lignans and Glioma

Glioma is difficult-to-treat because of its infiltrative nature and the presence of the blood-brain barrier. Temozolomide is the only FDA-approved drug for its management. Therefore, finding a novel chemotherapeutic agent for glioma is of utmost importance. Magnolol, a neolignan, has been known for its apoptotic role in glioma. In this work, we have explored a novel anti-glioma mechanism of Magnolol associated with its role in autophagy modulation. We found increased expression levels of Beclin-1, Atg5-Atg12, and LC3-II and lower p62 expression in Magnolol-treated glioma cells. PI3K/AKT/mTOR pathway proteins were also downregulated in Magnolol-treated glioma cells. Next, we treated the glioma cells with Insulin, a stimulator of PI3K/AKT/mTOR signaling, to confirm that Magnolol induced autophagy by inhibiting this pathway. Insulin reversed the effect on Magnolol-mediated autophagy induction. We also established the same in in vivo glioma model where Magnolol showed an anti-glioma effect by inducing autophagy. To confirm the cytotoxic effect of Magnolol-induced autophagy, we used Chloroquine, a late-stage autophagy inhibitor. Chloroquine efficiently reversed the anti-glioma effects of Magnolol both in vitro and in vivo. Our study revealed the cytotoxic effect of Magnolol-induced autophagy in glioma, which was not previously reported. Additionally, Magnolol showed no toxicity in non-cancerous cell lines as well as rat organs. Thus, we concluded that Magnolol is an excellent candidate for developing new therapeutic strategies for glioma management.

Topics: Animals; Antineoplastic Agents; Apoptosis; Autophagy; Cell Line, Tumor; Chloroquine; Glioma; Insulins; Lignans; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats; TOR Serine-Threonine Kinases

The aim of the current study was to investigate the anticancer potential of bioactive compounds isolated from the leaves of. The compounds were isolated from the ethyl acetate fraction of the leaves extract of. Overall, the findings suggest that the tested compounds from

Topics: ErbB Receptors; Glioma; Lignans; Molecular Docking Simulation; Olea; Plant Extracts

Glioma is a leading cause of central nervous system malignant tumor-associated deaths in the world. However, the molecular mechanisms for glioma progression are still unclear, lacking effective therapeutic strategies. Gomisin J (GomJ) is a derivative of lignan compound, and shows regulatory effects on virus, oxidative stress and tumor progression. However, the role of GomJ in the meditation of glioma progression has not been explored. In this study, we found that GomJ markedly reduced the proliferation of glioma cell lines. Mitochondrial apoptosis was highly induced by GomJ, as evidenced by the significantly up-regulated expression of cytoplastic Cyto-c and cleaved Caspase-3. In addition, mitochondrial membrane potential (MMP) and oxidative stress were highly triggered in GomJ-incubated glioma cells, accompanied with the glycolysis suppression. Importantly, we found that GomJ could dramatically reduce the expression of hexokinase II (HKII) in glioma cells. At the same time, the dissociation of HKII from voltage-dependent anion channel (VDAC) in mitochondria was markedly induced by GomJ, contributing to glycolytic repression. The in vivo experiments confirmed that GomJ obviously reduced the growth of glioma with HKII reduction and few side effects. Taken together, these results demonstrated that GomJ could inhibit the proliferation, induce apoptosis and restrain HKII-regulated glycolysis during glioma progression. Herein, GomJ with few toxicity might be served as a potential therapeutic strategy for the treatment of glioma in humans.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Cell Line, Tumor; Disease Progression; Glioma; Glycolysis; Hexokinase; Humans; Lignans; Membrane Potential, Mitochondrial; Mice; Mice, Inbred BALB C; Mice, Nude; Mitochondria; Oxidative Stress; Polycyclic Compounds; Schisandra; Voltage-Dependent Anion Channels; Xenograft Model Antitumor Assays

