UMLS:C0017638 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Target Concepts:

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

Temozolomide (TMZ) produces O(6)-methylguanine in DNA, which in turn mispairs with thymine, triggering futile DNA mismatch repair (MMR) and ultimately cell death. We found previously that in p53-proficient human glioma cells, TMZ-induced futile DNA MMR resulted not in apoptosis but rather in prolonged, p53- and p21-associated G(2)-M arrest and senescence. Additionally, p53-deficient cells were relatively more TMZ resistant than p53-deficient glioma cells, which underwent only transient G(2)-M arrest before death by mitotic catastrophe. These results suggested that prolonged G(2)-M arrest might protect cells from TMZ-induced cytotoxicity. In the present study, we therefore focused on the mechanism by which TMZ induces G(2)-M arrest and on whether inhibition of such G(2)-M arrest might sensitize glioma cells to TMZ-induced toxicity. U87MG glioma cells treated with TMZ underwent G(2)-M arrest associated with Chk1 activation and phosphorylation of both cdc25C and cdc2. These TMZ-induced effects were inhibited by the Chk1 kinase inhibitor UCN-01. Although not in itself toxic, UCN-01 increased the cytotoxicity of TMZ 5-fold, primarily by inhibiting cellular senescence and increasing the percentage of cells bypassing G(2)-M arrest and undergoing mitotic catastrophe. In addition to enhancing TMZ-induced cytotoxicity in p53-proficient cells, UCN-01 also blocked TMZ-induced Chk1 activation and transient G(2)-M arrest in p53-deficient U87MG-E6 cells and similarly enhanced TMZ-induced mitotic catastrophe and cell death. Taken together, these results indicate that Chk1 links TMZ-induced MMR to G(2)-M arrest. Furthermore, inhibition of the cytoprotective G(2) arrest pathway sensitizes cells to TMZ-induced cytotoxicity and may represent a novel, mechanism-based means of increasing TMZ efficacy in both p53 wild-type and p53 mutant glioma cells.
...
PMID:Abrogation of the Chk1-mediated G(2) checkpoint pathway potentiates temozolomide-induced toxicity in a p53-independent manner in human glioblastoma cells. 1147 24

Temozolomide (TZM) is a novel methylating agent currently under investigation for treatment of recurrent high-grade gliomas. Although TZM generates a wide spectrum of methyl adducts, its cytotoxicity has been attributed to mismatch repair (MR)-mediated processing of O(6)-methylguanine:T mispairs. N3-methyladenine and N7-methylguanine adducts are promptly repaired by the base excision repair system, unless a poly(ADP-ribose) polymerase (PARP) inhibitor is combined to TZM. In this case, the repair process of N-methylpurines cannot be completed and the deriving DNA strand breaks contribute to cytotoxicity. In this study, we investigated the influence on cell growth and cell cycle of treatment with TZM + PARP inhibitor in glioma cells characterized by different susceptibility to TZM. The results indicated that PARP inhibitor increases growth inhibition induced by TZM in either p53-wild-type or p53-mutant glioblastoma cells, as early as 24 h after drug exposure. The enhancing effect exerted by PARP inhibitor was particularly evident in glioma cells characterized by a defective expression of MR, since these cells are tolerant to O(6)-methylguanine damage and show low sensitivity to TZM. In O(6)-alkylguanine-DNA alkyltransferase (OGAT)-deficient and MR-proficient tumor cells bearing wild-type p53, the drug combination markedly reduced cell accumulation in the G(2)/M phase of cell cycle and induction of the G(2) checkpoint regulator Chk1 kinase. In short-term cultures of glioma cells derived from surgical specimens, PARP inhibitor enhanced chemosensitivity to TZM and this effect was especially evident in OGAT-proficient tumors. Thus, a pharmacological strategy based on the interruption of N-methylpurine repair might represent a novel strategy to restore or increase glioma sensitivity to TZM.
...
PMID:Poly(ADP-ribose) polymerase inhibitor increases growth inhibition and reduces G(2)/M cell accumulation induced by temozolomide in malignant glioma cells. 1223 42

