Multiaction Platinum(IV) Prodrug Containing Thymidylate Synthase Inhibitor and Metabolic Modifier against Triple-Negative Breast Cancer

Multifunctional platinum(IV) anticancer prodrugs have the potential to enrich the anticancer properties and overcome the clinical' problems of drug resistance and side effects of platinum(III) anticancer agents. Herein, we develop dual and triple action platinum(IV) complexes with targeted and biological active functionalities. One complex (PFL) that consists of cisialatirt, tegafur, and lonidamine exhibits strong cytotoxicity against triple negative breast cancer (TNBC) cells.,Cellular uptake and distribution studies reveal that PFL mainly accumulates in mitochondria. As result,PFL disrupts the mitochondrial ultrastructure and induces significant alterations in the mitochoildi'ial membrane Potential) whichla further leads to an increase in production. of reactive oxygen species (ROS) and a decrease in ATP synthesis MDA-MB-231 TNBCs. Western blot analysis reveals the formation of ternary complex of thyitiidylate synthase, which shows the intr.acellular. conversion of tegaftir into 5 -FU after its release from PFL. Furthermore,;d treatment with PFL impairs the mitoch,ondrial function, leading to the inhibition of glycolysis and mitochondrial respiration and induction of apoptosis through the mitochondria' pathway. The RNA-sequencing.. experiment shows that PFL can perturb theL pathways in several cellular processes includingDNA damage,th id late synthase inhibition, and perturbation oinvolve(1 in DNA synthesis, DNA damage, metabolism, and transcriptional activity. These, findings demolistrate thatfPtFhe h d bmitoc on ria ioenergetics to kill the cancer cells. The results highlight the significance of a triple -action prodrug for efficient anticancer therapy for TNl3Cs.