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  • 1
    Keywords: CANCER ; CELLS ; EXPRESSION ; CELL ; TUMORS ; DNA ; FAMILY ; MEMBERS ; IDENTIFICATION ; MEMBRANE ; METHYLATION ; CYTOTOXICITY ; INHIBITORS ; SUBSTRATE ; CANCER-CELL LINES ; METHYLTRANSFERASE INHIBITORS ; HCNT1 ; NOVIKOFF RAT HEPATOMA
    Abstract: The DNA methyltransferase inhibitors 5-azacytidine (5-azaCyd) and 5-aza-2'-deoxycytidine have found increasing use for the treatment of myeloid leukemias and solid tumors. Both nucleoside analogues must be transported into cells and phosphorylated before they can be incorporated into DNA and inactivate DNA methyltransferases. The members of the human equilibrative and concentrative nucleoside transporter families mediate transport of natural nucleosides and some nucleoside analogues into cells. However, the molecular identity of the transport proteins responsible for mediating the uptake of 5-azanucleosides has remained unknown. To this end, we have generated a stably transfected Madin-Darby canine kidney strain II cell line expressing recombinant hCNT1. An antiserum directed against hCNT1 specifically detected the protein in the apical membrane of hCNT1-expressing Madin-Darby canine kidney cells. Using [C-14]5-azaCyd, we show here that hCNT1 mediated the Na+-dependent uptake of this drug with a K-m value of 63 mu mol/L. Na+-dependent transport of radiolabeled cytidine, uridine, and 5-fluoro-5'-deoxyuridine further showed the functionality of the transporter. hCNT1-expressing cells were significantly more sensitive to 5-azaCyd, and drug-dependent covalent trapping of DNA methyltransferase 1 was substantially more pronounced. Importantly, these results correlated with a significant sensitization of hCNT1-expressing cells toward the demethylating effects of 5-azaCyd and 5-aza-2'-deoxycytidine. In conclusion, our study identifies 5-azaCyd as a novel substrate for hCNT1 and provides direct evidence that hCNT1 is involved in the DNA-demethylating effects of this drug. [Mol Cancer Ther 2009;8(1):225-31]
    Type of Publication: Journal article published
    PubMed ID: 19139132
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  • 2
    Abstract: Azacytidine is an established nucleoside drug that is well known for its ability to modulate epigenetic gene regulation by inhibition of DNA methylation. Despite recent advances in the clinical development of azacytidine, the use of the drug is limited by its low bioavailability and dependency on variably expressed nucleoside transporters for cellular uptake. We show here that CP-4200, an elaidic acid derivative of azacytidine, has strong epigenetic modulatory potency in human cancer cell lines, as evidenced by efficient depletion of DNA methyltransferase protein, genome-wide DNA demethylation, and robust reactivation of epigenetically silenced tumor suppressor genes. Importantly, however, the cellular uptake of CP-4200 was substantially less dependent on the nucleoside transporters that are known to be involved in azacytidine uptake. In agreement with this notion, CP-4200 showed a significantly higher antitumoral activity than azacytidine in an orthotopic mouse tumor model for acute lymphocytic leukemia. Together, these data represent a detailed characterization of the CP-4200 mode of action and suggest that elaidic acid modification improves the therapeutic efficacy of azacytidine.
    Type of Publication: Journal article published
    PubMed ID: 20442313
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  • 3
    Abstract: Enzymes involved in the epigenetic regulation of the genome represent promising starting points for therapeutic intervention by small molecules, and DNA methyltransferases (DNMT) are emerging targets for the development of a new class of cancer therapeutics. In this work, we present nanaomycin A, initially identified by a virtual screening for inhibitors against DNMT1, as a compound inducing antiproliferative effects in three different tumor cell lines originating from different tissues. Nanaomycin A treatment reduced the global methylation levels in all three cell lines and reactivated transcription of the RASSF1A tumor suppressor gene. In biochemical assays, nanaomycin A revealed selectivity toward DNMT3B. To the best of our knowledge, this is the first DNMT3B-selective inhibitor identified to induce genomic demethylation. Our study thus establishes the possibility of selectively inhibiting individual DNMT enzymes.
