Lobatin B inhibits NPM/ALK and NF-κB attenuating anaplastic-large-cell-lymphomagenesis and lymphendothelial tumour intravasation

Autor: Chi Nguyen Huu, Walter Jäger, Thomas Szekeres, Atanas G. Atanasov, Izabella Kiss, István Zupkó, Ruxandra McKinnon, Valery N. Bochkov, Brigitte Kopp, Judit Hohmann, Georg Krupitza, Stefan Brenner, Verena M. Dirsch, Philipp Saiko, Andrea Peschel, Andrea Vasas, Nina Kramer, Waranya Chatruphonprasert, Richard Frisch, Renate Kain, Claus M. Passreiter, Christine Unger, Ildikó Lajter, Lukas Kenner, Rene Diaz, Rainer de Martin, Michael Grusch, Helmut Dolznig, Robert M. Mader, Barbara Peter-Vörösmarty, Melanie R. Hassler
Rok vydání: 2014
Předmět:
Cyclin-Dependent Kinase Inhibitor p21
Cancer Research
medicine.drug_class
Proto-Oncogene Proteins c-jun
Cell
Blotting
Western
Caspase 3
Apoptosis
Asteraceae
Real-Time Polymerase Chain Reaction
hemic and lymphatic diseases
medicine
Tumor Cells
Cultured
Humans
Neoplasm Invasiveness
RNA
Messenger
Anaplastic large-cell lymphoma
Cell Proliferation
biology
Cell growth
Plant Extracts
Reverse Transcriptase Polymerase Chain Reaction
Cell Cycle
Intravasation
NF-kappa B
Protein-Tyrosine Kinases
medicine.disease
Antineoplastic Agents
Phytogenic
Mitochondria
ALK inhibitor
medicine.anatomical_structure
Oncology
Biochemistry
Cell culture
Caspases
Cancer research
biology.protein
Leukocytes
Mononuclear
Lymphoma
Large-Cell
Anaplastic
Endothelium
Lymphatic
Sesquiterpenes
Platelet-derived growth factor receptor
Zdroj: Cancer letters. 356(2 Pt)
ISSN: 1872-7980
Popis: An apolar extract of the traditional medicinal plant Neurolaena lobata inhibited the expression of the NPM/ALK chimera, which is causal for the majority of anaplastic large cell lymphomas (ALCLs). Therefore, an active principle of the extract, the furanoheliangolide sesquiterpene lactone lobatin B, was isolated and tested regarding the inhibition of ALCL expansion and tumour cell intravasation through the lymphendothelium. ALCL cell lines, HL-60 cells and PBMCs were treated with plant compounds and the ALK inhibitor TAE-684 to measure mitochondrial activity, proliferation and cell cycle progression and to correlate the results with protein- and mRNA-expression of selected gene products. Several endpoints indicative for cell death were analysed after lobatin B treatment. Tumour cell intravasation through lymphendothelial monolayers was measured and potential causal mechanisms were investigated analysing NF-κB- and cytochrome P450 activity, and 12(S)-HETE production. Lobatin B inhibited the expression of NPM/ALK, JunB and PDGF-Rβ, and attenuated proliferation of ALCL cells by arresting them in late M phase. Mitochondrial activity remained largely unaffected upon lobatin B treatment. Nevertheless, caspase 3 became activated in ALCL cells. Also HL-60 cell proliferation was attenuated whereas PBMCs of healthy donors were not affected by lobatin B. Additionally, tumour cell intravasation, which partly depends on NF-κB, was significantly suppressed by lobatin B most likely due to its NF-κB-inhibitory property. Lobatin B, which was isolated from a plant used in ethnomedicine, targets malignant cells by at least two properties: I) inhibition of NPM/ALK, thereby providing high specificity in combating this most prevalent fusion protein occurring in ALCL; II) inhibition of NF-κB, thereby not affecting normal cells with low constitutive NF-κB activity. This property also inhibits tumour cell intravasation into the lymphatic system and may provide an option to manage this early step of metastatic progression.
Databáze: OpenAIRE
Externí odkaz: