Hahn, Heidi Eva

[["dc.bibliographiccitation.firstpage","8722"],["dc.bibliographiccitation.issue","11"],["dc.bibliographiccitation.journal","Oncotarget"],["dc.bibliographiccitation.lastpage","8735"],["dc.bibliographiccitation.volume","6"],["dc.contributor.author","Graab, Ulrike"],["dc.contributor.author","Hahn, Heidi"],["dc.contributor.author","Fulda, Simone"],["dc.date.accessioned","2019-07-09T11:42:39Z"],["dc.date.available","2019-07-09T11:42:39Z"],["dc.date.issued","2015-04-20"],["dc.description.abstract","We previously reported that aberrant HH pathway activation confers a poor prognosis in rhabdomyosarcoma (RMS). Searching for new treatment strategies we therefore targeted HH signaling. Here, we identify a novel synthetic lethality of concomitant inhibition of HH and PI3K/AKT/mTOR pathways in RMS by GLI1/2 inhibitor GANT61 and PI3K/mTOR inhibitor PI103. Synergistic drug interaction is confirmed by calculation of combination index (CI < 0.2). Similarly, genetic silencing of GLI1/2 significantly increases PI103-induced apoptosis. GANT61 and PI103 also synergize to induce apoptosis in cultured primary RMS cells emphasizing the clinical relevance of this combination. Importantly, GANT61/PI103 cotreatment suppresses clonogenic survival, three-dimensional sphere formation and tumor growth in an in vivo model of RMS. Mechanistic studies reveal that GANT61 and PI103 cooperate to trigger caspase-dependent apoptosis via the mitochondrial pathway, as demonstrated by several lines of evidence. First, GANT61/PI103 cotreatment increases mRNA and protein expression of NOXA and BMF, which is required for apoptosis, since knockdown of NOXA or BMF significantly reduces GANT61/PI103-induced apoptosis. Second, GANT61/PI103 cotreatment triggers BAK/BAX activation, which contributes to GANT61/PI103-mediated apoptosis, since knockdown of BAK provides protection. Third, ectopic expression of BCL-2 or non-degradable phospho-mutant MCL-1 significantly rescue GANT61/PI103-triggered apoptosis. Fourth, GANT61/PI103 cotreatment initiate activation of the caspase cascade via apoptosome-mediated cleavage of the initiator caspase-9, as indicated by changes in the cleavage pattern of caspases (e.g. accumulation of the caspase-9 p35 cleavage fragment) upon addition of the caspase inhibitor zVAD.fmk. Thus, combined GLI1/2 and PI3K/mTOR inhibition represents a promising novel approach for synergistic apoptosis induction and tumor growth reduction with implications for new treatment strategies in RMS."],["dc.identifier.doi","10.18632/oncotarget.2726"],["dc.identifier.fs","613066"],["dc.identifier.pmid","25749378"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/13615"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/58714"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.relation.issn","1949-2553"],["dc.rights","CC BY 3.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/3.0"],["dc.subject.mesh","Amino Acid Chloromethyl Ketones"],["dc.subject.mesh","Animals"],["dc.subject.mesh","Apoptosis"],["dc.subject.mesh","Apoptosis Regulatory Proteins"],["dc.subject.mesh","Caspases"],["dc.subject.mesh","Cell Line, Tumor"],["dc.subject.mesh","Chick Embryo"],["dc.subject.mesh","Drug Screening Assays, Antitumor"],["dc.subject.mesh","Drug Synergism"],["dc.subject.mesh","Furans"],["dc.subject.mesh","Gene Expression Regulation, Neoplastic"],["dc.subject.mesh","Hedgehog Proteins"],["dc.subject.mesh","Humans"],["dc.subject.mesh","Kruppel-Like Transcription Factors"],["dc.subject.mesh","Molecular Targeted Therapy"],["dc.subject.mesh","Neoplasm Proteins"],["dc.subject.mesh","Nuclear Proteins"],["dc.subject.mesh","Phosphatidylinositol 3-Kinases"],["dc.subject.mesh","Protein Kinase Inhibitors"],["dc.subject.mesh","Proto-Oncogene Proteins c-akt"],["dc.subject.mesh","Pyridines"],["dc.subject.mesh","Pyrimidines"],["dc.subject.mesh","Rhabdomyosarcoma, Alveolar"],["dc.subject.mesh","Rhabdomyosarcoma, Embryonal"],["dc.subject.mesh","Signal Transduction"],["dc.subject.mesh","TOR Serine-Threonine Kinases"],["dc.subject.mesh","Transcription Factors"],["dc.title","Identification of a novel synthetic lethality of combined inhibition of hedgehog and PI3K signaling in rhabdomyosarcoma."],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","e52898"],["dc.bibliographiccitation.issue","12"],["dc.bibliographiccitation.journal","PLoS ONE"],["dc.bibliographiccitation.volume","7"],["dc.contributor.author","Marklein, Diana"],["dc.contributor.author","Graab, Ulrike"],["dc.contributor.author","Naumann, Ivonne"],["dc.contributor.author","Yan, T."],["dc.contributor.author","Ridzewski, Rosalie"],["dc.contributor.author","Nitzki, Frauke"],["dc.contributor.author","Rosenberger, Albert"],["dc.contributor.author","Dittmann, Kai"],["dc.contributor.author","Wienands, Juergen"],["dc.contributor.author","Wojnowski, Leszek"],["dc.contributor.author","Fulda, Simone"],["dc.contributor.author","Hahn, Heidi"],["dc.date.accessioned","2018-11-07T09:02:08Z"],["dc.date.available","2018-11-07T09:02:08Z"],["dc.date.issued","2012"],["dc.description.abstract","We