title: The germacranolide sesquiterpene lactone neurolenin B of the medicinal plant Neurolaena lobata (L.) R.Br. ex Cass inhibits NPM/ALK-driven cell expansion and NF-κB-driven tumour intravasation.
abstract: BACKGROUND
  The t(2;5)(p23;q35) chromosomal translocation results in the expression of the fusion protein NPM/ALK that when expressed in T-lymphocytes gives rise to anaplastic large cell lymphomas (ALCL). In search of new therapy options the dichloromethane extract of the ethnomedicinal plant Neurolaena lobata (L.) R.Br. ex Cass was shown to inhibit NPM/ALK expression.
  
  
  OBJECTIVE
  Therefore, we analysed whether the active principles that were recently isolated and found to inhibit inflammatory responses specifically inhibit growth of NPM/ALK+ ALCL, leukaemia and breast cancer cells, but not of normal cells, and the intravasation through the lymphendothelial barrier.
  
  
  METHODS
  ALCL, leukaemia and breast cancer cells, and normal peripheral blood mononuclear cells (PBMCs) were treated with isolated sesquiterpene lactones and analysed for cell cycle progression, proliferation, mitochondrial activity, apoptosis, protein and mRNA expression, NF-κB and cytochrome P450 activity, 12(S)-HETE production and lymphendothelial intravasation.
  
  
  RESULTS
  In vitro treatment of ALCL by neurolenin B suppressed NPM/ALK, JunB and PDGF-Rβ expression, inhibited the growth of ALCL cells late in M phase, and induced apoptosis via caspase 3 without compromising mitochondrial activity (as a measure of general exogenic toxicity). Moreover, neurolenin B attenuated tumour spheroid intravasation probably through inhibition of NF-κB and CYP1A1.
  
