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Article

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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Division of Food Chemistry and Toxicology, Department of Chemistry, Technical University of Kaiserslautern, 67663 Kaiserslautern, Germany
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Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat-Yai, Songkhla 90112, Thailand
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Rudolf Buchheim Institute of Pharmacology, Justus Liebig University Giessen, 35392 Giessen, Germany
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Institute of Toxicology, University Medical Center Mainz, 55131 Mainz, Germany
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Biochemical Pharmacology, Department of Biology, University of Konstanz, 78464 Konstanz, Germany
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Institute for Insect Biotechnology, Justus-Liebig-University Giessen, 35392 Giessen, Germany
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Faculty of Fisheries and Marine Science, Jenderal Soedirman University, Purwokerto 53122, Indonesia
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Fraunhofer Institute for Molecular Biology and Applied Ecology (IME), Branch for Bioresources, 35392 Giessen, Germany
*
Author to whom correspondence should be addressed.
Academic Editor: Fortunato Ciardiello
Cancers 2021, 13(13), 3282; https://doi.org/10.3390/cancers13133282
Received: 18 May 2021 / Revised: 19 June 2021 / Accepted: 27 June 2021 / Published: 30 June 2021
(This article belongs to the Special Issue The Tumor Suppressor TP53 in Colorectal Carcinoma)
Bowel cancer is a serious disease, which affects many people worldwide. Unfortunately, the disease is often diagnosed in an advanced stage, which impairs the chance of survival. Furthermore, resistance to therapy occurs frequently. Thus, novel therapeutic approaches are required to improve cancer therapy. Here, we studied whether merosesquiterpenes might be useful for cancer treatment. These compounds occur in marine sponges and were isolated by our group. We were able to identify three compounds with potent cytotoxic activity in different cell lines established from human large bowel cancer. Our experiments provided evidence that the compounds cause DNA damage and trigger cell death, so-called mitochondrial apoptosis, which was attested in cancer cells with expression of wild-type and mutated p53 tumor suppressor. Finally, we show that merosesquiterpenes also kill intestinal tumor organoids, an ex vivo model of large bowel cancer.
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. View Full-Text
Keywords: colorectal cancer; chemotherapy; tumor suppressor p53; apoptosis; natural compounds; DNA damage colorectal cancer; chemotherapy; tumor suppressor p53; apoptosis; natural compounds; DNA damage
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MDPI and ACS Style

Jiso, A.; Demuth, P.; Bachowsky, M.; Haas, M.; Seiwert, N.; Heylmann, D.; Rasenberger, B.; Christmann, M.; Dietrich, L.; Brunner, T.; Riyanti; Schäberle, T.F.; Plubrukarn, A.; Fahrer, J. 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. Cancers 2021, 13, 3282. https://doi.org/10.3390/cancers13133282

AMA Style

Jiso A, Demuth P, Bachowsky M, Haas M, Seiwert N, Heylmann D, Rasenberger B, Christmann M, Dietrich L, Brunner T, Riyanti, Schäberle TF, Plubrukarn A, Fahrer J. 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. Cancers. 2021; 13(13):3282. https://doi.org/10.3390/cancers13133282

Chicago/Turabian Style

Jiso, Apisada, Philipp Demuth, Madeleine Bachowsky, Manuel Haas, Nina Seiwert, Daniel Heylmann, Birgit Rasenberger, Markus Christmann, Lea Dietrich, Thomas Brunner, Riyanti, Till F. Schäberle, Anuchit Plubrukarn, and 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" Cancers 13, no. 13: 3282. https://doi.org/10.3390/cancers13133282

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