Arctigenin (ARG) is a natural lignan compound extracted from Arctium lappa and has displayed anticancer function and therapeutic effect in a variety of cancers. Arctigenin is mainly from Arctium lappa extract. It has been shown to induce autophagy in various cancers. However, as for whether arctigenin induces autophagy in gliomas or not, the specific mechanism is still worth exploring.. Using CCK8, the monoclonal experiment was made to detect the proliferation ability. The scratch experiment and the transwell experiment were applied to the migration and invasion ability. PI/RNase and FITC-conjugated anti-annexin V were used to detect the cell cycle and apoptosis. Western blotting was used to determine the specified protein level, and constructed LC3B-GFP plasmid was used for analysis of autophagy.. Our research showed that ARG inhibited the growth and proliferation and invasion and migration of glioma cells in a dose-dependent manner (U87MG and T98G) and arrested the cell cycle and induced apoptosis. Interestingly, ARG induced autophagy in a dose-dependent manner. We applied Western blotting to measure the increase in the key autophagy protein LC3B, as well as some other autophagy-related proteins (increase in Beclin-1 and decrease in P62). In order to further explore the mechanism that ARG passed initiating autophagy to inhibit cell growth, we further found by Western blotting that AKT and mTOR phosphorylation proteins (P-AKT, P-mTOR) were reduced after ARG treatment, and we used AKT agonists to rescue, and the phosphorylated proteins of AKT and mTOR increased, and we found that the autophagy-related proteins were also reversed. And interestingly, the protein of apoptosis was also reversed along with autophagy.. We thought ARG inhibited the proliferation of glioma cells by inducing autophagy and apoptosis through the AKT/mTOR pathway.

Topics: Apoptosis; Autophagy; Cell Cycle; Cell Line, Tumor; Cell Movement; Cell Proliferation; Furans; Glioblastoma; Glioma; Humans; Lignans; Phosphatidylinositol 3-Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases

The incidence, risk factors, and outcomes of low-grade glioma patients who undergo malignant transformation (MT) in the era of temozolomide are not well known. This study evaluates these factors in a large group of World Health Organization grade 2 glioma patients treated at a tertiary-care institution.. Patient, tumor, and treatment factors were analyzed using an institutional review board-approved low-grade glioma database. Characteristics were compared using χ. Of a total of 599 patients, 124 underwent MT; 76 (61.3%) had biopsy-proven MT. The MT incidence was 21%, and the median time to MT was 56.4 months. The 5- and 10-year progression-free survival rates were 30.6% ± 4.2% and 4.8% ± 1.9%, respectively, for MT patients and 60% ± 2.4% and 38% ± 2.7%, respectively, for non-MT patients. The 5- and 10-year overall survival rates were 75% ± 4.0% and 46% ± 5.0%, respectively, for MT patients and 87% ± 1.7% and 78% ± 2.3%, respectively, for non-MT patients. On multivariate analysis, older age (P = .001), male sex (P = .004), multiple tumor locations (P = .004), chemotherapy alone (P = .012), and extent of resection (P = .045) remained significant predictors of MT.. MT affects survival. Risk factors include older age, male sex, multiple tumor locations, use of chemotherapy alone, and presence of residual disease. Our finding that initial interventions could affect the rate of MT is provocative, but these data should be validated using data from prospective trials. In addition to improving survival, future therapeutic efforts should focus on preventing MT.

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Analysis of Variance; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Brain Neoplasms; Cell Transformation, Neoplastic; Chi-Square Distribution; Child; Child, Preschool; Female; Glioma; Glycosides; Humans; Incidence; Infant; Lignans; Male; Middle Aged; Progression-Free Survival; Risk Factors; Sex Factors; Statistics, Nonparametric; Temozolomide; Time Factors; Young Adult

Temozolomide (TMZ)-induced side effects and drug tolerance to human gliomas are still challenging issues now. Our previous studies showed that honokiol, a major bioactive constituent of Magnolia officinalis (Houpo), is safe for normal brain cells and can kill human glioma cells. This study was further aimed to evaluate the improved effects of honokiol and TMZ on drug-sensitive and -resistant glioma cells and the possible mechanisms.. TMZ-sensitive human U87-MG and murine GL261 glioma cells and TMZ-resistant human U87-MR-R9 glioma cells were exposed to honokiol and TMZ, and cell viability and LC50 of honokiol were assayed. To determine the death mechanisms, caspase-3 activity, DNA fragmentation, apoptotic cells, necrotic cells, cell cycle, and autophagic cells. The glioma cells were pretreated with 3-methyladenine (3-MA) and chloroquine (CLQ), two inhibitors of autophagy, and then exposed to honokiol or TMZ.. Exposure of human U87-MG glioma cells to honokiol caused cell death and significantly enhanced TMZ-induced insults. As to the mechanism, combined treatment of human U87-MG cells with honokiol and TMZ induced greater caspase-3 activation, DNA fragmentation, cell apoptosis, and cell-cycle arrest at the G. Taken together, this study demonstrated the improved effects of honokiol with TMZ on autophagy and subsequent apoptosis of drug-sensitive and -tolerant glioma cells. Thus, honokiol has the potential to be a drug candidate for treating human gliomas.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Autophagy; Biphenyl Compounds; Caspase 3; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Survival; Drug Resistance, Neoplasm; Drug Synergism; Glioma; Humans; Lignans; Temozolomide

