stilbenes and Astrocytoma

Topics: Animals; Antineoplastic Agents; Astrocytoma; Brain Neoplasms; Carcinogens; Carcinoma, Squamous Cell; Child; Ear Neoplasms; Ependymoma; Female; Humans; Immunosuppressive Agents; Isoniazid; Maternal-Fetal Exchange; Mice; Mycotoxins; Neoplasms; Nitrosourea Compounds; Occupational Diseases; Oligodendroglioma; Otorhinolaryngologic Diseases; Pregnancy; Rats; Stilbenes

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor. Patients diagnosed with GBM have a poor prognosis, and it has been reported that tumor malignancy and GBM recurrence are promoted by STAT3 signaling. As resveratrol (RV), a polyphenol in grapes, is reported to be a potent and non-toxic cancer-preventive compound, the aim of this study was to investigate the therapeutic effect and molecular mechanisms of RV on GBM-derived radioresistant tumor initiating cells (TIC). Firstly, our results showed that primary GBM-CD133(+) TIC presented high tumorigenic and radiochemoresistant properties as well as increased protein levels of phosphorylated STAT3. We consistently observed that treatment with shRNA-STAT3 (sh-STAT3) or AG490, a STAT3 inhibitor, significantly inhibited the cancer stem-like cell properties and radioresistance of GBM-CD133(+) in vitro and in vivo. Furthermore, treatment of GBM-CD133(+) with 100 µM RV induced apoptosis and enhanced radiosensitivity by suppressing STAT3 signaling. Microarray results suggested that RV or AG490 inhibited the stemness gene signatures of GBM-CD133(+) and facilitated the differentiation of GBM-CD133(+) into GBM-CD133(-) or astrocytoma cells. Finally, xenotransplant experiments indicated that RV or sh-STAT3 therapy could significantly improve the survival rate and synergistically enhance the radiosensitivity of radiation-treated GBM-TIC. In summary, RV can reduce in vivo tumorigenicity and enhance the sensitivity of GBM-TIC to radiotherapies through the STAT3 pathway.

Topics: Aged; Animals; Antineoplastic Agents, Phytogenic; Astrocytoma; Brain Neoplasms; Chemoradiotherapy; Female; Glioblastoma; Humans; Male; Mice; Mice, SCID; Middle Aged; Resveratrol; Signal Transduction; STAT3 Transcription Factor; Stilbenes; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Resveratrol (3,4',5-trans-trihydroxystilbene) and other hydroxystilbenes exhibit in vitro antioxidant as well as prooxidant effects. The antioxidant properties are assumed to enable these compounds to protect cells from oxidative damage. The prooxidant effects are held likely to be responsible for their cytotoxic, anti-proliferative or pro-apoptotic effects observed in vitro. Regarding antioxidant/prooxidant activities in the past various studies were performed aiming at defining structure-activity relationships for hydroxystilbenes using cell-free systems. In the present study cultured C6 glioma cells were used in order to investigate the relationship between the antioxidant, cytoprotective and cytotoxic activities of resveratrol and selected analogues, e.g., 3,3',4',5-trans-tetrahydroxystilbene (piceatannol), 3,3',5,5'-trans-tetrahydroxystilbene (3,3',5,5'-THS) and 3,3',4',5,5'-trans-pentahydroxystilbene (3,3',4',5,5'-PHS). All these compounds were cytotoxic to growth-arrested C6 cells, with EC50-values between 20 and 85 microM. A higher cytotoxic potency in proliferating cells indicated a specific cytostatic activity of resveratrol and 3,3',4',5,5'-PHS. All hydroxystilbenes studied inhibited cellular radical generation induced by cumene hydroperoxide (CHP). The rank order of antioxidant potency was resveratrol>piceatannol>3,3',5,5'-THS>3,3',4',5,5'-PHS. However, only resveratrol and piceatannol inhibited cellular radical generation at lower than cytotoxic concentrations. At subcytotoxic concentrations only piceatannol was able to protect the cells from damage caused by CHP. Taken together, these results show that neither the cytotoxic or cytostatic activities of hydroxystilbenes nor their cytoprotective and antioxidant activities in living cells can be predicted from their antioxidant and prooxidant activity, respectively, in cell-free systems.

Topics: Animals; Antineoplastic Agents, Phytogenic; Antioxidants; Astrocytoma; Cell Line, Tumor; Cell Proliferation; Free Radicals; Oxidative Stress; Rats; Reactive Oxygen Species; Resveratrol; Stilbenes

Plant polyphenols like flavonoids and hydroxystilbens have been found to possess radical scavenging/antioxidative activity, especially when studied in cell-free systems. A positive effect in such assays, however, does not necessarily indicate a protective activity against deleterious effects of oxidative stress in intact cells. In fact it has been shown that polyphenols can act as anti-oxidants as well as pro-oxidants. The aim of the present study was to investigate whether and with what potency selected polyphenols are able to inhibit cellular radical generation in C6 cells and whether they can induce oxidative stress themselves. Cumene hydroperoxide (CHP) was used as a model to induce radical generation which was measured by means of a fluorometric 2',7'-dichlorodihydro-fluorescein assay. CHP-induced, time and concentration dependent, a manifold increase of DCF fluorescence indicating intracellular radical generation. This process was inhibited by all the flavonoids and the hydroxystilben resveratrol, at low micromolar concentrations. The most potent compounds, luteolin and galangin, already at concentrations of 5 to 10 microM nearly completely abolished the radical generation in the presence of 500 microM CHP. The following ranking of anti-oxidative potency was obtained: luteolingalangin>kaempferol>quercetin>resveratrolgenisteintaxifolin. This ranking is completely different from that obtained by means of a trolox equivalent antioxidant capacity (TEAC) assay in a cell-free system, thus putting the biological relevance of the latter in question. Remarkably, one compound induced oxidative stress itself, namely genistein. This flavonoid inhibited the cellular radical generation in the presence of CHP while it significantly enhanced it in the absence of the peroxide.

