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

Izabella Kiss, Christine Unger, Chi Nguyen Huu, Atanas Georgiev Atanasov, Nina Kramer, Waranya Chatruphonprasert, Stefan Brenner, Ruxandra McKinnon, Andrea Peschel, Andrea Vasas, Ildiko Lajter, Renate Kain, Philipp Saiko, Thomas Szekeres, Lukas Kenner, Melanie R. Hassler, Rene Diaz, Richard Frisch, Verena M. Dirsch, Walter JägerRainer de Martin, Valery N. Bochkov, Claus M. Passreiter, Barbara Peter-Vörösmarty, Robert M. Mader, Michael Grusch, Helmut Dolznig, Brigitte Kopp, Istvan Zupko, Judit Hohmann, Georg Krupitza

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6 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)994-1006
Number of pages13
JournalCancer Letters
Volume356
Issue number2
DOIs
Publication statusPublished - Jan 28 2015

Keywords

  • 3D-compound testing
  • ALCL
  • Lobatin
  • Lymphendothelial intravasation
  • NPM/ALK

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Kiss, I., Unger, C., Huu, C. N., Atanasov, A. G., Kramer, N., Chatruphonprasert, W., Brenner, S., McKinnon, R., Peschel, A., Vasas, A., Lajter, I., Kain, R., Saiko, P., Szekeres, T., Kenner, L., Hassler, M. R., Diaz, R., Frisch, R., Dirsch, V. M., ... Krupitza, G. (2015). Lobatin B inhibits NPM/ALK and NF-κB attenuating anaplastic-large-cell-lymphomagenesis and lymphendothelial tumour intravasation. Cancer Letters, 356(2), 994-1006. https://doi.org/10.1016/j.canlet.2014.11.019