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dc.contributor.authorMansilla, Sylvia-
dc.contributor.authorRojas, Marta-
dc.contributor.authorBataller, Marc-
dc.contributor.authorPriebe, Waldemar-
dc.contributor.authorPortugal, José-
dc.identifierdoi: 10.1016/j.bcp.2006.12.005-
dc.identifierissn: 0006-2952-
dc.identifier.citationBiochemical Pharmacology 73(7): 934-942 (2007)-
dc.description.abstractMultidrug-resistance protein 1 (MRP-1) confers resistance to a number of clinically important chemotherapeutic agents. The promoter of the mrp-1 gene contains an Sp1-binding site, which we targeted using the antitumor bis-anthracycline WP631. When MCF-7/VP breast cancer cells, which overexpress MRP-1 protein, were incubated with WP631 the expression of the multidrug-resistance protein gene decreased. Conversely, doxorubicin did not alter mrp-1 gene expression. The inhibition of gene expression was followed by a decrease in the activity of the MRP-1 protein. The IC75 for WP631 (drug concentration required to inhibit cell growth by 75%) circumvented the drug-efflux pump, without addition of resistant modifiers. After treatment with WP631, MCF-7/VP cells were committed to die after entering mitosis (mitotic catastrophe), while treatment with doxorubicin did not affect cell growth. This is the first report on an antitumor drug molecule inhibiting the mrp-1 gene directly, rather than being simply a poor substrate for the transporter-mediated efflux. However, both situations appeared to coexist, thereby a superior cytotoxic effect was attained. Ours results suggest that WP631 offers great potential for the clinical treatment of tumors displaying a multidrug-resistance phenotype. © 2006 Elsevier Inc. All rights reserved.-
dc.description.sponsorshipSM was recipient of a doctoral fellowship from the CIRIT, Generalitat de Catalunya. MB is recipient of a fellowship from Parc Cientific de Barcelona-CSIC. Supported by grants from the Spanish Ministry of Education and Science (SAF2002-00371 and SAF2005-00551), the FEDER program of the European Community and The Welch Foundation, Houston, TX. This work was carried out within the framework of the Centre de Referencia en Biotecnologia (Generalitat de Catalunya)-
dc.titleCircumvention of the multidrug-resistance protein (MRP-1) by an antitumor drug through specific inhibition of gene transcription in breast tumor cells-
dc.description.versionPeer Reviewed-
dc.contributor.funderMinisterio de Educación y Ciencia (España)-
dc.contributor.funderEuropean Commission-
dc.contributor.funderWelch Foundation-
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