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Abstract 3213: Rosehip (Rosa canina) extracts prevent MAPK and AKT-mediated cell proliferation in African American triple-negative breast cancer cells
Cancer Research
Abstract
Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA
Triple Negative Breast Cancer (TNBC) is an aggressive form of breast cancer, characterized by its lack of the human epidermal growth factor receptor-2 (HER-2), the estrogen receptor (ER), and the progesterone receptor (PR). The high prevalence of triple negative tumors in young women is more commonly observed in young African American (AA) women. Currently, the existing targeted therapy is of minimal benefit in TNBCs. Akt and MAPK have been shown to promote cell proliferation in triple negative breast cancer and MAPK expression may be an underlying mechanism contributing to the generation of chemo-resistance in triple-negative breast cancer. Due to major concerns involving the occurrence of side effects and the emergence of drug-resistant cancer cells, there has been growing interest in the use of naturally occurring molecules with chemo-preventive and chemo- therapeutic properties in cancer treatment. Rosehip extracts have been used as dietary supplements to relieve symptoms associated with diarrhea, gastritis, and rheumatoid arthritis and have been shown to prevent cell proliferation in glioblastomas. This study investigated the efficacy of rosehip extracts in preventing cell proliferation in African American triple negative (HCC70, HCC1806) and luminal (HCC1500) breast cancer cell lines. Each of the breast cancer cell lines were treated with rosehip extracts (1mg/mL -25ng/mL) demonstrated a significant decrease in cell proliferation. The rosehip extract-mediated decrease in cell proliferation was equal to or better than the decrease of cell proliferation observed when known inhibitors of the MAPK (U0126, 10 μM) or AKT (LY294002, 20 μM) signaling pathways were utilized. Additionally, pretreatment of these cell lines with these Rosehip extracts (1mg/mL -25ng/mL) selectively decreased AKT, MAPK, p70S6K, and S6 phosphorylation suggesting these extracts prevent AA TNBC cell proliferation by blocking both the MAPK and AKT signaling mechanisms. Results from cell cycle analysis by flow cytometry, western blot analysis, as well as apoptosis studies demonstrate that rosehip extracts inhibit cell proliferation but do not promote apoptosis. Rosehip extracts also have a synergistic effect with Doxorubicin (20µM), a chemotherapeutic agent used to treat patients with breast cancer, in preventing triple negative breast cancer cell proliferation. Taken together these data suggest that rosehip extracts are capable of decreasing cell proliferation in African American triple negative breast cancer cells without promoting apoptosis and demonstrate a synergistic inhibition of cell proliferation with Doxorubicin, and rosehip extracts may serve as an alternative or compliment to current chemotherapeutic regimens for triple negative breast cancer.
Citation Format: Patrice Cagle, Tonisha Coburn, Patrick M. Martin. Rosehip (Rosa canina) extracts prevent MAPK and AKT-mediated cell proliferation in African American triple-negative breast cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3213. doi:10.1158/1538-7445.AM2014-3213
... 3. Importancia nutricional y beneficios para la salud de la Rosa mosqueta En los últimos años, el género Rosa se ha caracterizado por sus propiedades que van en beneficios para la salud (Uggla et al., 2005;Winther, 2014;Larsen et al., 2003;Winther y Hansen, 2013;Kirkeskov et al., 2011;Lattanzio et al., 2011). Por ejemplo, en los aspectos tales como complementos quimioterapéuticos (Cagle et al., 2014), en dermatología, como estimulador, reconstructor y eliminación de estrías en la piel (Benaiges, 2008); en cosmetología (Esther, 2013); en medicina natural, favoreciendo la resistencia del organismo a las enfermedades, combatiendo los resfriados y los síntomas de la gripe, en la mejora de la digestión, en el combate contra la depresión, en disolución de cálculos y limpieza de riñones y vejiga (Avello e Isaber, 2010;Chrubasik et al., 2008b;Warholm et al., 2003); en nutrición, por sus aportes en vitamina A (Esther, 2013;Valenzuela y Valenzuela, 2014;Parejas y Horst, 1990), en vitamina C (Pirones y Ochoa, 2002;Rodica et al., 2015;Benaiges, 2008;Crețescu y Leahu., 2013;Gomez et al., 1993), en vitamina F, en aceites esenciales (Moure et al., 2001a;Planes et al., 2003), en azucares y como antioxidante (Moure et al., 2001b;Silva dos Santos et al., 2009;Eurides et al., 2011;Cañellas et al., 2008). A raíz de estos hallazgos se comenzó a profundizar en investigaciones sobre las propiedades de las distintas partes de la planta como el aceite de sus semillas (da Silva et al., 2008;Dourado et al., 2000;Franco et al., 2007;Planes et al., 2003;Robert et al., 2006). ...
Consumers increasingly demand products in their diets that not only provide the nutrients required for a healthy life, they are also preferably those that can complement with beneficial health properties. In recent decades it has been recognized rosehip, Rosa and Rosa canina the rubiginosa as fruits contain many nutraceutical properties. This paper reviews the research papers carried the Rosehip from the point of view of their importance of their consumption and their health benefits; describing the chemical, physical and biochemical characteristics such as content of phenolic compounds, fatty acids, linoleic acid, mineral; and other important also from an industrial point of view, such as antioxidants, pigments, among other compounds. According to the information collected, the Rosehip is a source of micronutrients including vitamin C and lycopene, also delivering a good nutritional value; by the above it should be considered a functional food. Although a species that grows wild on forest soils; still less fruit and herb its importance in the consumer must be considered.
... 3. Importancia nutricional y beneficios para la salud de la Rosa mosqueta En los últimos años, el género Rosa se ha caracterizado por sus propiedades que van en beneficios para la salud (Uggla et al., 2005;Winther, 2014;Larsen et al., 2003;Winther y Hansen, 2013;Kirkeskov et al., 2011;Lattanzio et al., 2011). Por ejemplo, en los aspectos tales como complementos quimioterapéuticos (Cagle et al., 2014), en dermatología, como estimulador, reconstructor y eliminación de estrías en la piel (Benaiges, 2008); en cosmetología (Esther, 2013); en medicina natural, favoreciendo la resistencia del organismo a las enfermedades, combatiendo los resfriados y los síntomas de la gripe, en la mejora de la digestión, en el combate contra la depresión, en disolución de cálculos y limpieza de riñones y vejiga (Avello e Isaber, 2010;Chrubasik et al., 2008b;Warholm et al., 2003); en nutrición, por sus aportes en vitamina A (Esther, 2013;Valenzuela y Valenzuela, 2014;Parejas y Horst, 1990), en vitamina C (Pirones y Ochoa, 2002;Rodica et al., 2015;Benaiges, 2008;Crețescu y Leahu., 2013;Gomez et al., 1993), en vitamina F, en aceites esenciales (Moure et al., 2001a;Planes et al., 2003), en azucares y como antioxidante (Moure et al., 2001b;Silva dos Santos et al., 2009;Eurides et al., 2011;Cañellas et al., 2008). A raíz de estos hallazgos se comenzó a profundizar en investigaciones sobre las propiedades de las distintas partes de la planta como el aceite de sus semillas (da Silva et al., 2008;Dourado et al., 2000;Franco et al., 2007;Planes et al., 2003;Robert et al., 2006). ...
