Type

Journal Article

Authors

M Clynes
A Maguire
S Plunkett
R O'Connor
S Touhey

Subjects

Pharmacology

Topics
prostaglandin endoperoxide synthases antagonists inhibitors drug therapy analogs derivatives drug resistance multiple tumor cells cultured structure activity relationship cyclooxygenase inhibitors cyclooxygenase 1 ptgs1 protein human ptgs2 protein human cyclooxygenase 2 inhibitors humans cyclooxygenase 2 multidrug resistance associated proteins drug screening assays antitumor therapeutic use membrane proteins indomethacin isoenzymes neoplasms

Structure-activity relationship of indomethacin analogues for MRP-1, COX-1 and COX-2 inhibition. identification of novel chemotherapeutic drug resistance modulators. (2002)

Abstract We report the screening of analogues of indomethacin to investigate the structure-activity relationship (SAR) of indomethacin-mediated multidrug resistance associated protein-1 (MRP-1) inhibition. By examining the activities of compounds with minor variations of the parent structure, we were able to separate MRP-1, glutathione-S-transferase (GST), cyclooxygenase (COX)-1 and COX-2 inhibitory activities. Combination cytotoxicity assays were utilised to identify agents which possess synergistic potential in MRP-1-expressing cell lines. MRP-1 Inside Out Vesicles (IOVs) were utilised to demonstrate the ability of the indomethacin analogues to inhibit the pump directly. Most of the indomethacin analogues active as MRP-1 inhibitors were poor GST inhibitors when compared with the GST-inhibitory activity of indomethacin. Two of the MRP-1 inhibitory analogues were found to have no COX-1 inhibitory activity and low COX-2 inhibitory activity, suggesting potentially reduced clinical toxicity. One MRP-1 inhibitory indomethacin analogue was also found to have low COX-1 inhibitory activity, but significant COX-2 inhibitory activity, making this analogue again interesting in terms of low potential toxicity, but with the possibility of direct inhibitory effects on tumour growth.
Collections Ireland -> Dublin City University -> PubMed

Full list of authors on original publication

M Clynes, A Maguire, S Plunkett, R O'Connor, S Touhey

Experts in our system

1
Martin Clynes
Dublin City University
Total Publications: 209
 
2
Anita R. Maguire
University College Cork
Total Publications: 91
 
3
Robert O'Connor
Dublin City University
Total Publications: 71