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)

Chemotherapeutic drugs are cytotoxic by induction of apoptosis in drug-sensitive cells. We investigated the mechanism of bleomycin-induced cytotoxicity in hepatoma cells. At concentrations present in the sera of patients during therapy, bleomycin induced transient accumulation of nuclear wild-type (wt) p53 and upregulated expression of cell surface CD95 (APO-1/Fas) receptor in hepatoma cells carrying wt p53 (HepG2). Bleomycin did not increase CD95 in hepatoma cells with mutated p53 (Huh7) or in hepatoma cells which were p53-/- (Hep3B). In addition, sensitivity towards CD95-mediated apoptosis was also increased in wt p53 positive HepG2 cells. Microinjection of wt p53 cDNA into HepG2 cells had the same effect. In contrast, bleomycin did not enhance susceptibility towards CD95-mediated apoptosis in Huh7 and in Hep3B cells. Furthermore, bleomycin treatment of HepG2 cells increased CD95 ligand (CD95L) mRNA expression. Most notably, bleomycin-induced apoptosis in HepG2 cells was almost completely inhibited by antibodies which interfere with CD95 receptor/ligand interaction. These data suggest that apoptosis induced by bleomycin is mediated, at least in part, by p53-dependent stimulation of the CD95 receptor/ligand system. The same applies to other anti-cancer drugs such as cisplatin and methotrexate. These data may have major consequences for drug treatment of cancer and the explanation of drug sensitivity and resistance.
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PMID:Drug-induced apoptosis in hepatoma cells is mediated by the CD95 (APO-1/Fas) receptor/ligand system and involves activation of wild-type p53. 902 73

Malignant glioma cells are susceptible to CD95(Fas/APO-)-mediated apoptosis triggered by agonistic antibody. Here we examined the proapoptotic effects of the natural CD95 ligand, a cytotoxic cytokine homologous to tumor necrosis factor, on malignant glioma cell lines LN-229, LN-308 and T98G. We assessed whether glioma cell killing is synergistically enhanced by cotreatment with CD95 ligand and chemotherapeutic agents, including doxorubicin, carmustine, vincristine, etoposide, teniposide, 5-fluorouracil and cytarabine. Synergy was examined at low concentrations of cytotoxic drugs and CD95 ligand with a defined effect level (IC15). Short-term-cytotoxicity assays showed prominent killing of the glioma cells by CD95 ligand but not by the drugs at relevant concentrations. CD95 ligand induced apoptosis in the acute toxicity paradigm was augmented by doxorubicin and vincristine. Growth-inhibition assays revealed prominent synergy between CD95 ligand and all drugs examined. The best synergy was obtained with CD95 ligand and doxorubicin, vincristine or teniposide. The strong synergistic antiproliferative effects were observed at much lower concentrations of CD95 ligand and cytotoxic drugs than the moderate synergistic acute cytotoxic effects. All cell lines examined express the Bcl-2 protein. LN-229 has partial wild-type p53 activity. T98G has mutant p53, LN-308 has a deleted p53 gene and lacks p53 protein expression. Thus, synergistic effects of CD95 ligand and cytotoxic drugs were observed in cell lines exhibiting two features thought to play a role in the chemoresistance of human malignant glioma cells: loss of wild-type p53 activity and acquisition of bcl-2 expression. Ectopic expression of murine bcl-2 conferred partial protection from CD95 ligand and drugs when administered alone but did not interfere with the mechanisms underlying the synergistic effects of CD95 ligand and chemotherapeutic drugs.
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PMID:Immunochemotherapy of malignant glioma: synergistic activity of CD95 ligand and chemotherapeutics. 911 85

