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Updated: Dec 30, 2025
Visualizing and Quantifying Endonuclease-Based Site-Specific DNA Damage
Published on: August 21, 2021
Targeting the DNA damage response (DDR) by natural compounds
Jana van Stuijvenberg1, Peter Proksch2, Gerhard Fritz1
1Institute of Toxicology, Medical Faculty, Heinrich-Heine University Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany.
Abstract:
Natural compounds (NC) are an important source of anticancer drugs. The genomic DNA of tumor cells is a major target of conventional anticancer therapeutics (cAT). DNA damage elicits a complex stress response programme termed DNA damage response (DDR), with the PI3-like kinase ATM and ATR being the key regulators. Since the DDR coordinates mechanisms of DNA repair and apoptosis, hence regulating the balance between death and survival, it is an attractive target of novel anticancer strategies. The aim of the study was to identify natural compounds derived from endophytic fungi, lichens, marine sponges or plants that interfere with mechanisms of the DDR. To this end, the cytotoxic and DDR modulating potency of 296 natural compounds, used alone or in combination with the cAT cisplatin (Cis) and doxorubicin (Doxo) was investigated by fluorescence-based analysis of the ATM/ATR-catalyzed S139 phosphorylation of histone 2AX (γH2AX), a surrogate marker of DNA damage-triggered DDR. After initial screening, a total of ten natural compounds were identified that were toxic in pancreatic carcinoma cells and activated the DDR on their own and/or promoted the DDR if used in combination with cAT. Their mode of action was shown to be independent of drug transport mechanisms. Based on their chemical structures, DDR modulatory activity and published data we suggest the marine NC 5-epi-nakijiquinone Q and 5-epi-ilimaquinone as well as the fungal compound secalonic acid F as most promising NC-based drug candidates for future synthesis of DDR-modulating chemical derivatives and their preclinical in vitro and in vivo testing.
Insights
Natural compounds (NC) can be a source of anticancer drugs by targeting DNA damage response (DDR). Researchers identified ten NCs that are toxic to pancreatic cancer cells and modulate DDR, with three showing particular promise.
Area of Science:
- Natural product chemistry
- Cancer biology
- Molecular pharmacology
Background:
- Natural compounds (NCs) are vital sources for anticancer drug discovery.
- Conventional anticancer therapeutics (cATs) primarily target tumor cell genomic DNA.
- The DNA damage response (DDR) pathway, regulated by ATM and ATR kinases, is a crucial target for novel anticancer strategies due to its role in DNA repair and apoptosis.
Purpose of the Study:
- To identify natural compounds from diverse sources (fungi, lichens, sponges, plants) that interfere with DNA damage response (DDR) mechanisms.
- To evaluate the cytotoxic and DDR-modulating potential of these compounds, alone and in combination with cATs.
Main Methods:
- Screened 296 natural compounds for cytotoxicity and DDR modulation in pancreatic carcinoma cells.
- Utilized fluorescence-based analysis of γH2AX phosphorylation as a marker for DDR activation.
- Assessed compound efficacy both independently and in combination with cisplatin (Cis) and doxorubicin (Doxo).
Main Results:
- Identified ten natural compounds exhibiting cytotoxicity and DDR activation in pancreatic cancer cells.
- Demonstrated that the mode of action for these compounds is independent of drug transport mechanisms.
- Highlighted 5-epi-nakijiquinone Q, 5-epi-ilimaquinone, and secalonic acid F as promising candidates for further development.
Conclusions:
- Natural compounds can effectively modulate the DNA damage response pathway in cancer cells.
- Specific marine and fungal-derived compounds show significant potential as anticancer drug leads.
- Further preclinical investigation of these identified compounds is warranted for developing novel DDR-modulating therapies.
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