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  • DEATH  (11)
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  • 1
    Keywords: brain ; APOPTOSIS ; CANCER ; CELLS ; IN-VITRO ; SURVIVAL ; AGENTS ; CELL ; Germany ; IN-VIVO ; VITRO ; DEATH ; DRUG ; SURGERY ; LINES ; TIME ; PATIENT ; LIGAND ; primary ; INDUCTION ; tumour ; treatment ; culture ; ACID ; CELL-DEATH ; PLASMA ; RATES ; RESECTION ; PHARMACOKINETICS ; CISPLATIN ; FUTURE ; TRAIL ; AGENT ; POTENT ; REGRESSION ; IV ; GRADE ; brain tumour ; betulinic acid ; CERAMIDE ; glioblastoma multiforme WHOIV
    Abstract: Background. Glioblastoma multiforme (WHO Grade IV, GBM) is the most malignant brain tumour with a mean survival time of less than one year. Betulinic acid, ceramide and TRAIL (TNF-related apoptosis inducing ligand) represent novel therapeutic agents for potential use in GBM. Method. Primary GBM cells of 21 patients with macroscopically complete tumour resection were tested in vitro for cell death induction by betulinic acid, ceramide, TRAIL and established therapeutics (BCNU, cisplatin, doxorubicin, vincristin and gamma-irradiation). Findings. At peak plasma concentrations (PPC), Betulinic acid, ceramide and TRAIL induced cell death in primary GBM cells at higher rates than established cytotoxic drugs. Specific cell death greater than or equal to75% was observed in 43% (9/21), 38% (8/21), and 19% (4/21) for betulinic acid, ceramide, and TRAIL respectively, while this was only found in 5% (1/21) of gamma-irradiated and cisplatin-treated cells, and in none of the GBM cultures, where BCNU or vincristin were applied in PPC. Conclusion. Due to a markedly improved cell death of GBM cells as compared with established therapeutics, Betulinic acid, ceramide and TRAIL might represent potent substances for future treatment of GBM
    Type of Publication: Journal article published
    PubMed ID: 15197616
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  • 2
    Keywords: RECEPTOR ; APOPTOSIS ; EXPRESSION ; IN-VITRO ; tumor ; carcinoma ; CELL ; CELL LUNG-CANCER ; Germany ; human ; IN-VIVO ; LUNG ; MODEL ; MODELS ; VITRO ; VIVO ; DEATH ; NEW-YORK ; GENE ; TUMORS ; LINES ; MICE ; FAMILY ; MEMBER ; MEMBERS ; treatment ; immunohistochemistry ; MALIGNANCIES ; ASSAY ; resistance ; CELL-DEATH ; INDUCED APOPTOSIS ; Western-blot ; NUDE-MICE ; chemotherapy ; CARCINOMAS ; STRATEGIES ; western blot ; FAILURE ; LUNG-CARCINOMA ; CASPASE 8 ; nude mice ; Bcl-2 ; CD95 ; DRUG-INDUCED APOPTOSIS ; XENOGRAFTS ; CD95/Fas/APO-1,TRAIL,gene therapy,drug reststance,cancer therapy ; IMMUNE-SYSTEM
    Abstract: Non small cell lung carcinoma (NSCLC) is a highly lethal malignancy that often becomes resistant to chemotherapy. To determine whether alterations in apoptotic signaling might contribute to such resistance, we established in vitro and in vivo models for sensitive and resistant human NSCLC. We found that resistance is due to multiple defects found in expression of CD95-L, CD95 and members of the Bcl-2 and IAP family, as well as caspase-8, -9 and -3 as examined by immunohistochemistry, Western blot analysis, gene array analysis and functional assays. Failure to activate death receptor, as well as mitochondrial apoptosis signaling, points to a central role of caspases. To restore apoptosis signaling we transfected NSCLC xenografts on nude mice with caspase-8 and -9. This treatment strongly induced apoptosis per se and sensitized the tumors to cisplatin-induced cell death. Thus, these findings indicate that re-expression of caspases might be an effective strategy to restore sensitivity for chemotherapy in NSCLC in vivo. (C) 2003 Wiley-Liss, Inc
