Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glioblastoma (GBM) remains one of the most challenging solid cancers to treat due to its highly proliferative, angiogenic and invasive nature. The small molecule CDK inhibitor, flavopiridol, has demonstrated antitumor activity in human xenograft models and is currently in clinical trials showing efficacy in patients with advanced disease. We have developed an experimental animal model using the murine glioma GL261 cells as a novel in vivo system to screen potential therapeutic agents for GBM. Results of in vitro testing demonstrate that flavopiridol has several relevant clinical characteristics such as its ability to: 1. inhibit cell growth; 2. inhibit cell migration; 3. decrease expression of cyclin D1, CDK4 and p21; 4. induce apoptosis in cells with high levels of p27 expression; and 5. decrease the expression of the anti-apoptotic protein Bcl-2. The mechanism by which flavopiridol induces apoptosis is mitochondrial-mediated. We demonstrate by electron microscopy and immunohistochemistry that drug treatment induces mitochondrial damage that was accompanied by the release of cytochrome c into the cytosol together with the translocation of apoptosis inducing factor (AIF) into the nucleus. This finding in murine glioma cells differs from the mechanism of flavopiridolinduced cell death reported by us for human glioma cells (Alonso et al., Mol Cancer Ther 2003; 2:139) where drug treatment induced a caspase- and cytochrome c-independent pathway in the absence of detectable damage to mitochondria. In apoptotic human glioma cells only translocation of AIF into the nucleus occurred. Thus, the same drug kills different types of glioma cells by different mitochondrial-dependent pathways.
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PMID:Flavopiridol induces mitochondrial-mediated apoptosis in murine glioma GL261 cells via release of cytochrome c and apoptosis inducing factor. 1273 34

The cytotoxic effect of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is limited in many glioma cell lines. However, treatment with TRAIL in combination with subtoxic doses of roscovitine, a specific inhibitor of Cdc2 and Cdk2, induced rapid apoptosis in TRAIL-resistant glioma cells. Roscovitine could sensitize Bcl-2- or Bcl-xL-overexpressing glioma cells, but not human astrocytes, to TRAIL-induced apoptosis, offering an attractive strategy for safely treating resistant gliomas. Treatment with roscovitine significantly inhibited Cdc2 activity, and expression of a dominant-negative Cdc2 mutant sensitized glioma cells to TRAIL-induced apoptosis. While the proteolytic processing of procaspase-3 by TRAIL was partially blocked in U87MG and T98 glioma cells, treatment with roscovitine recovered TRAIL-induced activation of caspases very efficiently in these cells. We found that treatment with roscovitine or expression of a dominant-negative Cdc2 mutant downregulated the protein levels of survivin and XIAP, two major caspase inhibitors. Overexpression of survivin or XIAP attenuated the apoptosis induced by roscovitine and TRAIL. Taken together, these results suggest that downregulation of survivin and XIAP by subtoxic doses of roscovitine contributes to the amplification of caspase cascades, thereby overcoming glioma cell resistance to TRAIL-mediated apoptosis.
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PMID:Roscovitine sensitizes glioma cells to TRAIL-mediated apoptosis by downregulation of survivin and XIAP. 1472 73

Thallium acetate is a known neurotoxic agent. In this study, we investigated the mechanisms by which thallium acetate induces cell cycle arrest and cell apoptosis in cultured LC6 glioma cells. Exposure of C6 glioma cells to thallium acetate decreased cell viability as demonstrated by the MTT assay. Incubation of thallium acetate arrested cell cycle progression at the G2/M phase and caused cellular apoptosis at 300 microM as determined by trypan blue exclusion and flow cytometric analysis. The G2/M arrest was associated with a decrease in expression of CDK2 protein and an upregulation of p53 and the CDK inhibitor p21(Cip1), but not p27(Kip1). Thallium acetate did not alter the protein levels of cyclin A and B; cyclin D1, D2, and D3; and CDK4 expression in C6 glioma cells. Incubation of C6 glioma cells with thallium acetate upregulated the expression of proapoptotic proteins Bad and Apaf and downregulated the expression of anti-apoptotic proteins Bcl-xL and Bcl-2. In conclusion, these data suggest that thallium acetate inhibits cell cycle progression at G2/M phase by suppressing CDK activity through the p53-mediated induction of the CDK inhibitor p21(Cip1). Impairment of cell cycle progression may trigger the activation of a mitochondrial pathway and shifts the balance in the Bcl-2 family toward the proapoptotic members, promoting the formation of the apoptosome and, consequently, apoptosis.
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PMID:Thallium acetate induces C6 glioma cell apoptosis. 1596 99