Los consumidores cada día exigen productos en sus dietas que no solo aporten los nutrientes requeridos para una vida sana, sino que además son de preferencia aquellos que puedan complementar con propiedades benéficas para la salud. En las últimas décadas se ha reconocido a la Rosa mosqueta, la Rosa canina y a la Rosa rubiginosa, como frutos que contienen muchas propiedades nutracéuticas. El presente trabajo hace una revisión de los artículos de investigación realizados a la Rosa mosqueta desde un punto de vista de su importancia de su consumo y sus beneficios para la salud; describiendo las características químicas, físicas y bioquímicas tales como el contenido de componentes fenólicos, ácidos grasos, ácido linoleico, minerales; y de otros compuestos importantes también desde el punto de vista industrial, tales como el contenido de antioxidantes, pigmentos, entre otros. De acuerdo a los antecedentes recopilados, la Rosa mosqueta es una fuente de micronutrientes incluyendo la vitamina c y el licopeno, entregando además un buen aporte nutricional; por lo anterior debe ser considerado como un alimento funcional. Aun siendo una especie que crece en estado salvaje, sobre suelos forestales; siendo un frutal menor y una planta medicinal su importancia en el consumo masivo debe ser considerada.
The incidence of thyroid carcinoma has obviously been rising throughout the world during the past ten years. However, over-treatment has usually occurred in thyroid carcinoma without new and effective approaches being explored. In this study, Punica granatum (pomegranate) peel extract (PoPx), a kind of herb, was evaluated for its anticancer activity to thyroid carcinoma in vitro and in vivo. PoPx potently suppressed proliferation in two kinds of thyroid cancer cell lines, and induced cancer cell apoptosis. PoPx could also decrease the mitochondrial membrane potential (ΔΨm), indicating that PoPx may induce apoptosis via a mitochondria-mediated apoptotic pathway. In addition, PoPx markedly impaired thyroid cancer cell migration and invasion by down-regulating the expression of matrix metalloproteinase-9 (MMP-9). More importantly, PoPx significantly inhibited tumor growth in the BCPAP-bearing mice model by reducing cell proliferation and inducing apoptosis. These findings suggest that PoPx could be an effective phytochemical agent.
Prognosis of patients with glioblastoma (GBM) remains very poor, thus making the development of new drugs urgent. Resveratrol (Rsv) is a natural compound that has several beneficial effects such as neuroprotection and cytotoxicity for several GBM cell lines. Here we evaluated the mechanism of action of Rsv on human GBM cell lines, focusing on the role of autophagy and its crosstalk with apoptosis and cell cycle control. We further evaluated the role of autophagy and the effect of Rsv on GBM Cancer Stem Cells (gCSCs), involved in GBM resistance and recurrence. Glioma cells treated with Rsv was tested for autophagy, apoptosis, necrosis, cell cycle and phosphorylation or expression levels of key players of these processes. Rsv induced the formation of autophagosomes in three human GBM cell lines, accompanied by an upregulation of autophagy proteins Atg5, beclin-1 and LC3-II. Inhibition of Rsv-induced autophagy triggered apoptosis, with an increase in Bax and cleavage of caspase-3. While inhibition of apoptosis or autophagy alone did not revert Rsv-induced toxicity, inhibition of both processes blocked this toxicity. Rsv also induced a S-G2/M phase arrest, accompanied by an increase on levels of pCdc2(Y15), cyclin A, E and B, and pRb (S807/811) and a decrease of cyclin D1. Interestingly, this arrest was dependent on the induction of autophagy, since inhibition of Rsv-induced autophagy abolishes cell cycle arrest and returns the phosphorylation of Cdc2(Y15) and Rb(S807/811), and levels of cyclin A, and B to control levels. Finally, inhibition of autophagy or treatment with Rsv decreased the sphere formation and the percentage of CD133 and OCT4-positive cells, markers of gCSCs. In conclusion, the crosstalk among autophagy, cell cycle and apoptosis, together with the biology of gCSCs, has to be considered in tailoring pharmacological interventions aimed to reduce glioma growth using compounds with multiple targets such as Rsv.
Neurofibromatosis type 1 (NF1) is the most common genetic disease affecting the nervous system. Patients typically develop many tumors over their lifetime, leading to increased morbidity and mortality. The NF1 gene, mutated in NF1, is also commonly mutated in sporadic glioblastoma multiforme (GBM). Because both NF1 and GBM are currently incurable, new therapeutic approaches are clearly needed. Natural products represent an opportunity to develop new therapies, as they have been evolutionarily selected to play targeted roles in organisms. Schweinfurthin A is a prenylated stilbene natural product that has previously shown specific inhibitory activity against brain and hematopoietic tumor lines. We show that patient-derived GBM and NF1 malignant peripheral nerve sheath tumor (MPNST) lines, as well as tumor lines derived from the Nf1−/+;Trp53−/+ (NPcis) mouse model of astrocytoma and MPNST are highly sensitive to inhibition by schweinfurthin A and its synthetic analogs. In contrast, primary mouse astrocytes are resistant to the growth inhibitory effects of schweinfurthin A, suggesting that schweinfurthin A may act specifically on tumor cells. Stable transfection of the GTPase-activating protein related domain of Nf1 into Nf1−/−;Trp53−/− astrocytoma cells confers resistance to schweinfurthin A. In addition, the profound effect of schweinfurthin A on dynamic reorganization of the actin cytoskeleton led us to discover that schweinfurthin A inhibits growth factor–stimulated Rho signaling. In summary, we have identified a class of small molecules that specifically inhibit growth of cells from both central and peripheral nervous system tumors and seem to act on NF1-deficient cells through cytoskeletal reorganization correlating to changes in Rho signaling. Mol Cancer Ther; 9(5); 1234–43. ©2010 AACR.
The flavonoid quercetin has been reported to inhibit the proliferation of cancer cells, whereas it has no effect on nonneoplastic
cells. U87-MG, U251, A172, LN229, and U373 malignant glioma cells were treated with quercetin (50–200 μM). Quercetin did not
cause cytotoxicity 24 h after treatment. Combining quercetin with tumor necrosis factor–related apoptosis-inducing ligand
(TRAIL) strongly augmented TRAIL-mediated apoptosis in U87-MG, U251, A172, and LN229 glioma cells; U373 cells could not be
sensitized by quercetin to TRAIL-mediated apoptosis. TRAIL-induced apoptosis was enhanced by quercetin-induced reduction of
survivin protein levels. Upon treatment with quercetin, the protein level of survivin was strongly suppressed in U87-MG, U251,
and A172 but not in U373 glioma cells. Quercetin exposure resulted in proteasomal degradation of survivin. TRAIL-quercetin–induced
apoptosis was markedly reduced by overexpression of survivin. In addition, upon treatment with quercetin, downregulation of
survivin was also regulated by the Akt pathway. Taken together, the results of the present study suggest that quercetin sensitizes
glioma cells to death-receptor–mediated apoptosis by suppression of inhibitor of the apoptosis protein survivin.
