Abstract
Failure of cancer chemotherapy is mostly due to multidrug resistance (MDR). Overcoming MDR mediated by overexpression of ATP binding cassette (ABC) transporters in cancer cells remains a big challenge. In this study, we explore whether NVP-TAE684, a novel ALK inhibitor which has the potential to inhibit the function of ABC transport, could reverse ABC transporter-mediated MDR. MTT assay was carried out to determine cell viability and reversal effect of NVP-TAE684 in parental and drug resistant cells. Drug accumulation and efflux assay was performed to examine the effect of NVP-TAE684 on the cellular accumulation and efflux of chemotherapeutic drugs. The ATPase activity of ABCG2 transporter in the presence or absence of NVP-TAE684 was conducted to determine the impact of NVP-TAE684 on ATP hydrolysis. Western blot analysis and immunofluorescence assay were used to investigate protein molecules related to MDR. In addition, the interaction between NVP-TAE684 and ABCG2 transporter was investigated via in silico analysis. MTT assay showed that NVP-TAE684 significantly decreased MDR caused byABCG2-, but not ABCC1-transporter. Drug accumulation and efflux tests indicated that the effect of NVP-TAE684 in decreasing MDR was due to the inhibition of efflux function of ABCG2 transporter. However, NVP-TAE684 did not alter the expression or change the subcellular localization of ABCG2 protein. Furthermore, ATPase activity analysis indicated that NVP-TAE684 could stimulate ABCG2 ATPase activity. Molecular in silico analysis showed that NVP-TAE684 interacts with the substrate binding sites of the ABCG2 transporter. Taken together, our study indicates that NVP-TAE684 could reduce the resistance of MDR cells to chemotherapeutic agents, which provides a promising strategy to overcome MDR.
Highlights
Antineoplastic drugs can induce cancer cells resistant to treatment which makes the therapeutic effect of anti-cancer drugs greatly reduced and leads to multidrug resistance (MDR) [1]
We examined the cytotoxicity of NVP-TAE684 on cells overexpressed ABCG2 or ABCC1
The cytotoxicity of cisplatin, which is not a substrate of ABCG2, was not significantly affected by NVP-TAE684. These results indicated that NVP-TAE684 could antagonize MDR mediated by ABCG2-overexpression
Summary
Antineoplastic drugs can induce cancer cells resistant to treatment which makes the therapeutic effect of anti-cancer drugs greatly reduced and leads to multidrug resistance (MDR) [1]. ATP hydrolysis provides energy for ABC transporters to extrude substrates out of tumor cells and lower the intracellular concentration of anticancer drugs, which results in weakening of the efficacy of chemotherapeutic drugs and eventually produces MDR [10]. Nine MRPs with transport function have been found, ranging from MRP1 to MRP9 [11,12,13] Some of their structures (MRPs 4, 5, 7, 8, and 9) are similar to that of ABCB1. They contain two transmembrane regions and two ATP binding domains [14]. MRP1/ABCC1 mediates the transport of anticancer drugs, including anthracyclines, methotrexate and doxorubicin [15,16,17]
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