Temozolomide (TMZ) is a first-line chemotherapeutic drug for malignant gliomas. Nonetheless, TMZ-induced side effects and drug resistance remain challenges. Our previous study showed the suppressive effects of honokiol on growth of gliomas.. This study was further aimed to evaluate if honokiol could enhance TMZ-induced insults toward malignant glioma cells and its possible mechanisms.. Human U87 MG glioma cells were exposed to TMZ, honokiol, and a combination of TMZ and honokiol. Cell survival, apoptosis, necrosis, and proliferation were successively assayed. Fluorometric substrate assays were conducted to determine activities of caspase-3, -6, -8, and -9. Levels of Fas ligand, Bax, and cytochrome c were immunodetected. Translocation of Bax to mitochondria were examined using confocal microscopy. Mitochondrial function was evaluated by assaying the mitochondrial membrane potential (MMP), reactive oxygen species (ROS), and complex I enzyme activity. Caspase-6 activity was suppressed using specific peptide inhibitors. The honokiol-induced effects were further confirmed using human U373 MG and murine GL261 cells.. Exposure of human U87 MG glioma cells to honokiol significantly increased TMZ-induced DNA fragmentation and cell apoptosis. Interestingly, honokiol enhanced intrinsic caspase-9 activity without affecting extrinsic Fas ligand levels and caspase-8 activity. Sequentially, TMZ-induced changes in Bax translocation, the MMP, mitochondrial complex I enzyme activity, intracellular ROS levels, and cytochrome c release were enhanced by honokiol. Consequently, honokiol amplified TMZ-induced activation of caspases-3 and -6 in human U87 MG cells. Fascinatingly, suppressing caspase-6 activity concurrently decreased honokiol-induced DNA fragmentation and cell apoptosis. The honokiol-involved improvement in TMZ-induced intrinsic apoptosis was also confirmed in human U373 MG and murine GL261 glioma cells.. This study showed that honokiol can enhance TMZ-induced apoptotic insults to glioma cells via an intrinsic mitochondrion-dependent mechanism. Our results suggest the therapeutic potential of honokiol to attenuate TMZ-induced side effects.

Topics: Animals; Apoptosis; Biphenyl Compounds; Caspases; Cell Line, Tumor; Cell Survival; Cytochromes c; Dacarbazine; DNA Fragmentation; Drugs, Chinese Herbal; Fas Ligand Protein; Glioma; Humans; Lignans; Membrane Potential, Mitochondrial; Mice; Mitochondria; Reactive Oxygen Species; Signal Transduction; Temozolomide

Malignant brain glioma is the most common and aggressive type of primary intracranial neoplasm. Regular chemotherapy cannot eradicate brain glioma cells and the residual glioma cells could form vasculogenic mimicry (VM) channels under hypoxic conditions to provide nutrients for tumor cell invasion. In addition, the existence of the blood-brain barrier (BBB) restricts most antitumor drugs into brain glioma. In this study, we developed a kind of lactoferrin (Lf) modified daunorubicin plus honokiol liposomes to transport antitumor drugs across BBB, eliminate the VM channels and block tumor cell invasion. The evaluations were performed on BBB model, brain glioma cells and glioma-bearing mice. In vitro results showed that the targeting liposomes with suitable physicochemical property could enhance the drug transportation acrossing the BBB, inhibit C6 cells invasion and destroy VM channels. Action mechanism studies indicated that Lf modified daunorubicin plus honokiol liposomes could activate apoptotic enzymes caspase 3 as well as down-regulate VM protein indicators (PI3K, MMP-2, MMP-9, VE-Cadherin and FAK). In vivo results displayed the targeting liposomes improved accumulation in brain tumor tissue and exhibited obvious antitumor efficacy. Therefore, Lf modified daunorubicin plus honokiol liposomes could be used as a potential therapy for treatment of brain glioma.

