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.