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  • 1
    Keywords: RECEPTOR ; CANCER ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; INHIBITOR ; tumor ; carcinoma ; CELL ; FACTOR RECEPTOR ; Germany ; KINASE ; THERAPY ; TYROSINE KINASE ; DIAGNOSIS ; HYBRIDIZATION ; DRUG ; cell line ; TUMORS ; validation ; LINES ; DNA ; prognosis ; DOMAIN ; CELL-LINES ; GROWTH-FACTOR RECEPTOR ; treatment ; TYROSINE KINASE INHIBITOR ; chromosome ; COMPARATIVE GENOMIC HYBRIDIZATION ; COPY NUMBER ; NUMBER ; CELL-LINE ; LINE ; DATABASE ; PROGNOSTIC-FACTORS ; CANCER-CELLS ; CRYSTAL-STRUCTURE ; PROGNOSTIC-SIGNIFICANCE ; squamous cell carcinoma ; IMBALANCES ; cell lines ; CLUSTER ; NECK-CANCER ; INHIBITORS ; CELL CARCINOMA ; ONCOLOGY ; PROGRAM ; RE ; EGFR ; analysis ; TUMOR-CELL ; PROFILES ; hierarchical cluster analysis ; technique ; correlation ; DRUGS ; CANDIDATE ; COMPOUND ; CANCERS ; genomic ; SQUAMOUS-CELL ; epidermal growth factor receptor ; GROWTH-FACTOR-RECEPTOR ; PROGNOSTIC RELEVANCE ; CEM LEUKEMIA-CELLS ; modeling ; MOLECULAR-MODES ; oral squamous cell carcinoma ; docking studies ; LINDERA-MEGAPHYLLA ; molecular-targeted therapy ; RESISTANT TUMOR-CELLS
    Abstract: Oral squamous cell carcinoma ranks among the top ten most common cancers worldwide. Despite the success in diagnosis and therapy during the past 30 years, oral squamous cell carcinoma still belongs to the tumor types with a very unfavorable prognosis. In an effort to identify genomic alterations with prognostic relevance, we applied the comparative genomic hybridization technique on oral squamous cell carcinoma. The tumors exhibited from five up to 47 DNA copy number alterations, indicating a considerable degree of genomic imbalance. Out of 35 tumors, 19 showed a gain of chromosome band 7p12. Genomic imbalances were investigated by hierarchical cluster analysis and clustered image mapping to investigate whether genomic profiles correlate with clinical data. Results of the present investigation show that profiling of genomic imbalances in general, and especially of the epidermal growth factor receptor (EGFR) on 7p12, may be suitable as prognostic factors. In order to identify small-molecule inhibitors for EGFR, we established a database of 531 natural compounds derived from medicinal plants used in traditional Chinese medicine. Candidate compounds were identified by correlation analysis using the Kendall tau-test of IC50 values of tumor cell lines and microarray-based EGFR mRNA expression. Further validation was performed by molecular docking studies using the AutoDock program with the crystal structure of EGFR tyrosine kinase domain as docking template. We estimate these results will be a further step toward the ultimate goal of individualized, patient-adapted tumor treatment based on tumor molecular profiling
    Type of Publication: Journal article published
    PubMed ID: 17338652
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  • 2
    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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  • 3
    Keywords: RECEPTOR ; CANCER ; CELLS ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; CELL ; FACTOR RECEPTOR ; Germany ; INHIBITION ; KINASE ; PATHWAY ; PATHWAYS ; THERAPY ; TYROSINE KINASE ; GENE-EXPRESSION ; ACTIVATION ; DNA ; BIOLOGY ; cell cycle ; CELL-CYCLE ; CYCLE ; signal transduction ; TYROSINE KINASE INHIBITOR ; VARIANTS ; TARGET ; IDENTIFICATION ; LESIONS ; microarrays ; VECTOR ; DAMAGE ; CANCER-CELLS ; DNA-DAMAGE ; systems biology ; CANCER-THERAPY ; EPIDERMAL-GROWTH-FACTOR ; HUMAN GLIOBLASTOMA CELLS ; INHIBITORS ; VARIANT ; SCIENCE ; EGFR ; DNA damage ; pharmacogenomics ; pharmacology ; oncogenes ; HYDROCARBON RECEPTOR ; pharmacognosy ; LINDERA-MEGAPHYLLA ; tumours ; FACTOR-RECEPTOR ; natural product ; ALPHA-1-ADRENOCEPTOR ANTAGONIST ; APORPHINE ALKALOIDS ; CASSYTHA-FILIFORMIS ; DRUG-SENSITIVITY ; GLAUCIUM-FLAVUM-GRANTZ ; HUMAN LEUKEMIC-CELLS ; TOPOISOMERASE-I INHIBITOR
