Phenanthroindolizidine Alkaloids Isolated from Tylophora ovata as Potent Inhibitors of Inflammation, Spheroid Growth, and Invasion of Triple-Negative Breast Cancer.

Autor: Reimche I; Department of Biomedical Sciences, Institute of Health Research and Education, University of Osnabrück, 49090 Osnabrück, Germany.; Institute of Pharmaceutical Biology and Biotechnology, Heinrich Heine University, 40225 Düsseldorf, Germany., Yu H; Institute of Pharmaceutical Biology and Biotechnology, Heinrich Heine University, 40225 Düsseldorf, Germany., Ariantari NP; Institute of Pharmaceutical Biology and Biotechnology, Heinrich Heine University, 40225 Düsseldorf, Germany.; Department of Pharmacy, Faculty of Mathematics and Natural Sciences, Udayana University, Bali 80361, Indonesia., Liu Z; Institute of Pharmaceutical Biology and Biotechnology, Heinrich Heine University, 40225 Düsseldorf, Germany., Merkens K; Department of Chemistry, University of Cologne, 50923 Cologne, Germany., Rotfuß S; Department of Biomedical Sciences, Institute of Health Research and Education, University of Osnabrück, 49090 Osnabrück, Germany., Peter K; Department of Biomedical Sciences, Institute of Health Research and Education, University of Osnabrück, 49090 Osnabrück, Germany., Jungwirth U; Department of Life Sciences, Centre for Therapeutic Innovation, University of Bath, Bath BA2 7AY, UK., Bauer N; European Institute of Molecular Imaging, University of Münster, 48149 Münster, Germany., Kiefer F; European Institute of Molecular Imaging, University of Münster, 48149 Münster, Germany.; Max Planck Institute for Molecular Biomedicine, 48149 Münster, Germany., Neudörfl JM; Department of Chemistry, University of Cologne, 50923 Cologne, Germany., Schmalz HG; Department of Chemistry, University of Cologne, 50923 Cologne, Germany., Proksch P; Institute of Pharmaceutical Biology and Biotechnology, Heinrich Heine University, 40225 Düsseldorf, Germany., Teusch N; Department of Biomedical Sciences, Institute of Health Research and Education, University of Osnabrück, 49090 Osnabrück, Germany.; Institute of Pharmaceutical Biology and Biotechnology, Heinrich Heine University, 40225 Düsseldorf, Germany.
Jazyk: angličtina
Zdroj: International journal of molecular sciences [Int J Mol Sci] 2022 Sep 07; Vol. 23 (18). Date of Electronic Publication: 2022 Sep 07.
DOI: 10.3390/ijms231810319
Abstrakt: Triple-negative breast cancer (TNBC), representing the most aggressive form of breast cancer with currently no targeted therapy available, is characterized by an inflammatory and hypoxic tumor microenvironment. To date, a broad spectrum of anti-tumor activities has been reported for phenanthroindolizidine alkaloids (PAs), however, their mode of action in TNBC remains elusive. Thus, we investigated six naturally occurring PAs extracted from the plant Tylophora ovata : O -methyltylophorinidine ( 1 ) and its five derivatives tylophorinidine ( 2 ), tylophoridicine E ( 3 ), 2-demethoxytylophorine ( 4 ), tylophoridicine D ( 5 ), and anhydrodehydrotylophorinidine ( 6 ). In comparison to natural ( 1 ) and for more-in depth studies, we also utilized a sample of synthetic O -methyltylophorinidine ( 1s ). Our results indicate a remarkably effective blockade of nuclear factor kappa B (NFκB) within 2 h for compounds ( 1 ) and ( 1s ) (IC 50 = 17.1 ± 2.0 nM and 3.3 ± 0.2 nM) that is different from its effect on cell viability within 24 h (IC 50 = 13.6 ± 0.4 nM and 4.2 ± 1 nM). Furthermore, NFκB inhibition data for the additional five analogues indicate a structure-activity relationship (SAR). Mechanistically, NFκB is significantly blocked through the stabilization of its inhibitor protein kappa B alpha (IκBα) under normoxic as well as hypoxic conditions. To better mimic the TNBC microenvironment in vitro, we established a 3D co-culture by combining the human TNBC cell line MDA-MB-231 with primary murine cancer-associated fibroblasts (CAF) and type I collagen. Compound ( 1 ) demonstrates superiority against the therapeutic gold standard paclitaxel by diminishing spheroid growth by 40% at 100 nM. The anti-proliferative effect of ( 1s ) is distinct from paclitaxel in that it arrests the cell cycle at the G0/G1 state, thereby mediating a time-dependent delay in cell cycle progression. Furthermore, ( 1s ) inhibited invasion of TNBC monoculture spheroids into a matrigel ® -based environment at 10 nM. In conclusion, PAs serve as promising agents with presumably multiple target sites to combat inflammatory and hypoxia-driven cancer, such as TNBC, with a different mode of action than the currently applied chemotherapeutic drugs.
Competing Interests: The authors declare no conflict of interest.
Databáze: MEDLINE
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