Ligustrazine-Derived Chalcones-Modified Platinum(IV) Complexes Intervene in Cisplatin Resistance in Pancreatic Cancer through Ferroptosis and Apoptosis.

Developing multitarget platinum(IV) prodrugs is an important strategy to attenuate cisplatin (CDDP) resistance in tandem with reduced toxicity. Herein, six novel ligustrazine-derived chalcones-modified platinum(IV) complexes were synthesized and evaluated for their anti-proliferative activities. Among them, 16a displayed higher cytotoxicity toward the tested cancer cell lines and lower cytotoxicity toward the human normal cells than CDDP or the combined group. Mechanistic studies revealed that 16a efficiently induced DNA damage and initiated a mitochondria-dependent apoptosis pathway. Besides, 16a significantly triggered ferroptosis by down-regulating expression levels of nuclear factor erythroid 2-related factor 2, glutathione peroxidase 4, and solute carrier family 7 member 11. Further, 16a obtained superior in vivo anti-tumor efficiency than CDDP in CDDP-resistant pancreatic cancer xenograft models but showed no significant side effects. In summary, our study suggested that 16a acts via a different anti-cancer mechanistic pathway than CDDP and may therefore encompass a novel practical strategy for cancer treatment.