    Abstract: The extraordinary relevance of EGFR in turnout biology makes it an exquisite molecular target for tumour therapy. Despite considerable success with these EGFR tyrosine kinase inhibitors in cancer therapy, resistance against these chemical compounds develops owing to the selection of point-mutated variants of EGFR. Therefore, there is an urgent need for the identification of novel EGFR tyrosine kinase inhibitors for treating tumours with such EGFR mutants. We found a preferential cytotoxicity of dicentrine towards U87MG.Delta EGFR-transduced with a constitutively deletion-activated EGFR expression vector as compared to non-transduced wild-type U87MG cells. As determined by microarray-based mRNA expression profiling, this preferential cytotoxicity was accompanied with an activation of BRCA1-mediated DNA damage response, p53 signalling, G1/S and G2/M cell cycle regulation, and aryl hydrocarbon receptor pathways. The activation of these signalling routes might be explained by the fact that dicentrine intercalates DNA and induces DNA strand break by inhibition of DNA topoisomerases. The cell cycle might be arrested by dicentrine-induced DNA lesions. (C) 2009 Elsevier Inc. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 20005213
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  • 4
    Keywords: RECEPTOR ; EXPRESSION ; GROWTH ; IN-VITRO ; INHIBITOR ; CELL ; Germany ; INHIBITION ; PATHWAY ; PATHWAYS ; DISEASE ; GENE ; GENE-EXPRESSION ; GENES ; microarray ; PROTEIN ; METABOLISM ; LINES ; NF-KAPPA-B ; NITRIC-OXIDE ; MACROPHAGES ; TARGET ; MOUSE ; ASSAY ; microarrays ; NECROSIS-FACTOR-ALPHA ; CELL-LINE ; LINE ; PROGNOSTIC VALUE ; TARGETS ; inflammation ; CYTOTOXICITY ; INCREASED EXPRESSION ; INHIBITORS ; CELL-GROWTH ; signaling ; INTERFERENCE ; SCIENCE ; pharmacology ; nitric oxide ; NITROSATIVE STRESS ; INTERLEUKIN-10 ; TUMOR BIOLOGY ; NATURAL-PRODUCTS ; POOR SURVIVAL ; natural product ; Glucocorticoid receptor signaling pathway ; Griess assay ; Interleukin-10 signaling pathway ; RAW-264.7 CELLS ; THIOREDOXIN SYSTEM
    Abstract: Nitric oxide (NO) plays a role in various physiological and pathophysiological conditions such as immunoregulatory and inflammatory processes. Hence, NO and its generating enzyme, inducible nitric oxide synthase (iNOS) may not only be of diagnostic and prognostic value, but may also serve as targets for novel therapeutic options. In the present investigation, we have screened a phytochemical library by correlating the IC50 values for 531 natural products of 60 cell lines with the microarray-based mRNA expression of 95 genes known to be involved in NO metabolism and signaling with the aim to identify candidate compounds as inhibitors for NO metabolism and signaling. We identified bis(helenalinyl)glutarate (BHG) as putative candidate compound. Indeed. BHG inhibited NO production (IC50 value: 0.90 +/- 0.04 mu M) and down-regulated iNOS protein expression (IC50 value: 1.12 +/- 0.16 mu M) of RAW264.7 mouse macrophages in the presence of lipopolysaccharide. Performing XTT cytotoxicity assays, we found that BHG inhibited cell growth in a dose-dependent manner with an IC50 value of 5.6 mu M. To gain insight into molecular pathways involved in NO inhibition and cytotoxicity, we performed microarray experiments which were exemplarily validated by real-time RT-PCR. A total of 227 genes (67 