The growth suppression function of RB is dependent on its protein binding activity. RB contains at least three distinct protein binding functions: (i) the A/B pocket, which binds proteins with the LXCXE motif; (ii) the C pocket, which binds the c-Abl tyrosine kinase; and (iii) the large A/B pocket, which binds the E2F family of transcription factors. Phosphorylation of RB, which is catalyzed by cyclin-dependent protein kinases, inhibits all three protein binding activities. We have previously shown that LXCXE binding is inactivated by the phosphorylation of two threonines (Thr821 and Thr826), while the C pocket is inhibited by the phosphorylation of two serines (Ser807 and Ser811). In this report, we show that the E2F binding activity of RB is inhibited by two sets of phosphorylation sites acting through distinct mechanisms. Phosphorylation at several of the seven C-terminal sites can inhibit E2F binding. Additionally, phosphorylation of two serine sites in the insert domain can inhibit E2F binding, but this inhibition requires the presence of the RB N-terminal region. RB mutant proteins lacking all seven C-terminal sites and two insert domain serines can block Rat-1 cells in G1. These RB mutants can bind LXCXE proteins, c-Abl, and E2F even after they become phosphorylated at the remaining nonmutated sites. Thus, multiple phosphorylation sites regulate the protein binding activities of RB through different mechanisms, and a constitutive growth suppressor can be generated through the combined mutation of the relevant phosphorylation sites in RB.
We have studied the apoptotic response of poly(ADP-ribose) polymerase (PARP)−/− cells to different inducers and the consequences
of the expression of an uncleavable mutant of PARP on the apoptotic process. The absence of PARP drastically increases the
sensitivity of primary bone marrow PARP−/− cells to apoptosis induced by an alkylating agent but not by a topoisomerase I
inhibitor CPT-11 or by interleukin-3 removal. cDNA of wild type or of an uncleavable PARP mutant (D214A-PARP) has been introduced
into PARP−/− fibroblasts, which were exposed to anti-CD95 or an alkylating agent to induce apoptosis. The expression of D214A-PARP
results in a significant delay of cell death upon CD95 stimulation. Morphological analysis shows a retarded cell shrinkage
and nuclear condensation. Upon treatment with an alkylating agent, expression of wild-type PARP cDNA into PARP-deficient mouse
embryonic fibroblasts results in the restoration of the cell viability, and the D214A-PARP mutant had no further effect on
cell recovery. In conclusion, PARP−/− cells are extremely sensitive to apoptosis induced by triggers (like alkylating agents),
which activates the base excision repair pathway of DNA, and the cleavage of PARP during apoptosis facilitates cellular disassembly
and ensures the completion and irreversibility of the process.
Previously, we reported that in papilloma-producing 308 mouse keratinocytes, the tumor promoter okadaic acid, a serine-threonine phosphatase inhibitor, increased binding of activator protein 1 (AP-1) to a consensus 12-O-tetradecanoylphorbol-13-acetate-responsive element (Rosenberger, S. F., and Bowden, G. T. (1996) Oncogene 12, 2301-2308). In this study, we investigated the correlation between AP-1 DNA binding and transactivation and examined molecular mechanisms involved in this process. Using a luciferase reporter driven by region -74 to +63 of the human collagenase gene, we demonstrated induction of AP-1-mediated transcription following okadaic acid treatment. By performing in vitro kinase assays, we found elevated activities of extracellular signal-regulated kinase (ERK) 1/2, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase. The ERK-1/2-specific inhibitor PD 98059 completely abrogated okadaic acid-induced AP-1 transactivation without altering AP-1 expression, DNA binding, or complex composition. Phosphorylation analyses indicated that inhibition of ERK-1/2 decreased okadaic acid-elevated phosphorylation of JunD and FosB. To further examine the role of JunD and FosB in okadaic acid-induced AP-1 transactivation, we generated fusion proteins of the DNA-binding domain of the yeast transcription factor Gal4 and the transactivation domain of either JunD or FosB. Cotransfection experiments of these constructs with a Gal4-luciferase reporter demonstrated that both JunD and FosB are required for okadaic acid-induced transcription. Treatment with PD 98059 reduced JunD/FosB-dependent transactivation, suggesting that ERK-1/2-mediated phosphorylation is a critical component in this process.
Temozolomide (TMZ) is a DNA-methylating agent that has recently been introduced into Phase II and III trials for the treatment of gliomas. TMZ produces O6-methylguanine in DNA, which mispairs with thymine during the next cycle of DNA replication. Subsequent futile cycles of DNA mismatch repair can lead to a p53-associated apoptotic cell death, although this mechanism has been described mostly in hematopoietic neoplasms. We studied the action of TMZ in gliomas and the role p53 might play by using U87 glioma cells that were either p53-wild-type or p53-deficient (by virtue of expression of the viral oncoprotein E6). LN-Z308 cells, in which p53 gene is deleted, were also used. p53-proficient U87 MG cells underwent a prolonged, p53- and p21(Waf1/Cip1)-associated G2-M arrest beginning 2 days after TMZ treatment. Although very few of these cells underwent apoptosis, most underwent senescence over a 10-day period. p53-deficient (E6-transfected U87 and LN-Z308) cells similarly underwent G2-M arrest in response to TMZ, but this arrest was accompanied by only minor changes in p53 or p21(Waf1/Cip1) and was reversed within 7 days of TMZ treatment in association with the appearance of cells with either 8n or subG1 DNA content. These results suggest that glioma cells respond to TMZ by undergoing G2-M arrest. p53 is not necessary for this G2-M arrest to occur but is important in the duration of G2-M arrest and in the ultimate fate of TMZ-treated cells. Therefore, the integrity of the G2-M cell cycle checkpoint may be important in the cytotoxicity of TMZ in glioma cells.
The PI3 kinase signalling pathway is now accepted as being at least as important as the ras-MAP kinase pathway in cell survival and proliferation, and hence its potential role in cancer is of great interest. The purpose of this review is briefly to examine evidence for an involvement of PI3K in human cancers, discuss the mechanisms by which its activation promotes tumor progression, and consider its utility as a novel target for anticancer therapy.
A Medline review of recent literature concerning the role of PI3 kinase in tumor progression--mechanisms of action and clinical implications.
Evidence is presented that misregulation of the PI3 kinase pathway is a feature of many common cancers, either by loss of the suppressor protein PTEN, or by constitutive activation of PI3 kinase isoforms or downstream elements such as AKT and mTOR. This activation potentiates not only cell survival and proliferation, but also cytoskeletal deformability and motility; key elements in tumor invasion. In addition the PI3K pathway is implicated in many aspects of angiogenesis, including upregulation of angiogenic cytokines due to tumor hypoxia or oncogene activation and endothelial cell responses to them. These cytokines signal though receptors such as VEGF-R, FGF-R and Tie-2 and potentiate processes essential for neoangiogenesis including cell proliferation, migration, differentiation into tubules and "invasion" of these capillary sprouts into extracellular matrix (ECM).
A more complete understanding of the role of the PI3 kinase pathway in cancer will lead the way to the development of more potent and selective inhibitors which should be a useful adjunct to conventional therapies, potentially interfering with tumor progression at several pivotal points; in particular cell survival, invasion and angiogenesis.
