Reversal of MRP7 (ABCC10)-mediated multidrug resistance by tariquidar.

Abstract

Multidrug resistance protein 7 (MRP7, ABCC10) is a recently discovered member of the ATP-binding cassette (ABC) family which are capable of conferring resistance to a variety of anticancer drugs, including taxanes and nucleoside analogs, in vivo. MRP7 is highly expressed in non-small cell lung cancer cells, and Mrp7-KO mice are highly sensitive to paclitaxel, making MRP7 an attractive chemotherapeutic target of non-small cell lung cancer. However, only a few inhibitors of MRP7 are currently identified, with none of them having progressed to clinical trials. We used MRP7-expressing cells to investigate whether tariquidar, a third generation inhibitor of P-glycoprotein, could inhibit MRP7-mediated multidrug resistance (MDR). We found that tariquidar, at 0.1 and 0.3 µM, significantly potentiated the sensitivity of MRP7-transfected HEK293 cells to MRP7 substrates and increased the intracellular accumulation of paclitaxel. We further demonstrated that tariquidar directly impaired paclitaxel efflux and could downregulate MRP7 protein expression in a concentration- and time-dependent manner after prolonged treatment. Our findings suggest that tariquidar, at pharmacologically achievable concentrations, reverses MRP7-mediated MDR through inhibition of MRP7 protein expression and function, and thus represents a promising therapeutic agent in the clinical treatment of chemoresistant cancer patients.

• Authors: Yue-Li Sun, Jun-Jiang Chen, Priyank Kumar, Kang Chen, Kamlesh Sodani, Atish Patel, Yang-Lu Chen, Si-Dong Chen, Wen-Qi Jiang, Zhe-Sheng Chen
• Journal: PloS one (PLoS One) Vol. 8 Issue 2 Pg. e55576 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 23393594 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• ABCC10 protein, human
• Multidrug Resistance-Associated Proteins
• Quinolines
• tariquidar

Topics

• Cell Line
• Drug Resistance, Multiple (drug effects)
• Humans
• Multidrug Resistance-Associated Proteins (genetics, metabolism)
• Quinolines (chemistry, pharmacology)