    Type of Publication: Journal article published
    PubMed ID: 20833755
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  • 4
    Keywords: IN-VITRO ; NITRIC-OXIDE ; LIVER-MICROSOMES ; CELL-CYCLE ; BREAST-CANCER ; TRANSGENIC MICE ; FACTOR-KAPPA-B ; PRENYLATED FLAVONOIDS ; HUMULUS-LUPULUS L. ; INHIBITION CONSTANTS
    Abstract: Characterization and use of effective cancer chemopreventive agents have become important issues in public health-related research. Aiming to identify novel potential chemopreventive agents, we have established an interrelated series of bioassay systems targeting molecular mechanisms relevant for the prevention of tumor development. We report anticarcinogenic properties of Xanthohumol (XN), a prenylated chalcone from hop (Humulus Iupulus L.) with an exceptional broad spectrum of inhibitory mechanisms at the initiation, promotion, and progression stage of carcinogenesis. Consistent with anti-initiating potential, XN potently modulates the activity of enzymes involved in carcinogen metabolism and detoxification. Moreover, XN is able to scavenge reactive oxygen species, including hydroxyl- and peroxyl radicals, and to inhibit superoxide anion radical and nitric oxide production. As potential antitumor-promoting mechanisms, it demonstrates anti-inflammatory properties by inhibition of cyclooxygenase-1 and cyclooxygenase-2 activity and is antiestrogenic without possessing intrinsic estrogenic potential. Antiproliferative mechanisms of XN to prevent carcinogenesis in the progression phase include inhibition of DNA synthesis and induction of cell cycle arrest in S phase, apoptosis, and cell differentiation. Importantly, XN at nanomolar concentrations prevents carcinogen-induced preneoplastic lesions in mouse mammary gland organ culture. Because XN is easily cyclized to the flavanone isoxanthohumol, activities of both compounds were compared throughout the study. Together, our data provide evidence for the potential application of XN as a novel, readily available chemopreventive agent, and clinical investigations are warranted once efficacy and safety in animal models have been established.
    Type of Publication: Journal article published
    PubMed ID: 12481418
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  • 5
    Keywords: IN-VITRO ; RIBOSOMAL-RNA ; CANCER-THERAPY ; CYTO-TOXICITY ; ACUTE MYELOID-LEUKEMIA ; DECITABINE ; CELLULAR SENESCENCE ; ONCOGENE-INDUCED SENESCENCE ; THERAPY-INDUCED SENESCENCE ; BSC-1 CELLS
    Abstract: Epigenetic alterations are a hallmark of cancer that govern the silencing of genes. Up to now, 5-azacytidine (5-aza-CR, Vidaza) and 5-aza-2'-deoxycytidine (5-aza-dC, Dacogen) are the only clinically approved DNA methyltransferase inhibitors (DNMTi). Current effort tries to exploit DNMTi application beyond acute leukemia or myelodysplastic syndrome, especially to solid tumors. Although both drugs only differ by a minimal structural difference, they trigger distinct molecular mechanisms that are highly relevant for a rational choice of new combination therapies. Therefore, we investigated cell death pathways in vitro in human hepatoma, colon, renal, and lung cancer cells and in vivo in chorioallantoic membrane and xenograft models. Real-time cancer cell monitoring and cytokine profiling revealed a profoundly distinct response pattern to both drugs. 5-aza-dC induced p53-dependent tumor cell senescence and a high number of DNA double-strand breaks. In contrast, 5-aza-CR downregulated p53, induced caspase activation and apoptosis. These individual response patterns of tumor cells could be verified in vivo in chorioallantoic membrane assays and in a hepatoma xenograft model. Although 5-aza-CR and 5-aza-dC are viewed as drugs with similar therapeutic activity, they induce a diverse molecular response in tumor cells. These findings together with other reported differences enable and facilitate a rational design of new combination strategies to further exploit the epigenetic mode of action of these two drugs in different areas of clinical oncology. Mol Cancer Ther; 12(10); 2226-36. (c)2013 AACR.
