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Selected Publication:

Type of publication: Journal Article
Type of document: Full Paper

Year: 2015

Authors: Kiss, I; Unger, C; Huu, CN; Atanasov, AG; Kramer, N; Chatruphonprasert, W; Brenner, S; McKinnon, R; Peschel, A; Vasas, A; Lajter, I; Kain, R; Saiko, P; Szekeres, T; Kenner, L; Hassler, MR; Diaz, R; Frisch, R; Dirsch, VM; Jäger, W; de Martin, R; Bochkov, VN; Passreiter, CM; Peter-Vörösmarty, B; Mader, RM; Grusch, M; Dolznig, H; Kopp, B; Zupko, I; Hohmann, J; Krupitza, G

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

Source: Cancer Lett. 2015; 356(2 Pt B):994-1006

Authors Vetmeduni Vienna:

Kenner Lukas

Vetmed Research Units
Institute of Pathology, Pathology of Laboratory Animals

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.

Keywords Pubmed: Antineoplastic Agents, Phytogenic/pharmacology*
Apoptosis/drug effects
Blotting, Western
Cell Cycle/drug effects
Cell Proliferation/drug effects
Cyclin-Dependent Kinase Inhibitor p21/genetics
Cyclin-Dependent Kinase Inhibitor p21/metabolism
Endothelium, Lymphatic/drug effects*
Endothelium, Lymphatic/pathology
Leukocytes, Mononuclear/drug effects
Leukocytes, Mononuclear/metabolism
Leukocytes, Mononuclear/pathology
Lymphoma, Large-Cell, Anaplastic/drug therapy*
Lymphoma, Large-Cell, Anaplastic/metabolism
Lymphoma, Large-Cell, Anaplastic/pathology*
Mitochondria/drug effects
NF-kappa B/antagonists & inhibitors*
NF-kappa B/genetics
NF-kappa B/metabolism
Neoplasm Invasiveness
Plant Extracts/pharmacology*
Protein-Tyrosine Kinases/antagonists & inhibitors*
Protein-Tyrosine Kinases/genetics
Protein-Tyrosine Kinases/metabolism
Proto-Oncogene Proteins c-jun/genetics
Proto-Oncogene Proteins c-jun/metabolism
RNA, Messenger/genetics
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
Tumor Cells, Cultured

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