilbenes; Tumor Cells, Cultured; Tumor Suppressor Protein p53; Up-Regulation

2003
Role of Bax in resveratrol-induced apoptosis of colorectal carcinoma cells.
    BMC cancer, 2002, Oct-17, Volume: 2

    The natural plant polyphenol resveratrol present in some foods including grapes, wine, and peanuts, has been implicated in the inhibition, delay, and reversion of cellular events associated with heart diseases and tumorigenesis. Recent work has suggested that the cancer chemoprotective effect of the compound is primarily linked to its ability to induce cell division cycle arrest and apoptosis, the latter possibly through the activation of pro-apoptotic proteins such as Bax.. The expression, subcellular localization, and importance of Bax for resveratrol-provoked apoptosis were assessed in human HCT116 colon carcinoma cells and derivatives with both bax alleles inactivated.. Low to moderate concentrations of resveratrol induced co-localization of cellular Bax protein with mitochondria, collapse of the mitochondrial membrane potential, activation of caspases 3 and 9, and finally, apoptosis. In the absence of Bax, membrane potential collapse was delayed, and apoptosis was reduced but not absent. Resveratrol inhibited the formation of colonies by both HCT116 and HCT116 bax -/- cells.. Resveratrol at physiological doses can induce a Bax-mediated and a Bax-independent mitochondrial apoptosis. Both can limit the ability of the cells to form colonies.

    Topics: Anticarcinogenic Agents; Apoptosis; bcl-2-Associated X Protein; Carcinoma; Cell Survival; Colorectal Neoplasms; Humans; Membrane Potentials; Mitochondria; Mutation; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Resveratrol; Stilbenes; Tumor Cells, Cultured

2002
Combretastatin A4 phosphate has primary antineoplastic activity against human anaplastic thyroid carcinoma cell lines and xenograft tumors.
    Thyroid : official journal of the American Thyroid Association, 2002, Volume: 12, Issue:12

    Anaplastic thyroid carcinoma (ATC) is a fatal malignancy the clinical outcome of which is unaltered by current therapeutic modalities. A recent phase 1 clinical trial of combretastatin A4 phosphate (CA4P) produced a long-lasting total remission in a patient with ATC. CA4P is a tubulin-binding agent derived from the African bush willow, Combretum caffrum, which possesses tumor vascular-targeting activity. In order to discriminate primary antineoplastic effects from tumor antivascular activity, we evaluated CA4P cytotoxicity in eight human ATC cell lines and compared it to paclitaxel, another tubulin-binding agent with significant clinical activity. CA4P displayed significant cytotoxicity against the ATC cell lines, comparable to that of paclitaxel, and these effects were longer lasting in two cell lines compared to the duration of paclitaxel. We further investigated the effects of CA4P on xenograft tumors from four ATC cell lines injected in athymic nude mice. Significantly lower tumor weights were observed in animals treated with CA4P compared to those treated with vehicle alone. Continuous monitoring of xenograft tumor volumes from one of the ATC cell lines also revealed a significantly lower rate of tumor growth in the CA4P-treated mice compared to those receiving vehicle alone. These results suggest that antitumoral effects of CA4P can be consequent to a combination of primary antineoplastic effects as well as the potential destruction of tumor vasculature.

    Topics: Animals; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Cell Division; Dose-Response Relationship, Drug; Humans; Male; Mice; Mice, Nude; Paclitaxel; Stilbenes; Thyroid Neoplasms; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

2002
Interactive gene expression pattern in prostate cancer cells exposed to phenolic antioxidants.
    Life sciences, 2002, Mar-01, Volume: 70, Issue:15

    Dietary phenolic compounds are known to elicite vital cellular responses such as cell cycle arrest, apoptosis and differentiation by activating a cascade of molecular events. As there is an increasing interest to improve the efficacy of these compounds for use as potential chemopreventive agents, we wanted to understand the impact of phenolic compounds on target genes in prostate cancer. In this study we used human cDNA microarrays with 2400 clones consisting of 17 prosite motifs to characterize alterations in gene expression pattern in response to the phenolic antioxidants ellagic acid (EA) and resveratrol (RE). Over a 48-hr exposure of androgen - sensitive LNCaP cells to EA and RE, a total of 593 and 555 genes respectively, showed more than a two fold difference in expression. A distinct set of genes in both EA-and RE-treated cells may represent the signature profile of phenolic antioxidant-induced gene expression in LNCaP cells. Although extensive similarity was found between effects of EA - and RE - responsive genes in prostate cancer cells, out of 246 genes with overlapping responses, 25 genes showed an opposite effect. Quantitative RT-PCR was used to verify and validate the differential expression of selected genes identified from cDNA microarrays. In-depth analysis of the data from this study provided insight into the alterations in the p53 - responsive genes, p300, Apaf-1, NF-kBp50 and p65 and PPAR families of genes, suggesting the activation of multiple signaling pathways that leads to growth inhibition of LNCaP cells. This is a first study to look for changes in a large number of human genes in response to dietary compounds.