searched for a drug capable of sensitization of sarcoma cells to doxorubicin (DOX). We report that the dual PI3K/mTOR inhibitor PI103 enhances the efficacy of DOX in several sarcoma cell lines and interacts with DOX in the induction of apoptosis. PI103 decreased the expression of MDR1 and MRP1, which resulted in DOX accumulation. However, the enhancement of DOX-induced apoptosis was unrelated to DOX accumulation. Neither did it involve inhibition of mTOR. Instead, the combination treatment of DOX plus PI103 activated Bax, the mitochondrial apoptosis pathway, and caspase 3. Caspase 3 activation was also observed in xenografts of sarcoma cells in nude mice upon combination of DOX with the specific PI3K inhibitor GDC-0941. Although the increase in apoptosis did not further impact on tumor growth when compared to the efficient growth inhibition by GDC-0941 alone, these findings suggest that inhibition of PI3K may improve DOX-induced proapoptotic effects in sarcoma. Taken together with similar recent studies of neuroblastoma- and glioblastoma-derived cells, PI3K inhibition seems to be a more general option to sensitize tumor cells to anthracyclines."],["dc.description.sponsorship","DFG [GRK 1034, WO505/3-1]; Deutsche Krebshilfe [109837 (KoSAR)]"],["dc.identifier.doi","10.1371/journal.pone.0052898"],["dc.identifier.isi","000313872600033"],["dc.identifier.pmid","23300809"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/8548"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/24607"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Public Library Science"],["dc.relation.issn","1932-6203"],["dc.rights","CC BY 2.5"],["dc.rights.uri","https://creativecommons.org/licenses/by/2.5"],["dc.title","PI3K Inhibition Enhances Doxorubicin-Induced Apoptosis in Sarcoma Cells"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","287"],["dc.bibliographiccitation.issue","2"],["dc.bibliographiccitation.journal","Cancer Letters"],["dc.bibliographiccitation.lastpage","295"],["dc.bibliographiccitation.volume","381"],["dc.contributor.author","Meister, Michael Torsten"],["dc.contributor.author","Boedicker, Cathinka"],["dc.contributor.author","Graab, Ulrike"],["dc.contributor.author","Hugle, Manuela"],["dc.contributor.author","Hahn, Heidi"],["dc.contributor.author","Klingebiel, Thomas"],["dc.contributor.author","Fulda, Simone"],["dc.date.accessioned","2018-11-07T10:06:51Z"],["dc.date.available","2018-11-07T10:06:51Z"],["dc.date.issued","2016"],["dc.description.abstract","The prognosis of metastatic or relapsed rhabdomyosarcoma (RMS) is poor, highlighting the need of new treatment options. In the present study, we evaluated the in vitro efficacy of arsenic trioxide (ATO) in RMS, a FDA-approved drug used in pediatric leukemia. Here, we report that ATO exerts antitumor activity against RMS cells both as single agent and in combination with microtubule-targeting drugs. Monotherapy with ATO reduces cell viability, triggers apoptosis and suppresses clonogenic survival of RMS cells, at least in part, by transcriptional induction of the proapoptotic BH3-only protein Noxa. siRNA-mediated knockdown of Noxa significantly rescues ATO-mediated cell death, demonstrating that Noxa is required for cell death. Also, ATO suppresses endogenous Hedgehog (Hh) signaling, as it significantly reduces Gli1 transcriptional activity and expression levels of several Hh target genes. Furthermore, we identify synergistic induction of apoptosis by ATO together with several antimicrotubule agents including vincristine (VCR), vinblastine and eribulin. The addition of the broad-range caspase inhibitor zVAD.fmk or overexpression of the antiapoptotic protein Bcl-2 significantly reduce ATO/VCR-induced cell death, indicating that the ATO/VCR combination triggers caspase-dependent apoptosis via the mitochondrial pathway. In summary, ATO exerts antitumor activity against RMS, especially in combination with antimicrotubule drugs. These findings have important implications for the development of novel therapeutic strategies for RMS. (C) 2016 Elsevier Ireland Ltd. All rights reserved."],["dc.identifier.doi","10.1016/j.canlet.2016.07.007"],["dc.identifier.isi","000385332400002"],["dc.identifier.pmid","27521572"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/39176"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Elsevier Ireland Ltd"],["dc.relation.issn","1872-7980"],["dc.relation.issn","0304-3835"],["dc.title","Arsenic trioxide induces Noxa-dependent apoptosis in rhabdomyosarcoma cells and synergizes with antimicrotubule drugs"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]