Role of the MRP1/ABCC1 Multidrug Transporter Protein in Cancer

Munoz, Marcia A.; Henderson, Michelle J.; Haber, Michelle; Norris, Murray D.

doi:10.1080/15216540701736285

Cited by 203 publications

(149 citation statements)

References 41 publications

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“…It is thus essential to exclude that MDR1 and FZD1 amplification and overexpression are exclusively related to cell culture. Overexpression of MDR1 in patient tumour tissue following chemotherapy is well documented, whereas increased expression of FZD1 has not been reported Norris et al, 1997;Blanc et al, 2003;Munoz et al, 2007). Moreover, attempts to overcome P-gp-mediated drug resistance in patients using specific inhibitors of P-gp has had limited success (Duhem et al, 1996;Ludwig et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…This drug efflux is partially mediated by cell surface glycoproteins, which belong to the family of ATP-binding cassette (ABC) of multidrug transporters (Gottesman et al, 2002). ABC transporters, such as MDR1 (multidrug resistance gene) and MRP1 (MDR-related protein), are highly expressed in many human cancers including neuroblastoma (NB) Norris et al, 1997;Blanc et al, 2003;Munoz et al, 2007), and they are associated with the resistance of these tumours to chemotherapeutic drugs Norris et al, 1997;Gottesman et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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The Wnt receptor FZD1 mediates chemoresistance in neuroblastoma through activation of the Wnt/β-catenin pathway

et al. 2009

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The development of chemoresistance represents a major obstacle in the successful treatment of cancers such as neuroblastoma (NB), a particularly aggressive childhood solid tumour. The mechanisms underlying the chemoresistant phenotype in NB were addressed by gene expression profiling of two doxorubicin (DoxR)-resistant vs sensitive parental cell lines. Not surprisingly, the MDR1 gene was included in the identified upregulated genes, although the highest overexpressed transcript in both cell lines was the frizzled-1 Wnt receptor (FZD1) gene, an essential component of the Wnt/b-catenin pathway. FZD1 upregulation in resistant variants was shown to mediate sustained activation of the Wnt/b-catenin pathway as revealed by nuclear b-catenin translocation and target genes transactivation. Interestingly, specific microadapted short hairpin RNA (shRNAmir)-mediated FZD1 silencing induced parallel strong decrease in the expression of MDR1, another b-catenin target gene, revealing a complex, Wnt/b-catenin-mediated implication of FZD1 in chemoresistance. The significant restoration of drug sensitivity in FZD1-silenced cells confirmed the FZD1-associated chemoresistance. RNA samples from 21 patient tumours (diagnosis and postchemotherapy), showed a highly significant FZD1 and/or MDR1 overexpression after treatment, underlining a role for FZD1-mediated Wnt/b-catenin pathway in clinical chemoresistance. Our data represent the first implication of the Wnt/b-catenin pathway in NB chemoresistance and identify potential new targets to treat aggressive and resistant NB.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Wnt receptor FZD1 mediates chemoresistance in neuroblastoma through activation of the Wnt/β-catenin pathway

et al. 2009

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“…In addition to PHT and CBZ, other xenobiotics and endobiotics may also be the substrates of MRP1 [28] . Although changes in the properties of the targets of AEDs resulted in the decrease of its sensitivity, they do not explain the multidrug resistance.…”

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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“…As mentioned earlier, a remarkably wider variety of transport substrates have been identified for MRP1, in comparison with P-gp. Thus, whereas epirubicin, an anthracycline compound, is a substrate for both efflux pumps P-gp and MRP1, the oxazaphosphorine ifosfamide is extruded from the cell through MRP1 (5,19). More specifically, GSTs coparticipate in the detoxification of ifosfamide with GSH conjugation reactions (20) and it has been established that the active cellular efflux of GSH conjugates is mediated primarily by MRP1 (21,22).…”

Section: Discussionmentioning

confidence: 99%

“…These ATP-binding cassette (ABC superfamily) protein pumps include 49 genes, distributed in 7 families (from A to G). The "C" branch contains the largest number of transporters known at the present time, with ABCC1/MRP1 being the first to be characterized (5). P-glycoprotein (P-gp), encoded by the MDR1 gene, also called the ABCB1 gene, belongs to branch "B."…”

Section: Introductionmentioning

confidence: 99%

MRP1 Overexpression Determines Poor Prognosis in Prospectively Treated Patients with Localized High-Risk Soft Tissue Sarcoma of Limbs and Trunk Wall: An ISG/GEIS Study

Martin‐Broto

Gutiérrez

Ramos

et al. 2014

Molecular Cancer Therapeutics

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Patients with localized high-risk soft tissue sarcomas (STS) of the limbs and trunk wall still have a considerable metastatic recurrence rate of more than 50%, in spite of adjuvant chemotherapy. This drugceiling effect of chemotherapy in sarcoma setting could be explained, at least partially, by multidrug resistance (MDR) mechanisms. The aim of this study was to ascertain whether mRNA and protein expression of ABCB1 (P-glycoprotein), ABCC1 (MRP1), and GSTA1 (glutathione S-transferase pi) was prognostic in localized high-risk STS. Immunohistochemistry and reverse transcriptase-PCR studies were performed from biopsies at the time of diagnosis. Patients of this series were prospectively enrolled into a phase III trial that compared three versus five cycles of epirubicin plus ifosfamide. The series of 102 patients found 41 events of recurrence and 37 of death with a median follow-up of 68 months. In univariate analysis, variables with a statistically significant relationship with relapse-free survival (RFS) were: MRP1 expression (5-year RFS rate of 23% in positive cases and 63% in negative cases, P ¼ 0.029), histology (5-year RFS rate of 74% in undifferentiated pleomorphic sarcoma and 43% in synovial sarcoma, P ¼ 0.028), and ABCC1 expression (5-year RFS rate of 33% in overexpression and 65% in downregulation, P ¼ 0.012). Combined ABCC1/MRP1 was the only independent prognostic factor for both RFS (HR ¼ 2.704, P ¼ 0.005) and overall survival (HR ¼ 2.208, P ¼ 0.029). ABCC1/MRP1 expression shows robust prognostic relevance in patients with localized high-risk STS treated with anthracycline-based chemotherapy, which is the standard front line treatment in STS. This finding deserves attention as it points to a new targetable protein in STS.

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Role of the MRP1/ABCC1 Multidrug Transporter Protein in Cancer

Cited by 203 publications

References 41 publications

The Wnt receptor FZD1 mediates chemoresistance in neuroblastoma through activation of the Wnt/β-catenin pathway

The Wnt receptor FZD1 mediates chemoresistance in neuroblastoma through activation of the Wnt/β-catenin pathway

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

MRP1 Overexpression Determines Poor Prognosis in Prospectively Treated Patients with Localized High-Risk Soft Tissue Sarcoma of Limbs and Trunk Wall: An ISG/GEIS Study

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