Journal
CHEMMEDCHEM
Volume 10, Issue 1, Pages 183-192Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.201402353
Keywords
antitumor agents; cyclooxygenase inhibitors; drug design; platinum; prodrugs
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Funding
- Fonds der Chemischen Industrie
- Graduate School Building with Molecules and Nano-objects (BuildMoNa) - Deutsche Forschungsgemeinschaft
- Europaischer Sozialfond
- Freistaat Sachsen
- US National Institutes of Health [CA89450]
- German Academic Exchange Service (PPP USA)
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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.
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