UMLS:C0017638 - FACTA Search

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Query: UMLS:C0017638 (glioma)
30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The chemotherapeutic agent temozolomide (TMZ) and the anti-angiogenic agent thalidomide (THD) have both demonstrated anti-tumor activity in patients with recurrent malignant glioma. Combination treatment with TMZ and THD in patients with glioblastoma multiforme (GBM) appears to be more effective than treatment with either drug alone. To investigate the mechanism of this anti-tumor effect, we examined the combined effects of TMZ and THD in a rat glioma xenograft model. We found that combination treatment markedly inhibited the growth of tumors that were orthotopically implanted into rat brains. Using proliferating cell nuclear antigen (PCNA) staining, we observed a significant decrease in cell proliferation in these tumors. CD31 staining of the microvasculature revealed a significant decrease in angiogenesis. We also found increased apoptosis in treated tumors by terminal deoxynucleotidyl-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) assay. We further demonstrated that the expression of angiogenic factors, such as vascular endothelial cell growth factor (VEGF) and basic fibroblastic growth factor (bFGF), were inhibited by THD. THD also decreased the number of ED1-positive, activated macrophages or microglial cells, which produce pro-angiogenic molecules around the glioma. Taken together, these results suggest that combination treatment with TMZ and THD inhibits tumor growth via the induction of apoptosis and the inhibition of angiogenesis in a rat model and may be a promising therapy for malignant gliomas.
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PMID:Combination treatment with temozolomide and thalidomide inhibits tumor growth and angiogenesis in an orthotopic glioma model. 1632 79

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.
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PMID:The effects of antisense AKT2 RNA on the inhibition of malignant glioma cell growth in vitro and in vivo. 1640 76

In this review are presented various lead compounds bearing a polyphenolic moiety and their biological targets. The relevance of these targets to develop the desired compounds as potential anti-cancer agents is discussed. For instance, caffeic acid phenethyl ester (CAPE) has preliminary been studied in our group to hold various biochemical responses. When C6 glioma cells were grown as xenografts in nude mice, treatment with CAPE (1-10 mg/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. Moreover, the ability of flavonoids to scavenge free-radicals and block lipid peroxidation raises the possibility that they may act as protective factors against carcinogenesis. Furthermore, protocatechuic acid (PCA) seems to be a promising compound regarded as a candidate group for cancer preventive agents. We have isolated and investigated Hibiscus protocatechuic acid from Hibiscus sabdariffa L. Hibiscus PCA showed against oxidative damage induced by t-butyl hydroperoxide in rat primary hepatocytes, and inhibitory effect on tumor promotion in mouse skin. Finally, we review here recent progress with the analogs of natural and synthetic lead compounds in Asiatic folk medicine. Since phenolic dimmers or trimers are significantly more potent than monomer in vitro and in vivo, a large number of phenolic dimmers or trimers with linker lengths and their pharmacological properties have been investigated.
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PMID:Evaluation of natural and synthetic compounds from East Asiatic folk medicinal plants on the mediation of cancer. 1684 35

Recent evidence suggests that the thyroid hormone L-thyroxine (T4) stimulates growth of cancer cells via a plasma membrane receptor on integrin alphaVbeta3. The contribution of this recently described receptor for thyroid hormone and receptor-based stimulation of cellular mitogen-activated protein kinase [MAPK; extracellular signal-regulated kinase 1/2 (ERK1/2)] activity, to enhancement of cell proliferation by thyroid hormone was quantitated functionally and by immunologic means in three glioma cell lines exposed to T4. At concentrations of 1 to 100 nmol/L, T4 caused proliferation of C6, F98, and GL261 cells, measured by accumulation of proliferating cell nuclear antigen (PCNA) and radiolabeled thymidine incorporation. This effect was inhibited by the T4 analogue, tetraiodothyroacetic acid, and by an alphaVbeta3 RGD recognition site peptide, both of which block T4 binding to integrin alphaVbeta3 but are not agonists. Activation of MAPK by T4 was similarly inhibited by tetraiodothyroacetic acid and the RGD peptide. The thyroid hormone 3,5,3'-triiodo-L-thyronine (T3) and T4 were equipotent stimulators of PCNA accumulation in C6, F98, and GL261 cells, but physiologic concentrations of T3 are 50-fold lower than those of T4. In conclusion, our studies suggest that glioblastoma cells are thyroid hormone dependent and provide a molecular basis for recent clinical observations that induction of mild hypothyroidism may improve duration of survival in glioblastoma patients. The present experiments infer a novel cell membrane receptor-mediated basis for the growth-promoting activity of thyroid hormone in such tumors and suggest new therapeutic approaches to the treatment of patients with glioblastoma.
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PMID:Acting via a cell surface receptor, thyroid hormone is a growth factor for glioma cells. 1684 76