We previously demonstrated that protein kinase C-eta (PKC-eta) mediates a phorbol 12-myristate-13-acetate (PMA)-induced proliferative response in human glioblastoma (GBM) cells. In this report, we show that PMA-stimulated activation of PKC-eta in U-251 GBM cells resulted in activation of both Akt and the mammalian target of rapamycin (mTOR) signaling pathways and an increase in cell proliferation. Expression of a kinase dead PKC-eta (PKC-etaKR) construct reduced the basal and PMA-evoked proliferation of PKC-eta-expressing U-251 GBM cells, as well as abrogated the PMA-induced activation of Akt, mTOR, and the mTOR targets 4E-BP1 and STAT-3. Treatment of cells with the PI-3 kinase inhibitor LY294002 (10 muM) or the mTOR inhibitor rapamycin (10 nM) also reduced PMA-induced proliferation and cell-cycle progression. Expression of a constitutively active PKC-eta (PKC-etaDeltaNPS) construct in a GBM cell line with no endogenous PKC-eta (U-1242) also provided evidence that PKC-eta targets the Akt and mTOR signaling pathways. Moreover, activation of 4E-BP1 and STAT-3 in both PMA-treated U-251 and PKC-etaDeltaNPS-expressing U-1242 GBM cells was inhibited by rapamycin. However, activation of Akt, but not mTOR was inhibited by the PI-3 kinase inhibitor LY294002. This study identifies Akt and mTOR as downstream targets of PKC-eta that are involved in GBM cell proliferation.
The effects of 10 different extracts of fruits and berries on cell proliferation of colon cancer cells HT29 and breast cancer cells MCF-7 were investigated. The fruits and berries used were rosehips, blueberries, black currant, black chokeberries, apple, sea buckthorn, plum, lingonberries, cherries, and raspberries. The extracts decreased the proliferation of both colon cancer cells HT29 and breast cancer cells MCF-7, and the effect was concentration dependent. The inhibition effect for the highest concentration of the extracts varied 2-3-fold among the species, and it was in the ranges of 46-74% (average = 62%) for the HT29 cells and 24-68% (average = 52%) for the MCF-7 cells. There were great differences in the content of the analyzed antioxidants in the extracts. The level of the vitamin C content varied almost 100-fold, and the content of total carotenoids varied almost 150-fold among the species. Also in the composition and content of flavonols, hydroxycinnamic acids, anthocyanins, and phenolics were found great differences among the 10 species. The inhibition of cancer cell proliferation seen in these experiments correlated with levels of some carotenoids and with vitamin C levels, present at levels that can be found in human tissues. The same inhibition of cell proliferation could not be found by ascorbate standard alone. This correlation might indicate a synergistic effect of vitamin C and other substances. In MCF-7 cells, the anthocyanins may contribute to the inhibition of proliferation.
Malignant gliomas, and high-grade gliomas (HGG) in particular, are nonmetastasizing but locally infiltrating, hypervascularized brain tumors of poor prognosis. We found previously that a c-fos-inducible vascular endothelial growth factor D is ubiquitously up-regulated in HGG grade IV, glioblastoma multiforme, and that glioblastoma multiforme overexpress Fos-related antigen 1 (Fra-1) rather than the c-Fos. We have thus become interested in the role Fra-1 may play in malignant glioma progression/maintenance, because Fra-1 has the capacity to modulate transcription of a variety of target genes. In this work, we have analyzed the biological effects of ectopic Fra-1 expression or Fra-1 knockdown in malignant glioma cells. Ectopic Fra-1 induced prominent phenotypic changes in all three malignant glioma cell lines examined: H4, U-87 MG, and A-172 MG. These changes were reflected in cells becoming more elongated with larger number of cellular processes. Furthermore, Fra-1 transgene caused H4 cells, which do not form tumor xenografts, to regain tumorigenic capacity. The genotype of these cells changed too, because 50 of 1,056 genes examined became either up-regulated or down-regulated. Conversely, Fra-1 knockdown altered prominently the morphology, anchorage-independent growth, tumorigenic potential, and Fra-1 effector expression, such as vascular endothelial growth factor D, in HGG cells. For example, cells transfected with antisense fra-1 showed shorter cellular processes than the control cells that did not grow in agar, and their tumorigenic potential was significantly diminished. Thus, Fra-1 may likely play an important role in the maintenance/progression of malignant gliomas and potentially represents a new target for therapeutic interventions.
The oncogenic role of AKT2 in the development of malignant gliomas was examined by using antisense approach. AKT2 expression was significantly inhibited in rat C6 glioma cells transfected with antisense AKT2 cDNA construct (LXSN-AS-AKT2). In addition, the transfected cells proliferated at a lowered level and apoptosis was induced. For in vivo studies, parental C6 cells and C6 cells transfected with LXSN-AS-AKT2 were implanted stereotactically into the right caudate nucleus of SD rats (control C6 group and transfected group). The rats bearing well-established C6 gliomas were treated with LXSN-AS-AKT2 DNA or LXSN (empty vector)-lipofectamine complexes intratumorally (treated group and control treated group). The mean survival of the rats of control C6 group and treated control group was 17.8+/-0.92 days and 17.5+/-1.10 days, respectively. The mean survival of the rats of transfected and treated group was significantly prolonged. MR images revealed distinct cerebral tumor foci in all of the control rats, whereas four rats in transfected group did not develop tumors and the tumor foci in five rats of treated group were regressed and disappeared. The expression of AKT2, PCNA, MMP2/9, and cyclin D were inhibited in the tumors of rats in transfected and treated groups while GFAP expression was increased. These results suggest that AKT pathway may play an important role in the development and progression of gliomas. Anti-AKT approach will open a new perspective for a targeted molecular therapy of malignant gliomas.
EGFR overexpression is the most frequent and important molecular event in the development of astrocytic gliomas, and the P13K signaling pathway is one of the most important downstream pathways of EGFR. EGFR and other members of the receptor tyrosine kinases (RTKs) family, such as VEGFR, PDGFR, and IGFR, et cetera, are often overexpressed in most of malignant gliomas and share common downstream signaling pathways. Therefore, it is considered that directly targeting the downstream PI3K pathway may be more effective in blocking multiple inputs. The PIK3CB gene encoding the class 1A PI3K catalytic subunit p110beta was selected as the target of therapeutic approach for malignant gliomas in the present study. Human U251 glioblastoma cells with high endogenous p110beta expression were transfected with plasmid-based siRNA targeting PIK3CB gene. It was found that downregulation of p110beta expression resulted in the suppression of cell proliferation, arrest of cell cycle, reduction of cell invasion, and promotion of cell apoptosis in vitro. In addition, the growth of the subcutaneous U251 glioma in the nude mice treated with siRNA targeting PIK3CB was significantly inhibited. These results demonstrate that PIK3CB overexpression may play an oncogenic role in the PI3K pathway, and the plasmid-based siRNA targeting of PIK3CB is a potential and promising approach for the treatment of malignant gliomas.
