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  • 1
    Keywords: CANCER ; RECEPTOR ; CELL ; tumor ; radiotherapy ; DEATH ; TUMORS ; DIFFERENTIATION ; LIGAND ; LIGANDS ; RECEPTORS ; SERIES ; resistance ; death receptor ; SOLID TUMORS ; DEATH RECEPTORS
    Type of Publication: Book chapter
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  • 2
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    Global Research Network
    Keywords: DRUG ; NETWORK ; CANCER ; drug resistance ; DRUG-RESISTANCE ; resistance
    Type of Publication: Book chapter
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  • 4
    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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  • 5
    Keywords: APOPTOSIS ; CANCER ; CELLS ; EXPRESSION ; GROWTH ; IN-VITRO ; carcinoma ; Germany ; IN-VIVO ; INHIBITION ; THERAPY ; VITRO ; GENE ; GENES ; LINES ; MICE ; PATIENT ; IMPACT ; INDUCTION ; treatment ; 5-FLUOROURACIL ; prevention ; resistance ; AGE ; NUDE-MICE ; CELL-LINE ; chemotherapy ; LINE ; CARCINOMAS ; specificity ; CISPLATIN ; pancreatic cancer ; CANCER-THERAPY ; CYTOTOXICITY ; signaling ; GEMCITABINE ; RE ; PANCREATIC-CANCER ; cancer therapy ; pancreatic ; GENDER ; dexamethasone ; GLUCOCORTICOID-INDUCED APOPTOSIS ; NAUSEA ; HISTOLOGY ; in vivo ; surgical resection
    Abstract: Background: Chemotherapy for pancreatic carcinoma often has severe side effects that limit its efficacy. The glucocorticoid (GC) dexamethasone (DEX) is frequently used as co-treatment to prevent side effects of chemotherapy such as nausea, for palliative purposes and to treat allergic reactions. While the potent pro-apoptotic properties and the supportive effects of GCs to tumour therapy in lymphoid cells are well studied, the impact of GCs to cytotoxic treatment of pancreatic carcinoma is unknown. Methods: A prospective study of DEX-mediated resistance was performed using a pancreatic carcinoma xenografted to nude mice, 20 surgical resections and 10 established pancreatic carcinoma cell lines. Antiapoptotic signaling in response to DEX was examined by Western blot analysis. Results: In vitro, DEX inhibited drug-induced apoptosis and promoted the growth in all of 10 examined malignant cells. Ex vivo, DEX used in physiological concentrations significantly prevented the cytotoxic effect of gemcitabine and cisplatin in 18 of 20 freshly isolated cell lines from resected pancreatic tumours. No correlation with age, gender, histology, TNM and induction of therapy resistance by DEX co-treatment could be detected. In vivo, DEX totally prevented cytotoxicity of chemotherapy to pancreatic carcinoma cells xenografted to nude mice. Mechanistically, DEX upregulated pro-survival factors and anti-apoptotic genes in established pancreatic carcinoma cells. Conclusion: These data show that DEX induces therapy resistance in pancreatic carcinoma cells and raise the question whether GC-mediated protection of tumour cells from cancer therapy may be dangerous for patients
    Type of Publication: Journal article published
    PubMed ID: 16539710
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  • 6
    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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  • 7
    Keywords: CANCER ; CELLS ; EXPRESSION ; IN-VITRO ; tumor ; TUMOR-CELLS ; AGENTS ; CELL ; Germany ; LUNG ; THERAPY ; VITRO ; TOOL ; DRUG ; TUMORS ; PATIENT ; MECHANISM ; colon ; mechanisms ; CELL-LINES ; BREAST ; TRIAL ; TRIALS ; ASSAY ; DESIGN ; resistance ; chemotherapy ; leukemia ; DATABASE ; STRATEGIES ; sensitivity ; experimental design ; DRUG-RESISTANCE ; MULTIDRUG-RESISTANCE ; ANTICANCER DRUGS ; CLUSTER ; CYTOTOXICITY ; multidrug resistance ; traditional Chinese medicine ; AGENT ; ONCOLOGY ; RE ; THERAPIES ; P-GLYCOPROTEIN ; TRANSPORTER ; analysis ; ASSAYS ; TETRAZOLIUM ASSAY ; USA ; cancer research ; CANCERS ; TOOLS ; PREDICT ; anticancer drug ; MULTIDRUG ; PROFILE ; NUCLEOTIDE ; natural products ; CANCER-CHEMOTHERAPY ; CASSETTE TRANSPORTER GENES ; SHORT-TERM TEST
    Abstract: Purpose: Drug resistance is a major obstacle in cancer chemotherapy. Although the statistical probability of therapeutic success is known for larger patient groups from clinical therapy trials, it is difficult to predict the individual response of tumors. The concept of individualized therapy aims to determine in vitro the drug response of tumors beforehand to choose effective treatment options for each individual patient. Experimental Design: We analyzed the cross-resistance profiles of different tumor types (cancers of lung, breast, and colon, and leukemia) towards drugs from different classes (anthracyclines, antibiotics, Vinca alkaloids, epipodophyllotoxins, antimetabolites, and alkylating agents) by nucleotide incorporation and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Hierarchical cluster analysis and COMPARE analyses were applied. Results: Tumors exert broad resistance profiles, e.g., tumors resistant to one drug tend to also be resistant to other drugs, whereas sensitive tumors reveal sensitivity towards many drugs. Interestingly, the broad spectrum resistance phenotype could reliably be predicted by doxorubicin alone. Expression of the ATP-binding cassette transporter P-glycoprotein (ABCB1, MDR1) and the proliferative activity of tumors were identified as underlying mechanisms of broad spectrum resistance. To find novel compounds with activity against drug-resistant tumors, a database with 2,420 natural products was screened for compounds acting independent of P-glycoprotein and the proliferative state of tumor cells. Conclusions: umors exert cross-resistance profiles much broader than the classical multidrug resistance phenotype. Broad spectrum resistance can be predicted by doxorubicin due to the multifactorial mode of action of this drug. Novel cytotoxic compunds from natural resources might be valuable tools for strategies to bypass broad spectrum resistance
