Conjugates of cisplatin and cyclooxygenase inhibitors as potent antitumor agents overcoming cisplatin resistance.

Abstract

Cyclooxygenase-2 (COX-2) is an enzyme involved in tumorigenesis, and inhibitors of the enzyme are increasingly used as adjuvant modulators in anticancer therapies due to their synergistic effects with traditional chemotherapeutics. COX-2 is also reported to cause resistance towards antitumor agents, such as cisplatin. Here, the first covalently linked conjugates of cisplatin and COX inhibitors are reported. These conjugates exhibit concerted transport of both drugs into tumor cells and simultaneous action upon intracellular cleavage. These platinum(IV) complexes show highly increased cytotoxicity compared with cisplatin and are even able to overcome cisplatin-related resistance of tumor cells. While the results reported show that COX-2 inhibition is not directly responsible for the potent activities of these conjugates, they do represent useful tool compounds for the elucidation of the influence of COX inhibitors on the efficacy of antitumor agents.

• Authors: Wilma Neumann, Brenda C Crews, Lawrence J Marnett, Evamarie Hey-Hawkins
• Journal: ChemMedChem (ChemMedChem) Vol. 9 Issue 6 Pg. 1150-3 (Jun 2014) ISSN: 1860-7187 [Electronic] Germany
• PMID: 24801194 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• Antineoplastic Agents
• Cyclooxygenase Inhibitors
• Organoplatinum Compounds
• Cisplatin

Topics

• Antineoplastic Agents (chemistry, pharmacology, therapeutic use)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Cisplatin (chemistry, therapeutic use)
• Cyclooxygenase Inhibitors (chemistry, pharmacology, therapeutic use)
• Drug Design
• Drug Resistance, Neoplasm (drug effects)
• HCT116 Cells
• Humans
• Neoplasms (drug therapy)
• Organoplatinum Compounds (chemical synthesis, chemistry, pharmacology)