Natural Merosesquiterpenes Activate the DNA Damage Response via DNA Strand Break Formation and Trigger Apoptotic Cell Death in p53-Wild-Type and Mutant Colorectal Cancer

  • Abstract: Colorectal cancer (CRC) is a frequently occurring malignant disease with still low survival rates, highlighting the need for novel therapeutics. Merosesquiterpenes are secondary metabolites from marine sponges, which might be useful as antitumor agents. To address this issue, we made use of a compound library comprising 11 isolated merosesquiterpenes. The most cytotoxic compounds were smenospongine > ilimaquinone ≈ dactylospontriol as shown in different human CRC cell lines. Alkaline Comet assays and γH2AX immunofluorescence microscopy demonstrated DNA strand break formation in CRC cells. Western blot analysis revealed an activation of the DNA damage response with CHK1 phosphorylation, stabilization of p53 and p21, which occurred both in CRC cells with p53 knockout and in p53-mutated CRC cells. This resulted in cell cycle arrest followed by a strong increase in the subG1 population, indicative of apoptosis, and typical morphological alterations. In consistency, cell death measurements showed apoptosis following exposure to merosesquiterpenes. Gene expression studies and analysis of caspase cleavage revealed mitochondrial apoptosis via BAX, BIM and caspase-9 as main cell death pathway. Interestingly, the compounds were equally effective in p53-wildtype and p53-mutant CRC cells. Finally, the cytotoxic activity of the merosesquiterpenes was corroborated in intestinal tumor organoids, emphasizing their potential for CRC chemotherapy.

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Author:Jörg FahrerORCiD, Apisada JisoORCiD, Philipp Demuth, Madeleine Bachowsky, Manuel Haas, Nina Seiwert, Daniel Heylmann, Birgit Rasenberger, Markus ChristmannORCiD, Lea DietrichORCiD, Thomas Brunner, RiyantiORCiD, Till F. SchäberleORCiD, Anuchit PlubrukarnORCiD
URN (permanent link):urn:nbn:de:hbz:386-kluedo-65504
Parent Title (English):Cancers
Document Type:Article
Language of publication:English
Publication Date:2021/06/30
Year of Publication:2021
Publishing Institute:Technische Universität Kaiserslautern
Date of the Publication (Server):2021/09/01
Issue:2021, 13(13), 3282
Number of page:25
Faculties / Organisational entities:Fachbereich Chemie
DDC-Cassification:5 Naturwissenschaften und Mathematik / 540 Chemie
Licence (German):Zweitveröffentlichung