Topics: Animals; Antibiotics, Antineoplastic; Apoptosis; Biphenyl Compounds; Blood-Brain Barrier; Brain Neoplasms; Cell Line, Tumor; Daunorubicin; Drug Liberation; Glioma; Lactoferrin; Lignans; Liposomes; Mice, Inbred ICR; Rats

Glioma is one of the most common malignant central nervous system tumors in humans. Schisandrin B (Sch B) has been confirmed to cause the proliferation and invasion of glioma cells. In the present study, the potential mechanism underlying the antitumor effect of Sch B on glioma cells was investigated. The glioma cell lines, U251 and U87, were exposed to Sch B, and the cell viability, apoptosis, migration, and invasion were determined using the MTT assay, flow cytometry, and transwell assay, respectively. Then, the effects of HOTAIR and miR-125a on tumor biology and the mammalian target of rapamycin (mTOR) protein expression in cell lines exposed to Sch B were investigated. The results showed that Sch B decreased HOTAIR expression and increased miR-125a-5p expression. HOTAIR overexpression decreased miR-125a expression and increased mTOR expression in cells with the treatment of Sch B. The miR-125a inhibitor reversed the effects of HOTAIR downregulation on cell proliferation and migration. On co-incubation with rapamycin, a specific mTOR inhibitor, the cell viability, migration, and invasion were decreased and cell apoptosis was increased in two cell lines exposed to Sch B after the treatment of pcDNA-HOTAIR. In conclusion, Sch B played an inhibitory role in the proliferation and invasion of glioma cells by regulating the HOTAIR-micoRNA-125a-mTOR pathway.

Topics: Analysis of Variance; Anti-Inflammatory Agents; Cell Count; Cell Line, Tumor; Cell Proliferation; Cyclooctanes; Flow Cytometry; Gene Expression Regulation, Neoplastic; Glioma; Humans; Lignans; MicroRNAs; Neoplasm Invasiveness; Polycyclic Compounds; RNA, Long Noncoding; Signal Transduction; TOR Serine-Threonine Kinases; Transfection

Honokiol, an active constituent extracted from the bark of Magnolia officinalis, possesses anticancer effects. Apoptosis is classified as type I programmed cell death, while autophagy is type II programmed cell death. We previously proved that honokiol induces cell cycle arrest and apoptosis of U87 MG glioma cells. Subsequently in this study, we evaluated the effect of honokiol on autophagy of glioma cells and examined the molecular mechanisms. Administration of honokiol to mice with an intracranial glioma increased expressions of cleaved caspase 3 and light chain 3 (LC3)-II. Exposure of U87 MG cells to honokiol also induced autophagy in concentration- and time-dependent manners. Results from the addition of 3-methyladenine, an autophagy inhibitor, and rapamycin, an autophagy inducer confirmed that honokiol-induced autophagy contributed to cell death. Honokiol decreased protein levels of PI3K, phosphorylated (p)-Akt, and p-mammalian target of rapamycin (mTOR) in vitro and in vivo. Pretreatment with a p53 inhibitor or transfection with p53 small interfering (si)RNA suppressed honokiol-induced autophagy by reversing downregulation of p-Akt and p-mTOR expressions. In addition, honokiol caused generation of reactive oxygen species (ROS), which was suppressed by the antioxidant, vitamin C. Vitamin C also inhibited honokiol-induced autophagic and apoptotic cell death. Concurrently, honokiol-induced alterations in levels of p-p53, p53, p-Akt, and p-mTOR were attenuated following vitamin C administration. Taken together, our data indicated that honokiol induced ROS-mediated autophagic cell death through regulating the p53/PI3K/Akt/mTOR signaling pathway.