  
  CONCLUSIONS
  Neurolenin B specifically decreased pro-carcinogenic NPM/ALK expression in ALK+ ALCL cells and, via the inhibition of NF-kB signalling, attenuated tumour intra/extravasation into the lymphatics. Hence, neurolenin B may open new options to treat ALCL and to manage early metastatic processes to which no other therapies exist.
authors.affiliation: Institute of Medical Genetics, Medical University of Vienna, Währinger Strasse 10, A-1090 Vienna, Austria. Electronic address: christine.unger@meduniwien.ac.at.
authors.forename: Christine
authors.initials: C
authors.lastname: Unger
authors.affiliation: Institute of Medical Genetics, Medical University of Vienna, Währinger Strasse 10, A-1090 Vienna, Austria; Clinical Institute of Pathology, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
authors.forename: Izabella
authors.initials: I
authors.lastname: Kiss
authors.affiliation: Department of Pharmacognosy, University of Szeged, Eotvos Str. 6, H-6720 Szeged, Hungary.
authors.forename: Andrea
authors.initials: A
authors.lastname: Vasas
authors.affiliation: Department of Pharmacognosy, University of Szeged, Eotvos Str. 6, H-6720 Szeged, Hungary.
authors.forename: Ildikó
authors.initials: I
authors.lastname: Lajter
authors.affiliation: Institute of Medical Genetics, Medical University of Vienna, Währinger Strasse 10, A-1090 Vienna, Austria.
authors.forename: Nina
authors.initials: N
authors.lastname: Kramer
authors.affiliation: Department of Pharmacognosy, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria.
authors.forename: Atanas Georgiev
authors.initials: AG
authors.lastname: Atanasov
authors.affiliation: Clinical Institute of Pathology, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
authors.forename: Chi Huu
authors.initials: CH
authors.lastname: Nguyen
authors.affiliation: Department of Clinical Pharmacy and Diagnostics, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria; Department of Preclinic, Faculty of Medicine, Mahasarakham University, Mahasarakham 44000, Thailand.
authors.forename: Waranya
authors.initials: W
authors.lastname: Chatuphonprasert
authors.affiliation: Department of Clinical Pharmacy and Diagnostics, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria.
authors.forename: Stefan
authors.initials: S
authors.lastname: Brenner
authors.affiliation: Clinical Institute of Pathology, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
authors.forename: Sigurd
authors.initials: S
authors.lastname: Krieger
authors.affiliation: Department of Pharmacognosy, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria.
authors.forename: Ruxandra
authors.initials: R
authors.lastname: McKinnon
authors.affiliation: Clinical Institute of Pathology, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
authors.forename: Andrea
authors.initials: A
authors.lastname: Peschel
authors.affiliation: Clinical Institute of Pathology, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
authors.forename: Renate
authors.initials: R
authors.lastname: Kain
authors.affiliation: Department of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
authors.forename: Philipp
authors.initials: P
authors.lastname: Saiko
authors.affiliation: Department of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Szekeres
authors.affiliation: Clinical Institute of Pathology, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
authors.forename: Lukas
authors.initials: L
authors.lastname: Kenner
authors.affiliation: Clinical Institute of Pathology, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
authors.forename: Melanie R
authors.initials: MR
authors.lastname: Hassler
authors.affiliation: Institute for Ethnobiology, Playa Diana, San José/Petén, Guatemala.
authors.forename: Rene
authors.initials: R
authors.lastname: Diaz
authors.affiliation: Institute for Ethnobiology, Playa Diana, San José/Petén, Guatemala.
authors.forename: Richard
authors.initials: R
authors.lastname: Frisch
authors.affiliation: Department of Pharmacognosy, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria.
authors.forename: Verena M
authors.initials: VM
authors.lastname: Dirsch
authors.affiliation: Department of Clinical Pharmacy and Diagnostics, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria.
authors.forename: Walter
authors.initials: W
authors.lastname: Jäger
authors.affiliation: Department of Vascular Biology and Thrombosis Research, Center of Biomolecular Medicine and Pharmacology, Medical University of Vienna, Schwarzspanierstraße 17, A-1090 Vienna, Austria.
authors.forename: Rainer
authors.initials: R
authors.lastname: de Martin
authors.affiliation: Institute of Pharmaceutical Sciences, University of Graz, Schubertstraße 1, A-8010 Graz, Austria.
authors.forename: Valery N
authors.initials: VN
authors.lastname: Bochkov
authors.affiliation: Institute of Pharmaceutical Biology and Biotechnology, Heinrich-Heine-University Düsseldorf, Universitätsstrasse 1, D-40225 Düsseldorf, Germany.
authors.forename: Claus M
authors.initials: CM
authors.lastname: Passreiter
authors.affiliation: Department of Medicine I, Division: Institute of Cancer Research, Comprehensive Cancer Center, Medical University Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
authors.forename: Barbara
authors.initials: B
authors.lastname: Peter-Vörösmarty
authors.affiliation: Department of Medicine I, Comprehensive Cancer Center, Medical University Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Mader
authors.affiliation: Department of Medicine I, Division: Institute of Cancer Research, Comprehensive Cancer Center, Medical University Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Grusch
authors.affiliation: Institute of Medical Genetics, Medical University of Vienna, Währinger Strasse 10, A-1090 Vienna, Austria.
authors.forename: Helmut
authors.initials: H
authors.lastname: Dolznig
authors.affiliation: Department of Pharmacognosy, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Kopp
authors.affiliation: Department of Pharmacodynamics and Biopharmacy, University of Szeged, H-6720 Szeged, Hungary.
authors.forename: Istvan
authors.initials: I
authors.lastname: Zupko
authors.affiliation: Department of Pharmacognosy, University of Szeged, Eotvos Str. 6, H-6720 Szeged, Hungary.
authors.forename: Judit
authors.initials: J
authors.lastname: Hohmann
authors.affiliation: Clinical Institute of Pathology, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
authors.forename: Georg
authors.initials: G
authors.lastname: Krupitza
mesh_terms: D017209:Apoptosis; D019659:Asteraceae / Q000737:chemistry*; D002453:Cell Cycle; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation; D006801:Humans; D007783:Lactones / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D017728:Lymphoma, Large-Cell, Anaplastic / Q000473:pathology*; D015394:Molecular Structure; D016328:NF-kappa B / Q000378:metabolism*; D010946:Plants, Medicinal / Q000737:chemistry; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D012717:Sesquiterpenes / Q000494:pharmacology*; D045788:Sesquiterpenes, Germacrane / Q000494:pharmacology*; D015398:Signal Transduction
chemical_list: D007783:Lactones; D016328:NF-kappa B; D012717:Sesquiterpenes; D045788:Sesquiterpenes, Germacrane; C432449:germacranolide; C462159:neurolenin B; C107023:p80(NPM-ALK) protein; D011505:Protein-Tyrosine Kinases
keywords: 3D-compound testing; ALCL; Intravasation; NPM/ALK; Neurolenins; Toxicity