The chemotherapeutic agent temozolomide produces O(6)-methylguanine (O6MG) in DNA, which triggers futile DNA mismatch repair, DNA double-strand breaks (DSB), G(2) arrest, and ultimately cell death. Because the protein complex consisting of Mre11/Rad50/Nbs1 (MRN complex) plays a key role in DNA damage detection and signaling, we asked if this complex also played a role in the cellular response to temozolomide. Temozolomide exposure triggered the assembly of MRN complex into chromatin-associated nuclear foci. MRN foci formed significantly earlier than gamma-H2AX and 53BP1 foci that assembled in response to temozolomide-induced DNA DSBs. MRN foci formation was suppressed in cells that incurred lower levels of temozolomide-induced O6MG lesions and/or had decreased mismatch repair capabilities, suggesting that the MRN foci formed not in response to temozolomide-induced DSB but rather in response to mismatch repair processing of mispaired temozolomide-induced O6MG lesions. Consistent with this idea, the MRN foci colocalized with those of proliferating cell nuclear antigen (a component of the mismatch repair complex), and the MRN complex component Nbs1 coimmunoprecipitated with the mismatch repair protein Mlh1 specifically in response to temozolomide treatment. Furthermore, small inhibitory RNA-mediated suppression of Mre11 levels decreased temozolomide-induced G(2) arrest and cytotoxicity in a manner comparable to that achieved by suppression of mismatch repair. These data show that temozolomide-induced O6MG lesions, acted upon by the mismatch repair system, drive formation of the MRN complex foci and the interaction of this complex with the mismatch repair machinery. The MRN complex in turn contributes to the control of temozolomide-induced G(2) arrest and cytotoxicity, and as such is an additional determining factor in glioma sensitivity to DNA methylating chemotherapeutic drugs such as temozolomide.
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PMID:The Mre11/Rad50/Nbs1 complex interacts with the mismatch repair system and contributes to temozolomide-induced G2 arrest and cytotoxicity. 1712 22

Targeting chemotherapeutic agents directly to sites of DNA replication and repair within cancerous cells is problematic. This study attempts to address the issue of nuclear delivery of biologically active peptides with the potential to disrupt cancer cell growth. Herein, the protein transduction domain of the HIV-1 transactivator of transcription, Tat (Tat(48-60)), is used to deliver a cytotoxic peptide mimic of the cyclin-dependent kinase inhibitor, p21(WAF1/CIP1) into the nucleus. This construct, which we designate as Tat(48-60)-P10, contains the PCNA interacting protein (PIP) box. We demonstrate the utility of Tat(48-60) for peptide delivery to the nucleus and show that Tat(48-60)-P10 induces apoptosis specific to the inclusion of the wild type PIP box containing sequence. Colocalization of Tat(48-60)-P10 with nuclear PCNA was observed by immunofluorescence analysis, supporting the hypothesis that cytotoxicity is potentially related to disruption of nuclear PCNA function. The U251 and U373 glioma cell lines exhibited particular sensitivity to the construct.
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PMID:A sychnological cell penetrating peptide mimic of p21(WAF1/CIP1) is pro-apoptogenic. 1728 47

Since cancer stem cells in brain tumors were introduced, there have been few explanations regarding the role of cancer stem cells in the progression of glioma. Here, we investigated their major molecular changes in tumor progression in relation to the stem cell subpopulation. Using 12 surgical specimens of gliomatosis cerebri (GC) in the early and advanced stages, we measured the expression of a panel of cell proliferation, microvessel density, microvessel areas, angiogenic factors and their associated receptors. In addition, expression of neural stem cell markers and associated cytokines were examined in tumor tissues by quantitative real-time RT-PCR. Comparing the biological characteristics between the initial infiltrating lesions (n=7) and progressed lesions (n=5), Sox2 and Musashi-1 were expressed in the tumor tissue at an early and a progressed state. Contrary to the early infiltrative phase representing angiogenesis-independent growth, GC with progression showed that nestin (+), PCNA (+) cells and total vessel area (angioectasia) were markedly increased with a higher expression of proangiogenic molecules and their receptors. These results suggest that tumor progression is mediated by cancer stem cells and cross-talk of cancer stem cells along with their environment and are closely associated with angiogenesis-dependent progression and -independent growth.
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PMID:The progression of gliomas is associated with cancer stem cell phenotype. 1828 95

