The platinum(II) complex [Pt(1S,2S-diaminocyclohexane)(5,6-dimethyl-1,10-phenanthroline)]2+(PtII56MeSS,1) exhibits high potency
across numerous cancer cell lines acting by a multimodal mechanism.
However,1also displays side toxicity and in vivo activity;
all details of its mechanism of action are not entirely clear. Here,
we describe the synthesis and biological properties of new platinum(IV)
prodrugs that combine1with one or two axially coordinated
molecules of diclofenac (DCF), a non-steroidal anti-inflammatory cancer-selective
drug. The results suggest that these Pt(IV) complexes exhibit mechanisms
of action typical for Pt(II) complex1and DCF, simultaneously.
The presence of DCF ligand(s) in the Pt(IV) complexes promotes the
antiproliferative activity and selectivity of1by inhibiting
lactate transporters, resulting in blockage of the glycolytic process
and impairment of mitochondrial potential. Additionally, the investigated
Pt(IV) complexes selectively induce cell death in cancer cells, and
the Pt(IV) complexes containing DCF ligands induce hallmarks of immunogenic
cell death in cancer cells.