    Type of Publication: Journal article published
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  • 3
    Keywords: APOPTOSIS ; CELLS ; EXPRESSION ; GROWTH ; IN-VITRO ; CELL ; Germany ; human ; IN-VIVO ; THERAPY ; VITRO ; VIVO ; SYSTEM ; DEATH ; GENE ; PROTEIN ; DRUG ; LINES ; MICE ; gene transfer ; GENE-TRANSFER ; LIGAND ; INDUCTION ; tumour ; T cell ; T cells ; T-CELL ; T-CELLS ; ANTITUMOR-ACTIVITY ; TARGET ; LYMPHOMA ; resistance ; CELL-DEATH ; chemotherapy ; LINE ; CANCER-CELLS ; PRODUCT ; SURFACE ; sensitization ; SELECTION ; CELL-SURFACE ; TRAIL ; HUMAN HEPATOCYTES ; APOPTOSIS-INDUCING LIGAND ; DRINKING ; DRUG-INDUCED APOPTOSIS ; INDUCE APOPTOSIS ; TRAIL,gene therapy,Tet system,apoptosis,B cell lymphoma
    Abstract: In the present study, we demonstrate the utility of a non-tumour-forming T-cell line for the inducible gene transfer of tumour necrosis factor (TNF)-related apoptosis-inducing ligand (Apo2L/TRAIL), which has been shown to selectively induce apoptosis in malignant but not in normal cells. To generate T cells inducible for TRAIL expression, we stably transfected Jurkat cells with TRAIL in the context of the Tet-On system. The switched on cells strongly expressed TRAIL mRNA, whose protein product was expressed on the cell surface. Paracrine induction of apoptosis in human target tumour cells was solely found for membrane-bound TRAIL. The Jurkat-TRAIL cells itself survived due to clonal selection of TRAIL-resistant cells. Jurkat-TRAIL cells had an additive effect with cytotoxic drugs in vitro, since cell death was enhanced. To elucidate the antitumoral activity of these Jurkat-TRAIL cells in vivo, we injected them intratumorally in xenografts of human Burkitt lymphomas. Switching on expression of TRAIL by adding tetracycline to the drinking water of the mice strongly reduced tumour growth by apoptosis in a caspase-dependent manner. Thus, non-tumour-forming T-cell lines offer a novel method for gene transfer and inducible expression of TRAIL in tumour therapy
    Type of Publication: Journal article published
    PubMed ID: 14647152
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  • 4
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    Oncogene 23 (16), 2950-2966 
    Keywords: RECEPTOR ; APOPTOSIS ; CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; GROWTH ; proliferation ; tumor ; CELL ; CELL LUNG-CANCER ; Germany ; PATHWAY ; PATHWAYS ; THERAPY ; DEATH ; DRUG ; MOLECULES ; TISSUE ; NF-KAPPA-B ; MOLECULE ; TARGET ; resistance ; CELL-DEATH ; ELEMENTS ; EFFICACY ; chemotherapy ; ACUTE LYMPHOBLASTIC-LEUKEMIA ; SIGNALING PATHWAYS ; CANCER-CELLS ; FAILURE ; RECEPTORS ; REGULATOR ; DEATH RECEPTORS ; APOPTOSIS-INDUCING LIGAND ; FLICE-INHIBITORY PROTEIN ; NON-HODGKINS-LYMPHOMA ; DRUG-INDUCED APOPTOSIS ; ACUTE MYELOID-LEUKEMIA ; apoptosis,death receptors,CD95,drugs,resistance ; BAX PROTEIN EXPRESSION ; BCL-2 ANTISENSE OLIGONUCLEOTIDE
