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  • 11
    Keywords: brain ; APOPTOSIS ; CANCER ; CELLS ; GROWTH ; carcinoma ; CELL ; Germany ; THERAPY ; screening ; TISSUE ; LINES ; PATIENT ; MECHANISM ; CONTRAST ; CELL-LINES ; treatment ; BREAST ; breast cancer ; BREAST-CANCER ; resistance ; INDUCED APOPTOSIS ; CERVIX ; metastases ; CELL-LINE ; chemotherapy ; LINE ; MELANOMA ; RESECTION ; CISPLATIN ; cell lines ; CANCER-THERAPY ; LUNG-CARCINOMA ; neuroblastoma ; signaling ; MALIGNANT-CELLS ; RE ; cancer therapy ; SOLID TUMORS ; dexamethasone ; NAUSEA ; corticosteroids ; GLUCOCORTICOIDS ; prospective ; BONE ; EXTENT ; clinical studies ; surgical resection ; steroids
    Abstract: Glucocorticoids (GCs) such as dexamethasone (DEX) have been widely used as co-medication in cancer therapy because they have potent proapoptotic properties in lymphoid cells, can reduce nausea, and alleviate acute toxic effects in healthy tissue. However, GCs are used in a supportive-care role, even though no prospective clinical studies have assessed the effect of these steroids on the growth of solid tumours. Data from preclinical and, to some extent, clinical studies, suggest that GCs induce treatment resistance in some solid tumours. Since it is unknown whether GC-induced resistance occurs only occasionally or is a more common phenomenon, we performed a screening study using several established cell lines from bone, brain, breast and cervix carcinoma as well as melanoma and neuroblastoma together with fresh surgical resections from patients with breast cancer. We found that DEX inhibits cisplatin and 5-fluorouracil- induced apoptosis and promotes the growth of the majority of examined malignant cells. In contrast, and as expected, DEX acted pro-apoptotically and promoted the cytotoxic effect of chemotherapy in established and primary lymphoid cells. Thus, these data demonstrate the need for detailed molecular studies to clarify the mechanism of differential glucocorticoid signaling as well as controlled, prospective clinical studies
    Type of Publication: Journal article published
    PubMed ID: 17016664
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  • 12
    Keywords: APOPTOSIS ; CANCER ; CELLS ; EXPRESSION ; GROWTH ; IN-VITRO ; INHIBITOR ; SURVIVAL ; tumor ; carcinoma ; CELL ; COMBINATION ; Germany ; IN-VIVO ; MODEL ; MODELS ; THERAPY ; VITRO ; VIVO ; PROTEINS ; SAMPLE ; SAMPLES ; TIME ; NF-KAPPA-B ; ACTIVATION ; LIGAND ; INDEX ; TISSUES ; CONTRAST ; ANTITUMOR-ACTIVITY ; TARGET ; MOUSE ; resistance ; CARCINOMA CELLS ; CELL-DEATH ; MEMBRANE ; CARCINOMA-CELLS ; adenocarcinoma ; NORMAL TISSUE ; REVEALS ; CHILDREN ; pancreatic cancer ; pancreatic carcinoma ; TRAIL ; HUMAN PROSTATE-CANCER ; TRAIL-INDUCED APOPTOSIS ; APOPTOSIS-INDUCING LIGAND ; DRUG-INDUCED APOPTOSIS ; INHIBITORS ; PANCREATIC-CANCER ; THERAPIES ; DECOY RECEPTORS ; development ; X-LINKED INHIBITOR ; pancreatic adenocarcinoma ; USA ; ANTAGONISTS ; pancreatic tumor ; IRRADIATION-INDUCED APOPTOSIS ; XIAP ; therapeutic ; ALPHA-DEPENDENT APOPTOSIS
    Abstract: Evasion of apoptosis is a characteristic feature of pancreatic cancer, a prototypic cancer that is refractory to current treatment approaches. Hence, there is an urgent need to design rational strategies that counter apoptosis resistance. To explore X-linked inhibitor of apoptosis (XIAP) as a therapeutic target in pancreatic cancer, we analyzed the expression of XIAP in pancreatic tumor samples and evaluated the effect of small molecule XIAP inhibitors alone and in combination with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) against pancreatic carcinoma in vitro and in vivo. Here, we report that XIAP is highly expressed in pancreatic adenocarcinoma samples compared with normal pancreatic ducts. Small molecule XIAP inhibitors synergize with TRAIL to induce apoptosis and to inhibit long-term clonogenic survival of pancreatic carcinoma cells. In contrast, they do not reverse the lack of toxicity of TRAIL on nonmalignant cells in vitro or normal tissues in vivo, pointing to a therapeutic index. Most importantly, XIAP inhibitors cooperate with TRAIL to trigger apoptosis and suppress pancreatic carcinoma growth in vivo in two preclinical models, i.e., the chorioallantoic membrane model and a mouse xenograft model. Parallel immunohistochemical analysis of tumor tissue under therapy reveals that the XIAP inhibitor acts in concert with TRAIL to cause caspase-3 activation and apoptosis. In conclusion, our findings provide, for the first time, evidence in vivo that XIAP inhibitors prime pancreatic carcinoma cells for TRAM-induced apoptosis and potentiate the antitumor activity of TRAIL against established pancreatic carcinoma. These findings build the rationale for further (pre)clinical development of XIAP inhibitors and TRAIL against pancreatic cancer. [Cancer Res 2009;69(6):2425-34]
    Type of Publication: Journal article published
    PubMed ID: 19258513
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  • 13
    Keywords: APOPTOSIS ; CELLS ; EXPRESSION ; TUMOR-CELLS ; PATHWAYS ; DRUG ; COMPONENTS ; LINES ; IMPACT ; mechanisms ; DOWN-REGULATION ; BONE-MARROW ; RECOGNITION ; leukemia ; MHC CLASS-I ; NATURAL-KILLER-CELLS ; NK cells ; allogeneic ; BONE-MARROW-TRANSPLANTATION ; CROSS-RESISTANCE ; CYTOCHROME-C RELEASE ; CYTOSOLIC DELIVERY ; CYTOTOXIC EFFECTOR-CELLS ; graft-versus-leukemia ; GRANZYME-B ; HLA class I ; INITIATES APOPTOSIS ; PERFORIN ; TARGET-CELLS