Gardenia, the fruit of Gardenia jasminoides Ellis, has been widely used to treat liver and gall bladder disorders in Chinese medicine. It has been shown recently that geniposide, the main ingredient of Gardenia Fructus, exhibits the anti-tumor effect. In this review, we discuss the anti-tumor effect and possible mechanisms of a derivative from Gardenia Fructus, penta-acetyl geniposide ((Ac)5GP). It has been demonstrated that (Ac)5GP plays more potent roles than geniposide in chemoprevention. (Ac)5GP decreased DNA damage and hepatocarcinogenesis induced by aflatoxin B1 (AFB1) by activating the phase II enzymes glutathione S-transferase (GST) and GSH peroxidase (GSH-Px). It reduced the growth and development of inoculated C6 glioma cells especially in pre-treated rats. In addition to the preventive effect, (Ac)5GP exerts its actions on apoptosis and growth arrest. Treatment of (Ac)5GP caused DNA fragmentation of glioma cells. (Ac)5GP induced sub- G1 peak through the activation of apoptotic cascades PKCdelta/JNK/Fas/caspase8 and caspase 3. Besides, p53/Bax signaling was suggested to be involved in (Ac)5GP-induced apoptosis, though its downstream cascades needs further clarified. (Ac)5GP has also been shown to inhibit DNA synthesis of tumor cells. It arrested cell cycle at G0/ G1 by inducing the expression of p21, thus suppressing the cyclin D1/cdk4 complex formation and the phosphorylation of E2F. The phosphorylation status of p53 on serine 392 correlated with the process of growth arrest. Evidences from the in vivo experiments showed that (Ac)5GP is not harmful to liver, heart and kidney. In conclusion, (Ac)5GP is highly suggested to be an anti-tumor agent for development in the future.
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PMID:The anti-tumor effect and mechanisms of action of penta-acetyl geniposide. 1597 50

In TNF-related apoptosis-inducing ligand (TRAIL)-resistant glioma cells, co-treatment with nontoxic doses of sodium butyrate and TRAIL resulted in a marked increase of TRAIL-induced apoptosis. This combined treatment was also cytotoxic to glioma cells overexpressing Bcl-2 or Bcl-xL, but not to normal human astrocytes, thus offering an attractive strategy for safely treating resistant gliomas. Cotreatment with sodium butyrate facilitated completion of proteolytic processing of procaspase-3 that was partially blocked by treatment with TRAIL alone. We also found that treatment with sodium butyrate significantly decreased the protein levels of survivin and X-linked inhibitor of apoptosis protein (XIAP), two major caspase inhibitors. Overexpression of survivin and XIAP attenuated sodium butyrate-stimulated TRAIL-induced apoptosis, suggesting its involvement in conferring TRAIL resistance to glioma cells. Furthermore, the kinase activities of Cdc2 and Cdk2 were significantly decreased following sodium butyrate treatment, accompanying downregulation of cyclin A and cyclin B, as well as upregulation of p21. Forced expression of Cdc2 plus cyclin B, but not Cdk2 plus cyclin A, attenuated sodium butyrate/TRAIL-induced apoptosis, overriding sodium butyrate-mediated downregulation of survivin and XIAP. Therefore, Cdc2-mediated downregulation of survivin and XIAP by sodium butyrate may contribute to the recovery of TRAIL sensitivity in glioma cells.
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PMID:Sodium butyrate sensitizes human glioma cells to TRAIL-mediated apoptosis through inhibition of Cdc2 and the subsequent downregulation of survivin and XIAP. 1600 42