Topics: Adenine; Animals; Apoptosis; Ascorbic Acid; Autophagy; Biphenyl Compounds; Caspase 3; Cell Line, Tumor; Dose-Response Relationship, Drug; Down-Regulation; Glioma; Lignans; Mice; Microtubule-Associated Proteins; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; RNA, Small Interfering; Signal Transduction; Sirolimus; Time Factors; TOR Serine-Threonine Kinases; Tumor Suppressor Protein p53

Malignant glioma is the aggressive tumor in the brain and is characterized by high morbidity, high mortality. The main purpose of the present study was to investigate the therapeutic effects of Schisandrin B on glioma cells and preliminary explore the possible mechanism underlying anti-metastasis of Schisandrin B.. Two glioma cell lines, U251 and U87, were used in present study. The ability of metastasis of glioma cells was evaluated using transwell migration assay and invasion assay. Expression of Akt, mTOR, MMP-2 and MMP-9 was determined using Western blotting. Antagonist or agonist was used to activated or inactivated signal molecules.. Schisandrin B suppressed cell migration and invasion in manner of dose dependent as well as inhibited expression of p-Akt, p-mTOR and MMP-9. Activation of PI3K by 740Y-P treatment leaded to upregulation of p-Akt, mTOR and MMP-9; inactivation of mTOR by Rapamycin treatment inhibited expression MMP-9 while activation of mTOR by l-Leucine treatment enhanced MMP-9 expression in Schisandrin B incubated cells. Anti-migration and invasion action of Schisandrin B was also reversed by mTOR activation.. Our findings demonstrate that Schisandrin B can suppress migration and invasion of glioma cell via PI3K/Akt-mTOR-MMP-9 signaling pathway.

Topics: Antineoplastic Agents, Phytogenic; Brain Neoplasms; Cell Line, Tumor; Cell Movement; Cyclooctanes; Dose-Response Relationship, Drug; Glioma; Humans; Lignans; Matrix Metalloproteinase 9; Neoplasm Invasiveness; Neoplasm Metastasis; Phosphatidylinositol 3-Kinases; Polycyclic Compounds; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases

We recently reported that Phenethyl caffeate benzoxanthene lignan (PCBL), a semisynthetic compound derived from Caffeic Acid Phenethyl Ester (CAPE), induces DNA damage and apoptosis in tumor cells. In this study, we further investigated whether PCBL induces autophagy in WiDr cells. We also analyzed the pathways regulating autophagy and the role of autophagy in PCBL-induced cell death. Our acridine orange staining and LC3 II expression results suggest that PCBL induces autophagosomes in WiDr cells. The levels of LC3 II expression we observed after co-treatment of PCBL with bafilomycin A1 and the reductions in p62 expression we observed after PCBL treatment in WiDr cells demonstrate increased autophagic flux, a reliable indicator of autophagic induction. The increased Beclin 1 expression in PCBL-treated cells and the incapacity of PCBL to induce LC3 II in 3-methyladenine (3-MA)-treated cells we observed suggests that PCBL-induced autophagy is class III PI3-kinase dependent. PCBL did not alter phosphorylation of the mTOR substrate p70 S6 kinase, indicating that PCBL-induced autophagy was not mTOR regulated. Two autophagy related proteins, Atg5 and Atg12, also remained uninduced during PCBL treatment. The increased caspase activity and expression levels of LC3 II and p62 we observed in response to PCBL treatment in primary glioma cells demonstrates that PCBL-induced apoptosis and autophagy were not cell line specific. Pharmacological inhibition of autophagy did not alter the antitumor efficacy of PCBL in WiDr cells. This attests to the bystander nature of PCBL-induced autophagy (in terms of cell death). In toto, these data suggest that PCBL induces a class III kinase dependent, but mTOR independent, bystander mode of autophagy in WiDr cells.

Topics: Antineoplastic Agents; Autophagy; Autophagy-Related Protein 12; Autophagy-Related Protein 5; Bystander Effect; Cell Line, Tumor; Cell Survival; Drug Screening Assays, Antitumor; Gene Expression; Glioma; Humans; Lignans; Microtubule-Associated Proteins; Phosphatidylinositol 3-Kinases; Phosphorylation; Protein Processing, Post-Translational; Ribosomal Protein S6 Kinases, 70-kDa; Small Ubiquitin-Related Modifier Proteins

