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

• Published in: PloS one 2013-02, Vol.8 (2), p.e55576-e55576
• Main Authors: Sun, Yue-Li, Chen, Jun-Jiang, Kumar, Priyank, Chen, Kang, Sodani, Kamlesh, Patel, Atish, Chen, Yang-Lu, Chen, Si-Dong, Jiang, Wen-Qi, Chen, Zhe-Sheng
• Format: Article
• Language: English
• Subjects: ABC transporters; Adenosine triphosphate; Analogs; Antineoplastic agents; Antineoplastic drugs; Antitumor agents; Biology; Breast cancer; Cancer; Cancer therapies; Cell Line; Chemical compounds; Chemotherapy; Clinical trials; Cytokines; Drug Resistance, Multiple - drug effects; Drugs; Efflux; Epidemiology; Glycoproteins; Health sciences; Humans; Kinases; Laboratories; Lung cancer; Lung diseases; Medical research; Medicine; Microbial drug resistance; Multidrug resistance; Multidrug Resistance-Associated Proteins - genetics; Multidrug Resistance-Associated Proteins - metabolism; Multidrug resistant organisms; Non-small cell lung cancer; Non-small cell lung carcinoma; Nucleoside analogs; Oncology; P-Glycoprotein; Paclitaxel; Pharmaceutical sciences; Pharmacology; Pharmacy; Proteins; Public health; Quinolines - chemistry; Quinolines - pharmacology; Radiation measurement; Substrates; Taxanes
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0055576

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.