Previously, we have shown that PKC-eta (protein kinase C-eta) positively regulates glioblastoma proliferation and confers resistance to irradiation-induced apoptosis. In this study, we investigated the efficacy of rapamycin in inhibiting cell proliferation in two glioblastoma cell lines U-251MG (PKC-eta expressing) and U-1242MG (PKC-eta deficient) following PKC-eta activation. In U-251MG cells, rapamycin (10 nM) treatment was less effective as an antiproliferative agent when cells were concurrently stimulated with 10% serum and phorbol 12-myristate 13-acetate (PMA, 100 nM), a potent activator of PKC isozymes. Rapamycin-insensitive growth was owing to PKC-eta, as U-1242MG and U-251MG cells infected with a kinase-dead form of PKC-eta (U-251kr) were susceptible to rapamycin-induced inhibition of cell proliferation. Furthermore, U-251MG cells transfected with PKC-eta antisense oligonucleotides were sensitive to rapamycin. PKC-eta-expressing cells stimulated with PMA maintained p70S6K phosphorylation on Thr389 and phosphorylation of rpS6 (ser235/36), suggesting p70S6K kinase activity was still intact. Inhibition of p70S6K expression with small interfering RNA oligonucleotides inhibited cell proliferation greater than 50% in the presence of a combination of PMA and serum. Additionally, p70S6K co-precipitated with PKC-eta, suggesting a physical interaction between PKC-eta and p70S6K regulates the observed phosphorylation. Taken together, these data demonstrate that rapamycin-insensitive glioblastoma proliferation involves PKC-eta signaling.
Fra-1, a transcription factor that is phylogenetically and functionally related to the proto-oncoprotein c-Fos, controls many essential cell functions. It is expressed in many cell types, albeit with differing kinetics and abundances. In cells reentering the cell cycle, Fra-1 expression is transiently stimulated albeit later than that of c-Fos and for a longer time. Moreover, Fra-1 overexpression is found in cancer cells displaying high Erk1/2 activity and has been linked to tumorigenesis. One crucial point of regulation of Fra-1 levels is controlled protein degradation, the mechanism of which remains poorly characterized. Here, we have combined genetic, pharmacological, and signaling studies to investigate this process in nontransformed cells and to elucidate how it is altered in cancer cells. We report that the intrinsic instability of Fra-1 depends on a single destabilizer contained within the C-terminal 30 to 40 amino acids. Two serines therein, S252 and S265, are phosphorylated by kinases of the Erk1/2 pathway, which compromises protein destruction upon both normal physiological induction and tumorigenic constitutive activation of this cascade. Our data also indicate that Fra-1, like c-Fos, belongs to a small group of proteins that may, under certain circumstances, undergo ubiquitin-independent degradation by the proteasome. Our work reveals both similitudes and differences between Fra-1 and c-Fos degradation mechanisms. In particular, the presence of a single destabilizer within Fra-1, instead of two that are differentially regulated in c-Fos, explains the much faster turnover of the latter when cells traverse the G(0)/G(1)-to-S-phase transition. Finally, our study offers further insights into the signaling-regulated expression of the other Fos family proteins.
The fourth edition of the World Health Organization (WHO) classification of tumours of the central nervous system, published in 2007, lists several new entities, including angiocentric glioma, papillary glioneuronal tumour, rosette-forming glioneuronal tumour of the fourth ventricle, papillary tumour of the pineal region, pituicytoma and spindle cell oncocytoma of the adenohypophysis. Histological variants were added if there was evidence of a different age distribution, location, genetic profile or clinical behaviour; these included pilomyxoid astrocytoma, anaplastic medulloblastoma and medulloblastoma with extensive nodularity. The WHO grading scheme and the sections on genetic profiles were updated and the rhabdoid tumour predisposition syndrome was added to the list of familial tumour syndromes typically involving the nervous system. As in the previous, 2000 edition of the WHO 'Blue Book', the classification is accompanied by a concise commentary on clinico-pathological characteristics of each tumour type. The 2007 WHO classification is based on the consensus of an international Working Group of 25 pathologists and geneticists, as well as contributions from more than 70 international experts overall, and is presented as the standard for the definition of brain tumours to the clinical oncology and cancer research communities world-wide.
HIV type 1 (HIV-1) protease inhibitors (PI) have been shown to have anticancer activity in non-HIV-associated human cancer cells. The underlying mechanism of this effect is unclear. Here, we show that the PIs nelfinavir and atazanavir cause cell death in various malignant glioma cell lines in vitro. The underlying mechanism of this antitumor effect involves the potent stimulation of the endoplasmic reticulum (ER) stress response (ESR), as indicated by increased expression of two ESR markers, GRP78 and CHOP, and activation of ESR-associated caspase-4. Induction of ESR seems to play a central role in PI-induced cell death because small interfering RNA-mediated knockdown of the protective ER chaperone GRP78 sensitizes cells; whereas knockdown of proapoptotic caspase-4 protects cells from PI-induced cell death. Furthermore, the treatment of cells with PIs leads to aggresome formation and accumulation of polyubiquitinated proteins, implying proteasome inhibition. Thus, our results support a model whereby PIs cause tumor cell death via triggering of the ESR, inhibition of proteasome activity, and subsequent accumulation of misfolded proteins. Inhibition of glioma growth via ESR takes place in the in vivo setting as well, as nelfinavir inhibits the growth of xenografted human malignant glioma, with concomitant induction of the proapoptotic ER stress marker CHOP. Because ER stress has also been reported as the mechanism for insulin resistance and diabetes, our ER stress model of PI function may also explain why these drugs may induce insulin resistance as one of their most common side effects.
The commercial development of plants as sources of antioxidants that can be used to enhance the properties of foods, for nutritional purposes and preservation as well as for prevention of oxidation-related diseases, is currently of major interest. Rosehip (Rosa canina L.) is a rich source of vitamin C and polyphenols.
Phytochemicals in rosehip tea were separated into three fractions: Fr1 (vitamin C, 39.17 mg kg(-1)), Fr2 (flavonoids, 451.05 µg kg(-1)) and Fr3 (phenolic acids, 504.69 µg kg(-1)). Quercetin and ellagic acid were the most abundant polyphenolic compounds. Rosehip fractions, primarily rosehip flavonoids (EC(50) = 49 mg L(-1)), showed high antioxidant activity towards 2,2-diphenyl-1-picrylhydrazyl radicals (DPPH(•)). Cell growth effects of rosehip fractions were assessed in HeLa, MCF7 and HT-29 cell lines, with the lowest IC(50) values being determined for rosehip flavonoids, (80.63, 248.03 and 363.95 mg L(-1) respectively). However, the vitamin C fraction did not inhibit the growth of tested tumour cells.
The results of this study confirm that vitamin C and flavonoids are responsible for the antioxidant activity of rosehip tea, while only polyphenols contribute to its antiproliferative activity.