Gliosarcoma is one of the most common malignant brain tumors, and anti-angiogenesis is a promising approach for the treatment of gliosarcoma. However, chemotherapy is obstructed by the physical obstacle formed by the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB). Honokiol has been known to possess potent activities in the central nervous system diseases, and anti-angiogenic and anti-tumor properties. Here, we hypothesized that honokiol could cross the BBB and BCSFB for the treatment of gliosarcoma.. We first evaluated the abilities of honokiol to cross the BBB and BCSFB by measuring the penetration of honokiol into brain and blood-cerebrospinal fluid, and compared the honokiol amount taken up by brain with that by other tissues. Then we investigated the effect of honokiol on the growth inhibition of rat 9L gliosarcoma cells and human U251 glioma cells in vitro. Finally we established rat 9L intracerebral gliosarcoma model in Fisher 344 rats and human U251 xenograft glioma model in nude mice to investigate the anti-tumor activity.. We showed for the first time that honokiol could effectively cross BBB and BCSFB. The ratios of brain/plasma concentration were respectively 1.29, 2.54, 2.56 and 2.72 at 5, 30, 60 and 120 min. And about 10% of honokiol in plasma crossed BCSFB into cerebrospinal fluid (CSF). In vitro, honokiol produced dose-dependent inhibition of the growth of rat 9L gliosarcoma cells and human U251 glioma cells with IC(50) of 15.61 µg/mL and 16.38 µg/mL, respectively. In vivo, treatment with 20 mg/kg body weight of honokiol (honokiol was given twice per week for 3 weeks by intravenous injection) resulted in significant reduction of tumor volume (112.70±10.16 mm(3)) compared with vehicle group (238.63±19.69 mm(3), P = 0.000), with 52.77% inhibiting rate in rat 9L intracerebral gliosarcoma model, and (1450.83±348.36 mm(3)) compared with vehicle group (2914.17±780.52 mm(3), P = 0.002), with 50.21% inhibiting rate in human U251 xenograft glioma model. Honokiol also significantly improved the survival over vehicle group in the two models (P<0.05).. This study provided the first evidence that honokiol could effectively cross BBB and BCSFB and inhibit brain tumor growth in rat 9L intracerebral gliosarcoma model and human U251 xenograft glioma model. It suggested a significant strategy for offering a potential new therapy for the treatment of gliosarcoma.

Topics: Animals; Antineoplastic Agents; Apoptosis; Biphenyl Compounds; Blood-Brain Barrier; Brain Neoplasms; Cell Line, Tumor; Cerebrospinal Fluid; Chromatography, High Pressure Liquid; Female; Glioma; Gliosarcoma; Humans; Lignans; Male; Mice; Mice, Nude; Neoplasm Transplantation; Rats; Rats, Inbred F344; Rats, Sprague-Dawley

To study the effects of dibenzocyclooctadiene lignans isolated from Schisandra chinensis, such as wuweizisu C, gomisin N, gomisin A, and schisandrin, on the membrane potential in C6 glioma cells.. The membrane potential was estimated by measuring the fluorescence change in DiBAC-loaded glioma cells.. Wuweizisu C decreased the membrane potential in a concentration-dependent manner. Gomisin N and gomisin A, however, showed differential modulation and no change was induced by schisandrin or dimethyl- 4,4'-dimethoxy-5,6,5',6'-dimethylene dioxybiphenyl-2,2'-dicarboxylate, a synthetic drug derived from dibenzocyclooctadiene lignans. We found no involvement of G(i/o ) proteins, phospholipase C, and extracellular Na(+) on the wuweizisu C-induced decrease of the membrane potential. Wuweizisu C by itself did not change the intracellular Ca(2+)[Ca(2+)](i) concentration, but decreased the ATP-induced Ca(2+) increase in C6 glioma cells. The 4 lignans at all concentrations used in this study did not induce any effect on cell viability. Furthermore, we found a similar decrease of the membrane potential by wuweizisu C in PC12 neuronal cells.. Our results suggest that the decrease in the membrane potential and the modulation of [Ca(2+)](i) concentration by wuweizisu C could be important action mechanisms of wuweizisu C.

Topics: Animals; Calcium; Cell Line, Tumor; Cyclooctanes; Fruit; Glioma; GTP-Binding Proteins; Humans; Indicators and Reagents; Lignans; Membrane Potentials; PC12 Cells; Polycyclic Compounds; Rats; Schisandra; Type C Phospholipases

The chemokine receptor CXCR4 plays an important role in tumor growth, angiogenesis and metastasis. Our previous studies showed that Nordy, a synthetic chiral compound of nordihydroguaiaretic acid, inhibited the growth and angiogenesis of various malignant tumors. In this study we examined the capacity of Nordy to regulate CXCR4-mediated production of angiogenic factors by human glioblastoma cells. We found that Nordy potently inhibited CXCR4 ligand SDF-1-induced production of IL-8 and vascular endothelial cell growth factor, two important angiogenic factors implicated in the progression of malignant tumors. Further study revealed that the effect of Nordy was attributable to its down-regulation of the expression of functional CXCR4 in glioblastoma cells. These results suggest that the anti-cancer activity of Nordy is due, at least in part, to its suppression of the chemokine receptor CXCR4 thus reducing the production of angiogenic factors by tumor cells.

