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  • CELL  (16)
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  • 1
    Keywords: APOPTOSIS ; CANCER ; CELLS ; EXPRESSION ; GROWTH ; carcinoma ; CELL ; Germany ; INHIBITION ; THERAPY ; HEPATOCELLULAR-CARCINOMA ; PROTEIN ; TISSUE ; LINES ; MICE ; PATIENT ; IMPACT ; INDUCTION ; CELL-LINES ; treatment ; hepatocellular carcinoma ; resistance ; AGE ; metastases ; NUDE-MICE ; CELL-LINE ; chemotherapy ; leukemia ; LINE ; MODULATION ; p53 ; CANCER-PATIENTS ; CARCINOMAS ; CISPLATIN ; CANCER PATIENTS ; cell lines ; CANCER-THERAPY ; protein expression ; P53 STATUS ; GEMCITABINE ; RE ; cancer therapy ; GENDER ; dexamethasone ; GLUCOCORTICOID-INDUCED APOPTOSIS ; NAUSEA ; HISTOLOGY ; corticosteroids ; GLUCOCORTICOIDS ; correlation ; GAMMA-IRRADIATION ; viability ; 5-FU ; xenograft
    Abstract: The glucocorticoid dexamethasone is frequently used as 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 the supportive effects of glucocorticoids to tumour therapy in lymphoid cells are well studied, the impact to cytotoxic treatment of colorectal and hepatocellular carcinoma is unknown. We tested apoptosis-induction, viability, tumour growth and protein expression using 8 established cell lines, 18 surgical specimen and a xenograft on nude mice. In the presence of dexamethasone we found strong inhibition of apoptosis in response to 5-FU, cisplatin, gemcitabine or gamma-irradiation, enhanced viability and tumour growth of colorectal and hepatocellular carcinomas. No correlation with age, gender, histology, TNM, the p53 status and induction of therapy resistance by dexamethasone cotreatment could be detected. These data show that glucocorticoid-induced resistance occurs not occasionally but is common in colorectal and hepatocellular carcinomas implicating that the use of glucocorticoids may be harmful for cancer patients. (c) 2005 Elsevier Ireland Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 16338063
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  • 2
    Keywords: RECEPTOR ; APOPTOSIS ; CANCER ; CELLS ; IN-VITRO ; tumor ; AGENTS ; carcinoma ; CELL ; Germany ; IN-VIVO ; INHIBITION ; THERAPY ; VITRO ; VIVO ; SAMPLES ; TUMORS ; TIME ; PATIENT ; INDUCTION ; cell cycle ; CELL-CYCLE ; CYCLE ; treatment ; PROGRESSION ; resistance ; INDUCED APOPTOSIS ; PLASMA ; prostate cancer ; PROSTATE-CANCER ; chemotherapy ; ACUTE LYMPHOBLASTIC-LEUKEMIA ; DERIVATIVES ; HEPATOMA-CELLS ; EPITHELIAL-CELLS ; CARCINOMAS ; PHARMACOKINETICS ; AGENT ; SINGLE ; ONCOLOGY ; RE ; EX-VIVO ; SOLID TUMORS ; MEDIATED APOPTOSIS ; MOLECULAR-MECHANISMS ; LEVEL ; analysis ; methods ; PLASMA-LEVELS ; dexamethasone ; PROMOTION ; USA ; GLUCOCORTICOIDS ; prospective ; in vivo ; clinical study
    Abstract: Background: Glucocorticoids have been used widely in conjunction with cancer therapy due to their ability to induce apoptosis in hematological cells and to prevent nausea and emesis. However, recent data including ours, suggest induction of therapy resistance by glucocorticoids in solid tumors, although it is unclear whether this happens only in few carcinomas or is a more common cell type specific phenomenon. Material and Methods: We performed an overall statistical analysis of our new and recent data obtained with 157 tumor probes evaluated in vitro, ex vivo and in vivo. The effect of glucocorticoids on apoptosis, viability and cell cycle progression under diverse clinically important questions was examined. Results: New in vivo results demonstrate glucocorticoid - induced chemotherapy resistance in xenografted prostate cancer. In an overall statistical analysis we found glucocorticoid - induced resistance in 89% of 157 analysed tumor samples. Resistance is common for several cytotoxic treatments and for several glucocorticoid - derivatives and due to an inhibition of apoptosis, promotion of viability and cell cycle progression. Resistance occurred at clinically achievable peak plasma levels of patients under anti - emetic glucocorticoid therapy and below, lasted for a long time, after one single dose, but was reversible upon removal of glucocorticoids. Two nonsteroidal alternative anti - emetic agents did not counteract anticancer treatment and may be sufficient to replace gluco corticoids in cotreatment of carcinoma patients. Conclusion: These data demonstrate the need for prospective clinical studies as well as for detailed mechanistic studies of GC - induced cell - type specific pro - and anti - apoptotic signalling
    Type of Publication: Journal article published
    PubMed ID: 17224649
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  • 3
    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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  • 4
    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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  • 5
    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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  • 6
    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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  • 7
    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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  • 8
    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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  • 9
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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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  • 10
    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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