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Several exotic fruits are used in folk medicine as potential sources of healthy compounds. Rosa canina L. (dog rose) fruits and other parts used to be widely consumed in rural areas from Portugal. The present work intends to highlight the presence of bioactive compounds in those different parts, in order to improve their use based on scientific studies. The antioxidant activity was screened through: radical scavenging effects, reducing power, and inhibition of lipid peroxidation in brain homogenates. Phytochemical characterization included determination of sugars by HPLC-RI, fatty acids by GC-FID, tocopherols by HPLC-fluorescence, phenolics, flavonoids, carotenoids, chlorophylls and ascorbic acid, by spectrophotometric techniques. Galls revealed the highest antioxidant potential, ripen hips showed the highest tocopherols and β-carotene contents, as also the most adequate n-6/n-3 fatty acids ratios. Unripe hips gave the highest levels of ascorbic acid and petals revealed the highest concentration of sugars. Ethnobotanical studies conducted have mentioned different use-reports for seeds, petals, flowers and galls, as well as for fruits in different stages of maturity and, therefore, the comparison between chemical compounds and antioxidant properties of those different parts is a key-point of the present study. Furthermore, the levels of antioxidants found would make them suitable sources of compounds to be used commercially to retard rancidity in fatty materials in food manufacturing, to reduce the effects of ageing and to help to prevent oxidative-stress related diseases such as cancer and heart disease.
Black peppercorn, nutmeg, rosehip, cinnamon and oregano leaf were extracted with 50% acetone and 80% methanol, and evaluated for their radical-scavenging activities against cation (ABTS+), DPPH, peroxyl (ORAC) and hydroxyl (HO) radicals. For each extract, total phenolic content (TPC) and chelating activity were also determined. The extracts of all botanical samples showed significant radical-scavenging capacities, TPC and chelating abilities. The 50% acetone extract of cinnamon had the highest ABTS+-scavenging capacity of 1243 μmol TE/g and the greatest ORAC value of 1256 μmol TE/g on a per weight basis. The 50% acetone extracts of black peppercorn and cinnamon showed higher ABTS+-scavenging, ORAC, Fe+2 chelating ability and TPC value, but lower DPPH value than the corresponding 80% methanol extracts. The 80% methanol extract of nutmeg had greater ABTS+, ORAC and TPC values than the 50% acetone extract. Electronic spin resonance (ESR) measurements demonstrated that cinnamon had the strongest HO-scavenging activities among all the tested botanical materials. These data indicate that black peppercorn, nutmeg, rosehip, cinnamon and oregano leaf may serve as potential dietary sources of natural antioxidants for improving human nutrition and health. The extracting solvent may alter the antioxidant activity measurement for selected botanicals, including spices and herbs.
Background:
A standardized rose-hip powder produced from the seeds and husks of fruit from a subtype of Rosa canina has been reported to inhibit leukocyte functions that cause cell injury in osteoarthritis.
Objective:
The aim of this study was to assess the impact of standardized rose-hip powder on mobility of the hip and knee joints, activities of daily living, quality of life, and pain in patients with osteoarthritis.
Methods:
Patients with a diagnosis of osteoarthritis of either the hip or knee, verified on radiography, participated in this randomized, placebo-controlled, double-blind study. Half of the patients were given five 0.5-g capsules of standardized rose-hip powder twice daily for 4 months, and the other half received identical placebo capsules twice daily for the same period. Mobility of the hip or knee was measured in both groups after the initial screening and again after 4 months of therapy.
Results:
One hundred patients (65 women, 35 men; mean [SD] age, 65.2 [11.1] years) were divided into 2 treatment groups of 50 patients each. Hip joint mobility improved significantly in the treatment group compared with the placebo group (P = 0.033). Similarly, pain decreased significantly in the treatment group compared with the placebo group (P = 0.035). Two patients (4%) from each group withdrew during the early stages of the trial for reasons not related to treatment.
Conclusions:
In this study population, standardized rose-hip powder reduced symptoms of osteoarthritis, as 64.6% of patients reported at least some reduction of pain while receiving treatment. Standardized rose-hip powder may improve hip flexion and reduce pain in patients with osteoarthritis.
The anticancer activity of Amaryllidaceae isocarbostyrils is well documented. At pharmacological concentrations, that is, approximately 1 μM in vitro and approximately 10 mg/kg in vivo, narciclasine displays marked proapoptotic and cytotoxic activity, as does pancratistatin, and significant in vivo anticancer effects in various experimental models, but it is also associated with severe toxic side effects. At physiological doses, that is, approximately 50 nM in vitro and approximately 1 mg/kg in vivo, narciclasine is not cytotoxic but cytostatic and displays marked anticancer activity in vivo in experimental models of brain cancer (including gliomas and brain metastases), but it is not associated with toxic side effects. The cytostatic activity of narciclasine involves the impairment of actin cytoskeleton organization by targeting GTPases, including RhoA and the elongation factor eEF1A. We have demonstrated that chronic treatments of narciclasine (1 mg/kg) significantly increased the survival of immunodeficient mice orthotopically xenografted with highly invasive human glioblastomas and apoptosis-resistant brain metastases, including melanoma- and non-small-cell-lung cancer- (NSCLC) related brain metastases. Thus, narciclasine is a potentially promising agent for the treatment of primary brain cancers and various brain metastases. To date, efforts to develop synthetic analogs with anticancer properties superior to those of narciclasine have failed; thus, research efforts are now focused on narciclasine prodrugs.
Phytochemicals--the bioactive compounds found in plants--not only hold historical significance in various medical traditions, but also form the basis of many modern-day drugs. Phytochemicals are often used for primary disease prevention or as adjuncts to conventional therapies--despite uncertain effectiveness or safety. On the other hand, phytochemicals have given rise to numerous conventional drugs, which are widely used in mainstream medicine and compose the primary therapeutic strategies for numerous conditions (including cancer). In this review, we will discuss general safety considerations for integrating phytochemicals in the oncology setting. The supportive evidence and safety concerns of popular plant-based cancer therapies will also be summarized. Finally, a brief overview of the established and emerging anticancer drugs with botanical origins will be provided.
Fos-related antigen 1 (Fra-1) plays an important role in maintenance/progression of various cancers, including glioblastoma multiforme (GBM). In this study, we used both shRNA and siRNA to examine the effect of fra-1 knockdown in GBM cells over-expressing Fra-1. Furthermore, we analyzed both the expression of JunB and its knockdown, a previously identified target for Fra-1, and also examined its potential association with Fra-1. When using fra-1 shRNA and siRNA, we found that GBM cells has Fra-1 levels diminished together with the levels of JunB, but Fra-1 remains unchanged in cells with junB knockdown. This is accompanied by dramatic changes in cell morphology and significant alteration in their migration. We next uncovered that the expression of JunB increased in response to ectopic Fra-1 and also to EGF-induced signaling, similarly to Fra-1. This was associated with an avid pairing between phosphorylated Fra-1 and JunB. Importantly, we found that Fra-1 paired with JunB binds to an AP-1 site in the junB gene promoter. JunB knockdown did not affect Fra-1 and the changes in cell morphology did not fully replicate that seen with Fra-1 knockdown. Thus, Fra-1 takes part in a control of architecture and migratory nature of GBM cells. Moreover, Fra-1 is a phosphorylated factor that transactivates JunB with which it makes effectively AP-1 pairs in GBM cells.
