Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies have shown that the negative cell cycle regulator WAF1/Cip1 is often overexpressed in human gliomas and that WAF1/Cip1 overexpression may be a factor in cancer chemoresistance. We established a doxycycline-inducible WAF1/Cip1 expression system in two glioblastoma cell lines and examined the role of WAF1/Cip1 in their response to the chemotherapy agents 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and cis-diamminedichloroplatinum (cisplatin), in an isogeneic background. Our results showed that the induction of WAF1/Cip1 expression rendered glioma cells resistant to cell death induced by BCNU and cisplatin. Using an in vivo host-cell reactivation DNA repair assay, we demonstrated that WAF1/Cip1 enhances the repair of BCNU-induced DNA damage. We conclude that WAF1/Cip1 allows repair of BCNU- and cisplatin-damaged DNA and protects glioma cells from chemotherapy agent-induced apoptosis. Thus, blocking WAF1/Cip1 production or function may serve as a useful chemosensitization regimen for glioma.
 ...
PMID:Overexpressed WAF1/Cip1 renders glioblastoma cells resistant to chemotherapy agents 1,3-bis(2-chloroethyl)-1-nitrosourea and cisplatin. 953 61

The induction of WAF1 gene expression after the treatment with the anticancer agent 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU; nimustine hydrochloride) was studied in two human glioblastoma cell lines: U-87MG, which bears the wild-type p53 gene, and T98G, which bears the mutant p53 gene. A marked accumulation of WAF1 was observed 3 h after ACNU treatment in both cell lines. The induction of WAF1 mRNA by ACNU was detected by northern blot analysis in these cells. Binding activity of p53 to a p53 consensus sequence increased after treatment in U-87MG cells but not in T98G cells. The existence of a p53-independent WAF1 induction pathway was supported by the apparent accumulation of WAF1 after ACNU treatment in the p53-null human osteosarcoma cell line Saos-2. These findings suggest that there are two possible pathways for WAF1 induction: the p53-dependent pathway through the p53-responsive element and the p53-independent pathway through other elements.
 ...
PMID:p53-independent WAF1 induction by ACNU in human glioblastoma cells. 953 48

p53 and poly(ADP-ribose) polymerase (PARP) are both DNA damage recognition proteins and can be functionally activated by DNA strand breaks. To understand the functional interaction between these two proteins, the effects of a PARP inhibitor, 3-aminobenzamide (3AB), on the p53 pathway were investigated in human glioblastoma cells with different p53 status. Consistent with previous studies, irradiation with gamma-rays induced both p53 and WAF1 accumulation in A-172 cells (wtp53) but not in T98G cells (mp53). However, the presence of 3AB but not its analog suppressed radiation-induced accumulation of wtp53 and the expression of WAF1 and MDM2. Similar results were also obtained from U87MG, another human glioblastoma cell line with wtp53 status. Northern blotting analysis showed that 3AB inhibited the gamma-ray-induced WAF1 gene expression. Moreover, 3AB but not its analog inhibited irradiation-induced activation of sequence-specific DNA binding of wtp53 as detected using 32P-labeled or biotin-labeled p53 consensus sequence (p53CON). However, immunoblotting with an anti-poly(ADP-ribose) antibody showed that p53 proteins of the p53CON-bound fraction did not contain poly(ADP-ribose) (PAR). These findings suggested that poly(ADP-ribosyl)ation is required for rapid accumulation of p53, activation of p53 sequence-specific DNA binding and its transcriptional activity after DNA damage.
 ...
PMID:Poly(ADP-ribosyl)ation is required for p53-dependent signal transduction induced by radiation. 987 88

