Multiaction Platinum(IV) Prodrug Containing Thymidylate Synthase Inhibitor and Metabolic Modifier against...

Area of Science:

• Oncology
• Medicinal Chemistry
• Molecular Biology

Background:

• Platinum(II) anticancer agents face challenges like drug resistance and side effects.
• Multifunctional platinum(IV) prodrugs offer enhanced anticancer properties and improved therapeutic outcomes.
• Targeted delivery and multiple mechanisms of action are key for overcoming resistance.

Purpose of the Study:

• To develop and evaluate a dual and triple-action platinum(IV) complex (PFL) for enhanced anticancer therapy.
• To investigate the cytotoxicity and cellular mechanisms of PFL against triple-negative breast cancer (TNBC).
• To assess PFL's potential to overcome platinum resistance and reduce side effects.

Main Methods:

• Synthesis and characterization of the PFL platinum(IV) complex.
• In vitro cytotoxicity assays against TNBC cell lines (MDA-MB-231).
• Cellular uptake, mitochondrial localization, and distribution studies.
• Mitochondrial membrane potential, ROS production, and ATP synthesis assays.
• Western blot analysis for intracellular drug conversion and target engagement.
• RNA sequencing to identify perturbed cellular pathways.
• Assessment of apoptosis induction and metabolic pathway inhibition.

Main Results:

• PFL exhibited strong cytotoxicity against TNBC cells, primarily accumulating in mitochondria.
• PFL disrupted mitochondrial ultrastructure, altered membrane potential, increased ROS, and decreased ATP synthesis.
• Intracellular conversion of tegafur to 5-FU was confirmed, forming a thymidylate synthase complex.
• PFL inhibited glycolysis and mitochondrial respiration, inducing apoptosis via the mitochondrial pathway.
• RNA sequencing revealed PFL perturbed DNA synthesis, DNA damage, metabolism, and transcriptional pathways.

Conclusions:

• PFL acts as a triple-action prodrug, intervening in DNA damage, thymidylate synthase inhibition, and mitochondrial bioenergetics.
• The study highlights the significance of PFL as an efficient anticancer therapeutic for TNBC.
• PFL demonstrates a promising strategy for overcoming platinum resistance and improving cancer treatment outcomes.