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.
Graphical abstract
Keywords
- Neurolenins;
- NPM/ALK;
- ALCL;
- Intravasation;
- 3D-compound testing;
- Toxicity
Abbreviations
- ALCL, anaplastic large cell lymphoma;
- ALOX, lipoxygenase A;
- CCID, circular chemorepellent induced defect;
- CYP, cytochrome P450;
- DME, dichloro methane extract;
- EROD, ethoxyresorufin-O-deethylase;
- HO/PI, Hoechst 33258/propidium iodide;
- LEC, lymph endothelial cell;
- MYPT1, myosin phosphatase 1 target subunit 1;
- NF-κB, nuclear factor kappa B;
- NPM/ALK, nucleophosmin/anaplastic lymphoma kinase, the t(2;5)(p23;q35) chromosomal translocation;
- PARP, poly ADP-ribose polymerase;
- PBMC, peripheral blood mononuclear cell;
- PDGF-Rβ, platelet derived growth factor receptor;
- p21, tumour suppressor protein 21;
- 3D, 3-dimensional;
- 12(S)-HETE, 12(S) hydroxyeicosatetraenoic acid
