23 research outputs found

    PD173074, a selective FGFR inhibitor, reverses MRP7 (ABCC10)-mediated MDR

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    Multidrug resistance protein 7 (MRP7, ABCC10) is a recently identified member of the ATP-binding cassette (ABC) transporter family, which adequately confers resistance to a diverse group of antineoplastic agents, including taxanes, vinca alkaloids and nucleoside analogs among others. Clinical studies indicate an increased MRP7 expression in non-small cell lung carcinomas (NSCLC) compared to a normal healthy lung tissue. Recent studies revealed increased paclitaxel sensitivity in the Mrp7−/− mouse model compared to their wild-type counterparts. This demonstrates that MRP7 is a key contributor in developing drug resistance. Recently our group reported that PD173074, a specific fibroblast growth factor receptor (FGFR) inhibitor, could significantly reverse P-glycoprotein-mediated MDR. However, whether PD173074 can interact with and inhibit other MRP members is unknown. In the present study, we investigated the ability of PD173074 to reverse MRP7-mediated MDR. We found that PD173074, at non-toxic concentration, could significantly increase the cellular sensitivity to MRP7 substrates. Mechanistic studies indicated that PD173074 (1 μmol/L) significantly increased the intracellular accumulation and in-turn decreased the efflux of paclitaxel by inhibiting the transport activity without altering expression levels of the MRP7 protein, thereby representing a promising therapeutic agent in the clinical treatment of chemoresistant cancer patients

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

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    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

    BBA, a Synthetic Derivative of 23-hydroxybutulinic Acid, Reverses Multidrug Resistance by Inhibiting the Efflux Activity of MRP7 (ABCC10)

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    <div><p>Natural products are frequently used for adjuvant chemotherapy in cancer treatment. 23-<i>O</i>-(1,4'-bipiperidine-1-carbonyl) betulinic acid (BBA) is a synthetic derivative of 23-hydroxybutulinic acid (23-HBA), which is a natural pentacyclic triterpene and the major active constituent of the root of <i>Pulsatilla</i><i>chinensis</i>. We previously reported that BBA could reverse P-glycoprotein (P-gp/ABCB1)-mediated multidrug resistance (MDR). In the present study, we investigated whether BBA has the potential to reverse multidrug resistance protein 7 (MRP7/ABCC10)-mediated MDR. We found that BBA concentration-dependently enhanced the sensitivity of <i>MRP7</i>-transfected HEK293 cells to paclitaxel, docetaxel and vinblastine. Accumulation and efflux experiments demonstrated that BBA increased the intracellular accumulation of [<sup>3</sup>H]-paclitaxel by inhibiting the efflux of [<sup>3</sup>H]-paclitaxel from HEK293/MRP7 cells. In addition, immunoblotting and immunofluorescence analyses indicated no significant alteration of MRP7 protein expression and localization in plasma membranes after treatment with BBA. These results demonstrate that BBA reverses MRP7-mediated MDR through blocking the drug efflux function of MRP7 without affecting the intracellular ATP levels. Our findings suggest that BBA has the potential to be used in combination with conventional chemotherapeutic agents to augment the response to chemotherapy.</p> </div

    Effect of tariquidar treatment on the subcellular localization of MRP7.

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    <p>HEK/MRP7 cells were treated with 0.3 µM tariquidar for different periods of time. The subcellular localization of MRP7 was analyzed by immunofluorescence. MRP7 staining is shown in green. DAPI (blue) counterstains the nuclei.</p

    BBA, a Derivative of 23-Hydroxybetulinic Acid, Potently Reverses ABCB1-Mediated Drug Resistance <i>in Vitro</i> and <i>in Vivo</i>

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    23-<i>O</i>-(1,4′-Bipiperidine-1-carbonyl)­betulinic acid (BBA), a synthetic derivative of 23-hydroxybetulinic acid (23-HBA), shows a reversal effect on multidrug resistance (MDR) in our preliminary screening. Overexpression of ATP-binding cassette (ABC) transporters such as ABCB1, ABCG2, and ABCC1 has been reported in recent studies to be a major factor contributing to MDR. Our study results showed that BBA enhanced the cytotoxicity of ABCB1 substrates and increased the accumulation of doxorubicin or rhodamine123 in ABCB1 overexpressing cells, but had no effect on non ABCB1 substrate, such as cisplatin; what’s more, BBA slightly reversed ABCG2-mediated resistance to SN-38, but did not affect the ABCC1-mediated MDR. Further studies on the mechanism indicated that BBA did not alter the expression of ABCB1 at mRNA or protein levels, but affected the ABCB1 ATPase activity by stimulating the basal activity at lower concentrations and inhibiting the activity at higher concentrations. In addition, BBA inhibited the verapamil-stimulated ABCB1 ATPase activity and the photolabeling of ABCB1 with [<sup>125</sup>I] iodoarylazidoprazosin in a concentration-dependent manner, indicating that BBA directly interacts with ABCB1. The docking study confirmed this notion that BBA could bind to the drug binding site(s) on ABCB1, but its binding position was only partially overlapping with that of verapamil or iodoarylazidoprazosin. Importantly, BBA increased the inhibitory effect of paclitaxel in ABCB1 overexpressing KB-C2 cell xenografts in nude mice. Taken together, our findings suggest that BBA can reverse ABCB1-mediated MDR by inhibiting its efflux function of ABCB1, which supports the development of BBA as a novel potential MDR reversal agent used in the clinic

    Effect of tariquidar and cepharanthine on the cytotoxicity of paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine and cisplatin in <i>MRP7</i>-transfected cells.

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    a<p>Values represent mean ± SD of at least three independent experiments, each performed in triplicate.</p>b<p>Fold of resistance was calculated as the IC<sub>50</sub> values of paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine or cisplatin of HEK/pcDNA or HEK/MRP7 cells in the absence or presence of reversal agents divided by the IC<sub>50</sub> values of paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine or cisplatin of HEK/pcDNA cells without the reversing agents.</p>*<p>: <i>P<0.05</i>.</p

    BBA inhibits the efflux of [<sup>3</sup>H]-paclitaxel mediated by MRP7 in HEK293/MRP7 cells.

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    <p>Cells were pre-incubated with or without BBA at 2.5 µM (A) or 5 µM (B) for 2 h at 37 °C and further incubated with 0.1 µM [<sup>3</sup>H]-paclitaxel for another 2 h at 37 °C. Cells were then incubated in the fresh medium with or without BBA at 2.5 or 5 µM for different time periods at 37 °C. Thereafter cells were collected and the intracellular levels of [<sup>3</sup>H]-paclitaxel were measured by scintillation counting. A time course versus percentage of intracellular [<sup>3</sup>H]-paclitaxel was plotted (0, 30, 60 and 120 min). Data points represent the means ± SD of triplicate determinations. Experiments were performed at least three independent times.</p
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