Topics: Astrocytoma; Benzene Derivatives; Brain Neoplasms; Dose-Response Relationship, Drug; Flavonoids; Free Radical Scavengers; Free Radicals; Genistein; Luteolin; Oxidants; Oxidative Stress; Phenols; Plant Extracts; Polyphenols; Resveratrol; Stilbenes

Resveratrol, a natural polyphenolic antioxidant found in red wine and grapes, has been reported to exert a variety of important pharmacological effects, including anti-inflammatory, cardioprotective, and cancer chemopreventive properties. In the present study, we investigated the effect of resveratrol on the production of nitric oxide (NO) and prostaglandin (PG) E2 by lipopolysaccharide (LPS)-activated C6 microglia. Exposure of cultured rat C6 astroglioma cells to LPS increased their release of NO and PGE2 and their inducible expression of NO synthase and cyclooxygenase-2, all of which were significantly inhibited by resveratrol pretreatment. Further studies revealed that resveratrol suppressed LPS-induced nuclear translocation and activation of nuclear factor kappaB (NF-kappaB). These results demonstrate a potent suppressive effect of resveratrol on pro-inflammatory responses of microglia by modulation of NF-kappaB activity, suggesting a therapeutic potential for this compound in neurodegenerative diseases accompanied by microglial activation.

Topics: Animals; Astrocytoma; Cell Division; Cell Line, Tumor; Cell Nucleus; Cyclooxygenase 2; Dinoprostone; Gene Expression; Lipopolysaccharides; Microglia; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase Type II; Rats; Resveratrol; Stilbenes

Resveratrol, a constituent found in grapes and various other plants, has been shown to have chemo-preventive activity against cancer, and specifically demonstrated to induce apoptosis by p53-dependent pathways in murine cells. The goal of this research was to identify the role of p53-dependent or p53-independent pathways in the induction of apoptosis in human breast cancer cells by this natural product.. A number of human breast cancer cell lines, as well as a control of a wild-type line (astrocytoma N 1321N1), were investigated for induction of apoptosis by resveratrol using both microscopic evaluation and DNA fragmentation assays. Concurrently, we established the p53 gene status (wild-type or mutant) of each cell line by Western blot using p53-specific antibody.. Apoptosis induced by resveratrol was found to occur only in breast cancer cells expressing wild-type p53 but not in mutant p53-expressing cells.. We therefore conclude that the natural product, resveratrol, induces apoptosis in breast cancer cells via p53-dependent pathways.

Topics: Antineoplastic Agents, Phytogenic; Antioxidants; Apoptosis; Astrocytoma; Blotting, Western; Breast Neoplasms; Cell Division; Cell Line, Tumor; Cell Transformation, Neoplastic; DNA Fragmentation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Female; Humans; Resveratrol; Signal Transduction; Stilbenes; Time Factors; Transcriptional Activation; Tumor Suppressor Protein p53

Expression of voltage-activated ion channels was studied in primary cultures from seven freshly resected human primary brain tumors and in an established human astrocytoma cell line, STTG1. Astrocytoma cells consistently expressed voltage-dependent outwardly rectifying currents. Currents activated at potentials > 45 mV and showed outward transients on termination of voltage steps. Currents reversed at the Cl equilibrium potential, suggesting that they were largely carried by Cl-. Altering extracellular K- or Na+ concentration did not alter currents; neither did replacement of intracellular K+ by Cs+ or intracellular Na+ by N-methyl-D-glucosamine. Anion-substitution experiments suggest the following permeability sequence, determined from shifts in tail current reversal potential: I- > NO3- > Br- > Cl- > acetate > isethionate > F- > glutamate. Currents were sensitive to the Cl- channel blockers chlorotoxin, 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), and 4,4'-dinitrostilbene-2,2' disulfonic acid (DNDS), with chlorotoxin being most effective, yielding > 80% block at 590 nM. DIDS (100 microM) and DNDS (100 microM) reduced currents by 33.5 and 38.2%, respectively. Currents were also sensitive to Zn2+ (100 microM, 47% block) and Cd2- (25 microM, 42% block). Reducing extracellular Ca2+ concentration decreased outward currents by 58% and almost completely eliminated transients, suggesting that Cl- currents are Ca2+ dependent. Cl channel block resulted in altered cell proliferation as determined by [3H]thymidine incorporation, suggesting that these channels may be involved in astrocytoma growth control.

Topics: 4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid; Astrocytoma; Brain Neoplasms; Cell Division; Chloride Channels; Chlorides; Electric Conductivity; Humans; Scorpion Venoms; Stilbenes; Tumor Cells, Cultured