Wenzel, Dirk

[["dc.bibliographiccitation.firstpage","395"],["dc.bibliographiccitation.issue","2"],["dc.bibliographiccitation.journal","Clinical Cancer Research"],["dc.bibliographiccitation.lastpage","404"],["dc.bibliographiccitation.volume","22"],["dc.contributor.author","Koch, Raphael"],["dc.contributor.author","Aung, Thiha"],["dc.contributor.author","Vogel, Daniel"],["dc.contributor.author","Chapuy, Björn"],["dc.contributor.author","Wenzel, Dirk"],["dc.contributor.author","Becker, Sabrina"],["dc.contributor.author","Sinzig, Ursula"],["dc.contributor.author","Venkataramani, Vivek"],["dc.contributor.author","von Mach, Tobias"],["dc.contributor.author","Jacob, Ralf"],["dc.contributor.author","Truemper, Lorenz H."],["dc.contributor.author","Wulf, Gerald G."],["dc.date.accessioned","2018-11-07T10:19:22Z"],["dc.date.available","2018-11-07T10:19:22Z"],["dc.date.issued","2016"],["dc.description.abstract","Purpose: Although R-CHOP-based immunochemotherapy cures significant proportions of patients with aggressive B-cell lymphoma, tumor cell susceptibility to chemotherapy varies, with mostly fatal outcome in cases of resistant disease. We and others have shown before that export of cytostatic drugs contributes to drug resistance. Now we provide a novel approach to overcome exosome-mediated drug resistance in aggressive B-cell lymphomas. Experimental Design: We used well-established centrifugation protocols to purify exosomes from DLBCL cell lines and detected anthracyclines using FACS and HPLC. We used shRNA knockdown of ABCA3 to determine ABCA3 dependence of chemotherapy susceptibility and monitored ABCA3 expression after indomethacin treatment using qPCR. Finally, we established an in vivo assay using a chorioallantoic membrane (CAM) assay to determine the synergy of anthracycline and indomethacin treatment. Results: We show increased efficacy of the anthracycline doxorubicin and the anthracenedione pixantrone by suppression of exosomal drug resistance with indomethacin. B-cell lymphoma cells in vitro efficiently extruded doxorubicin and pixantrone, in part compacted in exosomes. Exosomal biogenesis was critically dependent on the expression of the ATP-transporter A3 (ABCA3). Genetic or chemical depletion of ABCA3 augmented intracellular retention of both drugs and shifted the subcellular drug accumulation to prolonged nuclear retention. Indomethacin increased the cytostatic efficacy of both drugs against DLBCL cell lines in vitro and in vivo in a CAM assay. Conclusions: We propose pretreatment with indomethacin toward enhanced antitumor efficacy of anthracyclines and anthracenediones. (C) 2015 AACR."],["dc.description.sponsorship","Deutsche Forschungsgemeinschaft; University Medicine Goettingen"],["dc.identifier.doi","10.1158/1078-0432.CCR-15-0577"],["dc.identifier.isi","000369076500016"],["dc.identifier.pmid","26369630"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/41643"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.relation.issn","1557-3265"],["dc.relation.issn","1078-0432"],["dc.title","Nuclear Trapping through Inhibition of Exosomal Export by Indomethacin Increases Cytostatic Efficacy of Doxorubicin and Pixantrone"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","1576"],["dc.bibliographiccitation.issue","8"],["dc.bibliographiccitation.journal","Leukemia"],["dc.bibliographiccitation.lastpage","1586"],["dc.bibliographiccitation.volume","22"],["dc.contributor.author","Chapuy, Björn"],["dc.contributor.author","Koch, R."],["dc.contributor.author","Radunski, Ulf"],["dc.contributor.author","Corsham, Sabrina"],["dc.contributor.author","Cheong, Naeun"],["dc.contributor.author","Inagaki, Nobuya"],["dc.contributor.author","Ban, N."],["dc.contributor.author","Wenzel, D."],["dc.contributor.author","Reinhardt, D."],["dc.contributor.author","Zapf, Antonia"],["dc.contributor.author","Schweyer, Stefan"],["dc.contributor.author","Kosari, F."],["dc.contributor.author","Klapper, Wolfram"],["dc.contributor.author","Truemper, Lorenz H."],["dc.contributor.author","Wulf, Gerald G."],["dc.date.accessioned","2018-11-07T11:12:37Z"],["dc.date.available","2018-11-07T11:12:37Z"],["dc.date.issued","2008"],["dc.description.abstract","Multidrug resistance (MDR) seriously limits the efficacy of chemotherapy in patients with cancer and leukemia. Active transport across membranes is essential for such cellular drug resistance, largely provided by ATP-binding cassette (ABC) transport proteins. Intracellular