    Abstract: Background and Objectives. Drug-resistant leukemia cells may exhibit cross-resistance towards immunological, effector mechanisms by alterations of apoptosis pathways. This is particularly relevant in allogeneic bone m, arrow transplantation for leukemia, where the graft-versus-leukemia effect acts on cells pretreated with cytostatic drugs. Here, we clarify the mechanism underlying cross-resistance of drug- resistant variants of the T-leukemia cell, line CEM towards natural killer cells. Design and Methods. We determined the sensitivity of. different CEM sublines to natural killer (NK) cytotoxicity, and separately analyzed the components of the killing machinery by detection of granzyme B-induced caspase, cleavage and HLA class I-dependent recognition mechanisms. Furthermore, We studied regulation of HLA class I expression comparing CEM with other cell lines. Results. We found that CEM cells resistant to cytostatic drugs or CD95 were cross- resistant towards NK cells from a variety of donors. Granzyme B-induced caspase and PARP cleavage in the sensitive and resistant cells were comparable, indicating that downstream apoptosis pathways were not altered in the drug-resistant cells, HLA class I molecules were upregulation in the resistant cells, inhibiting NK cells at the level of killer/target recognition. HLA class I upregulation was not found in other leukemia cell lines. Interpretation and Conclusions., This is the first description of HLA class I-mediated, NK cross- resistance, in drug-resistant cells. This finding may have a,clinical impact since it may be considered as a possible reason for resistance to a graft-versus-leukemia approach in allogeneic bone marrow transplantation
    Type of Publication: Journal article published
    PubMed ID: 12745270
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  • 14
    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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  • 15
    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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  • 16
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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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  • 17
    Keywords: APOPTOSIS ; CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; GROWTH ; IN-VITRO ; SURVIVAL ; carcinoma ; CELL ; Germany ; IN-VIVO ; INHIBITION ; THERAPY ; VITRO ; VIVO ; DENSITY ; GENE ; GENES ; PROTEIN ; TISSUE ; LINES ; MICE ; PATIENT ; IMPACT ; INDUCTION ; CELL-LINES ; treatment ; BREAST-CANCER ; prevention ; resistance ; PLASMA ; ovarian cancer ; OVARIAN-CANCER ; NUDE-MICE ; CELL-LINE ; chemotherapy ; LINE ; CANCER-CELLS ; CANCER-PATIENTS ; CARCINOMAS ; ovarian carcinoma ; CANCER PATIENTS ; cell lines ; CANCER-THERAPY ; protein expression ; ONCOLOGY ; RE ; TUMOR-GROWTH ; cancer therapy ; EX-VIVO ; LEVEL ; PLASMA-LEVELS ; dexamethasone ; NAUSEA ; OVARIAN CARCINOMAS ; corticosteroids ; GLUCOCORTICOIDS ; in vivo ; OVARIAN ; viability ; xenograft
    Abstract: The glucocorticoid dexamethasone is frequently used as a co-treatment in cytotoxic cancer therapy, e.g. to prevent nausea, to protect normal tissue or for other reasons. While the potent pro-apoptotic properties and supportive effects of glucocorticoids to tumour therapy in lymphoid cells are well studied, the impact on the cytotoxic treatment of ovarian carcinoma is unknown. We tested apoptosis-induction, viability, tumour growth and protein expression using established cell lines, primary cell lines freshly isolated from patient material and a xenograft on nude mice. We found a general induction of resistance toward cytotoxic therapy by DEX-co-treatment in most of the examined ovarian cancer cells treated in vitro, ex vivo or in vivo. Resistance occured independently of cell density and was found at peak plasma levels of dexamethasone and below. Mechanistically, the dexamethasone-induced expression of survival genes may be involved in the resistance. These data show that glucocorticoid-induced resistance is common in ovarian carcinomas implicating that the use of glucocorticoids may be harmful for cancer patients
    Type of Publication: Journal article published
    PubMed ID: 16391812
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  • 18
    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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  • 19
    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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  • 20
    Abstract: Chemotherapy for lung cancer not only has severe side effects but frequently also exhibits limited, if any clinical effectiveness. Dexamethasone (DEX) and similar glucocorticoids (GCs) such as prednisone are often used in the clinical setting, for example, as cotreatment to prevent nausea and other symptoms. Clinical trials evaluating the impact of GCs on tumour control and patient survival of lung carcinoma have never been performed. Therefore, we isolated cancer cells from resected lung tumour specimens and treated them with cisplatin in the presence or absence of DEX. Cell number of viable and dead cells was evaluated by trypan blue exclusion and viability was measured by the MTT-assay. We found that DEX induced resistance toward cisplatin in all of 10 examined tumour samples. Similar results were found using gemcitabine as cytotoxic drug. Survival of drug-treated lung carcinoma cells in the presence of DEX was longlasting as examined 2 and 3 weeks after cisplatin treatment of a lung carcinoma cell line. These data corroborate recent in vitro and in vivo xenograft findings and rise additional concerns about the widespread combined use of DEX with antineoplastic drugs in the clinical management of patients with lung cancer.
    Type of Publication: Journal article published
    PubMed ID: 15756274
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