Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sensitivity of CD95-mediated apoptosis has been reported to vary during cell cycle progression (FEBS Lett. (1997) 412, 91-93). Here, we report that three human glioma cell lines with different p53 status (i) undergo growth arrest and synchronous cell cycle re-entry after prolonged serum deprivation, (ii) do not exhibit cell cycle-related changes in CD95 expression at the cell surface, and (iii) do not exhibit cell cycle-related changes in susceptibility to DC95 ligand-induced apoptosis. In contrast, cell cycle-specific activity was demonstrated for various cancer chemotherapy drugs. Further, CD95 expression and susceptibility to CD95 ligand-induced apoptosis does not vary during cell cycle progression of Jurkat T cells, HeLa cervical carcinoma and HepG2 hepatocellular carcinoma cells. These results do not support a role for the cell cycle phase as an important predictor of vulnerability to CD95-mediated apoptosis.
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PMID:CD95-mediated apoptosis: no variation in cellular sensitivity during cell cycle progression. 972 Sep 15

Topotecan is a novel topoisomerase I inhibitor that may have a role in the adjuvant chemotherapy of several solid tumors, including malignant glioma. Here, we have characterized the time- and concentration-dependent toxicity of topotecan in four human malignant glioma cell lines, LN-18, LN-229, LN-308 and T98G. High micromolar concentrations of topotecan, which are unlikely to be achieved in plasma in human patients in vivo, were cytotoxic within 48 hr, induced DNA fragmentation, did not induce major cell cycle changes, failed to consistently alter BCL-2 or BAX protein levels but inhibited RNA synthesis and induced cleavable DNA/topoisomerase I complex formation. Prolonged exposure for 72 hr to high nanomolar to low micromolar concentrations of topotecan augmented p21 protein levels and induced G2/M arrest but failed to consistently alter BCL-2 and BAX protein levels, did not induce significant DNA/topoisomerase I complex formation and did not inhibit RNA synthesis. Neither short-term nor long-term topotecan toxicity was blocked by ectopic expression of bcl-2 or wild-type p53. Transfer of a mutant p53 gene enhanced topotecan sensitivity in wild-type p53 LN-229 but not mutant p53 LN-18 cells. CD95 ligand (CD95L)-induced apoptosis was synergistically enhanced by short-term/high concentration but not long-term/low concentration exposure to topotecan, suggesting that topotecan sensitizes human malignant glioma cells to CD95L-induced apoptosis via inhibition of RNA synthesis. These data suggest that topotecan needs to be administered in high concentrations, such as an intratumoral polymer, to limit glioma cell growth in synergy with CD95L in vivo.
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PMID:Potentiation of CD95L-induced apoptosis of human malignant glioma cells by topotecan involves inhibition of RNA synthesis but not changes in CD95 or CD95L protein expression. 973

Dexamethasone (DEX)-mediated inhibition of drug-induced, but not CD95 ligand-induced, apoptosis in malignant glioma cells correlates with wild-type p53 status. Here, we examined mechanisms underlying DEX-mediated protection from apoptosis. DEX did not induce p53 expression in two p53 wild-type cell lines (U87MG, LN-229) and did not alter drug-induced p53 accumulation. Forced expression of temperature-sensitive p53val135 in mutant conformation failed to prevent accumulation of endogenous wild-type p53 but acted in a transdominant negative manner to inhibit p53-mediated, camptothecin-induced p21WAF1/CIP1 expression. p53val135-transfected cells retained responsiveness to DEX at restrictive temperature, suggesting that p53 activity is not required for cytoprotection. Forced expression of wild-type p53val135 abrogated the protective effect of DEX, suggesting redundant cytoprotective effects of DEX and p53. Indeed, DEX induced moderate accumulation of p21WAF1/CIP1 in U87MG, LN-229 and p53 mutant LN-18 cells, but not in p53 mutant LN-308 or T98G cells. LN-18 is also the p53 mutant cell line with the best cytoprotective response to DEX. p21WAF1/CIP1 accumulation occurred in the absence of changes in p21WAF1/CIP1 mRNA expression. Wild-type p53 was not required for this DEX effect since DEX induced p21WAF1/CIP1 accumulation in p53val135-transfected LN-229 cells, too. DEX failed to induce p21WAF1/CIP1 expression or cytoprotection in untransformed rat astrocytes. The same lack of modulation of p21WAF1/CIP1 expression and drug toxicity was observed in p21(+/+), p21(+/-) and p21(-/-) human colon carcinoma cells. Paradoxically, while only p21(+/+) and p21(+/-) mouse embryonic fibroblasts showed enhance p21WAF1/CIP1 levels after exposure to DEX, only p21(-/-) fibroblasts were protected from drug toxicity by DEX. The present study links DEX-mediated protection from cancer chemotherapy to a p53-independent pathway of regulating p21WAF1/CIP1 expression in glioma cells but this effect appears to cell type-specific.
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PMID:Dexamethasone-mediated protection from drug cytotoxicity: association with p21WAF1/CIP1 protein accumulation? 979 34

