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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

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

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JISO, Apisada, Philipp DEMUTH, Madeleine BACHOWSKY, Manuel HAAS, Nina SEIWERT, Daniel HEYLMANN, Birgit RASENBERGER, Lea DIETRICH, Thomas BRUNNER, Jörg FAHRER, 2021. 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. In: Cancers. MDPI. 13(13), 3282. eISSN 2072-6694. Available under: doi: 10.3390/cancers13133282

@article{Jiso2021-06-30Natur-54377, title={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}, year={2021}, doi={10.3390/cancers13133282}, number={13}, volume={13}, journal={Cancers}, author={Jiso, Apisada and Demuth, Philipp and Bachowsky, Madeleine and Haas, Manuel and Seiwert, Nina and Heylmann, Daniel and Rasenberger, Birgit and Dietrich, Lea and Brunner, Thomas and Fahrer, Jörg}, note={Article Number: 3282} }

2021-07-21T08:55:01Z 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 2021-07-21T08:55:01Z Demuth, Philipp Bachowsky, Madeleine Brunner, Thomas eng Heylmann, Daniel Rasenberger, Birgit Fahrer, Jörg Demuth, Philipp 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 the main cell death pathway. Interestingly, the compounds were equally effective in p53-wild-type and p53-mutant CRC cells. Finally, the cytotoxic activity of the merosesquiterpenes was corroborated in intestinal tumor organoids, emphasizing their potential for CRC chemotherapy. Attribution 4.0 International Jiso, Apisada Heylmann, Daniel Haas, Manuel Haas, Manuel Brunner, Thomas Seiwert, Nina Jiso, Apisada Seiwert, Nina Bachowsky, Madeleine Dietrich, Lea 2021-06-30 Fahrer, Jörg Dietrich, Lea Rasenberger, Birgit

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