    Type of Publication: Journal article published
    PubMed ID: 23924947
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  • 6
    Keywords: THERAPY ; DOWN-REGULATION ; GROWTH-FACTOR RECEPTOR ; MUTATIONS ; DEGRADATION ; UBIQUITINATION ; ACQUIRED-RESISTANCE ; TYROSINE KINASES ; ubiquitylation ; ERBB FAMILY
    Abstract: Transmembrane receptors, such as the EGFR, are regulated by their turnover, which is dependent on the ubiquitin-proteasome system. We tested in two independent study cohorts whether SNPs in genes involved in EGFR turnover predict clinical outcome in cetuximab-treated metastatic colorectal cancer (mCRC) patients. The following SNPs involved in EGFR degradation were analyzed in a screening cohort of 108 patients treated with cetuximab in the chemorefractory setting: c-CBL (rs7105971; rs4938637; rs4938638; rs251837), EPS15 (rs17567; rs7308; rs1065754), NAE1 (rs363169; rs363170; rs363172), SH3KBP1 (rs7051590; rs5955820; rs1017874; rs11795873), SGIP1 (rs604737; rs6570808; rs7526812), UBE2M (rs895364; rs895374), and UBE2L3 (rs5754216). SNPs showing an association with response or survival were analyzed in BRAF and RAS wild-type samples from the FIRE-3 study. One hundred and fifty-three FOLFIRI plus cetuximab-treated patients served as validation set, and 168 patients of the FOLFIRI plus bevacizumab arm served as controls. EGFR FISH was done in 138 samples to test whether significant SNPs were associated with EGFR expression. UBE2M rs895374 was significantly associated with progression-free survival (log-rank P = 0.005; HR, 0.60) within cetuximab-treated patients. No association with bevacizumab-treated patients (n = 168) could be established (P = 0.56; HR, 0.90). rs895374 genotype did not affect EGFR FISH measurements. EGFR recycling is an interesting mechanism of secondary resistance to cetuximab in mCRC. This is the first report suggesting that germline polymorphisms in the degradation process predict efficacy of cetuximab in patients with mCRC. Genes involved in EGFR turnover may be new targets in the treatment of mCRC. Mol Cancer Ther; 14(10); 2374-81. (c)2015 AACR.
    Type of Publication: Journal article published
    PubMed ID: 26206335
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  • 7
    Abstract: Pancreatic ductal adenocarcinoma (PDAC) is likely the most aggressive and therapy-resistant of all cancers. The aim of this study was to investigate the emerging technology of matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) as a powerful tool to study drug delivery and spatial tissue distribution in PDAC. We utilized an established genetically engineered mouse model of spontaneous PDAC to examine the distribution of the small-molecule inhibitor erlotinib in healthy pancreas and PDAC. MALDI IMS was utilized on sections of single-dose or long-term-treated mice to measure drug tissue distribution. Histologic and statistical analyses were performed to correlate morphology, drug distribution, and survival. We found that erlotinib levels were significantly lower in PDAC compared with healthy tissue (P = 0.0078). Survival of long-term-treated mice did not correlate with overall levels of erlotinib or with overall histologic tumor grade but did correlate both with the percentage of atypical glands in the cancer (P = 0.021, rs = 0.59) and the level of erlotinib in those atypical glands (P = 0.019, rs = 0.60). The results of this pilot study present MALDI IMS as a reliable technology to study drug delivery and spatial distribution of compounds in a preclinical setting and support drug imaging-based translational approaches. Mol Cancer Ther; 15(5); 1145-52. (c)2016 AACR.