up- and 160 down-regulated) were obtained, which exhibited significant differences in mRNA regulation between BHG-treated and untreated RAW264.7 macrophages. Sixteen of 227 genes are known to be involved in NO-signaling. Pathway analyses revealed that further five and four down-regulated genes belong to the glucocorticoid receptor and interleukin-1 and interleukin-10 pathways, respectively. An interference of these two pathways and NO is known for inflammation and auto-immune diseases. The therapeutic potential of this compound has to be explored in the future. (C) 2010 Elsevier Inc. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 20105431
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  • 5
  • 6
    Keywords: CANCER ; IN-VITRO ; chemotherapy ; drug resistance ; MULTIDRUG-RESISTANCE ; LEUKEMIA-CELLS ; P-GLYCOPROTEIN ; MALARIA ; ANTIMALARIAL ARTESUNATE ; EXPRESSION PROFILES ; TUMOR-CELL LINES ; CASSETTE TRANSPORTER GENES ; INHIBITS ANGIOGENESIS ; DRUG-SENSITIVITY ; ENDOTHELIAL-GROWTH-FACTOR
    Abstract: Artemisinins are plant products with a wide range of medicinal applications. Most prominently, artesunate is a well tolerated and effective drug for treating malaria, but is also active against several protozoal and schistosomal infections, and additionally exhibits anti-angiogenic, anti-tumorigenic and anti-viral properties. The array of activities of the artemisinins, and the recent emergence of malaria resistance to artesunate, prompted us to synthesize and evaluate several novel artemisinin-like derivatives. Sixteen distinct derivatives were therefore synthesized and the in vitro cytotoxic effects of each were tested with different cell lines. The in vivo anti-angiogenic properties were evaluated using a zebrafish embryo model. We herein report the identification of several novel artemisinin-like compounds that are easily synthesized, stable at room temperature, may overcome drug-resistance pathways and are more active in vitro and in vivo than the commonly used artesunate. These promising findings raise the hopes of identifying safer and more effective strategies to treat a range of infections and cancer
    Type of Publication: Journal article published
    PubMed ID: 20629994
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  • 7
    Keywords: RECEPTOR ; CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; proliferation ; tumor ; TUMOR-CELLS ; CELL ; COMBINATION ; Germany ; human ; INHIBITION ; PROTEIN ; PROTEINS ; cell line ; DIFFERENTIATION ; TUMORS ; LINES ; CELL-LINES ; DOWN-REGULATION ; treatment ; SUSCEPTIBILITY ; BREAST ; breast cancer ; BREAST-CANCER ; MOUSE ; resistance ; RATES ; CELL-LINE ; leukemia ; LINE ; MODULATION ; oligonucleotides ; CANCER-CELLS ; sensitivity ; IMPROVES ; cell lines ; TUMOR CELLS ; ONCOLOGY ; TRANSPORTER ; IRON ; TUMOR-CELL ; INTERNALIZATION ; artesunate ; SULFATE ; USA ; uptake ; correlation ; HOMEOSTASIS ; ATP-BINDING ; ABC-TRANSPORTERS ; antisense
    Abstract: The anti-malarial artesunate also exerts profound anti-cancer activity. The susceptibility of tumor cells to artesunate can be enhanced by ferrous iron. The transferrin receptor (TfR) is involved in iron uptake by internalization of transferrin and is over-expressed in rapidly growing tumors. The ATP-binding cassette (ABC) transporters ABCB6 and ABCB7 are also involved in iron homeostasis. To investigate whether these proteins play a role for sensitivity towards artesunate, Oncotest's 36 cell line panel was treated with artesunate or artesunate plus iron(II) glycine sulfate (Ferrosanol. The majority of cell lines showed increased inhibition rates, for the combination of artesunate plus iron(II) glycine