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, A. 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, I. Zupkó, J. Hohmann, Georg Krupitza

Research output: Contribution to journalArticle

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

Fingerprint

Anaplastic Large-Cell Lymphoma
Neoplasms
HL-60 Cells
12-Hydroxy-5,8,10,14-eicosatetraenoic Acid
Activity Cycles
Lymphatic System
lobatin B
Sesquiterpenes
Traditional Medicine
Lactones
Medicinal Plants
Caspase 3
Cell Division
Cytochrome P-450 Enzyme System
Cell Cycle
Proteins
Cell Death
Cell Proliferation
Gene Expression
Cell Line

Keywords

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

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Kiss, I., Unger, C., Huu, C. N., Atanasov, A. G., Kramer, N., Chatruphonprasert, W., ... 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

Lobatin B inhibits NPM/ALK and NF-κB attenuating anaplastic-large-cell-lymphomagenesis and lymphendothelial tumour intravasation. / Kiss, Izabella; Unger, Christine; Huu, Chi Nguyen; Atanasov, Atanas Georgiev; Kramer, Nina; Chatruphonprasert, Waranya; Brenner, Stefan; McKinnon, Ruxandra; Peschel, Andrea; Vasas, A.; Lajter, Ildiko; Kain, Renate; Saiko, Philipp; Szekeres, Thomas; Kenner, Lukas; Hassler, Melanie R.; Diaz, Rene; Frisch, Richard; Dirsch, Verena M.; Jäger, Walter; de Martin, Rainer; Bochkov, Valery N.; Passreiter, Claus M.; Peter-Vörösmarty, Barbara; Mader, Robert M.; Grusch, Michael; Dolznig, Helmut; Kopp, Brigitte; Zupkó, I.; Hohmann, J.; Krupitza, Georg.

In: Cancer Letters, Vol. 356, No. 2, 28.01.2015, p. 994-1006.

Research output: Contribution to journalArticle

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, Zupkó, I, Hohmann, J & Krupitza, G 2015, 'Lobatin B inhibits NPM/ALK and NF-κB attenuating anaplastic-large-cell-lymphomagenesis and lymphendothelial tumour intravasation', Cancer Letters, vol. 356, no. 2, pp. 994-1006. https://doi.org/10.1016/j.canlet.2014.11.019
Kiss, Izabella ; Unger, Christine ; Huu, Chi Nguyen ; Atanasov, Atanas Georgiev ; Kramer, Nina ; Chatruphonprasert, Waranya ; Brenner, Stefan ; McKinnon, Ruxandra ; Peschel, Andrea ; Vasas, A. ; Lajter, Ildiko ; Kain, Renate ; Saiko, Philipp ; Szekeres, Thomas ; Kenner, Lukas ; Hassler, Melanie R. ; Diaz, Rene ; Frisch, Richard ; Dirsch, Verena M. ; Jäger, Walter ; de Martin, Rainer ; Bochkov, Valery N. ; Passreiter, Claus M. ; Peter-Vörösmarty, Barbara ; Mader, Robert M. ; Grusch, Michael ; Dolznig, Helmut ; Kopp, Brigitte ; Zupkó, I. ; Hohmann, J. ; Krupitza, Georg. / Lobatin B inhibits NPM/ALK and NF-κB attenuating anaplastic-large-cell-lymphomagenesis and lymphendothelial tumour intravasation. In: Cancer Letters. 2015 ; Vol. 356, No. 2. pp. 994-1006.
@article{96a68afab5a341728f6af402b6f9f72f,
title = "Lobatin B inhibits NPM/ALK and NF-κB attenuating anaplastic-large-cell-lymphomagenesis and lymphendothelial tumour intravasation",
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.",
keywords = "3D-compound testing, ALCL, Lobatin, Lymphendothelial intravasation, NPM/ALK",
author = "Izabella Kiss and Christine Unger and Huu, {Chi Nguyen} and Atanasov, {Atanas Georgiev} and Nina Kramer and Waranya Chatruphonprasert and Stefan Brenner and Ruxandra McKinnon and Andrea Peschel and A. Vasas and Ildiko Lajter and Renate Kain and Philipp Saiko and Thomas Szekeres and Lukas Kenner and Hassler, {Melanie R.} and Rene Diaz and Richard Frisch and Dirsch, {Verena M.} and Walter J{\"a}ger and {de Martin}, Rainer and Bochkov, {Valery N.} and Passreiter, {Claus M.} and Barbara Peter-V{\"o}r{\"o}smarty and Mader, {Robert M.} and Michael Grusch and Helmut Dolznig and Brigitte Kopp and I. Zupk{\'o} and J. Hohmann and Georg Krupitza",
year = "2015",
month = "1",
day = "28",
doi = "10.1016/j.canlet.2014.11.019",
language = "English",
volume = "356",
pages = "994--1006",
journal = "Cancer Letters",
issn = "0304-3835",
publisher = "Elsevier Ireland Ltd",
number = "2",

}

TY - JOUR

T1 - Lobatin B inhibits NPM/ALK and NF-κB attenuating anaplastic-large-cell-lymphomagenesis and lymphendothelial tumour intravasation

AU - Kiss, Izabella

AU - Unger, Christine

AU - Huu, Chi Nguyen

AU - Atanasov, Atanas Georgiev

AU - Kramer, Nina

AU - Chatruphonprasert, Waranya

AU - Brenner, Stefan

AU - McKinnon, Ruxandra

AU - Peschel, Andrea

AU - Vasas, A.

AU - Lajter, Ildiko

AU - Kain, Renate

AU - Saiko, Philipp

AU - Szekeres, Thomas

AU - Kenner, Lukas

AU - Hassler, Melanie R.

AU - Diaz, Rene

AU - Frisch, Richard

AU - Dirsch, Verena M.

AU - Jäger, Walter

AU - de Martin, Rainer

AU - Bochkov, Valery N.

AU - Passreiter, Claus M.

AU - Peter-Vörösmarty, Barbara

AU - Mader, Robert M.

AU - Grusch, Michael

AU - Dolznig, Helmut

AU - Kopp, Brigitte

AU - Zupkó, I.

AU - Hohmann, J.

AU - Krupitza, Georg

PY - 2015/1/28

Y1 - 2015/1/28

N2 - 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.

AB - 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.

KW - 3D-compound testing

KW - ALCL

KW - Lobatin

KW - Lymphendothelial intravasation

KW - NPM/ALK

UR - http://www.scopus.com/inward/record.url?scp=84919459458&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84919459458&partnerID=8YFLogxK

U2 - 10.1016/j.canlet.2014.11.019

DO - 10.1016/j.canlet.2014.11.019

M3 - Article

C2 - 25444930

AN - SCOPUS:84919459458

VL - 356

SP - 994

EP - 1006

JO - Cancer Letters

JF - Cancer Letters

SN - 0304-3835

IS - 2

ER -