Novel platinum(IV) complexes trigger apoptosis and ferroptosis to conquer cisplatin resistance in triple-negative breast cancer.

Platinum (II)-based agents are commonly used for the cancer treatment, but are limited by drug resistance and severe systemic toxicity. To address these limitations, sulfasalazine derivatives were employed as ligands to construct four platinum(IV) complexes, which exhibited superior anticancer activity compared to cisplatin (CDDP) and oxaliplatin (OXA) against those tested cancer cells. Among them, the optimal complex 14 can efficiently reverse CDDP resistance in MDA-MB-231 cells. Stability assays confirmed that 14 underwent efficient activation by ascorbic acid to release OXA and 11. Mechanistic studies revealed that the enhanced intracellular uptake of 14 efficiently triggered apoptosis via inducing DNA damage, increasing intracellular ROS accumulation and activating mitochondrial pathways. Notably, unlike OXA, 14 efficiently induced ferroptosis through increasing lipid peroxidation, and disrupting cystine/glutamate transporter-glutathione peroxidase axis signaling pathways transduction. Furthermore, 14 significantly suppresses tumor growth in MDA-MB-231/CDDP xenografts without inducing obvious toxicity. Given its high anticancer activity, complex 14 represents a promising therapeutic candidate for triple-negative breast cancer treatment.