sulfate compared to artesunate alone. However, in 11 out of the 36 cell lines the combination treatment was not superior. Cell lines with high TfR expression significantly correlated with high degrees of modulation indicating that high TfR expressing tumor cells would be more efficiently inhibited by this combination treatment than low TfR expressing ones. Furthermore, we found a significant relationship between cellular response to artesunate and TfR expression in 55 cell lines of the National Cancer Institute (NCI), USA. A significant correlation was also found for ABCB6, but not for ABCB7 in the NCI panel. Artesunate treatment of human CCRF-CEM leukemia and MCF7 breast cancer cells induced ABCB6 expression but repressed ABCB7 expression. Finally, artesunate inhibited proliferation and differentiation of mouse erythroleukemia (MEL) cells. Down-regulation of ABCB6 by antisense oligonucleotides inhibited differentiation of MEL cells indicating that artesunate and ABCB6 may cooperate. In conclusion, our results indicate that ferrous iron improves the activity of artesunate in some but not all tumor cell lines. Several factors involved in iron homeostasis such as TfR and ABCB6 may contribute to this effect.
    Type of Publication: Journal article published
    PubMed ID: 17726528
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  • 8
    Keywords: CANCER ; EXPRESSION ; CELL ; Germany ; IN-VIVO ; GENE ; GENES ; DRUG ; GROWTH-FACTOR RECEPTOR ; resistance ; RATES ; chemotherapy ; CANCER-CELLS ; sensitivity ; DRUG-RESISTANCE ; TUMOR-CELL-LINES ; ANTICANCER DRUGS ; CLUSTER ; traditional Chinese medicine ; RE ; CANDIDATE GENES ; methods ; HIGH-THROUGHPUT ; ANTIMALARIAL ARTESUNATE ; pharmacogenomics ; TETRAZOLIUM ASSAY ; TOPOISOMERASE-II ; pharmacology ; CANDIDATE ; anticancer drug ; MEDICINE ; CEM LEUKEMIA-CELLS ; MOLECULAR-MODES ; pharmacognosy ; phytochemistry ; VALUES ; molecular pharmacology ; natural products
    Abstract: The cure rates in cancer chemotherapy are affected by the development of drug resistance and severe side effects. Due to these limitations, there is an urgent need for improved therapeutics. Bioactive compounds from medicinal plants represent a valuable resource for novel anticancer drugs. To gain a systematic approach, we established a library of 531 cytotoxic natural products derived from traditional Chinese medicine. Cellular and pharmacogenomic profiling was performed for the 10 most cytotoxic natural products. One of these compounds, helebrin, was analyzed in more detail. The IC50 values for hellebrin of 60 NCI cell lines were associated with the microarray-based expression of 9,706 genes. By hierarchical cluster analyses, candidate genes were identified which significantly predicted sensitivity or resistance of cell lines to hellebrin
    Type of Publication: Journal article published
    PubMed ID: 18220539
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  • 9
    Keywords: CANCER ; INHIBITOR ; radiotherapy ; CLINICAL-TRIAL ; Germany ; THERAPY ; DISEASE ; TIME ; PATIENT ; FIELD ; RECOGNITION ; TARGET ; NO ; TRIAL ; TRIALS ; NUMBER ; CLINICAL-TRIALS ; meta-analysis ; RATES ; chemotherapy ; SAFETY ; TARGETS ; CANCER-THERAPY ; IMPLEMENTATION ; traditional Chinese medicine ; RE ; THERAPIES ; cancer therapy ; LEVEL ; methods ; POWER ; pharmacology ; NAUSEA ; DRUGS ; cancer research ; MEDICINE ; clinical trial ; FIELDS ; pharmacognosy ; interactions ; molecular pharmacology ; NATURAL-PRODUCTS
