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Chinese Journal of Oncology ; (12): 654-660, 2011.
Article Dans Chinois | WPRIM | ID: wpr-320112

Résumé

<p><b>OBJECTIVE</b>To explore the regulation mechanism of the reversal of breast cancer resistance protein-mediated multidrug resistance by toremifene.</p><p><b>METHODS</b>Two recombinant plasmids (pcDNA3-promoter-BCRP and pcDNA3-CMV-BCRP) were designed to express the wild-type full-length BCRP cDNA enforced driven by its endogenous promoter containing a functional ERE and a CMV promoter as control, respectively. Two recombinant plasmids were transfected into ERα-positive MCF-7 and ERα-negative MDA-MB-231 breast cancer cell lines. Four kinds of BCRP expressing cell lines of MCF-7/Promoter-BCRP, MCF-7/CMV-BCRP, MDA-MB-231/Promoter-BCRP and MDA-MB-231/CMV-BCRP were established in which BCRP was promoted by the BCRP promoter and a CMV promoter as control, respectively. The drug resistant cells were treated with toremifene. Then RT-PCR, Western blot, mitoxantrone efflux assays and cytotoxicity assay were performed to detect the reversal function of BCRP by toremifene on the drug resistance cell lines.</p><p><b>RESULTS</b>Toremifene significantly downregulated BCRP mRNA levels in a dose-dependent manner in ERα-positive MCF-7/Promoter-BCRP cells than that of untreated control cells. In MCF-7/Promoter-BCRP cells, toremifene at the dose of 0.1, 1 and 10 µmol/L decreased BCRP mRNA expression by 29.5% (P < 0.05), 68.1% (P < 0.01) and 97.4% (P < 0.01), respectively. After being treated with toremifene and 17β-estradiol, the BCRP mRNA level in MCF-7/Promoter-BCRP cells was 64.2% ± 1.3%, significantly higher than that of toremifene treatment control cells (3.8% ± 0.2%,P < 0.01). Furthermore, the effect of toremifene on BCRP protein is similar in BCRP mRNA. Toremifene obviously increased the mitoxantrone fluorescence intensity and decreased the efflux activity by 47.3% (P < 0.05) in MCF-7/promoter-BCRP cells when compared with the untreated control, whereas intracellular accumulation of mitoxantrone obviously decreased and the efflux activity increased by 61.5% were observed in combination with 17β-estradiol when compared with toremifene treatment alone. The results therefore suggested that toremifene reversed mitoxantrone resistance in MCF-7/Promoter-BCRP cells. However, in MCF-7/CMV-BCRP, MDA-MB-231/Promoter-BCRP and MDA-MB-231/CMV-BCRP cells, toremifene or in combination with 17β-estradiol did not affect intracellular mitoxantrone uptake.</p><p><b>CONCLUSION</b>Taken together, our findings indicate that expression of BCRP is downregulated by toremifene, via a novel transcriptional mechanism which might be involved in the ERE of BCRP promoter through ER-mediated to inactivate the transcription of BCRP gene.</p>


Sujets)
Femelle , Humains , Membre-2 de la sous-famille G des transporteurs à cassette liant l'ATP , Transporteurs ABC , Génétique , Métabolisme , Antinéoplasiques , Pharmacologie , Antinéoplasiques hormonaux , Pharmacologie , Tumeurs du sein , Génétique , Métabolisme , Anatomopathologie , Lignée cellulaire tumorale , Cytomegalovirus , Génétique , Relation dose-effet des médicaments , Régulation négative , Multirésistance aux médicaments , Résistance aux médicaments antinéoplasiques , Oestradiol , Pharmacologie , Récepteur alpha des oestrogènes , Métabolisme , Régulation de l'expression des gènes tumoraux , Mitoxantrone , Pharmacologie , Protéines tumorales , Génétique , Métabolisme , Plasmides , Régions promotrices (génétique) , ARN messager , Métabolisme , Protéines recombinantes , Génétique , Métabolisme , Éléments de réponse , Génétique , Torémifène , Pharmacologie
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