Novel Antitumor Platinum(II) Conjugates Containing the Nonsteroidal Anti-inflammatory Agent Diclofenac: Synthesis and Dual Mechanisms of Antiproliferative Effects

One
concept how to improve anticancer effects of conventional metallodrugs
consists in conjugation of these compounds with other biologically
(antitumor) active agents, acting by a different mechanism. Here,
we present synthesis, biological effects, and mechanisms of action
of new Pt­(II) derivatives containing one or two nonsteroidal anti-inflammatory
diclofenac (DCF) ligands also known for their antitumor effects. The
antiproliferative properties of these metallic conjugates show that
these compounds are potent and cancer cell selective cytotoxic agents
exhibiting activity in cisplatin resistant and the COX-2 positive
tumor cell lines. One of these compounds, compound 3,
in which DCF molecules are coordinated to Pt­(II) through their carboxylic
group, is more potent than parental conventional Pt­(II) drug cisplatin,
free DCF and the congeners of 3 in which DCF ligands
are conjugated to Pt­(II) via a diamine. The potency of 3 is due to several factors including enhanced internalization that
correlates with enhanced DNA binding and cytotoxicity. Mechanistic
studies show that 3 combines multiple effects. After
its accumulation in cells, it releases Pt­(II) drug capable of binding/damaging
DNA and DCF ligands, which affect distribution of cells in individual
phases of the cell cycle, inhibit glycolysis and lactate transport,
collapse mitochondrial membrane potential, and suppress the cellular
properties characteristic of metastatic progression.