ent-Kaurane diterpenoids induce apoptosis and ferroptosis through targeting redox resetting to overcome cisplatin resistance.

Reactive oxygen species (ROS) induction is an effective mechanism to kill cancer cells for many chemotherapeutics, while resettled redox homeostasis induced by the anticancer drugs will promote cancer chemoresistance. Natural ent-kaurane diterpenoids have been found to bind glutathione (GSH) and sulfhydryl group in antioxidant enzymes covalently, which leads to the destruction of intracellular redox homeostasis. Therefore, redox resetting destruction by ent-kaurane diterpenoids may emerge as a viable strategy for cancer therapy. In this study, we isolated 30 ent-kaurane diterpenoids including 20 new samples from Chinese liverworts Jungermannia tetragona Lindenb and studied their specific targets and possible application in cancer drug resistance through redox resetting destruction. 11β-hydroxy-ent-16-kaurene-15-one (23) possessed strong inhibitory activity against several cancer cell lines. Moreover, compound 23 induced both apoptosis and ferroptosis through increasing cellular ROS levels in HepG2 cells. ROS accumulation induced by compound 23 was caused by inhibition of antioxidant systems through targeting peroxiredoxin I/II (Prdx I/II) and depletion of GSH. Furthermore, compound 23 sensitized cisplatin (CDDP)-resistant A549/CDDP cancer cells in vitro and in vivo by inducing apoptosis and ferroptosis. Thus, the ent-kaurane derivative showed potential application for sensitizing CDDP resistance by redox resetting destruction through dual inhibition of Prdx I/II and GSH in cancer chemotherapy.