Targeting the DNA damage response (DDR) by natural compounds

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.