Acute low-dose irradiation (0.1-1 Gy, 1.33 Gy/min) of cells of a human glioblastoma cell line, A-172, induced a dose-dependent monophasic accumulation of TP53 (formerly known as p53) and CDKN1A (formerly known as WAF1). In contrast, chronic gamma irradiation (0.001 Gy/min) produced a clear biphasic response of accumulation TP53 with the first peak at 1.5 h (0.09 Gy) and the second peak at 10 h (0.54 Gy). Significantly, when the cells were preirradiated with a chronic dose of gamma irradiation for 24 h (1.44 Gy) or 50 h (3 Gy), they no longer responded to an acute challenging dose to produce a dose-dependent response of the TP53 pathway. These findings suggest that chronic irradiation at low dose rate alters the TP53-dependent signal transduction pathway. Wearing away of the TP53 pathway by chronic exposure to radiation may have important implications for radiation protection.
 ...
PMID:Low-dose-rate radiation attenuates the response of the tumor suppressor TP53. 1007 76

We have previously reported that heat stress induces expression of wild-type TP53 (formerly known as p53) activated factor 1 (CDKN1A, formerly known as WAF1) only when TP53 protein is wild-type using cells of a human glioblastoma cell line (A-172) and cells of its transformant (A-172/mp53/ 143) with a mutant TP53 (point mutation at codon 143 from Val to Ala) vector. Transfection of A-172 cells with the mutant TP53 vector abolished the heat-induced expression of CDKN1A, demonstrating the dominant negative nature of this TP53 mutant over the endogenous wild-type TP53. This kind of dominant negative TP53 mutant occurs frequently in various types of cancer. Overcoming this dominance or restoring the normal functions to these TP53 mutants is a new strategy for TP53-targeted cancer therapies. We examined whether glycerol can act as a chemical chaperone to correct the mutant TP53 conformation. No CDKN1A expression was induced after heating or treatment with glycerol at concentrations of 0.6 and 1.2 M in these transformants. In contrast, A-172/mp53/ 143 cells showed CDKN1A expression when they were heated in the presence of glycerol at 0.6 or 1.2 M, which was similar to the response of the parental and neo vector-transfected control cells. To test the generality of the effects of glycerol on mutant TP53, we used human osteosarcoma Saos-2 cells (lacking TP53) transfected with mutant TP53 and cells of two other human glioblastoma cell lines carrying mutant TP53. These cells showed similar CDKN1A expression when heated in the presence of glycerol at 0.6 or 1.2 M. These results suggest that glycerol is effective in restoring several TP53 mutants to normal TP53 function, leading to normal CDKN1A expression after heat stress. This observation provides a novel tool for correction of mutant TP53 conformation and may be applicable for TP53-targeted cancer therapy.
 ...
PMID:Restoration of mutant TP53 to normal TP53 function by glycerol as a chemical chaperone. 1019 May 3

The Cdk inhibitor p21/WAF1 can be transcriptionally activated by wild-type p53, not by mutant p53, and functions to block cell-cycle progression in many human neoplasms. We examined the immunohistochemical expression of p53 and p21 in 35 human primary glioblastomas in relation to tumor proliferation potential as assessed by the Ki-67 labeling index (LI) and the glioblastoma apoptosis index (AI). The expression of mutant p53 was observed in 74% of glioblastomas, wild-type p53 in 18% of glioblastomas, and p21 in 57% of glioblastomas. p21 expression was seen in 15 of 26 mutant p53-positive and 2 of 4 wild p53-positive tumors. Tumor Ki-67 LI correlated neither with p53 nor with p21 expression in glioblastomas. Apoptosis was identified in all 15 glioblastomas examined, with a mean (+/-SD) Al of 1.69+/-1.54, and correlated neither with p53 (wild or mutant) nor with p21 expression. The results of the present study suggest that p53 mutation and p21 protein expression are frequent in primary glioblastoma but lack correlation with tumor proliferation potential and apoptosis. The lack of correlation between p21 and p53 also suggests that p21 in glioblastomas may be induced by a p53-independent pathway.
 ...
PMID:Immunohistochemical analysis of p53 and p21 in human primary glioblastomas in relation to proliferative potential and apoptosis. 1032 45