Pharmacologic inhibition of the DNA signal transducers Chk1 and p38 blocks G2 arrest and sensitizes glioblastoma cells to chemotherapeutic methylating agent-induced cytotoxicity. Because Akt pathway activation has been suggested to also block G2 arrest induced by DNA-damaging agents and because glioma cells frequently have high levels of Akt activation, we examined the contribution of the Akt pathway to methylating agent-induced G2 arrest and toxicity. U87MG human glioma cells containing an inducible Akt expression construct were incubated with inducing agent or vehicle, after which the cells were exposed to temozolomide and assayed for activation of the components of the G2 arrest pathway and survival. Temozolomide-treated control cells activated the DNA damage signal transducers Chk1, Chk2, and p38, leading to Cdc25C and Cdc2 inactivation, prolonged G2 arrest, and loss of clonagenicity by a combination of senescence and mitotic catastrophe. Temozolomide-treated cells induced to overexpress Akt, however, exhibited significantly less drug-induced Cdc25C/Cdc2 inactivation and less G2 arrest. Akt-mediated suppression of G2 arrest was associated not with alterations in Chk1 or p38 activation but rather with suppression of Chk2 activation and reduced recruitment of Chk2 to sites of damage in chromatin. Unlike bypass of the G2 checkpoint induced by pharmacologic inhibitors of Chk1 or p38, however, Akt-induced bypass of G2 arrest suppressed, rather than enhanced, temozolomide-induced senescence and mitotic catastrophe. These results show that whereas Akt activation suppresses temozolomide-induced Chk2 activation and G2 arrest, the overriding effect is protection from temozolomide-induced cytotoxicity. The Akt pathway therefore represents a new target for the sensitization of gliomas to chemotherapeutic methylating agents such as temozolomide.
...
PMID:Akt activation suppresses Chk2-mediated, methylating agent-induced G2 arrest and protects from temozolomide-induced mitotic catastrophe and cellular senescence. 1593 Mar 7

We have evaluated the efficacy of the multinuclear platinum chemotherapeutics BBR3464, BBR3571, and BBR3610 against glioma cells in culture and animal models and investigated their mechanism of action at the cellular level. In a clonogenic assay, BBR3610, the most potent compound, had an IC90 dose (achieving 90% colony formation inhibition) that was 250 times lower than that of cisplatin for both LNZ308 and LN443 glioma cells. In subcutaneous xenografts of U87MG glioma cells, BBR3610 approximately doubled the time it took for a tumor to reach a predetermined size and significantly extended survival when these cells were implanted intracranially. Analysis of apoptosis and cell cycle distribution showed that BBR compounds induced G2/M arrest in the absence of cell death, while cisplatin predominantly induced apoptosis. Interestingly, the BBR compounds and cisplatin both induced extracellular signal-regulated kinase 1/2 phosphorylation, and inhibition of this pathway at the level of MEK antagonized the induction of G2/M arrest or apoptosis, respectively. Analysis of Chk1 and Chk2 status did not show any differential effects of the drugs, and it is thus unlikely to underlie the difference in response. Similarly, the drugs did not differentially modulate survivin levels, and knockdown of survivin did not convert the response to BBR3610 to apoptosis. Together, these findings support continued development of BBR3610 for clinical use against glioma and provide a framework for future investigation of mechanism of action.
...
PMID:Polynuclear platinum anticancer drugs are more potent than cisplatin and induce cell cycle arrest in glioma. 1672 33

Ionizing radiation represents the most effective therapy for glioblastoma (World Health Organization grade IV glioma), one of the most lethal human malignancies, but radiotherapy remains only palliative because of radioresistance. The mechanisms underlying tumour radioresistance have remained elusive. Here we show that cancer stem cells contribute to glioma radioresistance through preferential activation of the DNA damage checkpoint response and an increase in DNA repair capacity. The fraction of tumour cells expressing CD133 (Prominin-1), a marker for both neural stem cells and brain cancer stem cells, is enriched after radiation in gliomas. In both cell culture and the brains of immunocompromised mice, CD133-expressing glioma cells survive ionizing radiation in increased proportions relative to most tumour cells, which lack CD133. CD133-expressing tumour cells isolated from both human glioma xenografts and primary patient glioblastoma specimens preferentially activate the DNA damage checkpoint in response to radiation, and repair radiation-induced DNA damage more effectively than CD133-negative tumour cells. In addition, the radioresistance of CD133-positive glioma stem cells can be reversed with a specific inhibitor of the Chk1 and Chk2 checkpoint kinases. Our results suggest that CD133-positive tumour cells represent the cellular population that confers glioma radioresistance and could be the source of tumour recurrence after radiation. Targeting DNA damage checkpoint response in cancer stem cells may overcome this radioresistance and provide a therapeutic model for malignant brain cancers.
...
PMID:Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. 1715 44

