Sanguinarine activates ATM/ATR-mediated CHK-1 signaling to drive p53-dependent apoptosis in the C. elegans germline.

Sanguinarine (SNG) is a natural component belonging to the benzophenanthridine alkaloids. Various studies have reported its therapeutic potential in treating chronic human diseases such as cancer. SNG is reported to cause programmed cell death in various cancer cell lines. The mechanism by which SNG triggers apoptosis remains poorly elucidated, especially in vivo. Previous studies reported that sanguinarine induces apoptosis by increasing reactive oxygen species (ROS). In this study, we aimed to characterize the effects of SNG using an in vivo Caenorhabditis elegans (C. elegans) model. Treating C. elegans with various SNG concentrations resulted in apoptotic cell death in the proliferative germline. Interestingly, SNG-induced apoptosis depends on the core apoptotic machinery initiated by the DNA-damage-induced activity of the p53/CEP-1 protein. We have also demonstrated that the increase in germ cell apoptosis is caused by elevated levels of ROS following SNG treatment. Importantly, using a DNA end-labeling approach, we demonstrate that SNG induces DNA strand breaks in a ROS-dependent manner. Consistently, both DNA damage and apoptosis were significantly suppressed by treatment with the ROS scavenger N-acetylcysteine (NAC). Altogether, our study demonstrates that SNG induces ROS-dependent DNA damage, leading to activation of the DNA damage response and p53/CEP-1–mediated apoptosis in the proliferative germline of C. elegans.