Increased anti-tumour efficacy of doxorubicin when combined with sulindac in a xenograft model of an MRP-1-positive human lung cancer.
BACKGROUND
A number of cellular proteins, including P-glycoprotein (P-gp) and Multiple drug Resistance Protein (MRP-1), act as drug efflux pumps and are important in the resistance of many cancers to chemotherapy. We previously reported that a small number of NSAIDs could inhibit the activity of MRP-1.


METHODS
We chose sulindac as a candidate agent for further investigation as it has the most favourable efficacy and toxicity profile of the agents available for a potential specific MRP-1 inhibitor. NCI H460 cells expressed MRP-1 protein (by Western blot) and also the toxicity of doxorubicin (a substrate of MRP-1) could be potentiated in this line using non-toxic concentrations of the MRP-1 substrate/inhibitor sulindac. These cells were implanted in nude mice and the animals divided into various groups which were administered doxorubicin and/or sulindac.


RESULTS
Sulindac was shown to significantly potentiate the tumour growth inhibitor activity of doxorubicin in this MRP-1-overexpressing human tumour xenograft model.


CONCLUSIONS
Sulindac may be clinically useful as an inhibitor of the MRP-1 cancer resistance mechanism.
O'Connor
Robert
R
The National Institute for Cellular Biotechnology, Dublin City University, Dublin 9, Ireland. robert.oconnor@dcu.ie
Heenan
Mary
M
Connolly
Lisa
L
Larkin
Annemarie
A
Clynes
Martin
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000378:metabolism; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D018287:Carcinoma, Large Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology; D004357:Drug Synergism; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D013467:Sulindac / Q000008:administration & dosage / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D013467:Sulindac; D004317:Doxorubicin