Interactions between mitochondria-damaging platinum(iv) prodrugs and cytochrome c

Abstract

In this work, we present the first study about the interactions of mitochondria-damaging Pt(IV) prodrugs with cytochrome c. We synthesized a cisplatin-based Pt(IV) prodrug bearing a lipophilic hydrocarbon tail and anionic dansyl head group. The amphiphilic structure facilitates its accumulation in the mitochondria of cancer cells, which was validated using graphite furnace atomic absorption spectroscopy (GFAAS) and fluorescence imaging. Accordingly, this Pt(IV) prodrug is able to trigger mitochondrial damage and apoptosis. Overall, the Pt(IV) prodrug exhibits superior therapeutic effects against a panel of human cancer cells compared to cisplatin. It also overcomes drug resistance in ovarian cancer. Notably, HPLC analysis indicates that cytochrome c accelerates reduction (or activation) of the Pt(IV) prodrug in the presence of the electron donor nicotinamide adenine dinucleotide (NADH). More interestingly, additional studies indicate that cytochrome c was platinated by the reduced product of Pt(IV) prodrugs, and that empowers the proapoptotic peroxidase activity.