drug sequestration contributes to MDR; however, a genuine intracellular ABC transport protein with MDR function has not yet been identified. Analyzing the intrinsic drug efflux capacity of leukemic stem cells, we found the ABC transporter A3 (ABCA3) to be expressed consistently in acute myeloid leukemia (AML) samples. Greater expression of ABCA3 is associated with unfavorable treatment outcome, and in vitro, elevated expression induces resistance toward a broad spectrum of cytostatic agents. ABCA3 remains localized within the limiting membranes of lysosomes and multivesicular bodies, in which cytostatics are efficiently sequestered. In addition to AML, we also detected ABCA3 in a panel of lymphohematopoietic tissues and transformed cell lines. In conclusion, we identified subcellular drug sequestration mediated by the genuinely intracellular ABCA3 as being a clinically relevant mechanism of intrinsic MDR."],["dc.identifier.doi","10.1038/leu.2008.103"],["dc.identifier.isi","000258413400013"],["dc.identifier.pmid","18463677"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/6063"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/53706"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.relation.issn","0887-6924"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.title","Intracellular ABC transporter A3 confers multidrug resistance in leukemia cells by lysosomal drug sequestration"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","1528"],["dc.bibliographiccitation.issue","11"],["dc.bibliographiccitation.journal","HAEMATOLOGICA-THE HEMATOLOGY JOURNAL"],["dc.bibliographiccitation.lastpage","1536"],["dc.bibliographiccitation.volume","94"],["dc.contributor.author","Chapuy, Björn"],["dc.contributor.author","Panse, Melanie"],["dc.contributor.author","Radunski, Ulf"],["dc.contributor.author","Koch, Raphael"],["dc.contributor.author","Wenzel, Dirk"],["dc.contributor.author","lnagaki, Nobuya"],["dc.contributor.author","Haase, Detlef"],["dc.contributor.author","Truemper, Lorenz H."],["dc.contributor.author","Wulf, Gerald G."],["dc.date.accessioned","2018-11-07T11:22:41Z"],["dc.date.available","2018-11-07T11:22:41Z"],["dc.date.issued","2009"],["dc.description.abstract","Background Inhibition of BCR-ABL tyrosine kinase activity has evolved as a mainstay of therapy for patients with chronic myeloid leukemia. However, a fraction of leukemic cells persists under targeted therapy and can lead to disease progression on cessation of treatment. Design and Methods We analyzed bone marrow progenitor cells with the side population phenotype, and characterized the role of the intracellular ABC transporter A3 in imatinib detoxification. Results BCR-ABL-positive leukemic cells contribute to the side population cell compartment in untreated patients. Such leukemic side population cells, as well as CD34-positive progenitors from chronic myeloid leukemia samples, strongly express the intracellular ABCA3. Functionally, ABCA3 levels are critical for the susceptibility of chronic myeloid leukemia blast cell lines to specific BCR-A-BL inhibition by imatinib. The transporter is localized in the limiting membrane of lysosomes and multivesicular bodies, and intracellular [(14)C]-labeled imatinib accumulates in such organelles. The lysosomal storage capacity increases with ABCA3 expression, thus regulating imatinib sequestration. Conclusions The intracellular ABC transporter A3 is expressed in chronic myeloid leukemia progenitor cells and may contribute to intrinsic imatinib resistance by facilitating lysosomal sequestration in chronic myeloid leukemia cells."],["dc.identifier.doi","10.3324/haematol.2009.008631"],["dc.identifier.isi","000272165800009"],["dc.identifier.pmid","19880777"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/5958"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/56030"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.relation.issn","0390-6078"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.title","ABC transporter A3 facilitates lysosomal sequestration of imatinib and modulates susceptibility of chronic myeloid leukemia cell lines to this