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  • 1
    Keywords: RECEPTOR ; APOPTOSIS ; CANCER ; CELLS ; EXPRESSION ; IN-VITRO ; tumor ; TUMOR-CELLS ; carcinoma ; IN-VIVO ; THERAPY ; GENE ; GENE-EXPRESSION ; HYBRIDIZATION ; TUMORS ; radiation ; PATIENT ; NF-KAPPA-B ; FAMILY ; MEMBER ; NUCLEAR-FACTOR ; NORMAL TISSUE ; CISPLATIN ; PROGRAMMED CELL-DEATH ; ALPHA-INDUCED APOPTOSIS ; DNA-DAMAGING AGENTS ; GLOMERULAR ENDOTHELIAL-CELLS ; GRANULOSA-CELLS ; LEUKEMIA- CELLS ; LUNG-CARCINOMA ; T- LYMPHOCYTES
    Abstract: Chemotherapy and radiation therapy for cancer often have severe side effects that limit their efficacy. Glucocorticoids (GCs) are frequently used as cotreatment because they may have potent proapoptotic properties and reduce nausea, hyperemesis, and acute toxicity on normal tissue. In contrast to the proapoptotic effect of GCs in lymphoid cells, resistance toward cancer therapy-mediated apoptosis was induced in solid tumors of human cervix and lung carcinomas. Filter hybridization, expression data, as well as functional assays identified multiple core apoptosis molecules, which are regulated by GCs in a pro- or antiapoptotic manner. Both antiapoptotic genes such as FLIP and members of the Bcl-2 and IAP family as well as proapoptotic elements of the death receptor and mitochondrial apoptosis pathways were down-regulated in carcinomas resulting in a decreased activity of caspase-8, caspase-9, and caspase-3. In contrast, death receptor and mitochondrial apoptosis signaling as well as caspase activity was enhanced by dexamethasone in lymphoid cells. To restore apoptosis sensitivity in dexamethasone-treated carcinomas, caspase-8 and caspase-9 were transfected. This resensitized tumor cells in vitro and xenografts in vivo to cisplatin induced cell death. These data therefore raise concern about the widespread combined use of GCs with antineoplastic drugs or agents in the clinical management of cancer patients
    Type of Publication: Journal article published
    PubMed ID: 12810637
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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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    Keywords: APOPTOSIS ; CANCER ; CANCER CELLS ; CELLS ; INHIBITOR ; CELL ; Germany ; human ; INHIBITION ; KINASE ; PATHWAY ; THERAPY ; EXPOSURE ; NEW-YORK ; RELEASE ; TIME ; STRESS-INDUCED APOPTOSIS ; ACTIVATION ; DNA ; INDUCTION ; T cell ; T-CELL ; CLEAVAGE ; PROGRESSION ; resistance ; MEMBRANE ; STRESS ; ALKYLATING-AGENTS ; fragmentation ; LINE ; CANCER-CELLS ; SURFACE ; PROTEIN-KINASES ; CYTOCHROME-C ; doxorubicin ; CISPLATIN ; CELL-SURFACE ; FAS LIGAND EXPRESSION ; stable transfection ; apoptosis,JNK,cancer therapy,caspases ; FACTOR C-JUN ; INITIATION ; JNK/SAPK ACTIVITY ; JUN NH2-TERMINAL KINASE ; MAP KINASES ; N-TERMINAL KINASE ; THERAPY-INDUCED APOPTOSIS ; TNF-ALPHA
    Abstract: The human leukemic T-cell line Jurkat was used to define the role of the cellular stress pathway with its key player kinase JNK in cancer therapy-induced apoptosis. JNK activity was inhibited by stable transfection with a dominant negative mutant of the upstream kinase JNKK/MKK4 or with the novel, potent and selective JNKI, -2 and -3 inhibitor SP600125. Inhibition of JNK activity delayed the onset of apoptosis induced by cisplatin, doxorubicin, gamma-irradiation and CD95-L but did not prevent apoptosis per se. Early events during apoptosis such as induction of CD95-L, activation of caspase-8 and exposure of phosphatidylserine on the cell surface were strongly inhibited. Also, at early time points of apoptosis, loss of the mitochondrial membrane potential and release of cytochrome c were markedly impaired. However, late signaling events during apoptosis such as cleavage of PARP and DNA fragmentation apoptosis were only marginally affected. These findings are in accordance with the activity of initiator and effector caspases. Whereas activity of the initiator caspase-8 was strongly inhibited early and late after induction, an inhibition of caspase-3 activity was only observed early after induction of apoptosis. We therefore suggest that cellular stress signaling contributes to the initiation of apoptosis, whereas it might be dispensable for the progression of apoptosis. Dysfunction of this pathway under pathological conditions might contribute to therapy resistance of cancer cells. (C) 2003 Wiley-Liss, Inc
    Type of Publication: Journal article published
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  • 5
    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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