ent-Kaurane diterpenoids induce apoptosis and ferroptosis through targeting redox resetting to overcome cisplatin resistance
Yong Sun,
Yanan Qiao,
Yue Liu,
Jinchuan Zhou,
Xue Wang,
Hongbo Zheng,
Zejun Xu,
Jiaozhen Zhang,
Yi Zhou,
Lilin Qian,
Chunyang Zhang,
Hongxiang Lou
Affiliations
Yong Sun
Department of Natural Product Chemistry, Key Lab of Chemical Biology of Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, China
Yanan Qiao
Department of Natural Product Chemistry, Key Lab of Chemical Biology of Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, China
Yue Liu
Department of Natural Product Chemistry, Key Lab of Chemical Biology of Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, China
Jinchuan Zhou
School of Pharmacy, Linyi University, Linyi, 276000, China
Xue Wang
Department of Natural Product Chemistry, Key Lab of Chemical Biology of Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, China
Hongbo Zheng
Department of Natural Product Chemistry, Key Lab of Chemical Biology of Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, China
Zejun Xu
Department of Natural Product Chemistry, Key Lab of Chemical Biology of Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, China
Jiaozhen Zhang
Department of Natural Product Chemistry, Key Lab of Chemical Biology of Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, China
Yi Zhou
Department of Natural Product Chemistry, Key Lab of Chemical Biology of Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, China
Lilin Qian
Department of Natural Product Chemistry, Key Lab of Chemical Biology of Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, China
Chunyang Zhang
Department of Natural Product Chemistry, Key Lab of Chemical Biology of Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, China
Hongxiang Lou
Department of Natural Product Chemistry, Key Lab of Chemical Biology of Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, China; Corresponding author.
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.