    Abstract: Apoptosis, the cell's intrinsic death program, is a key regulator of tissue homeostasis. An imbalance between cell death and proliferation may result in tumor formation. Also, killing of cancer cells by cytotoxic therapies such as chemotherapy, gamma-irradiation or ligation of death receptors is predominantly mediated by triggering apoptosis in target cells. In addition to the intrinsic mitochondrial pathway, elements of death receptor signaling pathways have been implied to contribute to the efficacy of cancer therapy. Failure to undergo apoptosis in response to anticancer therapy may lead to resistance. Also, deregulated expression of death receptor pathway molecules may contribute to tumorigenesis and tumor escape from endogenous growth control. Understanding the molecular events that regulate apoptosis induced by anticancer therapy and how cancer cells evade apoptosis may provide new opportunities for pathway-based rational therapy and for drug development
    Type of Publication: Journal article published
    PubMed ID: 15077156
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  • 5
    Keywords: APOPTOSIS ; CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; GROWTH ; IN-VITRO ; tumor ; TUMOR-CELLS ; CELL ; Germany ; human ; IN-VIVO ; LUNG ; VITRO ; VIVO ; lung cancer ; LUNG-CANCER ; DEATH ; PROTEIN ; EFFICIENCY ; TISSUE ; TUMORS ; MICE ; TRANSDUCTION ; ACTIVATION ; LIGAND ; INDUCTION ; T-CELLS ; SUPPRESSION ; PARTICLES ; virus ; VECTOR ; CELL-DEATH ; COLORECTAL-CANCER ; NUDE-MICE ; EFFICIENT ; CANCER-CELLS ; NORMAL TISSUE ; RETROVIRAL VECTORS ; CONSTRUCTION ; VIRAL VECTORS ; TUMOR CELLS ; TRAIL ; TRANSDUCTION EFFICIENCY ; APOPTOSIS-INDUCING LIGAND ; INTEGRATION ; RECOMBINANT ; RE ; TUMOR-GROWTH ; EX-VIVO ; LENTIVIRAL VECTOR ; analysis ; TUMOR-CELL ; TRANSFORMED-CELLS ; EVALUATE ; in vivo ; EXTENT ; NECROSIS ; APO2L/TRAIL ; anticancer agent ; translational research ; CANCER GENE-THERAPY ; gene therapy for solid tumors
    Abstract: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent, which selectively induces apoptosis in many transformed cells without apparent toxic side effects in normal tissue. We recently described the construction and characterization of a lentiviral vector for expression of TRAIL. In this report, we evaluate its suitability for therapeutic application. In vitro, we observed specific induction of apoptosis upon transduction in human lung cancer cells. Cell death was partially dependent on successful integration and TRAIL expression by the vectors, but was to some extent mediated by protein carryover, as we found TRAIL protein associated with virus particles. Transduction of subcutaneously growing lung tumors on nude mice with lentiviral TRAIL mediated a transient suppression of tumor growth. Analysis of tumor sections revealed that transduction efficiency of lentiviral control vector but not of lentiviral TRAIL vector was high. This was because of the direct cytotoxic activity of recombinant TRAIL present in viral particles, which prevented efficient tumor transduction. These data therefore suggest that enveloped viral vectors constitutively expressing TRAIL are well suited for ex vivo applications, such as the transduction of tumor-homing cells, but may have a lower effect when used directly for the transduction of tumor cells in vivo
    Type of Publication: Journal article published
    PubMed ID: 17186015
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  • 6
