Chemosensitisation of spontaneous multidrug resistance by a 1,4-dihydropyridine analogue and verapamil in human glioma cell lines overexpressing MRP or MDR1

Abe, Tetsutaro; Koike, KohjiK.; Ohga, Takefumi; Kubo, Takeshi; Wada, Morimasa; Kohno, Kimitoshi; Mori, T; Hidaka, Katsuhiko; Kuwano, Michihiko

doi:10.1038/bjc.1995.348

Cited by 56 publications

(39 citation statements)

References 19 publications

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“…Digoxin is not a substrate for Bcrp [58], but other studies have indicated that the poor BBB permeability of digoxin is not explained by P-gp alone [11,38]. Verapamil has been used as a P-gp inhibitor in concentrations from 5 to 150 μM [23,[59][60][61], but it has also been shown to inhibit Mrp activity in concentrations of 5-10 μM [45,62] as well as Bcrp activity, although not in the concentration range applied here [63,64]. In our study, 50 μM verapamil lowered the efflux ratio of digoxin to 1.1, whereas the Bcrp inhibitor, Ko 143, had no effect on the digoxin transport indicating that the verapamil inhibition of A-L digoxin transport we observed was due to inhibition of P-gp or Mrp's.…”

Section: Efflux Transporter Activity In Bovine Blood-brain Barrier Momentioning

confidence: 99%

An Electrically Tight In Vitro Blood–Brain Barrier Model Displays Net Brain-to-Blood Efflux of Substrates for the ABC Transporters, P-gp, Bcrp and Mrp-1

Helms

Hersom

Kuhlmann

et al. 2014

AAPS J

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Abstract. Efflux transporters of the ATP-binding cassette superfamily including breast cancer resistance protein (Bcrp/Abcg2), P-glycoprotein (P-gp/Abcb1) and multidrug resistance-associated proteins (Mrp's/ Abcc's) are expressed in the blood-brain barrier (BBB). The aim of this study was to investigate if a bovine endothelial/rat astrocyte in vitro BBB co-culture model displayed polarized transport of known efflux transporter substrates. The co-culture model displayed low mannitol permeabilities of 0.95±0.1·10 H-etoposide revealed polarized transport favouring the brain-to-blood direction for all substrates. Steady state efflux ratios of 2.5±0.2 for digoxin, 4.4±0.5 for estrone-3-sulphate and 2.4±0.1 for etoposide were observed. These were reduced to 1.1±0.08, 1.4±0.2 and 1.5±0.1, by addition of verapamil (digoxin), Ko143 (estrone-3-sulphate) or zosuquidar+reversan (etoposide), respectively. Brain-toblood permeability of all substrates was investigated in the presence of the efflux transporter inhibitors verapamil, Ko143, zosuquidar, reversan and MK 571 alone or in combinations. Digoxin was mainly transported via P-gp, estrone-3-sulphate via Bcrp and Mrp's and etoposide via P-gp and Mrp's. The expression of P-gp, Bcrp and Mrp-1 was confirmed using immunocytochemistry. The findings indicate that P-gp, Bcrp and at least one isoform of Mrp are functionally expressed in our bovine/rat co-culture model and that the model is suitable for investigations of small molecule transport.KEY WORDS: blood-brain barrier; breast cancer resistance protein; multidrug resistance-associated protein; p-glycoprotein; polarized small molecule transport.

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Section: Efflux Transporter Activity In Bovine Blood-brain Barrier Momentioning

confidence: 99%

An Electrically Tight In Vitro Blood–Brain Barrier Model Displays Net Brain-to-Blood Efflux of Substrates for the ABC Transporters, P-gp, Bcrp and Mrp-1

Helms

Hersom

Kuhlmann

et al. 2014

AAPS J

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“…24) To determine the expression of the individual MRP1, MRP2, MRP3, we established specific probes for each MRP family member by polymerase chain reaction (PCR) amplification. Levels of mRNA were quantified densitometrically with a Fujix BAS 2000 bio imaging analyzer (Fuji Photo Film Co., Tokyo).…”

Section: )mentioning

confidence: 99%

Involvement of the Multidrug Resistance Protein 3 in Drug Sensitivity and Its Expression in Human Glioma