    Type of Publication: Journal article published
    PubMed ID: 26823494
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  • 8
    Keywords: RECEPTOR ; ANGIOGENESIS ; CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; IN-VITRO ; proliferation ; FACTOR RECEPTOR ; Germany ; human ; INHIBITION ; PATHWAY ; PATHWAYS ; VITRO ; RISK ; GENE-EXPRESSION ; transcription ; TISSUE ; TIME ; NF-KAPPA-B ; ACTIVATION ; MECHANISM ; TRANSCRIPTION FACTOR ; RISK-FACTORS ; mechanisms ; TRANSCRIPTION FACTORS ; ASSAY ; risk factors ; CELL-LINE ; LINE ; SIGNALING PATHWAYS ; MIGRATION ; DEGRADATION ; C-MYC ; CELL-GROWTH ; signaling ; MATRIX ; RE ; MATRIX METALLOPROTEINASES ; REVERSE TRANSCRIPTION-PCR ; LEVEL ; CYCLE ARREST ; ANTIOXIDANT RESPONSE ELEMENT ; function ; RISK-FACTOR ; MATRIX METALLOPROTEINASE-2 ; THIOREDOXIN REDUCTASE-ACTIVITY
    Abstract: Sulforaphane, an aliphatic isothiocyanate, is a known cancer chemopreventive agent. Aiming to investigate antiangiogenic potential of sulforaphane, we here report a potent decrease of newly formed microcapillaries in a human in vitro antiangiogenesis model, with an IC50 of 0.08 mu mol/L. The effects of sulforaphane on endothelial cell functions essential for angiogenesis were investigated in HMEC-1, an immortalized human microvascular endothelial cell line. Molecular signaling pathways leading to activation of endothelial cell proliferation and degradation of the basement membrane were analyzed by reverse transcription-PCR. Sulforaphane showed time- and concentration-dependent inhibitory effects on hypoxia-induced mRNA expression of vascular endothelial growth factor and two angiogenesis-associated transcription factors, hypoxia-inducible factor-1 alpha and c-Myc, in a concentration range of 0.8 to 25 mu mol/L. In addition, the expression of the vascular endothelial growth factor receptor KDR/flk-1 was inhibited by sulforaphane at the transcriptional level. Sulforaphane could also affect basement membrane integrity, as it suppressed transcription of the predominant endothelial collagenase matrix metalloproteinase-2 and its tissue inhibitor of metalloproteinase-2. Migration of HMEC-1 cells in a wound healing assay was effectively prevented by sulforaphane at submicromolar concentrations, and we determined an IC50 of 0.69 mu mol/L. In addition, within 6 hours of incubation, sulforaphane inhibited tube formation of HMEC-1 cells on basement membrane matrix at 0.1, 1, and 10 mu mol/L concentrations. These effects were not due to inhibition of HMEC-1 cell proliferation; however, after 72 hours of incubation, sulforaphane nonselectively reduced HMEC-1 cell growth with an IC50 of 11.3 mu mol/L. In conclusion, we have shown that sulforaphane interferes with all essential steps of neovascularization from proangiogenic signaling and basement membrane integrity to endothelial cell proliferation, migration, and tube formation. These novel antiangiogenic activities of sulforaphane are likely to contribute to its cancer chemopreventive and therapeutic potential
    Type of Publication: Journal article published
    PubMed ID: 16546971
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  • 9
    Keywords: CELLS ; EXPRESSION ; Germany ; QUANTIFICATION ; GENE ; GENES ; microarray ; PROTEIN ; PROTEINS ; RNA ; DRUG ; REDUCTION ; INDUCTION ; DOWN-REGULATION ; treatment ; ASSOCIATION ; resistance ; UP-REGULATION ; leukemia ; doxorubicin ; sensitization ; DE-NOVO ; OVEREXPRESSION ; drug resistance ; DRUG-RESISTANCE ; MULTIDRUG-RESISTANCE ; expression profiling ; HUMAN TUMOR-CELLS ; CHILDHOOD ; RE ; INTERFERENCE ; RNA INTERFERENCE ; INCREASE ; ACUTE MYELOID-LEUKEMIA ; TRANSPORTER ; PROGNOSTIC-FACTOR ; TECHNOLOGY ; TETRAZOLIUM ASSAY ; downregulation ; DRUGS ; P-GLYCOPROTEIN EXPRESSION ; RESISTANCE-ASSOCIATED PROTEIN
