Bekämpfung von Tumorprogression und Behandlungsresistenz durch Beeinflussung der metabolischen Reprogramierung und Plastizität von Krebs-Stammzellen
Zusammenfassung der Projektergebnisse
Tumor development, progression and treatment failures are likely supported by a subpopulation of cancer cells with stem-like properties or cancer stem cells (CSCs). A better understanding of the pathways determining the ability of CSCs to adapt and survive to metabolic and micro-environmental stress may lead to identification of key nodes and targetable elements for development of novel strategies for cancer treatment. An increased expression of σ1 receptors in human cancer cell lines and human tumors of different histology including CSCs has been observed. Herein, four compound classes with high affinity and selectivity for σ1 receptors were developed showing a strong potential to target cancer cells. The compound classes are: (1) 2-(3- phenylcyclohexyl)ethanamines 2, (2) 2-(6-phenyltetrahydropyran-2-yl)ethanamines 3, (3) 2-(2-phenylpiperidin-4-yl)ethanamines 4 and (4) spirocyclic piperidines 40, pyrrolidines 41 and morpholines 45. The enantioselective synthesis of tetrahydropyrans 3 included a chemoenzymatic key step. The investigation of spirocyclic compounds is currently ongoing. After synthesis, the ligands were biologically evaluated including receptor affinity and selectivity, and in particular antitumor activity including growth inhibition against tumor cells and activity against CSCs. The androgen negative human prostate cancer cell line DU145 was selected for further investigations. Strong growth inhibition of this tumor cell line was detected for the cyclohexane and tetrahydropyran derivatives 2a and 3a and in particular for the enantiomerically pure cyclohexane derivatives (1R,3S)-2a (WMS-2609) and (1S,3R)- 2a (WMS-2610). The proliferative potential and survival of CSC-enriched subpopulation in multiple tumor models was reduced by knockdown of the σ1 receptor using siRNAs. The same effect was observed with the σ1 receptor ligands (1R,3S)-2a and (1S,3R)-2a. Mitochondrial dynamics is essential for asymmetric stem cell division and unlimited propagation of CSCs. Interestingly, both σ1 receptor knockdown and pharmacological antagonists led to impaired mitochondrial plasticity and Wnt/β-catenin signaling in cancer cells resulting in loss of self-renewal capability and progressive exhaustion of the CSC progeny. Thus, addressing CSCs might provide a new efficient strategy to combat cancer.
Projektbezogene Publikationen (Auswahl)
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Chemoenzymatic synthesis of 2,6-disubsttuted tetrahydropyrans with high σ1 receptor affinity, antitumor and analgesic activity. Eur. J. Med. Chem. 2021, 219, 113443
N. Kopp, G. Civenni, D. Marson, E. Laurini, S. Pricl, C. V. Catapano, H.-U. Humpf, C. Almansa, F. R. Nieto, D. Schepmann, B. Wünsch
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Novel σ1 antagonists designed for tumor therapy: structure - activity relationships of aminoethyl substituted cyclohexanes. Eur. J. Med. Chem. 2021, 210, 112950
N. Kopp, C. Holtschulte, F. Börgel, K. Lehmkuhl, K. Friedland, G. Civenni, E. Laurini, C. V. Catapano, S. Pricl, H.-U. Humpf, D. Schepmann, B. Wünsch
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Synthesis of aminoethyl substituted piperidine derivatives with high σ1 receptor affinity, selectivity and antiprolifeative properties. ChemMedChem 2022, 17, e202100735
C. Holtschulte, F. Börgel, S. Westphälinger, D. Schepmann, G. Civenni, E. Laurini, D. Marson, C. V. Catapano, S. Pricl, B. Wünsch
