Conjugation of Cisplatin Analogues and Cyclooxygenase Inhibitors to Overcome Cisplatin Resistance

Abstract

Cyclooxygenase (COX) is an enzyme involved in tumorigenesis and is associated with tumor cell resistance against platinum-based antitumor drugs. Cisplatin analogues were conjugated with COX inhibitors (indomethacin, ibuprofen) to study the synergistic effects that were previously observed in combination treatments. The conjugates ensure concerted transport of both drugs into cells, and subsequent intracellular cleavage enables a dual-action mode. Whereas the platinum(II) complexes showed cytotoxicities similar to those of cisplatin, the platinum(IV) conjugates revealed highly increased cytotoxic activities and were able to completely overcome cisplatin-related resistance. Although some of the complexes are potent COX inhibitors, the conjugates appear to execute their cytotoxic action via COX-independent mechanisms. Instead, the increased lipophilicity and kinetic inertness of the conjugates seem to facilitate cellular accumulation of the platinum drugs and thus improve the efficacy of the antitumor agents. These conjugates are important tools for the elucidation of the direct influence of COX inhibitors on platinum-based anticancer drugs in tumor cells.

Defining the Anti‐Cancer Activity of Tricarbonyl Rhenium Complexes: Induction of G2/M Cell Cycle Arrest and Blockade of Aurora‐A Kinase Phosphorylation

“…For this scope, we decided to study the complexes alone or conjugated to the nonsteroidal anti‐inflammatory drug (NSAID) indomethacin. This chemical design was inspired by the fact that molecular units comprising a metal fragment and NSAID have been previously reported to enhance anticancer properties . Remarkably, it was found that the rhenium complexes were active against pancreatic cell lines, whereas the ruthenium complexes did not show any significant activity.…”

“…This chemicald esign wasi nspired by the fact that molecular units comprising am etal fragment and NSAID have been previously reported to enhancea nticancerp roperties. [20][21][22][23][24][25][26] Remarkably,i t was found that the rhenium complexes were active against pancreatic cell lines, whereas the ruthenium complexes did not show any significant activity.F urthermore,c onjugation to indomethacin did not seem to enhancet he anticancer activity, which was traced back exclusively to the presence of the Re(CO) 3 fragment. With this study,f or the first time, it was possible to elucidate that the anticancer properties of the rhenium tricarbonyl fragment originatef rom the labilityo ft he monodentate ancillary ligand coordinated to the rheniumc enter by inducing G2/M cell cyclea rrest and blockade of Aurora-A kinase phosphorylation.…”

Perspectives in the development of hybrid bifunctional antitumour agents

“…Specifically, the conjugation with cyclooxygenase inhibitors was reported to facilitate the cellular accumulation of Pt(IV) complexes and to overcome cisplatin resistance [49]. In the reported conjugates (24) the COX-2 inhibitor served as axial ligand, allowing the release of platinum complex and of two molecules of the COX-2 inhibitor following intracellular thio-mediated reduction.…”

The Platin-X series: activation, targeting, and delivery

“…73 In this regard, Hey-Hawkins and coworkers also reported covalently linked conjugates of cisplatin and cyclooxegenase COX inhibitors which demonstrated similar mechanism of action after intracellular cleavage of the components (Figure 4A). 74 They used indomethacin or ibuprofen as the axial ligands. Preliminary studies could not decipher the precise reasons for improved cytotoxicity and increased lipophilicity of the overall molecules leading to greater cellular uptake was thought to be the predominating factor.…”