    Type of Publication: Journal article published
    PubMed ID: 18413831
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  • 8
    Abstract: Background: In breast cancer, overexpression of the transmembrane tyrosine kinase ERBB2 is an adverse prognostic marker, and occurs in almost 30% of the patients. For therapeutic intervention, ERBB2 is targeted by monoclonal antibody trastuzumab in adjuvant settings; however, de novo resistance to this antibody is still a serious issue, requiring the identification of additional targets to overcome resistance. In this study, we have combined computational simulations, experimental testing of simulation results, and finally reverse engineering of a protein interaction network to define potential therapeutic strategies for de novo trastuzumab resistant breast cancer. Results: First, we employed Boolean logic to model regulatory interactions and simulated single and multiple protein loss-of-functions. Then, our simulation results were tested experimentally by producing single and double knockdowns of the network components and measuring their effects on G1/S transition during cell cycle progression. Combinatorial targeting of ERBB2 and EGFR did not affect the response to trastuzumab in de novo resistant cells, which might be due to decoupling of receptor activation and cell cycle progression. Furthermore, examination of c-MYC in resistant as well as in sensitive cell lines, using a specific chemical inhibitor of c-MYC (alone or in combination with trastuzumab), demonstrated that both trastuzumab sensitive and resistant cells responded to c-MYC perturbation. Conclusion: In this study, we connected ERBB signaling with G1/S transition of the cell cycle via two major cell signaling pathways and two key transcription factors, to model an interaction network that allows for the identification of novel targets in the treatment of trastuzumab resistant breast cancer. Applying this new strategy, we found that, in contrast to trastuzumab sensitive breast cancer cells, combinatorial targeting of ERBB receptors or of key signaling intermediates does not have potential for treatment of de novo trastuzumab resistant cells. Instead, c-MYC was identified as a novel potential target protein in breast cancer cells
    Type of Publication: Journal article published
    PubMed ID: 19118495
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  • 9
    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 co-treatment 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.
    Type of Publication: Journal article published
    PubMed ID: 16338063
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  • 10
    Keywords: ANGIOGENESIS ; APOPTOSIS ; CANCER ; CELLS ; EXPRESSION ; GROWTH ; INHIBITOR ; proliferation ; SURVIVAL ; tumor ; carcinoma ; CELL ; COMBINATION ; Germany ; IN-VIVO ; INHIBITION ; THERAPY ; VIVO ; liver ; PROTEIN ; PROTEINS ; TUMORS ; MICE ; NF-KAPPA-B ; ACTIVATION ; kidney ; INDUCTION ; BINDING ; PROGRESSION ; resistance ; INDUCED APOPTOSIS ; METASTASIS ; IMMUNODEFICIENT MICE ; STEM-CELLS ; STRATEGIES ; side effects ; pancreatic cancer ; ELIMINATION ; ONCOLOGY ; PANCREATIC-CANCER ; development ; SIZE ; COMBINATION THERAPY ; CANCERS ; STEM ; EPITHELIAL-MESENCHYMAL TRANSITION ; MESENCHYMAL TRANSITION ; sorafenib ; TUMOR-INITIATING CELLS ; STRATEGY ; CONTRIBUTE ; Combination treatment ; RAF/MEK/ERK PATHWAY
    Abstract: Recent evidence suggests that pancreatic cancer and other solid tumors contain a subset of tumorigenic cells capable of extensive self-renewal that contribute to metastasis and treatment resistance. Sorafenib (SO) is a promising new multikinase inhibitor for treatment of advanced kidney and liver cancers. We report here targeting of pancreatic cancer stem cells (CSC) by SO and the development of a strategy to enhance this effect. Although SO administration diminished clonogenicity, spheroid formation, aldehyde dehydrogenase 1 (ALDH1) activity, growth on immunodeficient mice, proliferation, and angiogenesis and induced apoptosis, we observed SO-induced activation of NF-kappa B associated with survival and regrowth of spheroids. For enhanced elimination of CSC characteristics by SO, we cotreated cells with sulforaphane (SF). This broccoli isothiocyanate was recently described to eliminate pancreatic CSCs by downregulation of NF-kappa B activity without inducing toxic side effects. On combination treatment, SF completely eradicated SO-induced NF-kappa B binding, which was associated with abrogated clonogenicity, spheroid formation, ALDH1 activity, migratory capacity, and induction of apoptosis. In vivo, combination therapy reduced the tumor size in a synergistic manner. This was due to induction of apoptosis, inhibition of proliferation and angiogenesis, and downregulation of SO-induced expression of proteins involved in epithelial-mesenchymal transition. Our data suggest that SF may be suited to increase targeting of CSCs by SO. Cancer Res; 70(12); 5004-13. (C)2010 AACR
    Type of Publication: Journal article published
    PubMed ID: 20530687
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