    Keywords: RECEPTOR ; APOPTOSIS ; INHIBITOR ; tumor ; CELL ; COMBINATION ; Germany ; THERAPY ; SUPPORT ; DEATH ; DISEASE ; GENE ; GENES ; SAMPLE ; SAMPLES ; cell line ; LINES ; PATIENT ; ACTIVATION ; LIGAND ; prognosis ; CELL-LINES ; FORM ; DELETION ; resistance ; MUTATION ; CELL-LINE ; leukemia ; STRATEGIES ; CHILDREN ; cell lines ; TRAIL ; TP53 ; TRAIL-INDUCED APOPTOSIS ; APOPTOSIS-INDUCING LIGAND ; INHIBITORS ; signaling ; FEATURES ; THERAPIES ; CLL ; regulation ; CD95-MEDIATED APOPTOSIS ; interaction ; development ; X-LINKED INHIBITOR ; LEVEL ; B-CELL ; NECROSIS ; caspase-3 ; XIAP ; STRATEGY ; death-receptor ; TP53 mutation ; FORMS ; 17p deletion ; UNFAVORABLE PROGNOSIS
    Abstract: Evasion of apoptosis is a hallmark of chronic lymphocytic leukemia (CLL), calling for new strategies to bypass resistance. Here, we provide first evidence that small-molecule X-linked inhibitor of apoptosis (XIAP) inhibitors in combination with the death receptor ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) present a novel approach to trigger apoptosis in CLL, including subgroups with resistant disease or unfavorable prognosis. XIAP, cellular IAP (cIAP) 1, and cIAP2 are expressed at high levels in primary CLL samples. Proof-of-concept studies in CLL cell lines show that subtoxic concentrations of XIAP inhibitors significantly enhance TRAIL-induced apoptosis and also sensitize for CD95-mediated apoptosis. Importantly also in primary CLL samples, XIAP inhibitor acts in concert with TRAIL to trigger apoptosis in 18 of 27 (67%) cases. This XIAP inhibitor-induced and TRAIL-induced apoptosis involves caspase-3 activation and is blocked by the caspase inhibitor zVAD.fmk. The cooperative interaction of XIAP inhibitor and TRAIL is even evident in distinct subgroups of patients with poor prognostic features (i.e., with 17p deletion, TP53 mutation, chemotherapy-refractory disease, or unmutated V(H) genes). Interestingly, cases with unmutated V(H) genes were significantly more sensitive to XIAP inhibitor-induced and TRAIL-induced apoptosis compared with V(H) gene-mutated samples, pointing to a role of B-cell receptor signaling in apoptosis regulation. By showing that XIAP inhibitors in combination with TRAIL present a new strategy to trigger apoptosis even in resistant forms and poor prognostic subgroups of CLL, our findings have important implications for the development of apoptosis-based therapies in CLL.
    Type of Publication: Journal article published
    PubMed ID: 19920200
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  • 7
    Keywords: APOPTOSIS ; CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; GROWTH ; IN-VITRO ; INHIBITOR ; tumor ; CELL ; Germany ; human ; IN-VIVO ; THERAPY ; VITRO ; VIVO ; DEATH ; GENE ; PROTEIN ; cell line ; TUMORS ; gene therapy ; LINES ; MICE ; RELEASE ; TRANSDUCTION ; ACTIVATION ; LIGAND ; RESPONSES ; MECHANISM ; INDUCTION ; CELL-LINES ; ANTITUMOR-ACTIVITY ; IMMUNE-RESPONSES ; virus ; VECTORS ; CELL-DEATH ; CELL-LINE ; LINE ; CANCER-CELLS ; DELIVERY ; SUPERFAMILY ; immune response ; IMMUNE-RESPONSE ; GENE-THERAPY ; RECOMBINANT ADENOASSOCIATED VIRUS ; adeno-associated virus ; ADENOASSOCIATED VIRUS ; AAV ; DEATH RECEPTORS ; GENE DELIVERY ; HUMAN HEPATOCYTES ; APOPTOSIS-INDUCING LIGAND ; AAV,TRAIL,colon cancer,apoptosis
