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Daphnane diterpenoids for cancer therapy by suppressing ATR-mediated DNA damage response pathway

Shu-Qi Wu1, Lei-Ming Wu1, Fang-Yu Yuan1

  • 1School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.

Bioorganic Chemistry
|August 6, 2025
PubMed

Insights

Natural compounds from Daphne odora show potential against non-small-cell lung cancer (NSCLC). Compounds 1 and 2 effectively inhibited NSCLC cell growth by inducing cell cycle arrest and apoptosis, offering new therapeutic leads.

Area of Science:

  • Natural Product Chemistry
  • Cancer Biology
  • Pharmacology

Background:

  • Non-small-cell lung cancer (NSCLC) remains a leading cause of cancer mortality.
  • Identifying novel therapeutic agents for NSCLC is a critical unmet need.

Purpose of the Study:

  • To isolate and characterize daphnane diterpenoids from Daphne odora.
  • To evaluate the anti-NSCLC activity of these compounds.
  • To elucidate the mechanism of action for active compounds.

Main Methods:

  • Isolation and structural elucidation of 26 daphnane diterpenoids using spectroscopic, ECD, and chemical methods.
  • In vitro anti-proliferative assays using the HCC827 NSCLC cell line.
  • Cell cycle analysis, apoptosis assays, and transcriptome sequencing.

Main Results:

  • Six new daphnane diterpenoids (1-6) were identified alongside 20 known compounds.
  • Seven compounds exhibited significant inhibitory effects on HCC827 cells.
  • Compounds 1 and 2 demonstrated potent activity (IC50 values of 3.57 ± 0.32 μM and 4.35 ± 0.14 μM, respectively).
  • Compounds 1 and 2 induced G2/M phase cell cycle arrest and apoptosis.
  • Transcriptome analysis revealed suppression of ATR-mediated DNA damage response and cell cycle checkpoints by compounds 1 and 2.

Conclusions:

  • Daphnane diterpenoids isolated from Daphne odora possess significant anti-NSCLC activity.
  • Compounds 1 and 2 are promising lead compounds for NSCLC drug development.
  • The mechanism involves disruption of DNA damage response and cell cycle regulation.
Keywords:
ATRAnticancer agentDNA damage responseDaphnane diterpenoidDaphne odoraNon-small-cell lung cancer

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