Topics: Analysis of Variance; Angiogenic Proteins; Animals; Antineoplastic Agents; Brain Neoplasms; Cell Line, Tumor; Down-Regulation; Gene Expression Regulation, Neoplastic; Glioma; Humans; Interleukin-8; Lignans; Lipoxygenase Inhibitors; Masoprocol; Mice; Mice, Inbred BALB C; Mice, Nude; Receptors, CXCR4; RNA, Messenger; Vascular Endothelial Growth Factor A

A new tetrahydrofuranoid lignan named seselinone was isolated from the aerial parts of Seseli annuum, together with three known lignans (eudesmin, magnone A and hernone) and prenylated coumarin umbelliprenin. Seselinone and eudesmin showed cytotoxic activity against C6 rat glioma cell cultures.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apiaceae; Cell Line, Tumor; Glioma; Lignans; Plant Components, Aerial; Rats

Vascular endothelial cells (ECs) that initiate tumor angiogenesis may acquire distinct properties after conditioning in tumor microenvironment as compared to ECs in non-malignant tissues. Thus far, most in vitro studies of angiogenesis used ECs isolated from normal tissues, which may not fully represent the nature of ECs in tumor vasculature. In this study, glioma-derived microvascular ECs (GDMEC) were purified from human glioma tissues by incubating with magnetic beads coated with anti-CD105 antibody and highly pure (98%) preparations of GDMEC were obtained. These cells exhibited typical EC phenotype, and proliferated rapidly in culture. Interestingly, GDMEC expressed higher levels of VEGF receptors, flt-1 and flk-1, as compared to an established human EC cell line ECV304 and primary human umbilical vascular EC (HUVEC). Functionally, GDMEC were capable of forming intercellular junctions and tubule-like structures (TLS) of various sizes. Stimulation by VEGF further promoted TLS formation with diverse tubular walls by GDMEC. In contrast, TLS formed by ECV304 and HUVEC showed significantly different features. We further observed that Nordy, a synthetic lipoxygenase inhibitor, potently inhibited TLS formation by GDMEC. The results suggest that isolation of highly pure ECs derived from tumor tissues is more appropriate for studies of tumor angiogenesis and for test of potential anti-cancer therapeutic targets.

Topics: Astrocytoma; Brain Neoplasms; Cell Line; Cells, Cultured; Endothelium, Vascular; Glioblastoma; Glioma; Humans; Immunomagnetic Separation; In Vitro Techniques; Lignans; Masoprocol; Microcirculation; Models, Biological; Neovascularization, Pathologic; Spheroids, Cellular; Vascular Endothelial Growth Factor A

We recently found that formylpeptide receptor (FPR), a G-protein-coupled receptor that mediates chemotaxis of phagocytic leukocytes induced by bacterial peptide N-formyl-methionyl-leucyl-phenylalanine, is expressed by malignant human glioma cells and promotes tumor growth and angiogenesis. In this study, we examined the effect of Nordy, a novel chiral lipoxygenase inhibitor which was synthesized based on the structure of a natural nordihydroguaiaretic acid, on the expression of FPR by human glioblastoma cells. We found that FPR was expressed at the protein level by highly malignant human glioma cell lines U87 and BT325, and a rat glioma cell line C6. The expression level of FPR was correlated with the degree of the malignancy of tumor cells. The poorly differentiated glioma cell line U87 expressed the highest level of FPR. In U87 glioma cells, the expression of FPR was attenuated at the protein level by Nordy treatment for 48 (P<0.05). Nordy did not affect FPR mRNA expression in U87 cells. In addition, Nordy treatment seemed to promote glioma cell differentiation, as evidenced by their reduced expression of vimentin and increased expression of GFAP. Our results suggest that Nordy was capable of reducing the level of malignancy of glioma cells.

Topics: Animals; Antineoplastic Agents; Cell Differentiation; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Glioma; Humans; Lignans; Lipoxygenase Inhibitors; Masoprocol; Rats; Receptors, Formyl Peptide