    Abstract: Gene transfer vectors based on the adeno-associated virus (AAV) are used for various experimental and clinical therapeutic approaches. In the present study, we demonstrate the utility of rAAV as a tumoricidal agent in human colorectal cancer. We constructed an rAAV vector that expresses tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL/Apo2L) and used it to transduce human colorectal cancer cells. TRAIL belongs to the TNF superfamily of cytokines that are involved in various immune responses and apoptotic processes. It has been shown to induce cell death specifically in cancer cells. Transduction with AAV. TRAIL gave rise to rapid expression of TRAIL, followed by induction of apoptosis, which could be inhibited by the caspase inhibitor z-VAD. fmk, in several human colon cancer cell lines. The apoptotic mechanism included activation of caspase-3, as well as cytochrome c release from mitochondria. The outgrowth of human colorectal tumors grown in mice was completely blocked by transduction with AAV. TRAIL in vitro, while in vivo transduction significantly inhibited the growth of established tumors. AAV vectors could provide a safe method of gene delivery and offer a novel method of using TRAIL as a therapeutic protein
    Type of Publication: Journal article published
    PubMed ID: 14999225
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  • 8
    Keywords: RECEPTOR ; APOPTOSIS ; CANCER ; CELLS ; EXPRESSION ; tumor ; CELL ; Germany ; human ; IN-VIVO ; THERAPY ; DEATH ; GENE ; gene therapy ; LINES ; NF-KAPPA-B ; LIGAND ; DNA ; MECHANISM ; INDUCTION ; CELL-LINES ; ANTITUMOR-ACTIVITY ; resistance ; VECTOR ; CELL-LINE ; LINE ; DAMAGE ; DNA-DAMAGE ; CISPLATIN ; CELL-SURFACE ; RECEPTORS ; OVEREXPRESSION ; cell lines ; CANCER-THERAPY ; TRAIL ; ENDOPLASMIC-RETICULUM ; HUMAN HEPATOCYTES ; APOPTOSIS-INDUCING LIGAND ; CD95 ; MALIGNANT-CELLS ; HUMAN T-CELLS ; RE ; HUMAN CANCER ; cancer therapy ; LENTIVIRAL VECTOR ; GENE INDUCTION ; TUMOR-CELL ; DNA damage ; TRANSFORMED-CELLS ; CANDIDATE ; RESISTANT ; VARIETIES ; NECROSIS ; CANCER-CELLS RESISTANT ; resistance mechanism
    Abstract: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in many transformed cells, suggesting TRAIL as an ideal candidate for cancer gene therapy. A main obstacle in cancer therapy is intrinsic or acquired therapy resistance of malignant cells. To study induction of resistance against TRAIL, we generated lentiviral vectors allowing efficient TRAIL expression and apoptosis induction in a variety of human cancer cell lines. Within days upon TRAIL overexpression, cells became resistant towards TRAIL, but not to CD95 ligation or DNA damage by cisplatin. Cell surface expression of TRAIL receptors 1 and 2 was completely abrogated in resistant cells due to intracellular retention of the receptors by TRAIL. SiRNA directed against TRAIL resensitized the resistant cells by restoring cell surface expression of TRAIL receptors. These findings represent a novel resistance mechanism towards TRAIL, specifically caused by TRAIL overexpression, and question the use of TRAIL expression in tumor-cell targeting gene therapy
    Type of Publication: Journal article published
    PubMed ID: 16470224
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  • 9
    Keywords: APOPTOSIS ; CELLS ; IN-VITRO ; CELL ; Germany ; human ; IN-VIVO ; INHIBITION ; VITRO ; SYSTEM ; SYSTEMS ; DEATH ; DISEASE ; DISEASES ; ACTIVATION ; LIGAND ; TRANSPLANTATION ; INDUCTION ; ANTIGEN ; ANTIGENS ; T cell ; T cells ; T-CELL ; T-CELLS ; TOLERANCE ; DOWN-REGULATION ; culture ; ASSAY ; CD95 ligand ; UP-REGULATION ; LYMPHOCYTES ; ANTIGEN-PRESENTING CELLS ; CD8(+) ; CHILDREN ; FAS-LIGAND ; CYTOTOXICITY ; CD95 ; development ; IMPAIRMENT ; ASSAYS ; DEPLETION ; EXPANSION ; SHORT-TERM ; PREVENTS ; CD95L ; CELL RESPONSE ; immunomodulation ; KILLER DENDRITIC CELLS ; TUMOR COUNTERATTACK