We determined the cytotoxicity of AG490 as a single agent and in combination with 7-hydroxystaurosporine (UCN-01) in a panel of malignant human glioma cell lines. Because p53 has important roles in cell cycle checkpoints, it has been anticipated that modulation of checkpoint pathways should sensitize p53 defective cells while sparing the normal cells. Cell proliferation was determined from dose-response curves. AG490 was effective as a cytotoxic agent alone regardless of p53 status. Combining the Chk1 inhibitor UCN-01 dramatically enhanced the response to AG490 in p53-mutated or deleted glioma cells. An opposite effect was noted in p53-wild type cells, in which UCN-01 and AG490 had antagonistic effects on cell proliferation and viability. We found that AG490 enhanced BAD phosphorylation in p53 wild type glioma cells, which appeared to protect against UCN-01-induced cytotoxicity, whereas AG490 enhanced UCN-01-induced cytotoxicity in p53 defective cell lines by suppression of BAD phosphorylation and induction of BAX and PARP cleavage. These observations highlight the potential for genotype-dependent factors to strongly influence response to signaling-targeted therapies in malignant gliomas and the importance of considering such factors in correlative response analyses for these agents.
...
PMID:AG490 influences UCN-01-induced cytotoxicity in glioma cells in a p53-dependent fashion, correlating with effects on BAX cleavage and BAD phosphorylation. 1790 Aug 1

2'-C-cyano-2'-deoxy-1-beta-D-arabino-pentofuranosylcytosine (CNDAC), the prodrug (sapacitabine) of which is in clinical trials, has the novel mechanism of action of causing single-strand breaks after incorporating into DNA. Cells respond to this unique lesion by activating the G2 checkpoint, affected by the Chk1-Cdc25C-cyclin-dependent kinase 1/cyclin B pathway. This study aims at defining DNA damage checkpoint sensors that activate this response to CNDAC, particularly focusing on the major phosphatidylinositol 3-kinase-like protein kinase family proteins. First, fibroblasts, deficient in ataxia-telangiectasia mutated (ATM), transfected with empty vector or repleted with ATM, were arrested in G2 by CNDAC to similar extents, suggesting ATM is not required to activate the G2 checkpoint. Second, chromatin associations of RPA70 and RPA32, subunits of the ssDNA-binding protein, and the ataxia-telangiectasia and Rad3-related (ATR) substrate Rad17 and its phosphorylated form were increased on CNDAC exposure, suggesting activation of ATR kinase. The G2 checkpoint was abrogated due to depletion of ATR by small interfering RNA, and impaired in ATR-Seckel cells, indicating participation of ATR in this G2 checkpoint pathway. Third, the G2 checkpoint was more stringent in glioma cells with wild-type DNA-dependent protein kinase catalytic subunit (DNA-PKcs) than those with mutant DNA-PKcs, as shown by mitotic index counting. CNDAC-induced G2 arrest was abrogated by specific DNA-PKcs inhibitors or small interfering RNA knockdown in ML-1 and/or HeLa cells. Finally, two phosphatidylinositol 3-kinase-like protein kinase inhibitors, caffeine and wortmannin, abolished the CNDAC-induced G2 checkpoint in a spectrum of cell lines. Together, our data showed that ATR and DNA-PK cooperate in CNDAC-induced activation of the G2 checkpoint pathway.
...
PMID:Ataxia-telangiectasia and Rad3-related and DNA-dependent protein kinase cooperate in G2 checkpoint activation by the DNA strand-breaking nucleoside analogue 2'-C-cyano-2'-deoxy-1-beta-D-arabino-pentofuranosylcytosine. 1820 16