To examine the functional role of tumor suppressor p53 in radiosensitivity of glioblastoma multiforme cells, I analyzed radiosensitivity of three glioblastoma cell lines with different p53 statuses: LN444 (wild-type p53), U251MG (mutant R273Q), and LN382 (mutant V197L). The mutant V197L is a temperature-sensitive (ts) mutant, of which transcriptional activity is almost normal at 34 degrees C but lost at 37 degrees C in yeast p53 functional assay. Transcriptional activity V197L p53 on mdm2, p21/WAF1, and Bax promoters determined by a luciferase assay increased respectively by 6.5, 33.4, and 4.9 folds at 34 degrees C, compared to those at 37 degrees C. Semiquantitative multiplex RT-PCR showed a slight increase of Bax mRNA expression at 34 degrees C but a marked increase of p21 mRNA expression, indicating that this ts mutant restored transcriptional activity predominantly on p21 promoter at the permissible temperature. Corresponding to the p21 transactivation, growth of LN382 cells was completely arrested without apoptosis when cultured at 34 degrees C but this arrest was reversed at 37 degrees C with a delay time subsequently to 24 or 48 h of culture at 34 degrees C. Clonogenic assay showed that dose-dependent radiosensitivity of LN382 cells to gamma-irradiation was markedly enhanced at 34 degrees C compared to that at 37 degrees C, whereas those of LN444 and U251MG were not changed between 34 and 37 degrees C. This sensitization was not attributable to apoptosis induction, since no DNA ladder formation nor sub-G1/0 phase cells were observed. Instead, cell cycle analysis demonstrated G1 and G2M arrest of the LN382 cells cultured at 34 degrees C after irradiation. In agreement to this, an increase of p21 expression was further enhanced by irradiation. In conclusion, these findings altogether suggest that p21 expression by restoration of p53 function can increase the radiosensitivity of glioblastoma cells by arresting the cells at G1 and G2M phases.
 ...
PMID:[Functional restoration of tumor suppressor p53 alters susceptibility of glioblastoma cells to irradiation--analysis using a cell line containing a temperature-sensitive mutant]. 1097 6

The purpose of this paper is to investigate the effect of wortmannin, a specific inhibitor of phosphatidylinositol 3-kinase (PI3K), on TP53 (formerly known as p53) signal transduction initiated by ionizing radiation and radiosensitization in isogenic derivatives of human glioblastoma cells differing in TP53 status. Wortmannin inhibited the accumulation of TP53 and CDKN1A (formerly known as WAF1) after 6 Gy irradiation in A-172/neo cells bearing wild-type TP53. In A-172/Trp248 cells carrying mutant TP53, X-rays induced no significant accumulation of TP53 and slight increase of CDKN1A. There were, consequently, little differences in the expression of TP53 and CDKN1A between A-172/Trp248 cells exposed to 6 Gy alone and wortmannin plus 6 Gy. However, wortmannin sensitized both A-172/neo and A-172/Trp248 cells to radiation. These studies indicate that wortmannin inhibits TP53 upregulation, but this suppression does not account for the radiosensitization by this drug. These results indicate that inhibitors of PI3K-related kinases may present a new class of radiosensitizers, regardless of the TP53 status of tumor cells.
 ...
PMID:Wortmannin sensitizes human glioblastoma cell lines carrying mutant and wild type TP53 gene to radiation. 1109 Sep 62

