Action mechanism and clinical application of leukotriene receptor antagonist as multidrug resistance protein 1 (MRP1) modulator

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Our purpose of research is to clarify the mechanism of anticancer drug resistance by tumor cells and developing effective resistance modulators. Multidrug resistance can be mediated by overexpression of the multidrug resistance protein 1(MRP1). MRP function as transmembrane efflux pumps, which decrease intracellular drug accumulation, thereby conferring multidrug resistance. One of the ways to overcome MRP1 mediated multidrug resistance is to use an inhibitor to block the function of MRP1. This is called MRP1 modulator. To date, several MRP1 modulator have entered study and clinical trials. Recently, leukotriene receptor antagonist(LTRA) is thought to be one of the MRP1 modulator. We studied effect to overcome drug resistance by LTRA and have developed original candidate medications.In our study duration, we got results as below; The resistance cancer cells was established by two methods. The cells were selected from Jurkat (human leukemia cell line) by chronic exposure to doxorubicin over 2 months and transfection of MRP1cDNA. In the resistant cells, the overexpression of MRP1 resulted from an increased MRPmRNA level transcribed from amplified MRP gene. The dose-response effects of LTRA in the presence or absence of doxorubicin were examined in both drug-sensitive Jurkat and MRP-overexpressing resistant cells. LTRA reversed Jurkat resistance. The fluorescent accumulation analysis revealed a significant increase of fluorescence in resistant Jurkat pre-incubated LTRA. We demonstrated that LTRA modulate MRP1 scientifically by the measurement of intracellular glutathione, ATPase assay, analysis of cell-cycle pathway. We have written the report now.