Hypericin and tamoxifen are experimental agents for the adjuvant chemotherapy of malignant glioma. We report that hypericin and tamoxifen induce apoptosis of 7 human malignant glioma cell lines in a concentration- and time-dependent manner. Illumination is essential for the cytotoxicity of hypericin but not tamoxifen. Apoptosis is unaffected by inhibitors of RNA and protein synthesis or free radical scavengers, does not require wild-type p53 activity, and occurs in glioma cells expressing high levels of bcl-2. There is no correlation between hypericin and tamoxifen-induced cytotoxicity and inhibition of protein kinase C (PKC). Ectopic expression of a murine bcl-2 transgene provides modest protection from tamoxifen but does not affect hypericin toxicity. Hypericin and tamoxifen do not modulate glioma cell killing induced by tumor necrosis factor-alpha (TNF-alpha) or CD95 ligand. Both drugs augment the acute cytotoxicity of various cancer chemotherapy drugs but fail to shift their EC50 values in modified colony formation assays. These data do not provide further supportive evidence how to enhance the limited efficacy of tamoxifen treatment for human malignant glioma. However, hypericin is a promising agent for the treatment of malignant glioma if local photodynamic activation of hypericin in the glioma tissue can be achieved.
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PMID:Hypericin-induced apoptosis of human malignant glioma cells is light-dependent, independent of bcl-2 expression, and does not require wild-type p53. 932 22

During liver tissue repair, hepatic stellate cells (HSC), a pericyte-like mesenchymal liver cell population, transform from a "quiescent" status ("resting" HSC) into myofibroblast-like cells ("activated" HSC) with the latter representing the principle matrix synthesizing cell of the liver. Presently, the mechanisms that terminate HSC cell proliferation when tissue repair is concluded are poorly understood. Controlled cell death known as apoptosis could be a mechanism underlying this phenomenon. Therefore, apoptosis and its regulation were studied in HSC using an in vitro and in vivo approach. Spontaneous apoptosis became detectable in parallel with HSC activation because resting cells (2 days after isolation) displayed no sign of apoptosis, whereas apoptosis was present in 8% (+/- 5%) of "transitional" cells (day 4) and in 18% (+/- 8%) of fully activated cells (day 7). Both CD95 (APO-1/Fas) and CD95L (APO-1-/Fas-ligand) became increasingly expressed during the course of activation. Apoptosis could be fully blocked by CD95-blocking antibodies in normal cells and HSC already entering the apoptotic cycle. Using CD95-activating antibodies, transition of more than 95% cells into apoptosis was evident at each activation step. The apoptosis-regulating proteins Bcl-2 and p53 could not be detected in resting cells but were found in increasing amounts at days 4 and 7 of cultivation. Whereas p53 expression was induced by the CD95-activating antibody, no change was inducible in Bcl-2 expression. The Bcl-2-related protein bax could be found at days 2 and 4 in similar expression, was considerably up-regulated at day 7, but was not regulated by CD95-agonistic antibodies. In vivo, acute tissue damage was first accompanied by activation and proliferation of HSC displaying no sign of apoptosis. In the recovery phase, apoptotic HSC were detectable in parallel to a reduction in the total number of HSC present in the liver tissue. The data demonstrate that apoptosis becomes detectable in parallel with HSC activation, which suggests that apoptosis might represent an important mechanism terminating proliferation of activated HSC.
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PMID:CD95/CD95L-mediated apoptosis of the hepatic stellate cell. A mechanism terminating uncontrolled hepatic stellate cell proliferation during hepatic tissue repair. 935 52

Beta-lapachone and camptothecin are structurally unrelated agents thought to inhibit topoisomerase-I activity through distinct mechanisms. We find that beta-lapachone is much more potent than camptothecin in inducing acute cytotoxic effects on human malignant glioma cells. Acute cytotoxicity induced by both drugs is apoptotic by electron microscopy, but not blocked by inhibitors of RNA or protein synthesis and not associated with changes in the expression of bcl-2, bax, p53, p21 or GADD45 proteins. In contrast, prolonged exposure of glioma cells to both drugs for 72 hr results in growth inhibition and apoptosis, with EC50 values around 1 microM. None of 7 glioma cell lines tested were resistant to either drug. LN-229 cells which have partial p53-wild-type activity show enhanced expression of p53, p21 and bax protein, whereas bcl-2 levels decrease, after exposure to camptothecin. In contrast, beta-lapachone increases bax protein expression in the absence of p53 activation. T98G cells are mutant for p53. In these cells, p53 levels do not change and p21 is not induced. bax accumulation in T98G cells is induced by both drugs, with bcl-2 levels unaltered. Surprisingly, ectopic expression of murine bcl-2 fails to abrogate the toxicity of either drug. Camptothecin, but not beta-lapachone, sensitizes human malignant glioma cells to apoptosis induced by the cytotoxic cytokines, tumor necrosis factor-alpha and CD95 ligand. Thus, both drugs have potent anti-glioma activity that may be mediated by enhanced bax expression but is not inhibited by ectopic bcl-2 expression. Camptothecin-like agents are particularly promising for immunochemotherapy of malignant glioma using cytotoxic drugs and CD95 ligand.
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PMID:Topoisomerase-I inhibitors for human malignant glioma: differential modulation of p53, p21, bax and bcl-2 expression and of CD95-mediated apoptosis by camptothecin and beta-lapachone. 939 50