Nitric oxide (NO) is thought to play an important role in neurotransmission, inflammation, and regulation of cell death in the mammalian brain. Here, we examined the synthesis and biological effects of NO in human malignant glioma cells. Exposure to cytokines such as interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha or interleukin (IL)-1beta and lipopolysaccharide (LPS) induced NO synthesis in rat C6 and A172 human glioma cells, but not in LN-229, T98G or LN-18 human malignant glioma cells. Induced release of NO involved enhanced expression of inducible NO synthase (iNOS). Failure to detect NO release in the latter cell lines was not overcome by neutralization of endogenous TGF-beta or by coexposure to cytokines, LPS, and antioxidants. Apoptosis induced by CD95 ligand (CD95L) did not involve NO formation. Neither NOS inhibitors nor NO donators modulated CD95L-induced apoptosis. Dexamethasone (DEX)-mediated protection of glioma cells from CD95L-induced apoptosis was also independent of DEX effects on NO metabolism. DEX inhibited not only cytokine/LPS-evoked NO release but also attenuated the toxicity of NO in three of five cell lines. Forced expression of temperature-sensitive p53 val135 in C6 cells in either mutant or wild-type conformation inhibited cytokine/LPS-induced NO synthesis. Further, accumulation of p53 in both mutant or wild-type conformation protected glioma cells from the toxicity of exogenous NO, consistent with a gain of p53 function associated with p53 accumulation. We conclude that resistance to NO-dependent immune defense mechanisms may contribute to the malignant progression of human cancers with p53 alterations, notably those associated with the accumulation of mutant p53 protein.
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PMID:Synthesis and biological effects of NO in malignant glioma cells: modulation by cytokines including CD95L and TGF-beta, dexamethasone, and p53 gene transfer. 981 63

Chemotherapeutic drugs cause DNA damage and kill cancer cells mainly by apoptosis. p53 mediates apoptosis after DNA damage. To explore the pathway of p53-dependent cell death, we investigated if p53-dependent apoptosis after DNA damage is mediated by the CD95 (APO-1/Fas) receptor/ligand system. We investigated hepatoma, gastric cancer, colon cancer, and breast cancer cell lines upon treatment with different anticancer agents known to act via p53 accumulation. Cisplatin, mitomycin, methotrexate, mitoxantrone, doxorubicin, and bleomycin at concentrations present in the sera of patients during therapy led to an upregulation of both CD95 receptor and CD95 ligand. Induction of the CD95 ligand occurred in p53 wild-type (wt), p53 mutant (mt), and p53 deficient (p53(-/-)) cell lines and at wt and mt conformation of temperature-sensitive p53 mutants. In contrast, upregulation of the CD95 receptor was observed only in cells with wt p53, not in cells with mt or without any p53. Restitution of inducible wt p53 function restored the ability of p53(-/-) Hep3B cells to upregulate the CD95 receptor in response to anticancer drugs. This rendered the cells sensitive to CD95-mediated apoptosis. In an attempt to understand how CD95 expression is regulated by p53, we identified a p53-responsive element within the first intron of the CD95 gene, as well as three putative elements within the promoter. The intronic element conferred transcriptional activation by p53 and cooperated with p53-responsive elements in the promoter of the CD95 gene. wt p53 bound to and transactivated the CD95 gene, whereas mt p53 failed to induce apoptosis via activation of the CD95 gene. These observations provide a mechanistic explanation for the ability of p53 to contribute to tumor progression and to resistance of cancer cells to chemotherapy.
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PMID:p53 activates the CD95 (APO-1/Fas) gene in response to DNA damage by anticancer drugs. 984 17

