Sanguinarine, a promising anticancer drug, triggers p53-dependent ROS-induced apoptosis in the C. elegans germline

Abstract

The benzophenanthridine alkaloid drug sanguinarine is known for its antibacterial, antifungal, anti-inflammatory, and anticancer properties. In vitro studies on cancer cells have demonstrated sanguinarine’s ability to inhibit tumor growth by causing apoptosis through reactive oxygen species (ROS) induction. Despite extensive studies in cell lines, the participants of sanguinarine’s apoptosis induction remain unclear; with some reports suggesting the involvement of P53, while others show P53 independence. The exact mechanism by which sanguinarine triggers apoptosis is yet to be fully elucidated, especially in vivo, which is critical information should this drug be considered for clinical trials. Recent studies in zebrafish and mice cast doubt on sanguinarine’s safety in vivo, as it was shown to induce apoptosis and developmental abnormalities in embryos and larvae. In this study, we aimed to characterize the effect of sanguinarine in vivo on an adult organism using C. elegans as our model system. We investigated apoptosis induction by sanguinarine, its p53-dependency, and the involvement of ROS in causing apoptosis. Our results demonstrate that sanguinarine induces apoptosis in the C. elegans germline in a dose-dependent manner. Furthermore, the apoptotic phenotype observed upon sanguinarine exposure was dependent on C. elegans CED-3/ Caspase and CEP-1/ P53. Treating C. elegans with sanguinarine activated the evolutionarily conserved DNA damage checkpoint signaling, confirmed by observed phosphorylation of CHK-1. Interestingly, sanguinarine induced a sharp increase in ROS levels exclusively in germ cells. Additionally, the apoptotic effect of sanguinarine was relieved by treatment with the ROS scavenger N-acetyl-L-cysteine (NAC). All in all, our in vivo study demonstrates that sanguinarine induces apoptosis in the C. elegans germline in a Caspase and P53-dependent manner, through a critical increase in reactive oxygen species in the germline.

Date of Award	2024
Original language	American English
Awarding Institution	HBKU College of Health & Life Sciences