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Phytomedicine. 2015 Aug 15;22(9):862-74. doi: 10.1016/j.phymed.2015.06.003. Epub 2015 Jun 26.

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.

Author information

1
Institute of Medical Genetics, Medical University of Vienna, Währinger Strasse 10, A-1090 Vienna, Austria. Electronic address: christine.unger@meduniwien.ac.at.
2
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.
3
Department of Pharmacognosy, University of Szeged, Eotvos Str. 6, H-6720 Szeged, Hungary.
4
Institute of Medical Genetics, Medical University of Vienna, Währinger Strasse 10, A-1090 Vienna, Austria.
5
Department of Pharmacognosy, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria.
6
Clinical Institute of Pathology, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
7
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.
8
Department of Clinical Pharmacy and Diagnostics, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria.
9
Department of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
10
Institute for Ethnobiology, Playa Diana, San José/Petén, Guatemala.
11
Department of Vascular Biology and Thrombosis Research, Center of Biomolecular Medicine and Pharmacology, Medical University of Vienna, Schwarzspanierstraße 17, A-1090 Vienna, Austria.
12
Institute of Pharmaceutical Sciences, University of Graz, Schubertstraße 1, A-8010 Graz, Austria.
13
Institute of Pharmaceutical Biology and Biotechnology, Heinrich-Heine-University Düsseldorf, Universitätsstrasse 1, D-40225 Düsseldorf, Germany.
14
Department of Medicine I, Division: Institute of Cancer Research, Comprehensive Cancer Center, Medical University Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
15
Department of Medicine I, Comprehensive Cancer Center, Medical University Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
16
Department of Pharmacodynamics and Biopharmacy, University of Szeged, H-6720 Szeged, Hungary.

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.

PURPOSE:

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.

CONCLUSION:

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.

KEYWORDS:

3D-compound testing; ALCL; Intravasation; NPM/ALK; Neurolenins; Toxicity

PMID:
26220634
DOI:
10.1016/j.phymed.2015.06.003
[Indexed for MEDLINE]

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