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively kills tumor cells. However, its short half-life, poor delivery, and TRAIL-resistant tumor cells have diminished its clinical efficacy. In this study, we explored whether novel delivery methods will represent new and effective ways to treat gliomas and if adjuvant therapy with the chemotherapeutic agent temozolomide would enhance the cytotoxic properties of TRAIL in glioma lines resistant to TRAIL monotherapy. We have engineered adeno-associated virus (AAV) vectors encoding recombinant secreted TRAIL (S-TRAIL) and bioluminescent-fluorescent marker fusion proteins and show that AAV-delivered S-TRAIL leads to varying degrees of killing in multiple glioma lines, which correspond with caspase-3/7 activation. In vivo, dual bioluminescent imaging revealed efficient delivery of therapeutic AAV vectors directly into the tumor mass, which induced marked attenuation of tumor progression. Treatment of glioma cells with the chemotherapeutic agent temozolomide alone lead to a significant accumulation of cells in G(2)-M phase, activated the cell cycle checkpoint protein Chk1, and increased death receptor expression in a time-dependent manner. Furthermore, combined treatment with AAV-S-TRAIL or neural stem cell-S-TRAIL and temozolomide induced cell killing and markedly up-regulated proapoptotic proteins in glioma cells least sensitive to TRAIL. This study elucidates novel means of delivering S-TRAIL to gliomas and suggests combination of clinically relevant temozolomide and S-TRAIL may represent a new therapeutic option with increased potency for glioblastoma patients.
...
PMID:Targeting multiple pathways in gliomas with stem cell and viral delivered S-TRAIL and Temozolomide. 1900 40

It has been reported that cancer stem cells may contribute to glioma radioresistance through preferential activation of the DNA damage checkpoint response and an increase in DNA repair capacity. We have examined DNA repair in five stem and nonstem glioma cell lines. The population doubling time was significantly increased in stem compared with nonstem cells, and enhanced activation of Chk1 and Chk2 kinases was observed in untreated CD133(+) compared with CD133(-) cells. Neither DNA base excision or single-strand break repair nor resolution of pH2AX nuclear foci were increased in CD133(+) compared with CD133(-) cells. We conclude that glioma stem cells display elongated cell cycle and enhanced basal activation of checkpoint proteins that might contribute to their radioresistance, whereas enhanced DNA repair is not a common feature of these cells.
...
PMID:Comparative analysis of DNA repair in stem and nonstem glioma cell cultures. 1927 80

Previous studies have revealed that p38, a member of the family of stress-activated protein kinases (SAPKs), cooperates with the Chk1-pathway to bring about temozolomide (TMZ)-induced G2 arrest, and that the inhibition of either pathway alone is sufficient to sensitize U87MG glioma cells to TMZ-induced cytotoxicity. c-Jun N-terminal kinase (JNK), another SAPK, has been reported to have several roles of cell survival, oncogenesis, growth, differentiation and cell death. To elucidate the functions of JNK in glioma cells treated with TMZ, we analyzed alterations in JNK and the effect of modification of JNK in U87MG human glioma cells treated with TMZ. We found that JNK was phosphorylated 1-2 days after TMZ treatment and that pretreatment (for 24 h) and post-treatment (for 72 h) with a JNK inhibitor SP600125 at a concentration of 200 nM or higher remarkably reduced clonogenicity in the TMZ-treated cells. The phosphorylation of the JNK target protein c-Jun, but not of ATF-2, was inhibited by this concentration of SP600125. Therefore JNK was proved to have a role of survival in glioma cells treated with TMZ, and c-Jun-related responses were suggested to be more important in the JNK-mediated survival of glioma cells with DNA damage. SP600125 amplified the percentage of senescence-like cells and of mitotic catastrophe cells in TMZ-treated U87MG and U87MG-E6 cells, respectively, suggesting that the enhancement of TMZ-induced cytotoxicity by a JNK inhibitor in glioma cells is induced (at least in part) by the potentiation of cell death pathways induced by TMZ alone. Further investigation based on the present data may provide a viable approach for enhancing TMZ-induced cytotoxicity in human gliomas.
...
PMID:Inhibition of c-Jun N-terminal kinase enhances temozolomide-induced cytotoxicity in human glioma cells. 1951 66

1 2 3 4 Next >>