    Topics: Anticarcinogenic Agents; Antioxidants; Carcinoma; DNA, Neoplasm; Ellagic Acid; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Male; Oligonucleotide Array Sequence Analysis; Phenols; Prostatic Neoplasms; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Stilbenes; Tumor Cells, Cultured

2002
Molecular mechanism of action at estrogen receptor alpha of a new clinically relevant antiestrogen (GW7604) related to tamoxifen.
    Endocrinology, 2001, Volume: 142, Issue:2

    Tamoxifen is the endocrine treatment of choice for all stages of estrogen receptor (ER)-positive breast cancer, and it is the first drug approved to reduce the incidence of breast cancer in high-risk women. Unfortunately, tamoxifen also possesses some estrogen-like effects in the uterus that cause a modest increase in the risk of endometrial cancer. GW5638 is a tamoxifen derivative with a novel carboxylic acid side chain with no uterotropic activity in the rat (Willson et al., J Med Chem, 1994, 37:1550-1552). We have compared and contrasted the actions of 4-hydroxytamoxifen (4-OHT, the active metabolite of tamoxifen) with GW7604 [the presumed metabolite of GW5638 in breast (MCF-7) and endometrial (ECC-1) cell lines in vitro]. GW7604 did not cause the growth of ECC-1 cells at any concentration (10(-11)-10(-6) M), but 4-OHT was weakly estrogen-like at low concentrations (10(-11)-10(-10) M). Compounds (10(-7) M) blocked the growth promoting action of estradiol (10(-10) M) in both ECC-1 and MCF-7 cells. Western blotting was used to show that GW7604 and raloxifene did not affect ER levels significantly, compared with controls, in MCF-7 cells; whereas the pure antiestrogen ICI182,780 decreased ER levels (P < 0.05). An assay system was used that can classify compounds into tamoxifen-like, raloxifene-like, or pure antiestrogens. The assay depends on the activation of the transforming growth factor alpha (TGFalpha) gene in situ by wild-type or D351Y mutant ER stably transfected into MDA-MB-231 cells (MacGregor-Schafer et al., Cancer Res, 1999, 59:4308-4313). GW7604 inhibited both estradiol (10(-9) M) and 4-OHT (10(-8), 10(-7) M) induction of TGFalpha in a concentration related manner (10(-9)-10(-6) M). GW7604 and raloxifene stimulated TGFalpha with the D351Y ER. In contrast, ICI 182,780 (10(-6) M) did not initiate TGFalpha and blocked the induction of TGFalpha with GW7604, raloxifene, and 4-OHT in D351Y-transfected cells. Using computer-assisted molecular models of ER complexes, we found that the antiestrogenic side chain of 4-OHT weakly interacted with the surface amino acid 351 (aspartate), but the carboxylic acid of GW7604 caused a strong repulsion of aspartate 351. We propose that GW7604 is less estrogen-like than 4-OHT, because it disrupts the surface charge around aa351 required for coactivator docking in the 4-OHT:ER complex. This charge is restored in the D351Y ER, thus converting GW7604 from an antiestrogen to an estrogen-like molecule.

    Topics: Carcinoma; Cell Division; Cinnamates; Endometrial Neoplasms; Estrogen Receptor alpha; Estrogen Receptor Modulators; Estrogens; Female; Gene Expression Regulation; Humans; Models, Molecular; Receptors, Estrogen; RNA, Messenger; Selective Estrogen Receptor Modulators; Stilbenes; Tamoxifen; Transforming Growth Factor alpha; Tumor Cells, Cultured

2001
cGMP-dependent protein kinase regulation of a chloride channel in T84 cells.
    The American journal of physiology, 1992, Volume: 262, Issue:5 Pt 1

