Tandutinib (MLN518) reverses multidrug resistance by inhibiting the efflux activity of the multidrug resistance protein 7 (ABCC10)

Deng,Wen; Dai,Chun-Ling; Chen,Jun-Jiang; Kathawala,Rishil  J.; Sun,Yue-Li; Chen,Hai-Fan; Fu,Li-Wu; Chen,Zhe-Sheng

doi:10.3892/or.2013.2362

Tandutinib (MLN518) reverses multidrug resistance by inhibiting the efflux activity of the multidrug resistance protein 7 (ABCC10)

Authors:
- Wen Deng
- Chun-Ling Dai
- Jun-Jiang Chen
- Rishil J. Kathawala
- Yue-Li Sun
- Hai-Fan Chen
- Li-Wu Fu
- Zhe-Sheng Chen
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Affiliations: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, New York, NY 11439, USA, Primary Care Medicine Associates, P.C., Flushing, New York, NY 11354, USA, State Key Laboratory for Oncology in South China, Cancer Center, Sun Yat‑Sen University, Guangzhou, Guangdong 510060, P.R. China
Published online on: March 22, 2013 https://doi.org/10.3892/or.2013.2362
Pages: 2479-2485

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Abstract

It is well established that ATP-binding cassette (ABC) transporter-mediated multidrug resistance (MDR) is one of the major mechanisms that causes resistance to antineoplastic drugs in cancer cells. ABC transporters can significantly decrease the intracellular concentration of antineoplastic drugs by increasing their efflux, thereby lowering their cytotoxic activity. One of these transporters, the multidrug resistance protein 7 (MRP7/ABCC10), has already been shown to produce resistance to antineoplastic drugs by increasing the efflux of the drugs. In the present study, we investigated whether tandutinib, an FMS-like tyrosine kinase 3 (FLT3) inhibitor, has the potential to reverse MRP7-mediated MDR. Our results revealed that tandutinib significantly enhanced the sensitivity of MRP7-transfected HEK293 cells to the 2 established MRP7 substrates, paclitaxel and vincristine, whereas there was less or no effect on the control vector-transfected HEK293 cells. [³H]-paclitaxel accumulation and efflux studies demonstrated that tandutinib increased the intracellular accumulation of [³H]-paclitaxel and inhibited the efflux of [³H]-paclitaxel from HEK-MRP7 cells. In addition, western blot analysis showed that tandutinib did not significantly affect MRP7 expression. Thus, we conclude that the FLT3 inhibitor tandutinib can reverse MRP7-mediated MDR through inhibition of the drug efflux function and may have potential to be used clinically in combination therapy for cancer patients.

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