Gemfibrozil-Platinum(IV) Precursors for New Enhanced-Starvation and Chemotherapy In Vitro and In Vivo

A brand-new enhanced starvation is put forward to trigger sensitized chemotherapy: blocking tumor-relation blood vessel formation and accelerating nutrient degradation and efflux. Following this concept, two cisplatin-like gemfibrozil-derived Pt(IV) prodrugs, GP and GPG, are synthesized. GP and GPG had nanomolar IC₅₀ against A2780 cells and higher selectivity against normal cells than cisplatin. Bioactivity results confirmed that GP and GPG highly accumulated in cells and induced DNA damage, G2-phase arrest, and p53 expression. Besides, they could increase ROS and MDA levels and reduce mitochondrial membrane potential and Bcl-2 expression to promote cell apoptosis. In vivo, GP showed superior antitumor activity in A2780 tumor-bearing mice with no observable tissue damage. Mechanistic studies suggested that highly selective chemotherapy could be due to the new enhanced starvation effect: blocking vasculature formation via inhibiting the CYP2C8/EETs pathway and VEGFR2, NF-κB, and COX-2 expression and cholesterol efflux and degradation acceleration via increasing ABCA1 and PPARα.