The antiproliferative effect of IFNalpha was tested on the human glioblastoma cell lines, U-373MG and T98G. IFNalpha significantly inhibited the growth of both cell lines, but was more effective in retarding the growth of U-373MG cells. Flow cytometry analysis indicated that synchronized IFNalpha-treated U-373MG cells showed a strong block in the progression of cells out of the S phase of the cell cycle. T98G cells, on the other hand, showed a moderate delay in the transition of cells from G1 to S phase and only a slight delay in the S phase, consistent with the decreased antiproliferative effect of IFNalpha on this cell line. IFNalpha-treated cells were then tested for the induction of the tumor suppressor gene product, p21(WAF1/CIP1). Higher levels of p21(WAF1/CIP1) were detected in lysates from IFNalpha-treated U-373MG cells as compared to media controls for as long as 18 h. In IFNalpha-treated T98G cells, p21(WAF1/CIP1) levels were slightly elevated at 4 and 6 h, but decreased to levels similar to controls thereafter, correlating with the antiproliferative effects of IFNalpha on each cell line. Immunoprecipitation studies on lysates from IFNalpha-treated U-373MG and T98G cells indicated that increased amounts of p21(WAF1/CIP1) were complexed to both cyclin D1 and cyclin E. Further, reduced cyclin-dependent kinase 2 (cdk2) activity was found in both IFNalpha-treated U-373MG and T98G cells, suggesting a mechanism by which p21(WAF1/CIP1) exerted its antiproliferative effects. Lastly, we analyzed the time-dependent production of the cyclins D1, E, and A. No differences in cyclin D1 levels were found between IFNalpha-treated and media-treated U-373MG and T98G cells. However, both IFNalpha-treated U-373MG and T98G cells showed a prolonged elevation in cyclin E, correlating with the G1 to S phase delays observed in these cell lines. Further, the duration of cyclin E production corresponded with the magnitude of the cell cycle delays seen in IFNalpha-treated U-373MG and T98G cells. Prolonged elevation of cyclin A was also seen in both IFNalpha-treated U-373MG and T98G cells, the magnitude of which correlated with the S phase delay observed in these cell lines. Thus, the data indicate that IFNalpha has significant antiproliferative activity against glioblastoma cells that is mediated, at least in part, by the tumor suppressor gene product, p21(WAF1/CIP1).
 ...
PMID:Inhibition of the glioblastoma cell cycle by type I IFNs occurs at both the G1 and S phases and correlates with the upregulation of p21(WAF1/CIP1). 1110 Aug 20

Organotin compounds, particularly tri-organotin, have demonstrated cytotoxic properties against a number of tumor cell lines. On this basis, triethyltin(IV)lupinylsulfide hydrochloride (IST-FS 29), a quinolizidine derivative, was synthesized and developed as a potential antitumor agent. This tin-derived compound exhibited potent antiproliferative effects on three different human cancer cell lines: teratocarcinoma of the ovary (PA-1), colon carcinoma (HCT-8) and glioblastoma (A-172). Cytotoxic activity was assessed by MTT and cell count assays during time course experiments with cell recovery after compound withdrawal. Significant cell growth inhibition (up to 95% in HCT-8 after 72 h of exposure), which also persisted after drug-free medium change, was reported in all the cell lines by both assays. In addition, the cytocidal effects exerted by IST-FS 29 appeared more consistent with necrosis or delayed cell death, rather than apoptosis, as shown by morphologic observations under light microscope, DNA fragmentation analysis and flow cytometry. In the attempt to elucidate whether this compound might affect genes playing a role in G1/S phase transition, the expressions of p53, p21(WAF1), cyclin D1 and Rb, mainly involved in response to DNA-damaging stress, were analyzed by Western blot. Heterogeneous patterns of expression during exposure to IST-FS 29 were evidenced in the different cell lines suggesting that these cell-cycle-related genes are not likely the primary targets of this compound. Thus, the present data seem more indicative of a direct effect of IST-FS-29 on macromolecular synthesis and cellular homeostasis, as previously hypothesized for other organotin complexes.
 ...
PMID:Antiproliferative activity and interactions with cell-cycle related proteins of the organotin compound triethyltin(IV)lupinylsulfide hydrochloride. 1124 20


<< Previous 1 2 3 4 5 Next >>