See commentary: Fos-related antigen-1 (Fra-1) is a regulator of glioma cell malignant phenotype
The aim of the present study was to investigate the effect of Temozolomide (an alkylating chemotherapeutic agent) and quercetin (natural flavonoid) on cell death in the human astrocytoma cell line MOGGCCM (WHO grade III). Our results indicate that Temozolomide induces autophagy, while quercetin promotes severe necrosis in the cell line in a manner dependent on the drug concentration. We demonstrated for the first time that combinations of both drugs were much more effective in programmed cell death induction in glioma cells. At a low (5muM) drug concentration, quercetin potentiated a pro-autophagic effect of Temozolomide, while after treatment with a higher drug concentration (30muM), autophagy switched to apoptosis. Temozolomide attenuated the toxic effect of quercetin. Apoptosis was mediated by the mitochondrial pathway and the activation of caspase 3 and cytochrome C release, but no changes in caspase 8 expression was observed. It was accompanied by decreased mitochondrial membrane potential and inhibition of Hsp27 and Hsp72 expression. Autophagy was correlated with an increased level of LC3II. Temozolomide and quercetin also inhibited migratory phenotype of MOGGCCM cells and changed the nuclei morphology from a circular to an irregular shape. Our results indicate that quercetin acts in synergy with Temozolomide and when used in combination rather than in separate pharmacological application, both drugs are more effective in programmed cell death induction. Temozolomide administered with quercetin seems to be a potent and promising combination which might be useful in glioma therapy.
Among the natural products shown to possess chemopreventive and anticancer properties, curcumin is one of the most potent. In the current study, we investigated the effects of this natural product on the growth of human glioma U-87 cells xenografted into athymic mice. We show here that curcumin administration exerted significant anti-tumor effects on subcutaneous and intracerebral gliomas as demonstrated by the slower tumor growth rate and the increase of animal survival time. While investigating the mechanism of its action in vivo, we observed that curcumin decreased the gelatinolytic activities of matrix metalloproteinase-9. Furthermore, treatment with curcumin inhibited glioma-induced angiogenesis as indicated by the decrease of endothelial cell marker from newly formed vessels and by the diminution of the concentration of hemoglobin in curcumin-treated tumors. We also demonstrate, using an in vitro model of blood-brain barrier, that curcumin can cross the blood-brain barrier to a high level. These are the first results showing that curcumin suppresses tumor growth of gliomas in xenograft models. The mechanisms of the anti-tumor effects of curcumin were related, at least partly, to the inhibition of glioma-induced angiogenesis.
There is growing interest in dietary phytochemicals as potential cancer chemopreventive agents. Resveratrol (3,4',5-trihydroxy-trans-stilbene), a naturally occurring phytoalexin that is present in grapes, red wine, berries and peanuts, has been studied extensively for its ability to interfere with multistage carcinogenesis. Resveratrol is known to have antioxidant, anti-inflammatory and antiproliferative effects on a variety of cancer cells in vitro and in various animal models. However, the effect(s) of resveratrol in vivo on humans are still controversial. This study discusses current knowledge with regard to the effects of resveratrol in relation to its potential as a chemopreventive and/or chemotherapeutic molecule against human gliomas.
Resveratrol (trans-3,4', 5-trihydroxystilbene) is a naturally occurring polyphenolic compound that has antiinflammatory, antioxidant, neuroprotective properties and acts as a chemopreventive agent. Resveratrol causes cell cycle arrest and induces apoptotic cell death in various types of cancer cells. In the current studies, the effect of resveratrol on phosphoinositide kinase-3 (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway was examined in human U251 glioma cells. Resveratrol decreased both the expression and phosphorylation of Akt. Inhibitors of PI3K (LY294002) and Akt (SH-6) enhanced resveratrol-induced LDH release and caspase-3 activation. Resveratrol reduced phosphorylation of ribosomal protein S6 and the mTOR inhibitor rapamycin further enhanced resveratrol-induced cell death. These results suggest that the downregulation of PI3K/Akt/mTOR signaling pathways may be an important mediator in resveratrol-induced apoptosis in glioma cells.
We investigated the effects of compounds isolated from a methanolic extract of rose hips on melanin biosynthesis in B16 mouse melanoma cells and the possible mechanisms responsible for the inhibition of melanin biosynthesis. We found that, among the isolated compounds, quercetin was a particularly potent melanogenesis inhibitor. To reveal the mechanism for this inhibition, the effects on tyrosinase of B16 mouse melanoma were measured. Quercetin decreased the intracellular tyrosinase activity as well as the tyrosinase activity in a cell culture-free system. We also examined the cellular level of tyrosinase protein and found that quercetin dose-dependently inhibited tyrosinase protein expression. We consider from these results that the inhibition of melanogenesis by quercetin was due to the inhibition of both tyrosinase activity and of the protein expression.
Major advances in molecular biology, cellular biology and genomics have substantially improved our understanding of cancer. Now, these advances are being translated into therapy. Targeted therapy directed at specific molecular alterations is already creating a shift in the treatment of cancer patients. Glioblastoma (GBM), the most common brain cancer of adults, is highly suited for this new approach. GBMs commonly overexpress the oncogenes EGFR and PDGFR, and contain mutations and deletions of tumor suppressor genes PTEN and TP53. Some of these alterations lead to activation of the P13K/Akt and Ras/MAPK pathways, which provide targets for therapy. In this paper, we review the ways in which molecular therapies are being applied to GBM patients, and describe the tools of these approaches: pathway inhibitors, monoclonal antibodies and oncolytic viruses. We describe strategies to: i) target EGFR, its ligand-independent variant EGFRvIII, and PDGFR on the cell surface, ii) inhibit constitutively activate RAS/MAPK and PI3K/Akt signaling pathways, iii) target TP53 mutant tumors, and iv) block GBM angiogenesis and invasion. These new approaches are likely to revolutionize the treatment of GBM patients. They will also present new challenges and opportunities for neuropathology.
Gliomas are the most common primary neoplasm of the brain. Unfortunately, they are often refractory to treatment and portend a poor prognosis. However, recent discoveries have shed light on the molecular events driving glioma growth, including abnormalities of three major molecular pathways: extracellular growth factors and their receptors (eg, EGF/EGFR and PDGF/PDGFR), signal transduction cascades (eg, RAS and AKT), and cell proliferation controls (eg, INK4A-ARF). Each of these abnormalities is described in detail. Efforts to inhibit abnormally activated pathways are underway through multi-institutional clinical trials.
The treatment of osteoarthritis, a disease that eventually affects the majority of the older population, involves the alleviation of symptoms such as pain and stiffness, and the reduction of inflammation. The double-blind, placebo-controlled, crossover study reported here examined the effect of Hyben Vital, a herbal remedy made from a subtype of Rosa canina and recently reported to have anti-inflammatory properties, on the symptoms of osteoarthritis. One hundred and twelve patients with osteoarthritis were randomly allocated to treatment with either Hyben Vital 5 g daily or an identical placebo for 3 months, followed immediately by the alternative treatment. The patients assessed changes in joint pain and stiffness after each treatment period on a 5-point categorical scale. General wellbeing, including mood, sleep quality and energy were also assessed and recorded in a personal diary. The results in the two arms of the crossover differed markedly. Group A (placebo first) showed significantly more improvement from Hyben Vital than from placebo, p < 0.0078 for pain and < 0.0025 for stiffness. But Group B (Hyben Vital first) revealed a positive effect of the same order as for Hyben Vital in group A, not only from the active drug, but also from placebo (difference not significant). An identical pattern was observed when we evaluated general wellbeing from the diary records. When patients, on the basis of reduction in joint pain, were divided into responders and non-responders, the first 3 months of active treatment (group A) showed a response rate of 31/47 (66%) compared to that of placebo (group B) 18/50 (36%), p < 0.0185. No major side effects occurred in either group. The data indicate that Hyben Vital reduces the symptoms of osteoarthritis. We interpret the marked differences in the responses of the two groups as indicating a strong "carryover" effect of Hyben Vital.
