Relation between the ability of some compounds to modulate the MRP1-mediated efflux of glutathione and to inhibit the MRPl-mediated efflux of daunorubicin

2区 · 医学

Article

作者: P. Loechariyakul ; C. Saengkhae ; A. Garnier-Suillerot ; M. Salerno

Much effort has been recently directed to identify the transport-modulating agents in order to overcome the P-gp- and MRP1-mediated drug resistance. Contrary to what is observed for P-gp, very few compounds have been shown to reverse multi-drug resistance (MDR) mediated by MRP1. On the other hand, despite of critical role of GSH in transporting the MRP1 substrates, not much is known about GSH interactions with MRP1. In this work, three compounds that were shown to inhibit the MRP1-mediated efflux of daunorubicin (DNR) have been studied. Depending on their nature the selected compounds have different effects, e.g. at 40 microM, verapamil inhibits 50% of DNR efflux whereas GSH efflux is increased about two-fold. PAK-104P has shown the same effect, i.e. the inhibition of the MRP1-mediated efflux of DNR is accompanied by a stimulation of GSH efflux. However, the PAK-104P concentration required to obtain the same effect is about 40 times smaller that in the case of verapamil. MK571 has been shown to inhibit the efflux of both DNR and GSH. Based on these observations and those reported earlier, a working model is proposed.

2001-01-01·International Journal of Cancer1区 · 医学

Reversal of LRP-associated drug resistance in colon carcinoma sw-620 cells

1区 · 医学

Article

作者: Takashi Aikou ; Shin-ichi Akiyama ; Kiyotomo Seto ; Hiroshi Okumura ; Ryuji Ikeda ; Shuichi Nagayama ; Tomoyuki Sumizawa ; Tatsuhiko Furukawa ; Masaki Kitazono

Resistance to multiple drugs is mediated by lung resistance-related protein (LRP) as well as P-glycoprotein (P-gp) and multidrug resistance protein (MRP). The levels of expression of LRP mRNA and LRP in a human colon carcinoma cell line, SW-620, were increased by the differentiation-inducing agent, sodium butyrate (NaB). Treatment of SW-620 cells with NaB for 2 weeks conferred resistance to adriamycin (ADM) and VP-16. The resistance was almost completely reversed by PAK-104P, a pyridine analog, but not by cepharanthine. ADM accumulated mainly in the nuclei of SW-620 cells not treated with NaB and in the cytoplasm of SW-620 cells treated with NaB. When the NaB-treated SW-620 cells were incubated with ADM in the presence of PAK-104P, the accumulation of ADM in nuclei was substantially increased. Isolated nuclei from untreated cells accumulated more ADM than nuclei from NaB-treated cells. Efflux of ADM from the nuclei isolated from NaB-treated cells was enhanced. PAK-104P and an antibody against LRP increased the accumulation of ADM in the isolated nuclei from NaB-treated cells, and inhibited the enhanced efflux of ADM from the nuclei. These findings suggest that at least in part, PAK-104P reverses LRP-mediated drug resistance by inhibiting the efflux of ADM from nuclei. PAK-104P may be useful for reversing MDR in tumors that overexpress LRP.

2000-04-01·Biochemical and Biophysical Research Communications3区 · 生物学

Functional Comparison between YCF1 and MRP1 Expressed in Sf21 Insect Cells

3区 · 生物学

Article

作者: Shunji Aoki ; Ayako Tani ; Xiao-Qin Ren ; Xiao-Dong Mei ; Tatsuhiko Furukawa ; Zhe-Sheng Chen ; Masaharu Komatsu ; Hiroshi Okumura ; Shin-ichi Akiyama ; Tomoyuki Sumizawa

YCF1 is a yeast vacuole membrane transporter involved in resistance to Cd(2+) and to exogenous glutathione S-conjugate precursors. MRP1 contributes to multidrug resistance (MDR) in tumor cells. MRP1 and YCF1 have extensive amino acid sequence homology (63% amino acid similarity). We expressed MRP1 or YCF1 in insect cell membranes and compared their functions to know more about their structure-function relationships. YCF1 and MRP1 with His epitopes were expressed in Sf21 insect cells; both of them in the plasma membrane. The ATP-dependent transport of [(3)H]LTC(4) in Sf/YCF1-His vesicles was osmotically sensitive and showed saturable kinetics with an apparent K(m) of 758 nM for LTC(4) and 94 microM for ATP which were similar to those in yeast cells. The K(m) of YCF1 for LTC(4) (758 nM) was sevenfold higher than that of MRP1 (108 nM). MK-571 and ONO-1078, reversing agents for MRP1-mediated MDR, considerably inhibited the transport of LTC(4) by both YCF1 and MRP1. However, PAK-104P, a pyridine analog that reverses MDR associated with P-gp and MRP1, inhibited the transporting activity of MRP1 stronger than that of YCF1. KE1, another MDR reversing agent, moderately inhibited the transport of LTC(4) by MRP1 but not that of YCF1. In conclusion, we successfully expressed yeast YCF1 in Sf21 insect cells and found that the localization of the protein was different from that in yeast. The function of YCF1 in Sf21 insect cells was similar but not identical to that of MRP1.

100 项与 PAK-104P 相关的药物交易

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