Induction of apoptosis in keratinocytes by UV light is a critical event in photocarcinogenesis. Although p53 is of importance in this process, evidence exists that other pathways play a role as well. Therefore, we studied whether the apoptosis-related surface molecule CD95 (Fas/APO-1) is involved. The human keratinocyte cell line HaCaT expresses CD95 and undergoes apoptosis after treatment with UV light or with the ligand of CD95 (CD95L). Incubation with a neutralizing CD95 antibody completely prevented CD95L-induced apoptosis but not UV-induced apoptosis, initially suggesting that the CD95 pathway may not be involved. However, the protease CPP32, a downstream molecule of the CD95 pathway, was activated in UV-exposed HaCaT cells, and UV-induced apoptosis was blocked by the ICE protease inhibitor zVAD, implying that at least similar downstream events are involved in CD95- and UV-induced apoptosis. Activation of CD95 results in recruitment of the Fas-associated protein with death domain (FADD) that activates ICE proteases. Immunoprecipitation of UV-exposed HaCaT cells revealed that UV light also induces recruitment of FADD to CD95. Since neutralizing anti-CD95 antibodies failed to prevent UV-induced apoptosis, this suggested that UV light directly activates CD95 independently of the ligand CD95L. Confocal laser scanning microscopy showed that UV light induced clustering of CD95 in the same fashion as CD95L. Prevention of UV-induced CD95 clustering by irradiating cells at 10 degrees C was associated with a significantly reduced death rate. Together, these data indicate that UV light directly stimulates CD95 and thereby activates the CD95 pathway to induce apoptosis independently of the natural ligand CD95L. These findings further support the concept that UV light can affect targets at the plasma membrane, thereby even inducing apoptosis.
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PMID:Ultraviolet light induces apoptosis via direct activation of CD95 (Fas/APO-1) independently of its ligand CD95L. 942 65

The anti-tumour alkaloid taxol shows strong cytotoxic and antiproliferative activity in two human malignant glioma cell lines, T98G and LN-229. CD95 (Fas/APO-1) ligand is a novel cytotoxic cytokine of the tumour necrosis factor (TNF) family that exerts prominent antiglioma activity. At clinically relevant taxol concentrations of 5-100 nM, taxol and CD95 ligand showed significant synergistic cytotoxicity and growth inhibition. High concentrations of taxol induced G/M cell cycle arrest in both cell lines. The synergy of taxol and CD95 ligand was independent of cell cycle effects of taxol as synergy was achieved at much lower taxol concentrations than G2/M arrest and as cell cycle effects of taxol were unaffected by co-exposure to CD95 ligand. Similarly, high concentrations of taxol were required to induce p53 activity in the p53 wild-type cell line LN-229. This effect was not modulated by CD95 ligand, suggesting that synergy is also independent of p53 activation. However, taxol induced a mobility shift of the bcl-2 protein on immunoblot analysis, indicative of bcl-2 phosphorylation. Bcl-2 phosphorylation on serine was confirmed by immunoprecipitation and phosphoserine immunoblot analysis. Considering (1) that phosphorylation of bcl-2 interferes with its heterodimerization with bax and (2) the inhibition of CD95-mediated apoptosis by bcl-2, we propose that taxol sensitizes malignant glioma cells to CD95 ligand by increasing the functional bax/bcl-2 rheostat in favour of bax and thus cell death.
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PMID:Taxol-mediated augmentation of CD95 ligand-induced apoptosis of human malignant glioma cells: association with bcl-2 phosphorylation but neither activation of p53 nor G2/M cell cycle arrest. 947 35