    Abstract: A major issue in the treatment of T-cell acute lymphoblastic leukemia (T-ALL) is resistance to chemotherapeutic drugs. Multidrug resistance can be caused by ATP-binding cassette (ABC) transporters. The majority of these proteins have not yet been examined in T-ALL. Using a newly developed microarray for the simultaneous quantification of 38 ABC transporter genes, we observed a consistent overexpression of ABCA2/ABCA3 in clinical samples of ALL. Therefore, we analyzed the association of these two genes with drug resistance. Treatment of CCRF-CEM and Jurkat cells with methotrexate, vinblastine, or doxorubicin led to an induction of ABCA3 expression, whereas a significant increase of ABCA2 expression was only observed in Jurkat cells. To study the causal relationship of ABCA2/A3 overexpression with drug resistance, we applied RNA interference (RNAi) technology. RINAi specific for ABCA2 or ABCA3 led to a partial decrease of expression in these two ABC transporters. Upon cotreatment of RNAi for ABCA2 with methotrexate and vinblastine, a partial decrease of ABCA2 expression as well as a simultaneous increase of ABCA3 expression was observed. Vice versa, ABCA3 RNAi plus drugs decreased ABCA3 and increased ABCA2 expression. This indicates that down-regulation of one ABC transporter was compensated by the up-regulation of the other. Application of RNAi for both ABCA2 and ABCA3 resulted in a more efficient reduction of the expression sensitization of cells to cytostatic drugs was achieved. In conclusion, ABCA2 and ABCA3 are expressed in many T-ALL and contribute to drug resistance
    Type of Publication: Journal article published
    PubMed ID: 16928819
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  • 10
    Keywords: RECEPTOR ; ANGIOGENESIS ; CANCER ; CELLS ; ENDOTHELIAL-CELLS ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; INHIBITOR ; tumor ; carcinoma ; CELL ; FACTOR RECEPTOR ; Germany ; IN-VIVO ; THERAPY ; tumor growth ; VIVO ; DENSITY ; imaging ; QUANTIFICATION ; TUMORS ; ACCUMULATION ; MICE ; LIGAND ; MARKER ; BIOMARKERS ; CONTRAST AGENT ; BINDING ; UP-REGULATION ; TUMOR PROGRESSION ; MARKERS ; LIGANDS ; tomography ; INTEGRIN ; squamous cell carcinoma ; SELECTION ; specificity ; TUMOR ANGIOGENESIS ; CANCER-THERAPY ; ultrasound ; MICROBUBBLES ; molecular ; MATRIX ; CELL CARCINOMA ; ONCOLOGY ; RE ; XENOGRAFTS ; TUMOR-GROWTH ; THERAPIES ; INCREASE ; endothelial cells ; antiangiogenic therapy ; technique ; USA ; vascular endothelial growth factor ; cancer research ; SQUAMOUS-CELL ; GROWTH-FACTOR-RECEPTOR ; matrix metalloproteinase ; MATRIX-METALLOPROTEINASE ; xenograft ; quantitative ; EMISSION ; ENDOTHELIAL GROWTH ; response ; EXCESS ; FACTOR-RECEPTOR ; growth factor ; cyanoacrylate ; vascular endothelial growth factor receptor
    Abstract: Molecular ultrasound is capable of elucidating the expression of angiogenic markers in vivo. However, the capability of the method for volumetric "multitarget quantification" and for the assessment of antiangiogenic therapy response has rather been investigated. Therefore, we generated cyanoacrylate microbubbles linked to vascular endothelial growth factor receptor 2 (VEGFR2) and alpha(v)beta(3) integrin binding ligands and quantified their accumulation in squamous cell carcinoma xenografts (HaCaT-ras-A-5RT3) in mice with the quantitative volumetric ultrasound scanning technique, sensitive particle acoustic quantification. Specificity of VEGFR2 and alpha(v)beta(3) integrin binding microbubbles was shown, and changes in marker expression during matrix metalloproteinase inhibitor treatment were investigated. In tumors, accumulation of targeted microbubbles was significantly higher compared with nonspecific ones and could be inhibited competitively by addition of the free ligand in excess. Also, multimarker imaging could successfully be done during the same imaging session. Molecular ultrasound further indicated a significant increase of VEGFR2 and alpha(v)beta(3) integrin expression during tumor growth and a considerable decrease in both marker densities after matrix metalloproteinase inhibitor treatment. Histologic data suggested that the increasing VEGFR2 and alpha(v)beta(3) integrin concentrations in tumors during growth are related to an up-regulation of its expression by the endothelial cells, whereas its decrease under therapy is more related to the decreasing relative vessel density. In conclusion, targeted ultrasound appears feasible for the longitudinal molecular profiling of tumor angiogenesis and for the sensitive assessment of therapy effects in vivo
    Type of Publication: Journal article published
    PubMed ID: 18202013
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