drug"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","2189"],["dc.bibliographiccitation.issue","14"],["dc.bibliographiccitation.journal","Blood"],["dc.bibliographiccitation.lastpage","2198"],["dc.bibliographiccitation.volume","123"],["dc.contributor.author","Koch, Raphael"],["dc.contributor.author","Demant, Martin"],["dc.contributor.author","Aung, Thiha"],["dc.contributor.author","Diering, Nina"],["dc.contributor.author","Cicholas, Anna"],["dc.contributor.author","Chapuy, Björn"],["dc.contributor.author","Wenzel, Dirk"],["dc.contributor.author","Lahmann, Marlen"],["dc.contributor.author","Guentsch, Annemarie"],["dc.contributor.author","Kiecke, Christina"],["dc.contributor.author","Becker, Sabrina"],["dc.contributor.author","Hupfeld, Timo"],["dc.contributor.author","Venkataramani, Vivek"],["dc.contributor.author","Ziepert, Marita"],["dc.contributor.author","Opitz, Lennart"],["dc.contributor.author","Klapper, Wolfram"],["dc.contributor.author","Truemper, Lorenz H."],["dc.contributor.author","Wulf, Gerald G."],["dc.date.accessioned","2018-11-07T09:41:23Z"],["dc.date.available","2018-11-07T09:41:23Z"],["dc.date.issued","2014"],["dc.description.abstract","Tumors are composed of phenotypically heterogeneous cell populations. The non-genomic mechanisms underlying transitions and interactions between cell populations are largely unknown. Here, we show that diffuse large B-cell lymphomas possess a self-organized infrastructure comprising side population (SP) and non-SP cells, where transitions between clonogenic states are modulated by exosome-mediated Wnt signaling. DNA methylation modulated SP-non-SP transitions and was correlated with the reciprocal expressions of Wnt signaling pathway agonist Wnt3a in SP cells and the antagonist secreted frizzled-related protein 4 in non-SP cells. Lymphoma SP cells exhibited autonomous clonogenicity and exported Wnt3a via exosomes to neighboring cells, thus modulating population equilibrium in the tumor."],["dc.identifier.doi","10.1182/blood-2013-08-523886"],["dc.identifier.isi","000335889600015"],["dc.identifier.pmid","24563408"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/33715"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.relation.issn","1528-0020"],["dc.relation.issn","0006-4971"],["dc.title","Populational equilibrium through exosome-mediated Wnt signaling in tumor progression of diffuse large B-cell lymphoma"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","1157"],["dc.bibliographiccitation.issue","7"],["dc.bibliographiccitation.journal","Traffic"],["dc.bibliographiccitation.lastpage","1172"],["dc.bibliographiccitation.volume","9"],["dc.contributor.author","Chapuy, Björn"],["dc.contributor.author","Tikkanen, Ritva"],["dc.contributor.author","Muehlhausen, Chris"],["dc.contributor.author","Wenzel, Dirk"],["dc.contributor.author","von Figura, Kurt"],["dc.contributor.author","Hoening, Stefan"],["dc.date.accessioned","2018-11-07T11:13:50Z"],["dc.date.available","2018-11-07T11:13:50Z"],["dc.date.issued","2008"],["dc.description.abstract","The adaptor complexes AP-1 and AP-3 are localized to endosomes and/or the trans Golgi network (TGN). Because of limitations in analysing intracellular adaptor function directly, their site of function is a matter of ongoing uncertainty. To overcome this problem and to analyse adaptor sorting at the TGN, we reconstituted vesicle formation from Golgi/TGN-enriched membranes in a novel in vitro budding assay. Melanocytes were metabolically labelled followed by a 19 degrees C temperature block to accumulate newly synthesized proteins in Golgi membranes, which were then enriched by subcellular fractionation and used as donor membranes for vesicle formation in vitro. The incorporation of the melanosomal proteins tyrosinase and tyrosinase-related protein 1 (TRP-1) as well as Lamp-1 and 46 kDa mannose-6-phosphate receptor (MPR46) into Golgi/TGN-derived vesicles was temperature, nucleotide, cytosol, ADP ribosylation factor 1 and adaptor dependent. We show that sorting of TRP-1 and MPR46 was AP-1 dependent, while budding of tyrosinase and Lamp-1 required AP-3. Depletion of clathrin inhibited sorting of all four cargo proteins, suggesting that AP-1 and AP-3 are involved in the formation of distinct types of clathrin-coated vesicles, each of which is characterized by the incorporation of specific cargo membrane proteins."],["dc.identifier.doi","10.1111/j.1600-0854.2008.00745.x"],["dc.identifier.isi","000256860100011"],["dc.identifier.pmid","18410487"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/53991"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.relation.issn","1398-9219"],["dc.title","AP-1 and AP-3 mediate sorting of melanosomal and lysosomal membrane proteins into distinct post-Golgi trafficking