Teniposide (VM26) enhanced the anti-glioma activity of the cytotoxic cytokine, CD95 ligand. Synergy was observed at concentrations of teniposide that were insufficient for cleavable DNA topoisomerase II complex formation. CD95 ligand did not modulate the formation or removal of such complexes after teniposide treatment. These processes were also unaffected by ectopic expression of bcl-2. Teniposide enhanced CD95 expression in a glioma cell line with wild-type p53 (LN-229) but not in two p53 mutant cell lines (T98G, LN-308). Forced expression of a transdominant negative p53 mutant prevented the teniposide induced augmentation of CD95 expression in LN-229 cells but did not prevent the synergy of CD95 ligand and teniposide. Teniposide did not alter CD95 ligand expression, and forced expression of CD95 did not modulate sensitivity to VM26. Thus, teniposide-induced DNA lesions and alterations in CD95 or CD95 ligand are not necessary for teniposide-induced sensitization of human malignant glioma cells to CD95-mediated apoptosis.
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PMID:Synergy of CD95 ligand and teniposide: no role of cleavable complex formation and enhanced CD95 expression. 954 55

Loss of wild-type p53 activity is thought to be a major predictor of failure to respond to radiotherapy and chemotherapy in various human cancers. This assumption is largely based on some cell-death studies in p53-knockout mice and on correlations of p53 status assessed by immunochemistry or single-strand conformational polymorphism (SSCP) analysis, and responses to therapy in human cancers in vivo. In principle, p53 may enhance chemosensitivity by promoting apoptosis via transcription-independent mechanisms as well as transcriptional activation of proapoptotic genes such as bax and transcriptional repression of antiapoptotic genes such as bcl-2. Drug-induced suicide mediated by the CD95/CD95 ligand system may also involve a p53-controlled pathway. Yet, p53 may decrease chemosensitivity by promoting p21-mediated and p21-independent growth arrest, DNA repair, and differentiation, and by enhancing the transcription of antiapoptotic genes such as bcl-x. Cell-culture work indicates that the effects of altering the p53 status on chemosensitivity depend very much on the cellular context. Disruption of p53 function in otherwise normal, nonneoplastic cells may enhance rather than decrease chemosensitivity. However, targeted p53 gene disruption in some cell types obtained from p53-knockout mice results in enhanced rather than decreased sensitivity, e.g., to irradiation. Transformed cells that have retained wild-type p53 function tend to acquire chemoresistance when p53 function is disabled, with few exceptions. Thus, preexisting molecular alterations or consecutive accumulation of molecular alterations after loss of p53 rather than the loss of wild-type p53 activity per se may confer chemoresistence to tumor cells. Moreover, p53 accumulation resulting from the increased half-life of mutant p53 proteins can act as a gain-of-function mutation, presumably as a consequence of multiple protein-protein interactions. Finally, significant tumor cell-type- and drug-specific patterns of modulation of chemosensitivity by p53 are beginning to emerge. Transfer of wild-type p53 genes into tumor cells commonly induces growth arrest but may render these cells relatively more resistant to most chemotherapeutic drugs. Therefore, careful experimental in vitro and in vivo studies are required before chemotherapy-supported p53 gene therapy for human cancer is introduced into clinical practice.
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PMID:Predicting response to cancer chemotherapy: the role of p53. 958

APO2L (TRAIL) is a novel CD95L (Fas/APO-1-L) homologous cytotoxic cytokine that interacts with various receptors which transmit (DR4, DR5) or inhibit (DcR1, DcR2) an apoptotic signal. Here, we report that human glioma cell lines preferentially express mRNAs for agonistic death receptors DR4 (8/12) and DR5 (11/12) rather than the death-inhibitory decoy receptors DcR1 (4/12) and DcR2 (2/12). Ten of 12 cell lines are susceptible to APO2L-induced apoptosis. The resistant cell lines, U138MG and U373MG, are cross-resistant to CD95L-induced apoptosis. Similar to CD95L-induced apoptosis, APO2L-induced apoptosis is inhibited by ectopic expression of the caspase inhibitor, crm-A, or of bcl-2, or by coexposure to the corticosteroid, dexamethasone, or the lipoxygenase inhibitor, nordihydroguaretic acid. There is no correlation between p53 genetic status of the cell lines and their susceptibility to APO2L-induced apoptosis, but the latter is moderately enhanced by ectopic expression of wild-type p53. APO2L targeting may be a promising approach for selectively targeting apoptosis to human malignant glioma cells.
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PMID:APO2 ligand: a novel lethal weapon against malignant glioma? 961 12


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