Phosphatidylinositol 3-kinase (PI3K)/Akt plays a critical role in the formation of many malignant tumors, and has been shown to be an important therapeutic target. In the present study, small hairpin RNA (shRNA) expression constructs that target sequences of human Akt1 and PIK3R1 were used to examine the proliferation and invasion inhibition effects on SGC7901 gastric adenocarcinoma cells and U251 glioma cells. Cell growth was inhibited by over 60%, as indicated by a MTT assay, and was accompanied by G(1)/G(0) phase arrest in the shRNA treated group, indicating poor cell growth activities. The number of cells invading through the matrigel in the shRNA treated group were significantly decreased (51.6 +/- 3.9) compared with that of the control group (105 +/- 4.0) and the nonsense sequence group (102.5 +/- 6.4). In addition, the tumor volumes in the SGC7901 subcutaneous nude mouse model treated with shRNA were significantly smaller than those of the control group and nonsense sequence group. When Akt1 and PIK3R1 were dramatically downregulated, proliferating cell nuclear antigen (PCNA), CyclinD1 and matrix metalloproteinases (MMP-2, MMP-9) were downregulated, while tissue-Inhibitor of Metalloproteinase-2 (TIMP-2) and p53 were upregulated. Our results demonstrated that shRNA targeting Akt1 and PIK3R1 downregulates their expression significantly in a sequence-specific manner, exerting proliferation and invasion inhibition effects on SGC7901 and U251 cells. In conclusion, our data suggests a novel mechanism for the regulation of malignant tumor cell growth and provides evidence for new combinatory gene therapy for malignant tumors.
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PMID:Inhibitory effects of adenovirus mediated Akt1 and PIK3R1 shRNA on the growth of malignant tumor cells in vitro and in vivo. 1930 46

Cyclooxygenase-2 (COX-2) and phosphatidylinositol 3-kinase (PI3K)/Akt play a critical role in the formation of many malignant tumors, and have been shown to be important therapeutic targets. In the present study, small hairpin RNA (shRNA) expression constructs that target sequences of human COX-2, Akt1 and PIK3R1 were used to examine the proliferation and invasion inhibition effects on SGC7901 gastric adenocarcinoma cells and U251 glioma cells. Cell growth was inhibited by over 70%, as indicated by a MTT assay, and was accompanied by G1/G0 phase arrest in the shRNA treated group, indicating poor cell growth activities. The number of cells invading through the matrigel in the shRNA treated group were significantly decreased (26.4+/-4.6) compared with that of the control group (105+/-4.0) and the nonsense sequence group (102.5+/-6.4). In addition, the tumor volumes in the SGC7901 subcutaneous nude mouse model treated with shRNA was significantly smaller than those of the control group and nonsense sequence group. When COX-2, Akt1 and PIK3R1 were dramatically downregulated, proliferating cell nuclear antigen (PCNA), CyclinD1 and matrix metalloproteinases (MMP-2, MMP-9) were downregulated, while tissue-inhibitor of metalloproteinase-2 (TIMP-2) and P53 were upregulated. Our results demonstrated that shRNA targeting COX-2, Akt1 and PIK3R1 downregulates their expression significantly in a sequence-specific manner, exerting proliferation and invasion inhibition effects on SGC7901 and U251 cells. In conclusion, our data suggest a novel mechanism for the regulation of malignant tumor cell growth and provide evidence for new combinatory gene therapy for malignant tumors.
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PMID:Inhibitory effects of adenovirus mediated COX-2, Akt1 and PIK3R1 shRNA on the growth of malignant tumor cells in vitro and in vivo. 1963 78

Alphavirus, a genus of arthropod-borne togavirus, is well-known for its pro-apoptotic capability. However, the underlying mechanism remains to be further clarified. Here, we have identified that M1, an alphavirus isolated in 1960s, targeted C6 malignant glioma cells for apoptosis. Flow cytometry analysis showed that more cells enter S-phase post M1 infection, and subsequently undergo a classic apoptosis. To elucidate the mechanism of S-phase arrest and its relationship to apoptosis, we tested the expression of several critical cell cycle regulatory proteins and found elevated phosphorylation of cyclin-dependent kinase 2 (CDK2), decreased expression of cyclin A and proliferating cell nuclear antigen (PCNA). Notably, the protein level of p21(WAF1/CIP1) was downregulated earliest and most effectively among all tested changes of cell cycle regulators, though its mRNA level was strongly upregulated. To evaluate the role of p21(WAF1/CIP1) in S-phase accumulation and subsequent apoptosis, we confirmed that exogenous p21(WAF1/CIP1) overexpression or treatment with roscovitine (a selective chemical inhibitor of CDK2) efficiently protected against apoptosis with a reduced S-phase accumulation. Thus, it is indicated that the downregulation of p21(WAF1/CIP1) mediated C6 apoptosis via overactivation of CDK2. In addition, confocal microscopy showed that p21(WAF1/CIP1) totally translocated to nucleolus during M1-induced C6 apoptosis. Altogether, downregulation and nucleolar translocation of the p21(WAF1/CIP1) protein played an active role in M1-induced C6 apoptosis.
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PMID:Alphavirus M1 induces apoptosis of malignant glioma cells via downregulation and nucleolar translocation of p21WAF1/CIP1 protein. 1985 83

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