pathways"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.journal","Onkologie"],["dc.bibliographiccitation.volume","35"],["dc.contributor.author","Aung, T."],["dc.contributor.author","Chapuy, Björn"],["dc.contributor.author","Vogel, Daniel"],["dc.contributor.author","Kiecke, Christina"],["dc.contributor.author","Koch, R."],["dc.contributor.author","Wenzel, D."],["dc.contributor.author","Oppermann, Martin"],["dc.contributor.author","Hupfeld, Timo"],["dc.contributor.author","Truemper, Lorenz H."],["dc.contributor.author","Wulf, Gerald G."],["dc.date.accessioned","2018-11-07T09:04:53Z"],["dc.date.available","2018-11-07T09:04:53Z"],["dc.date.issued","2012"],["dc.format.extent","33"],["dc.identifier.isi","000310766700076"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/25201"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Karger"],["dc.publisher.place","Basel"],["dc.relation.issn","0378-584X"],["dc.title","The role of vesicular transport in reduced susceptibility of lymphoma cells for humoral immunotherapy"],["dc.type","conference_abstract"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.journal","Onkologie"],["dc.bibliographiccitation.volume","34"],["dc.contributor.author","Thiha, Aung"],["dc.contributor.author","Vogel, Daniel"],["dc.contributor.author","Chapuy, Björn"],["dc.contributor.author","Wenzel, D."],["dc.contributor.author","Oppermann, Martin"],["dc.contributor.author","Koch, R."],["dc.contributor.author","Hupfeld, Timo"],["dc.contributor.author","Truemper, Lorenz H."],["dc.contributor.author","Wulf, Gerald G."],["dc.date.accessioned","2018-11-07T08:52:16Z"],["dc.date.available","2018-11-07T08:52:16Z"],["dc.date.issued","2011"],["dc.format.extent","76"],["dc.identifier.isi","000295160600190"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/22128"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Karger"],["dc.publisher.place","Basel"],["dc.relation.issn","0378-584X"],["dc.title","Exosomal shielding of B-cell lymphoma from humoral immunotherapy"],["dc.type","conference_abstract"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","15336"],["dc.bibliographiccitation.issue","37"],["dc.bibliographiccitation.journal","PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA"],["dc.bibliographiccitation.lastpage","15341"],["dc.bibliographiccitation.volume","108"],["dc.contributor.author","Aung, Thiha"],["dc.contributor.author","Chapuy, Björn"],["dc.contributor.author","Vogel, Daniel"],["dc.contributor.author","Wenzel, Dirk"],["dc.contributor.author","Oppermann, Martin"],["dc.contributor.author","Lahmann, Marlen"],["dc.contributor.author","Weinhage, Toni"],["dc.contributor.author","Menck, Kerstin"],["dc.contributor.author","Hupfeld, Timo"],["dc.contributor.author","Koch, Raphael"],["dc.contributor.author","Truemper, Lorenz H."],["dc.contributor.author","Wulf, Gerald G."],["dc.date.accessioned","2018-11-07T08:51:45Z"],["dc.date.available","2018-11-07T08:51:45Z"],["dc.date.issued","2011"],["dc.description.abstract","Targeting the surface of malignant cells has evolved into a cornerstone in cancer therapy, paradigmatically introduced by the success of humoral immunotherapy against CD20 in malignant lymphoma. However, tumor cell susceptibility to immunochemotherapy varies, with mostly a fatal outcome in cases of resistant disease. Here, we show that lymphoma exosomes shield target cells from antibody attack and that exosome biogenesis is modulated by the lysosome-related organelle-associated ATP-binding cassette (ABC) transporter A3 (ABCA3). B-cell lymphoma cells released exosomes that carried CD20, bound therapeutic anti-CD20 antibodies, consumed complement, and protected target cells from antibody attack. ABCA3, previously shown to mediate resistance to chemotherapy, was critical for the amounts of exosomes released, and both pharmacological blockade and the silencing of ABCA3 enhanced susceptibility of target cells to antibody-mediated lysis. Mechanisms of cancer cell resistance to drugs and antibodies are linked in an ABCA3-dependent pathway of exosome secretion."],["dc.identifier.doi","10.1073/pnas.1102855108"],["dc.identifier.isi","000294804900069"],["dc.identifier.pmid","21873242"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/22012"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.relation.issn","0027-8424"],["dc.title","Exosomal evasion of humoral immunotherapy in aggressive B-cell lymphoma modulated by ATP-binding cassette transporter A3"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]