Pt(IV)-Deferasirox Prodrug Combats DNA Damage Repair by Regulating RNA N6-Methyladenosine Methylation

DNA damage repair is considered to be an important mechanism of cisplatin resistance, and the roles of iron homeostasis in action mechanisms of cisplatin have not been studied yet. Herein, a Pt(IV) prodrug (DFX-Pt) integrating cisplatin and the clinical oral iron-chelating agent deferasirox (DFX) is found to be highly active toward cisplatininsensitive triple-negative breast cancer cells both in vitro and in vivo. RNAsequencing shows that DFX-Pt can downregulate genes related to the double-strand break (DSB) damage pathway significantly. DFX-Pt can reduce cellular free iron, regulate the expression of the RNA demethylase, and elevate the levels of RNA N-6-methyladenosine (m(6)A), which degrades the DSB-related genes in an m(6)A-dependent manner. In all, we first reveal the roles of RNA modification in mechanisms of combating DNA damage repair and show that the combination of iron homeostasis intervention may bring new treatment regimens for cisplatin resistance.

Automated summary

This study reveals a novel Pt(IV) prodrug (DFX-Pt) with high activity against cisplatin-insensitive breast cancer cells, which degrades genes related to the DSB damage pathway by regulating RNA modification and reducing cellular free iron.