    Abstract: Genetically modified antigen-presenting cells (APC) represent an attractive strategy for in vitro immunomodulation. In the human system, APC expressing HLA-A1 and a membrane-bound form of CD95L (m-CD95L) were used for selective depletion of HLA-A1-specific T cells. In short-term assays, m-CD95L-expressing APC-induced apoptosis in activated T cells and the constitutive presence of m- CD95L and HLA-A1 expressing APC in long-term T cell cultures prevented the expansion of CD4(+) and CD8(+) HLA-A1-specifc T cells and the development of HLA-A1-specific cytotoxicity. However, immunity towards third party, viral and bacterial antigens was maintained and T cells spared from depletion could be induced to develop cytotoxicity towards unrelated antigens. Interestingly, inhibition of HLA-A1-specific T cell response absolutely requires the coexpression of m- CD95L and HLA-A1 antigen on the same APC. Thus, m-CD95L expressing APC might be used in clinical settings to obtain tolerance induction in allogeneic transplantation systems or autoimmune diseases
    Type of Publication: Journal article published
    PubMed ID: 16902496
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  • 10
    Keywords: RECEPTOR ; APOPTOSIS ; CELLS ; EXPRESSION ; proliferation ; CELL ; Germany ; human ; INHIBITION ; DEATH ; PROTEIN ; transcription ; NF-KAPPA-B ; ACTIVATION ; LIGAND ; INFECTION ; MECHANISM ; TRANSCRIPTION FACTOR ; DENDRITIC CELLS ; T cells ; T-CELL ; T-CELLS ; PHOSPHORYLATION ; PROTEIN-KINASE ; SIGNAL ; antibody ; FORM ; TRANSCRIPTION FACTORS ; CELL-DEATH ; UP-REGULATION ; MEMBRANE ; ANTIGEN-PRESENTING CELLS ; LIPID RAFTS ; TRANSLOCATION ; CHILDREN ; PROTEIN-PHOSPHORYLATION ; signaling ; CYTOKINE ; secretion ; T-CELL-ACTIVATION ; SOLUBLE FAS LIGAND ; HIV ; USA ; immunology ; lipid ; CA2+ MOBILIZATION ; TRANSCRIPTION-FACTOR ; TYROSINE ; REGULATORS BIM ; VETO CELLS
    Abstract: CD95 is a multifunctional receptor that induces cell death or proliferation depending on the signal, cell type, and cellular context. Here, we describe a thus far unknown function of CD95 as a silencer of T cell activation. Naive human T cells triggered by antigen-presenting cells expressing a membrane-bound form of CD95 ligand (CD95L) or stimulated by anti-CD3 and -CD28 antibodies in the presence of recombinant CD95L had reduced activation and proliferation, whereas preactivated, CD95-sensitive T cells underwent apoptosis. Triggering of CD95 during T cell priming interfered with proximal T cell receptor signaling by inhibiting the recruitment of zeta-chain-associated protein of 70 kD, phospholipase-gamma, and protein kinase C-theta into lipid rafts, thereby preventing their mutual tyrosine protein phosphorylation. Subsequently, Ca2+ mobilization and nuclear translocation of transcription factors NFAT, AP1, and NF-kappa B were strongly reduced, leading to impaired cytokine secretion. CD95-mediated inhibition of proliferation in naive T cells could not be reverted by the addition of exogenous interleukin-2 and T cells primed by CD95 co-stimulation remained partially unresponsive upon secondary T cell stimulation. HIV infection induced CD95L expression in primary human antigeen-presenting cells, and thereby suppressed T cell activation, suggesting that CD95/CD95L-mediated silencing of T cell activation represents a novel mechanism of immune evasion
    Type of Publication: Journal article published
    PubMed ID: 19487421
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