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

Lung cancer persists as the leading cause of cancer-related morbidity and mortality, in which non-small-cell lung cancer (NSCLC) constitutes the predominant histological subtype of the disease. In this study, 26 structurally diverse daphnane diterpenoids (1-26) including six undescribed ones (1-6) were isolated from the whole plants of Daphne odora. Their structures were elucidated by spectroscopic, ECD, and chemical methods. Seven daphnane diterpenoids showed significant inhibitory effect on NSCLC cell line HCC827, among which compounds 1 and 2 were the most active with IC50 values of 3.57 ± 0.32 and 4.35 ± 0.14 μM, respectively. Mechanistic study indicated that 1 and 2 could significantly induce cell cycle arrest at the G2/M phase and cause cell apoptosis. Further examination by transcriptome sequencing analysis revealed that 1 and 2 significantly suppressed ATR-mediated DNA damage response and cell cycle checkpoint. These findings demonstrate that these compounds might be promising lead compounds for the development of treatment for NSCLC.