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.