Staurosporine was found to bring about complete growth inhibition of human glioma cell lines. U87 MG cells were arrested in S phase while U373 MG cells in G2/M phase on staurosporine treatment. Consistent with this observation, no change in G1 phase regulators viz., Cyclin D1, D3 and CDK4 was seen on staurosporine treatment. The levels of CDK2, CDC2, Cyclin A and Cyclin B proteins decreased, while the levels of CDK inhibitors viz., p21 and p27 were found to increase on staurosporine treatment. The mRNA levels of CDK2 and CDC2 genes were also found to decrease on staurosporine treatment. Thus apart from staurosporine's known direct inhibitory effect on CDK2 and CDC2 activities, staurosporine was found to down-regulate activities of these two kinases by modulating the expression of the kinases themselves as well that of their activating partners (Cyclins) and their inhibitors.
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PMID:Staurosporine-induced growth inhibition of glioma cells is accompanied by altered expression of cyclins, CDKs and CDK inhibitors. 1677 Jul 40

We previously identified SIRT2, an nicotinamide adenine dinucleotide (NAD)-dependent tubulin deacetylase, as a protein downregulated in gliomas and glioma cell lines, which are characterized by aneuploidy. Other studies reported SIRT2 to be involved in mitotic progression in the normal cell cycle. We herein investigated whether SIRT2 functions in the mitotic checkpoint in response to mitotic stress caused by microtubule poisons. By monitoring chromosome condensation, the exogenously expressed SIRT2 was found to block the entry to chromosome condensation and subsequent hyperploid cell formation in glioma cell lines with a persistence of the cyclin B/cdc2 activity in response to mitotic stress. SIRT2 is thus a novel mitotic checkpoint protein that functions in the early metaphase to prevent chromosomal instability (CIN), characteristics previously reported for the CHFR protein. We further found that histone deacetylation, but not the aberrant DNA methylation of SIRT2 5'untranslated region is involved in the downregulation of SIRT2. Although SIRT2 is normally exclusively located in the cytoplasm, the rapid accumulation of SIRT2 in the nucleus was observed after treatment with a nuclear export inhibitor, leptomycin B and ionizing radiation in normal human fibroblasts, suggesting that nucleo-cytoplasmic shuttling regulates the SIRT2 function. Collectively, our results suggest that the further study of SIRT2 may thus provide new insights into the relationships among CIN, epigenetic regulation and tumorigenesis.
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PMID:SIRT2, a tubulin deacetylase, acts to block the entry to chromosome condensation in response to mitotic stress. 1690 7

Mitogen-activated protein kinase (MAPK) and protein kinase C (PKC) are activated in the majority of gliomas and contribute to tumor cell growth and survival. Sorafenib (Bay43-9006; Nexavar) is a dual-action Raf and vascular endothelial growth factor receptor inhibitor that blocks receptor phosphorylation and MAPK-mediated signaling and inhibits growth in a number of tumor types. Because our initial studies of this agent in a series of glioma cell lines showed only partial growth inhibition at clinically achievable concentrations, we questioned whether inhibition of PKC signaling using the PKC-delta inhibitor rottlerin might potentiate therapeutic efficacy. Proliferation assays, apoptosis induction studies, and Western immunoblot analysis were conducted in cells treated with sorafenib and rottlerin as single agents or in combination. Sorafenib and rottlerin reduced proliferation in all cell lines when used as single agents, and the combination produced marked potentiation of growth inhibition. Flow-cytometric measurements of cells stained with Annexin V-propidium iodide and immunocytochemical assessment of cytochrome c and apoptosis-inducing factor release demonstrated that addition of rottlerin resulted in significantly higher levels of apoptosis than sorafenib alone. In addition, the combination of sorafenib and rottlerin reduced or completely inhibited the phosphorylation of extracellular signal-regulated kinase and Akt and down-regulated cell cycle regulatory proteins such as cyclin-D1, cyclin-D3, cyclin-dependent kinase (cdk)4, and cdk6 in a dose- and time-dependent manner. Our results clearly indicate that inhibition of PKC-delta signaling enhances the antiproliferative effect of sorafenib in malignant human glioma cell lines and support the examination of combinations of signaling inhibitors in these tumors.
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PMID:Coadministration of sorafenib with rottlerin potently inhibits cell proliferation and migration in human malignant glioma cells. 1695 60