    Chloride channels at the apical membrane of intestinal epithelial cells are involved in the excessive fluid secretion in diarrhea and diminished secretion in cystic fibrosis (CF). Diarrhea induced by heat-stable toxin from Escherichia coli is associated with elevated guanosine 3',5'-cyclic monophosphate (cGMP) in intestinal epithelial cells, but it is unknown whether chloride secretion is regulated by cGMP directly or via cGMP-dependent protein kinase (PKG). Single-channel recordings (inside-out excised patches) from the apical membrane of T84 cells reveal a 10-pS chloride channel with a linear current-voltage relationship, which is opened when an endogenous membrane-bound PKG is activated with ATP (1 mM) and cGMP (100 microM). Soluble PKG (200 nM) isolated from bovine lung, added to the intracellular face of patches, also opens this channel. No activation occurs with Ringer solution alone or only ATP or cGMP. Addition of nonhydrolyzable forms of ATP (AMP-PNP, 1 mM) or a combination of ATP, cGMP, plus H-8 (5 microM), an inhibitor of PKG, also does not stimulate the channel. The catalytic subunit of adenosine 3',5'-cyclic mono-phosphate-dependent protein kinase (PKA, 200 nM, with 1 mM ATP) activates a channel with similar characteristics. The 10 pS channel has a PNa/PCl ratio of 0.06, an anion selectivity of Br- (1.2) greater than Cl- (1.0) greater than I- (0.8) greater than F- (0.4), and a low affinity for the chloride channel blockers, 4,4-dinitrostilbene-2,2-disulfonic acid and 5-nitro-2-(3-phenylpropylamino)benzoic acid.(ABSTRACT TRUNCATED AT 250 WORDS)

    Topics: Adenosine Triphosphate; Carcinoma; Chloride Channels; Chlorides; Colonic Neoplasms; Cyclic GMP; Electric Conductivity; Humans; Ion Channel Gating; Membrane Proteins; Nitrobenzoates; Protein Kinases; Stilbenes; Tumor Cells, Cultured

1992
I.C.I. 46,474 in breast cancer.
    Journal of the Irish Medical Association, 1974, Jan-26, Volume: 67, Issue:2

    Topics: Adult; Aged; Antineoplastic Agents; Breast Neoplasms; Carcinoma; Dimethylamines; Drug Evaluation; Female; Humans; Middle Aged; Phenyl Ethers; Stilbenes

1974
[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
Combined action of optical brighteners and ultraviolet light in the production of tumours.
    Food and cosmetics toxicology, 1970, Volume: 8, Issue:2

    Topics: Animals; Carcinoma; Coumarins; Detergents; Male; Mice; Skin Neoplasms; Skin Ulcer; Stilbenes; Ultraviolet Rays

1970
The effects of clomiphene citrate on the endometrium.
    American journal of obstetrics and gynecology, 1965, Nov-15, Volume: 93, Issue:6

    Topics: Carcinoma; Endometrial Hyperplasia; Endometrium; Female; Humans; Menopause; Stilbenes; Uterine Neoplasms

1965
[STEROID HORMONE EXCRETION OF PATIENTS WITH DISEASES OF THE PROSTATE UNDER TREATMENT WITH NATURAL AND SYNTHETIC ESTROGENS].
    Acta endocrinologica, 1964, Volume: 45

    Topics: 17-Ketosteroids; Adenoma; Adrenal Cortex Hormones; Carcinoma; Estradiol; Estradiol Congeners; Estriol; Estrone; Geriatrics; Humans; Male; Prostatic Neoplasms; Stilbenes; Urine

1964
THE USE OF CLOMIPHENE IN DYSFUNCTIONAL BLEEDING DUE TO ENDOMETRIAL HYPERPLASIA.
    The Journal of obstetrics and gynaecology of the British Commonwealth, 1964, Volume: 71

    Topics: Carcinoma; Carcinoma, Squamous Cell; Clomiphene; Endometrial Hyperplasia; Female; Hemorrhage; Humans; Metrorrhagia; Pathology; Stilbenes; Uterine Neoplasms

1964
TACE in the treatment of carcinoma of the prostate: an 80-month survey.
    The Journal of urology, 1958, Volume: 80, Issue:2

    Topics: Carcinoma; Data Collection; Humans; Male; Prostatic Neoplasms; Stilbenes

1958
TACE in the treatment of carcinoma of the prostate: an 80-month surgery.
    Transactions. American Urological Association. South Central Section, 1957, Volume: 52

    Topics: Carcinoma; Humans; Male; Prostatic Neoplasms; Stilbenes

1957
Endocrine therapy in carcinoma of the prostate.
    Journal of the American Medical Association, 1955, Feb-12, Volume: 157, Issue:7

    Topics: Carcinoma; Hormones; Humans; Male; Prostatic Neoplasms; Stilbenes

1955
[Stilbene indications and dosage in the therapy of prostatic carcinoma].
    Munchener medizinische Wochenschrift (1950), 1951, Jun-01, Volume: 93, Issue:22

    Topics: Carcinoma; Humans; Male; Prostate; Prostatic Neoplasms; Stilbenes

1951