Glioblastoma multiforme is the most common primary brain tumor in adults. Despite major research efforts and progress in neuroimaging, neurosurgery, and radiation and medical oncology, the overall survival of patients with this disease has changed little over the past 30 years. Surgery and radiation therapy remain critical components in the care of patients with glioblastoma multiforme. Treatment with chemotherapy has been hampered by the apparent resistance of these tumor cells to available agents and challenges in delivering agents to the tumor cells. The blood-brain barrier can restrict entry of some agents and the effect of antiepileptic drugs inducing hepatic P450 can significantly affect the pharmacology of a wide range of antineoplastic agents. As a result, new agents and novel approaches are required. Translational research efforts should: (1) pursue a broad research agenda until productive avenues are identified; (2) quantify the delivery of novel agents to the malignant brain tumor cells; (3) determine the maximum tolerated dose (MTD) and preliminary efficacy data on novel agents before initiating combination therapies; (4) optimize trial designs; and (5) improve psychosocial and supportive care for patients with this devastating illness.
Glioblastomas, the most frequent and malignant human brain tumors, may develop de novo (primary glioblastoma) or by progression from low-grade or anaplastic astrocytoma (secondary glioblastoma). These glioblastoma subtypes constitute distinct disease entities that affect patients of different ages and develop through different genetic pathways. Our recent population-based study in the Canton of Zürich, Switzerland, shows that primary glioblastomas develop in older patients (mean age, 62 years) and typically show LOH on chromosome 10q (69%) and other genetic alterations (EGFR amplification, TP53 mutations, p16INK4a deletion, and PTEN mutations) at frequencies of 24-34%. Secondary glioblastomas develop in younger patients (mean, 45 years) and frequently show TP53 mutations (65%) and LOH 10q (63%). Common to both primary and secondary glioblastoma is LOH on 10q, distal to the PTEN locus; a putative suppressor gene at 10q25-qter may be responsible for the glioblastoma phenotype. Of the TP53 point mutations in secondary glioblastomas, 57% were located in hotspot codons 248 and 273, while in primary glioblastomas, mutations were more widely distributed. Furthermore, G:C-->A:T mutations at CpG sites were more frequent in secondary than in primary glioblastomas (56% vs 30%). These data suggest that the TP53 mutations in these glioblastoma subtypes arise through different mechanisms. There is evidence that G:C-->A:T transition mutations at CpG sites in the TP53 gene are significantly more frequent in low-grade astrocytomas with promoter methylation of the O6-methylguanine-DNA methyltransferase (MGMT) gene than in those without methylation. This suggests that, in addition to deamination of 5-methylcytosine (the best known mechanism of formation of G:C-->A:T transitions at CpG sites), involvement of alkylating agents that produce O6-methylguanine or related adducts recognized by MGMT cannot be excluded in the pathway leading to secondary glioblastomas.
Caffeic acid phenethyl ester (CAPE), a component of honeybee propolis, has been reported to hold various biochemical responses. In the preliminary study, we found that CAPE inhibited the growth of C6 glioma cells in a dose dependent and time dependent manner as shown by the results of trypan blue dye exclusion assay and cell proliferation assay. In addition, the cell number percentage of the G0/G1 phase increased to 85% after the treatment with 50 microM of CAPE for 24h. After treatment with CAPE (50 microM) for 6h, it demonstrated that the protein level of hyperphosphorylated pRb decreased, and cyclin dependent kinase inhibitors p21, p27, and p16 were marked up-regulated. The association of CDK2 and cyclin E that affects the CDK2 activity decreased. When C6 cells were grown as xenografts in nude mice, treatment with CAPE (1-10mg/kg; ip) induced a significant dose dependent decrease in tumor growth by evaluating tumor volume and tumor weight. Histochemical and immunohistochemical analysis revealed that CAPE treatment significantly reduced the number of mitotic cells and proliferating cell nuclear antigen (PCNA)-positive cells in C6 glioma. These results suggest that CAPE presents an antitumor potential for glioma by inhibiting the growth of tumor cells.
Recent epidemiological and dietary intervention studies in animals and humans have suggested that diet-derived flavonoids, in particular quercetin, may play a beneficial role by preventing or inhibiting tumorigenesis. The aim of this study was to evaluate whether quercetin may act differently on cancer and normal neuronal tissue. In order to investigate this, the U138MG human glioma cell line and hippocampal organotypic cultures were used. The study showed that quercetin induced in glioma cell cultures results in (a) a decrease in cell proliferation and viability, (b) necrotic and apoptotic cell death, (c) arrest in the G2 checkpoint of the cell cycle, and (d) a decrease of the mitotic index. Furthermore, we demonstrated that while quercetin promotes cancer regression it was able to protect the hippocampal organotypic cultures from ischemic damage. To sum up, our results suggest that quercetin induced growth inhibition and cell death in the U138MG human glioma cell line, while exerting a cytoprotective effect in normal cell cultures.
c-Fos is regulated by phosphorylation and multiple turnover mechanisms. We found that c-Fos was ubiquitylated in the cytoplasm during IL-6/gp130 stimulation under MEK inhibition and sought the mechanisms involved in the regulation. We show that sustained ERK5 activity and the E3 ligase UBR1 regulate the stability and subcellular localization of c-Fos. UBR1, rapidly induced by STAT3, interacts with and ubiquitylates c-Fos in the cytoplasm for its accelerated degradation. ERK5 inhibits the nuclear export of c-Fos by phosphorylating Thr232 in the c-Fos NES(221-233) and disrupts the interaction of c-Fos with UBR1 by phosphorylating Ser32. Moreover, UBR1 depletion in HeLa cells, which constitutively express UBR1 at a high level, enhances both c-Fos expression and cell growth, whereas ERK5 depletion reduces both of them. Interestingly, an NES mutant of c-Fos, but not wild-type, substitutes ERK5 activity for HeLa cell proliferation. Thus, this spatiotemporal regulation of c-Fos by ERK5 and UBR1 is critical for the regulation of c-Fos/AP-1.
Genetic Pathways to Glioblastomas
- H Ohgaki
H. Ohgaki, " Genetic Pathways to Glioblastomas, " Neuropathology, Vol. 25, No. 1, 2005, pp. 1-7.
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- A Kornienko
- A Evidente
A. Kornienko and A. Evidente, "Chemistry, Biology, and
Medicinal Potential of Narciclasine and Its Congeners,"
Chemical Reviews, Vol. 108, No. 6, 2008, pp. 1982-2014.
- C E Ulbricht
- W Chao
C. E. Ulbricht and W. Chao, "Phytochemicals in the Oncology Setting," Current Treatment Options in Oncology,
Vol. 11, No. 3-4, 2010, pp. 95-106.
Modulates Malignant Features of Glioma Cells
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