The aim of the study was to determine whether the topoisomerase I inhibitors, camptothecin and beta-lapachone, are suitable agents for the adjuvant pharmacotherapy of proliferative vitreoretinopathy (PVR). The effects of the drugs on cultured human retinal pigment epithelial (RPE) cells were examined using growth assays, cytotoxicity assays, single cell agarose gel electrophoresis, in situ DNA end labeling and immunoblot analysis for apoptosis-regulatory proteins. Both agents killed RPE cells in a concentration-and time-dependent manner. Cell death was apoptotic as assessed by single cell agarose gel electrophoresis and in situ DNA end labeling. Camptothecin, but not beta-lapachone, induced accumulation of p53 and the major growth arrest-associated p53 response protein, p21. Both drugs enhanced expression of the proapoptotic BAX protein. Camptothecin, but not beta-lapachone, synergistically enhanced RPE cell apoptosis induced by the cytotoxic cytokine, CD95 ligand (CD95L). This effect was linked to camptothecin-induced inhibition of RNA synthesis. Atypical topoisomerase I inhibitors may be promising agents for the adjuvant pharmacotherapy of PVR. Experimental studies to assess possible ocular toxicity upon local administration and to confirm its therapeutic efficacy in an animal model of PVR are required.
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PMID:The topoisomerase I inhibitors, camptothecin and beta-lapachone, induce apoptosis of human retinal pigment epithelial cells. 987 14

To explore the pathway of p53 dependent cell death, we investigated if p53 dependent apoptosis following DNA damage is mediated by the CD95 (APO-1/Fas) receptor/ligand system. We investigated cell lines of solid human tumors upon treatment with clinically relevant chemotherapeutic drugs known to act via p53 accumulation. Treatment with these cytotoxic drugs led to an upregulation of both, the CD95 receptor (CD95) and the CD95L (CD95L). Induction of the CD95L occurred in p53 wild-type (wt), p53 mutant (mt) and in cell lines lacking p53 altogether (p53-/-). Thus, the regulation of the CD95L in response to chemotherapeutic drugs clearly involves p53 independent mechanisms. Most importantly, upregulation of CD95 occurred only in cell lines with wild-type p53, thereby strongly increasing the responsiveness towards CD95 mediated apoptosis. Thus, upregulation of the CD95 receptor seems to be dependent on intact wild-type p53. Apoptosis was mediated by cleavage of the receptor proximal caspase, caspase-8 (FLICE/MACH). Caspase-8 cleavage was observed, independent of the p53 status of the tumor cells and irrespective whether or not apoptosis was dependent on the CD95 system. Hence, additional effector pathways besides CD95/CD95L signaling are likely to contribute to drug-induced apoptosis.
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PMID:The role of p53 and the CD95 (APO-1/Fas) death system in chemotherapy-induced apoptosis. 988 15

Many anticancer drugs are able to induce apoptosis in tumor cells but the mechanisms underlying this phenomenon are poorly understood. Some authors reported that the p53 tumor suppressor gene may be responsible for drug-induced apoptosis; however, chemotherapy-induced apoptosis can also be observed in p53 negative cells. Recently, doxorubicin (DXR) was reported to induce CD95L expression to mediate apoptosis through the CD95/CD95L system. Thus, an impairment of such a system may be involved in drug resistance. We evaluated the in vitro antitumor activity of several cytotoxic drugs on two human p53-negative T-cell lymphoma cell lines, the HUT78-B1 CD95L-resistant cell line and the HUT78 parental CD95L-sensitive cell line. We demostrated by Western blotting assay that DXR and etoposide (VP-16) were able to induce CD95L expression after 4 h of treatment. In contrast, they were unable to induce the expression of p53. DXR, at concentrations ranging from 0.001 - 1 microg/ml, and VP16, at concentrations ranging from 0.05 - 1 microg/ml, were equally cytotoxic and induced apoptosis in both cell lines as assessed by fluorescence microscopy and flow cytometry analyses. Although we observed a slightly reduced percentage of apoptotic cells in HUT78B1 when compared with the parental HUT78 cells after few hours of drug exposure, this difference was no longer evident at 48 or 72 h. Similarly, the exposure of HUT78 cells to a CD95-blocking antibody partially reduced early apoptosis (24 h) without affecting the long-term effects of the drugs including cytotoxicity. Furthermore, as observed with DXR and VP-16, both the CD95L-sensitive and the CD95L-resistant cell lines resulted equally sensitive to the cytotoxic effects of a number of different cytotoxic drugs (vincristine, camptothecin, 5-fluorouracil and methotrexate). The treatment with the Caspase-3 tetrapeptide aldehyde inhibitor, Ac-DEVD-CHO, did not affect the DXR-induced apoptosis whereas it only modestly inhibited apoptosis and cytotoxicity of VP-16, while Z-VAD.FMK, a Caspase inhibitor that prevents the processing of Caspase-3 to its active form, was able to block DXR-induced apoptosis at 24 h but not at 48 h. Thus, our results do not confirm a crucial role for the CD95/CD95L system in drug-induced apoptosis and suggest the involvement of alternative p53-independent pathways at least in this experimental model system.
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PMID:The CD95/CD95 ligand system is not the major effector in anticancer drug-mediated apoptosis. 1020 May 32

