Peer-Reviewed Journal Details
Mandatory Fields
Touhey, S,O'Connor, R,Plunkett, S,Maguire, A,Clynes, M;
2002
February
Cancer
Structure-activity relationship of indomethacin analogues for MRP-1, COX-1 and COX-2 inhibition: identification of novel chemotherapeutic drug resistance modulators
Validated
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Optional Fields
cancer MRP NSAID resistance circumvention indomethacin GST cyclooxygenase structure-activity relationship COX-1 COX-2 NONSTEROIDAL ANTIINFLAMMATORY DRUGS MULTIDRUG-RESISTANCE PROTEIN MRP CELL-LINES CYCLOOXYGENASE TRANSPORTER EXPRESSION CANCER NSAIDS CYTOTOXICITY
38
1661
1670
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. (C) 2002 Elsevier Science Ltd. All rights reserved.
PII S0959-8049(02)00128-4
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