Up-regulation of transporters of the MRP family by drugs and toxins

Schrenk, Dieter; Baus, Petra R.; Ermel, Nadine; Klein, Christine A.; Vorderstemann, Birgit; Kauffmann, Hans-Martin

doi:10.1016/s0378-4274(01)00306-x

Cited by 111 publications

(80 citation statements)

References 26 publications

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“…MRP1 has also been found to be expressed in astrocytes, a sub-type of glial cells, at lesion sites [18] . In addition, several studies have shown that chemical carcinogens and chemotherapeutic agents, such as cisplatin, barbiturates, as well as the antibiotic rifampicin can increase the expression of MRP1 [19] . Our findings are in agreement with the recent data showing that the overexpression of MRP1 causes resistance to antiepileptic drugs [20,21] .…”

Section: Discussionmentioning

confidence: 99%

Multidrug resistance-associated protein 1 decreases the concentrations of antiepileptic drugs in cortical extracellular fluid in amygdale kindling rats

et al. 2013

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Aim: To investigate whether multidrug resistance-associated protein 1 (MRP1) was responsible for drug resistence in refractory epilepsy in amygdale kindling rats. Methods: Rat amygdale kindling was used as a model of refractory epilepsy. The expression of MRP1 mRNA and protein in the brains was examined using RT-PCR and Western blot. MRP1-positive cells in the cortex and hippocampus were studied with immunohistochemical staining. The rats were intraperitoneally injected with phenytoin (50 mg/kg) or carbamazepine (20 mg/kg), and their concentrations in the cortical extracellular fluid were measured using microdialysis and HPLC. Probenecid, a MRP1 inhibitor (40 mmol/L, 50 μL) was administered through an inflow tube into the cortex 30 min before injection of the antiepileptic drugs. Results: The expression of MRP1 mRNA and protein was significantly up-regulated in the cortex and hippocampus in amygdale kindling rats compared with the control group. Furthermore, the number of MRP1-positive cells in the cortex and hippocampus was also significantly increased in amygdale kindling rats. Microdialysis studies showed that the concentrations of phenytoin and carbamazepine in the cortical extracellular fluid were significantly decreased in amygdale kindling rats. Pre-administration of probenecid could restore the concentrations back to their control levels. Conclusion: Up-regulation of MRP1 is responsible for the resistance of brain cells to antiepileptic drugs in the amygdale kindling rats.

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Section: Discussionmentioning

confidence: 99%

Multidrug resistance-associated protein 1 decreases the concentrations of antiepileptic drugs in cortical extracellular fluid in amygdale kindling rats

et al. 2013

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“…Cancer cells resistant to CDDP express various ABC transporters, 16,18 though it is not certain if all of these genes are involved in CDDP resistance.…”

Section: Discussionmentioning

confidence: 99%

“…14 -19 In human cancer cells, the expression of several ABC transporters was found in CDDP -resistant cells together with up -regulation of GSH and GST . 15,16,18 Then, CDDP resistance may be obtained through multiple pathways. Notably, a role for MRP1 and cMOAT in the efflux of CDDP was indicated.…”

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confidence: 99%

Hammerhead ribozyme against γ-glutamylcysteine synthetase sensitizes human colonic cancer cells to cisplatin by down-regulating both the glutathione synthesis and the expression of multidrug resistance proteins

et al. 2001

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Multidrug resistance in cancer cells is often associated with an elevation in the concentration of glutathione ( GSH ) and the expression of -glutamylcysteine synthetase ( -GCS ), a rate -limiting enzyme for GSH. We constructed a hammerhead ribozyme against a -GCS heavy subunit ( -GCSh ) mRNA transcript and transfected it to human colonic cancer cells ( HCT8DDP ) resistant to cisplatin ( CDDP ). The effect of the ribozyme transfection on the drug resistance of cancer cells was studied.