Multiple genetic aberrations in human gliomas contribute to their highly infiltrative and rapid growth characteristics. Focal adhesion kinase (FAK) regulates tumor migration and invasion. Insulin-like growth factor-I receptor (IGF-IR), whose expression correlates with tumor grade, is involved in proliferation and survival. We hypothesized that inhibiting the phosphorylation of FAK and IGF-IR by NVP-TAE226 (hereafter called TAE226), a novel dual tyrosine kinase inhibitor of FAK and IGF-IR, would suppress the growth and invasion of glioma cells. In culture, TAE226 inhibited extracellular matrix-induced autophosphorylation of FAK (Tyr(397)). TAE226 also inhibited IGF-I-induced phosphorylation of IGF-IR and activity of its downstream target genes such as MAPK and Akt. TAE226 retarded tumor cell growth as assessed by a cell viability assay and attenuated G(2)-M cell cycle progression associated with a decrease in cyclin B1 and phosphorylated cdc2 (Tyr(15)) protein expression. TAE226 treatment inhibited tumor cell invasion by at least 50% compared with the control in an in vitro Matrigel invasion assay. Interestingly, TAE226 treatment of tumor cells containing wild-type p53 mainly exhibited G(2)-M arrest, whereas tumor cells bearing mutant p53 underwent apoptosis. Induction of apoptosis by TAE226 was substantiated by detection of caspase-3/7 activation and poly(ADP-ribose) polymerase cleavage and by an Annexin V apoptosis assay. More importantly, TAE226 treatment significantly increased the survival rate of animals in an intracranial glioma xenograft model. Collectively, these data show that blocking the signaling pathways of FAK and IGF-IR with TAE226 has the potential to be an efficacious treatment for human gliomas.
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PMID:Inhibition of both focal adhesion kinase and insulin-like growth factor-I receptor kinase suppresses glioma proliferation in vitro and in vivo. 1743 Nov 14

Malignant gliomas are one of the leading causes of cancer deaths worldwide, but chemoprevention strategies for them are few and poorly investigated. Here, we show that cholera toxin, the traditional biotoxin and well known inducer of accumulation of cellular cAMP, is capable of inducing differentiation on malignant gliomas in vitro with rat C6 and primary cultured human glioma cells. Cholera toxin-induced differentiation was characterized by typical morphological changes, increased expression of glial fibrillary acid protein, decreased expression of Ki-67, inhibition of cellular proliferation, and accumulation of cells in the G(1) phase of the cell cycle. Cholera toxin also triggered a significant reduction in the G(1) cell-cycle regulatory proteins cyclin D1 and Cdk2 along with an overexpression of cell-cycle inhibitory proteins p21(Cip1) and p27(Kip1). Abrogation of cAMP-dependent protein kinase A activity by protein kinase A inhibitor or silencing of cAMP-responsive element binding proteins by RNA interference resulted in suppressed differentiation. These findings imply the attractiveness of cholera toxin as a drug candidate for further development of differentiation therapy. Furthermore, activation of the protein kinase A/cAMP-responsive element binding protein pathway may be a key and requisite factor in glioma differentiation.
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PMID:Cholera toxin induces malignant glioma cell differentiation via the PKA/CREB pathway. 1767 96


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