Haga¹,

Hinoshita²,

Ikezaki³

et al. 2001

Japanese Journal of Cancer Research

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The multidrug resistance protein (MRP) family belongs to the ATP-binding cassette superfamily (ABC) of transporters, which are involved in ATP-dependent transport of hydrophobic compounds. One of the MRP family, MRP1, is partially associated with the multidrug resistance phenotype in brain tumors. In this study, we asked whether another MRP family gene, MRP3, could affect drug sensitivity to anticancer agents in human glioma cell lines and clinical glioma specimens. We first produced two antisense transfectants by introduction of antisense MRP3 cDNA into the glioma cell line NHG2, which endogenously expresses MRP3. The two MRP3 antisense transfectants showed 2-to 5-fold increases in drug sensitivity to etoposide and cisplatin compared with NHG2 cells, but their sensitivity to vincristine or nitrosourea was not changed. Two MRP3 cDNA sense transfectants of pig kidney cell lines showed 4-to 6-fold drug resistance to etoposide, but only 1.4-to 1.5-fold to cisplatin. We next compared the mRNA levels of four ABC transporters, multidrug resistance 1 (MDR1), MRP1, MRP2 and MRP3 in clinical samples, including 34 patients with gliomas, by quantitative RT-PCR analysis. In some of the clinical samples, increased expression of MRP1 and MRP3 was apparent in malignant gliomas. In situ hybridization revealed that glioma cells were stained with MRP3 probe. MRP3 may modulate drug sensitivity to certain anticancer agents in human gliomas.

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“…Moreover, DOX shows reduced efficacy against tumor cell populations that exhibit the 'classical' P-gp MDR phenotype, as well as those with an altered topoisomerase II activity. Thus, numerous efforts were made to both generate structural analogues that improve the antitumor potency of DOX while lowering its toxicity and to circumvent cellular drug resistance mechanisms [11][12][13]. Recently, P-gp expression and in vitro uptake of DOX were studied in glioblastoma and endothelial cell lines [14].…”

Section: Introductionmentioning

confidence: 99%

Modulation of Multidrug-Resistance-Associated P-Glycoprotein in Human U-87 MG and HUV-ECC Cells with Antisense Oligodeoxynucleotides to MDR1 mRNA

Rittierodt¹,

Tschernig

Harada

2004

Pathobiology

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Objective: Glioblastoma is the highest dedifferentiated form of astrocytic brain tumors, and it is refractory to chemotherapy in most cases. To improve the clinical outcome of such tumors, new therapeutic strategies are needed. While malignancy is mainly associated with a nonfunctional apoptotic pathway, the lack of chemotherapeutic success correlates with overexpression of the multidrug resistance 1 (MDR1) gene product P-glycoprotein (P-gp). Previous investigations have shown that not only glioblastoma cells but also endothelial cells are important in the response to chemotherapy. The aim of the present investigations was to reduce the expression of P-gp in the human glioblastoma cell line U-87 MG and in the human endothelial cell line HUV-ECC. Methods: Therefore, these cells were treated with antisense oligodeoxynucleotides (asn-ODN) directed against the P-gp mRNA in order to increase the intracellular retention of doxorubicin (DOX) which had been given previously. Results: Flow cytometry revealed about 4-fold increased intracellular retention of DOX in both asn-ODN-treated cell lines as compared to asn-ODN non-treated cell lines. Conclusion: These results suggest that asn-ODN-mediated inhibition of P-gp expression is an efficient way to increase intracellular retention of DOX.

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Chemosensitisation of spontaneous multidrug resistance by a 1,4-dihydropyridine analogue and verapamil in human glioma cell lines overexpressing MRP or MDR1

Cited by 56 publications

References 19 publications

An Electrically Tight In Vitro Blood–Brain Barrier Model Displays Net Brain-to-Blood Efflux of Substrates for the ABC Transporters, P-gp, Bcrp and Mrp-1

An Electrically Tight In Vitro Blood–Brain Barrier Model Displays Net Brain-to-Blood Efflux of Substrates for the ABC Transporters, P-gp, Bcrp and Mrp-1

Involvement of the Multidrug Resistance Protein 3 in Drug Sensitivity and Its Expression in Human Glioma

Modulation of Multidrug-Resistance-Associated P-Glycoprotein in Human U-87 MG and HUV-ECC Cells with Antisense Oligodeoxynucleotides to MDR1 mRNA

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