Structure-activity relationship of indomethacin analogues for MRP-1, COX-1 and COX-2 inhibition. identification of novel chemotherapeutic drug resistance modulators.
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.
Touhey
S
S
The National Cell and Tissue Culture Centre, Dublin City University, Glasneuin, 9, Dublin, Ireland.
O'Connor
R
R
Plunkett
S
S
Maguire
A
A
Clynes
M
M
D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use*; D018432:Drug Resistance, Multiple; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D006801:Humans; D007213:Indomethacin / Q000031:analogs & derivatives*; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008565:Membrane Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009369:Neoplasms / Q000188:drug therapy*; D011451:Prostaglandin-Endoperoxide Synthases; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007213:Indomethacin; D007527:Isoenzymes; D008565:Membrane Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011451:Prostaglandin-Endoperoxide Synthases; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human