title: 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.
authors.affiliation: Institut für Anorganische Chemie, Universität Leipzig, Johannisallee 29, 04103 Leipzig (Germany).
authors.forename: Wilma
authors.initials: W
authors.lastname: Neumann
authors.forename: Brenda C
authors.initials: BC
authors.lastname: Crews
authors.forename: Menyhárt B
authors.initials: MB
authors.lastname: Sárosi
authors.forename: Cristina M
authors.initials: CM
authors.lastname: Daniel
authors.forename: Kebreab
authors.initials: K
authors.lastname: Ghebreselasie
authors.forename: Matthias S
authors.initials: MS
authors.lastname: Scholz
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Marnett
authors.forename: Evamarie
authors.initials: E
authors.lastname: Hey-Hawkins
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D051545:Cyclooxygenase 1 / Q000737:chemistry* / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000737:chemistry* / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans
chemical_list: D000970:Antineoplastic Agents; D016861:Cyclooxygenase Inhibitors; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D002945:Cisplatin
keywords: antitumor agents; cyclooxygenase inhibitors; drug design; platinum; prodrugs