Induction of CD95 (Fas/APO-1) and CD95 ligand during chemotherapeutic treatment may contribute to the death by apoptosis of some tumor cells. In this study, we have analyzed the role of the CD95 system in genotoxic drug-induced death of human breast tumor cells. Incubation of the breast tumor cell lines MCF-7 and EVSA-T with doxorubicin or methotrexate caused apoptosis after 48 h of treatment. These drugs induced a marked increase in the level of CD95 mRNA and protein in wild-type p53-expressing MCF-7 cells. On the contrary, the breast cancer cell line EVSA-T that expresses high levels of an inactive form of p53, did not up-regulate CD95 upon drug treatment. Elevation of CD95 expression by DNA-damaging drugs was notably blocked in MCF-7 cells expressing the human papillomavirus type 16 E6 protein (E6 cells) which prevented p53 accumulation upon DNA damage. However, E6 cells were still killed by the drugs. Furthermore, the genotoxic drugs did not induce the expression of CD95 ligand in MCF-7 cells at doses that caused apoptosis in these breast tumor cells. Moreover, drug-induced apoptosis of breast tumor cells was not prevented in the presence of either a CD95 antagonistic antibody or a CD95 ligand blocking antibody. We also observed a strong synergism between lower doses of DNA-damaging drugs and CD95 agonistic antibody in the induction of apoptosis in MCF-7 cells. In summary, our data indicate that drug-induced apoptosis of breast tumor cells occurs by a CD95/CD95L-independent mechanism although by elevating the tumor suppressor proteins p53 and CD95, genotoxic drugs may sensitize breast tumor cells to CD95-mediated apoptosis.
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PMID:p53-mediated up-regulation of CD95 is not involved in genotoxic drug-induced apoptosis of human breast tumor cells. 1020 May 78

Chemotherapeutic agents and gamma-irradiation used in the treatment of brain tumors, the most common solid tumors of childhood, have been shown to act primarily by inducing apoptosis. Here, we report that activation of the CD95 pathway was involved in drug- and gamma-irradiation-induced apoptosis of medulloblastoma and glioblastoma cells. Upon treatment CD95 ligand (CD95-L) was induced that stimulated the CD95 pathway by crosslinking CD95 via an autocrine/paracrine loop. Blocking CD95-L/receptor interaction using F(ab')2 anti-CD95 antibody fragments strongly reduced apoptosis. Apoptosis depended on activation of caspases (interleukin 1beta-converting enzyme/Ced-3 like proteases) as it was almost completely abrograted by the broad range caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone. Apoptosis was mediated by cleavage of the receptor proximal caspase FLICE/MACH (caspase-8) and the downstream caspase CPP32 (caspase-3, Apopain) resulting in cleavage of the prototype caspase substrate PARP. Moreover, CD95 was upregulated in wild-type p53 cells thereby increasing responsiveness towards CD95 triggering. Since activation of the CD95 system upon treatment was also found in primary medulloblastoma cells ex vivo, these findings may have implications to define chemosensitivity and to develop novel therapeutic strategies in the management of malignant brain tumors.
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PMID:Activation of the CD95 (APO-1/Fas) pathway in drug- and gamma-irradiation-induced apoptosis of brain tumor cells. 1020 87


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