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“…[10][11][12][13][14][15][16][17] MRP1 expression is upregulated by various stimuli, such as oxidative stress, 18 heavy metals, 19 irradiation 20 and a variety of anticancer agents including DOX. 21,22 Osborn et al 23 suggested that c-jun N-terminal kinase (JNK) activation is an important component of the cellular responses to several anticancer drugs and may play a role in the MDR phenotype. JNK activity was found to be increased upon exposure to DOX in several human tumor cell lines.…”

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confidence: 99%

Doxorubicin induces expression of multidrug resistance-associated protein 1 in human small cell lung cancer cell lines by the c-jun N-terminal kinase pathway

et al. 2005

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Multidrug resistance (MDR) is a major impediment to successful chemotherapy for lung cancer. Overexpression of multidrug resistance-associated protein 1 (MRP1) appears to be involved in MDR development in lung cancer cells. A number of chemotherapeutic agents including doxorubicin (DOX) were reported to induce MRP1 expression in human lung cancer cells. In our study, we investigated the mechanism by which DOX induces MRP1 expression in human small cell lung cancer (SCLC) cell lines, GLC4 and NCI-H82. These cells expressed MRP1 protein at low levels and were sensitive to DOX. Doxorubicin at 50 nM induced a marked increase in MRP1 expression in 24 hr, and stimulated c-jun N-terminal kinase (JNK) activity. Treatment with a JNK inhibitor, SP600125, significantly inhibited MRP1 induction. Furthermore, transfection with JNK1 and JNK2 antisense oligonucleotides markedly inhibited DOX-induced MRP1 expression. Chromatin immunoprecipitation assays revealed an enhanced recruitment of phosphorylated c-jun to the MRP1 promoter containing the AP-1 site upon DOX stimulation, which was inhibited by pretreatment with SP600125. Surprisingly, GLC4 cells exposed to DOX for 24 hr maintained increased MRP1 expression and resistance to DOX for at least 3 weeks. Pretreatment with SP600125 before DOX stimulation blocked the appearance of the MDR phenotype as well as MRP1 induction in GLC4 cells. These findings suggest that JNK activation may play an essential role for the induction of MRP1 protein in human SCLC cells by chemotherapeutic agents and that combined treatment of a JNK inhibitor with anticancer drugs may prevent the development of MDR by the abrogation of MRP1 induction. ' 2005 Wiley-Liss, Inc.Key words: MRP1; JNK; doxorubicin; small-cell lung cancer; multidrug resistance Small cell lung cancer (SCLC) accounts for 15-25% of all lung cancer patients.1,2 Although up to 90% of SCLC tumors initially respond to chemotherapy, patients with SCLC often relapse with multidrug resistant state. There are several types of multidrug resistance (MDR) to anticancer agents, and some of them were identified in human carcinoma cell lines in vitro. One of the mechanisms of MDR is decreased accumulation of drug within cells because of reduced inward transport or increased drug efflux, such as overexpression of adenosine triphosphate (ATP)-binding cassette (ABC) transporters. 3 P-glycoprotein (P-gp) that was cloned from KB-C 2.5 cells was the first ABC transporter identified. 4 Overexpression of P-gp has been detected in many multidrug resistant tumor cell lines and a variety of tumors from patients with both acquired and inherent drug resistance.5 Although P-gp is implicated in drug resistance in a number of tumor types, it is infrequently expressed in lung cancer cells. Another ABC transporter was cloned from the doxorubicin (DOX) resistant H69/AR SCLC cell line by Cole et al. 6 The transporter was designated as multidrug resistance-associated protein 1 (MRP1). The MRP family is now composed of 9 related ABC transporters that are able to transp...

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Up-regulation of transporters of the MRP family by drugs and toxins

Cited by 111 publications

References 26 publications

Multidrug resistance-associated protein 1 decreases the concentrations of antiepileptic drugs in cortical extracellular fluid in amygdale kindling rats

Multidrug resistance-associated protein 1 decreases the concentrations of antiepileptic drugs in cortical extracellular fluid in amygdale kindling rats

Hammerhead ribozyme against γ-glutamylcysteine synthetase sensitizes human colonic cancer cells to cisplatin by down-regulating both the glutathione synthesis and the expression of multidrug resistance proteins

Doxorubicin induces expression of multidrug resistance-associated protein 1 in human small cell lung cancer cell lines by the c-jun N-terminal kinase pathway

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