Effective platinum(IV) prodrugs conjugated with lonidamine as a functional group working on the mitochondria

Platinum-based anticancer drugs are one of the most widely used anticancer chemotherapeutics in oncology. Lonidamine (LND) could increase the response of human tumor cells to platinum(II) drugs in preclinical studies by working on the mitochondria. Herein, five platinum(IV) prodrugs conjugated with their potentiator LND are prepared, and most of the target complexes achieve improved anticancer activities compared with their platinum(II) precursors. Notably, Pt(NH₃)₂(LND)Cl₃ (complex 1) derived from cisplatin achieve significantly improved anticancer activities against LNCaP cells and could trigger cancer cell death via an apoptotic pathway and the cell cycle arrest mainly at S phases. And the induction of apoptosis by complex 1 in LNCaP cells is closely associated with mitochondrial function disruption and reactive oxygen species (ROS) accumulation. Moreover, it is possessed of the ability to overcome cisplatin-resistance. Further research revealed that complex 1 could be easily reduced to release its platinum(II) precursor and axial ligand by ascorbic acid. All the results provid evidence to support the design strategy of conjugating platinum complexes with its potentiator to improve their anticancer effect.