    Abstract: In contrast to western medicine (WM), traditional Chinese medicine (TCM) does not focus on a single target but on multiple targets involved in a particular disease condition by applying diverse modalities, such as herbal medicine, acupuncture, moxibustion, etc. There is no pre-determined treatment procedure in TCM, and every patient condition is handled individually. Such patient-tailored treatments have a millennia-old tradition in TCM. Illustrative examples of the power of TCM have been documented in cancer research, i.e., camptothecin, homoharringtonine, or arsenic trioxide. On the other hand, one major reason for reluctance of western academia towards TCM is due to the lack of clinical studies of TCM receipts. This situation is changing very recently, and a number of clinical studies were conducted on TCM providing convincing evidence for the first time to gain credibility and reputation outside China. Clinical trials with TCM remedies focus on three major fields in cancer research: (1) improvement of poor treatment response rates towards standard chemo- and radiotherapy, (2) reduction of severe adverse effects of standard cancer therapy, and (3) unwanted interactions of standard therapy with herbal medicines. Efficacy and safety of TCM treatments depend on the quality of TCM products. Appropriate quality assurance and control of TCM products as well as sustainable production methods are pre-conditions for the implementation of TCM in cancer therapy at an international level. In conclusion, the most important question for recognition and implementation of TCM into WM concerns the clinical evidence for the efficacy of TCM and international quality standards for TCM products. (C) 2007 Elsevier Ireland Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 18243610
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  • 10
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    In Vivo 22 (3), 279-283 
    Keywords: CANCER ; EXPRESSION ; carcinoma ; CELL ; Germany ; IN-VIVO ; THERAPY ; VIVO ; TOOL ; GENE ; GENES ; microarray ; DRUG ; FAMILY ; IONS ; CELL-LINES ; TRANSPORT ; resistance ; MEMBRANE ; CELL-LINE ; CANCER-CELLS ; PREDICTION ; sensitivity ; CISPLATIN ; drug resistance ; DRUG-RESISTANCE ; MULTIDRUG-RESISTANCE ; TUMOR-CELL-LINES ; CLUSTER ; CARBOPLATIN ; RE ; FAMILIES ; THERAPIES ; TRANSPORTER ; LEVEL ; analysis ; pharmacogenomics ; TETRAZOLIUM ASSAY ; pharmacology ; USA ; MEDICINE ; VALUES ; ATPASES ; ABC transporter ; ADENOSINE-TRIPHOSPHATASE ATP7B ; CHEMORESISTANCE MARKER ; copper transporter
    Abstract: The 50% inhibitory concentration (IC50) values for cisplatin from 60 cell lines of the National Cancer Institute (NCI), USA, were correlated with the microarray-based mRNA expression levels of 55 transporter genes. The transporters are known to be involved in multiple drug resistance and belong to different classes, e.g. lysosomal H+ transporting ATPases, Cu2+ transporting ATPases, glutamate transporters of the solute carrier family 31, copper transporters of the solute carrier family 31, and ATP-binding cassette (ABC) transporter genes. The expression levels of 17 genes represented by 21 clones correlated significantly with the IC50 values for cisplatin. Hierarchical cluster analysis further enabled the prediction of the sensitivity or resistance of these cell lines to cisplatin with respect to the mRNA expression of these set of transporter genes under study. One among the 17 genes studied is ATP7B which is involved in the transport of copper ions across the cell membrane into the cell. We conclude that our microarray-based approach is a feasible and effective tool in identifying prognostic markets for drug resistance in antitumor therapy
    Type of Publication: Journal article published
    PubMed ID: 18610736
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