Estradiol and progesterone-mediated regulation of P-gp in P-gp overexpressing cells (NCI-ADR-RES) and placental cells (JAR)
Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, 20 Penn Street, Baltimore, Maryland 21201, USA. Molecular Pharmaceutics
(Impact Factor: 4.38).
12/2009; 6(6). DOI: 10.1021/mp900077q
The effect of progesterone and estrogen treatment on the expression and function of P-glycoprotein (P-gp) was evaluated in JAR cells and a P-gp overexpressing cell line, NCI-ADR-RES. Western blot analysis and real-time Q-PCR were used to evaluate P-gp protein and MDR1 mRNA expression respectively in the cells following incubation with progesterone (P4) and/or β-estradiol (E2). Cellular uptake studies of the P-gp substrates, saquinavir and paclitaxel, were performed to evaluate function. Treatment with either E2 or P4 resulted in a significant increase in P-gp protein levels in the NCI-ADR-RES cells at concentrations of or greater than 100 nM or 10 nM, respectively. JAR cells also had increased levels of P-gp with 100 nM of P4 but were much more sensitive to E2 showing increased P-gp at a concentration of 1 nM. Furthermore, E2 or P4 treatment resulted in a significant decrease in cellular uptake of the P-gp substrates tested in these cells lines. Based on mRNA quantitation, a transient increase (2-fold) in MDR1 levels was observed at 8 h postincubation with either E2 or P4, while MDR1 levels remained high in the JAR cells treated with E2 for 72 h postincubation. The addition of actinomycin D, a transcription inhibitor negated the increase in P-gp by P4 and E2. P4 and E2 increase P-gp expression and function in NCI-ADR-RES and JAR cells with the ERα-expressing cells (JAR) much more sensitive to E2. Furthermore, transcriptional regulation by E2 and P4 likely contributes to the modulation of P-gp levels.Keywords: Hormones; pregnancy; estradiol; progesterone; JAR cells; NCI-ADR-RES cells; regulation
Available from: PubMed Central
- "These proteins decrease the accumulation of ADR in the cells, thereby reducing the effects of ADR (19). P-gp, encoded by the MDR1 gene, is one of the multi-drug resistance-associated proteins acting as an efflux pump (20,21). The overexpression of P-gp may lower intracellular drug accumulation and decrease the cellular toxicity of chemo-therapeutics, including ADR, epirubicin, mitoxantrone and paclitaxel (22,23). "
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ABSTRACT: Multidrug resistance (MDR) is a major obstacle to the chemotherapeutic treatment of breast cancer. Germacrone, the main component of Rhizoma Curcuma, has been shown to possess antitumor, anti-inflammatory and immunomodulatory properties. The aim of the present study was to investigate the effect of germacrone on MCF-7/Adriamycin (ADR) multidrug-resistant human breast cancer cells. The treatment of MCF-7/ADR cells with a combination of germacrone and ADR resulted in an increase in cytotoxicity compared with that of ADR alone, as determined using an MTT assay. Flow cytometric analysis revealed that germacrone promoted cell apoptosis in a dose-dependent manner, whilst treatment with germacrone plus ADR enhanced the apoptotic effect synergistically. Furthermore, the results from the western blot analysis demonstrated that augmenting ADR treatment with germacrone resulted in a reduction of anti-apoptotic protein expression levels (bcl-2) and enhancement of pro-apoptotic protein expression levels (p53 and bax) in MCF-7/ADR cells compared with the levels achieved by treatment with ADR alone. In addition, germacrone significantly reduced the expression of P-glycoprotein via the inhibition of the multidrug resistance 1 (MDR1) gene promoter. These findings demonstrate that germacrone has a critical role against MDR and may be a novel MDR reversal agent for breast cancer chemotherapy.
Experimental and therapeutic medicine 11/2014; 8(5):1611-1615. DOI:10.3892/etm.2014.1932 · 1.27 Impact Factor
Available from: Caroline Prouillac
- "In addition, Zhang et al. (2006) reported the induction of ABCG2 mRNA by E2 in the ESR1 positive MCF-7 cells. Human ABCB1 and rodent Abcb1a–b genes were shown to be transcriptionally regulated by progesterone and estrogens in vivo and in vitro (Arceji et al., 1990; Coles et al., 2009; Evseenko et al., 2007; Vore and Leggas, 2008). Abcc3 gene was transcriptionally down-regulated in rat liver during pregnancy, and human ABCC3 gene was inhibited by E2 through an ESR-dependent mechanism, in the human breast cancer MVLN cell line (Cao et al., 2002; Vendrell et al., 2004). "
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ABSTRACT: The mycotoxin zearalenone (ZEN) is produced by a variety of Fusarium fungi and contaminates numerous cereals, fruits and vegetables. Interacting with the estrogen receptors, ZEN and reduced metabolites zearalenols cause hormonal effects in animals. Few data are available on the effects of repeated exposure to ZEN, particularly during pregnancy. The aim of our work was to assess the impact of this toxin on the expression of ABC transporters and nuclear receptors in fetal liver and pregnant rats that were exposed daily (gestation day 7-20) to 1 mg/kg ZEN. Significant variations were observed, depending on the tissue type, the tissue origin (maternal or fetal), and the time of analysis after the last exposure to ZEN (4 h or 24 h). The modulations of expression were independent of the magnitude of tissue impregnation by ZEN and its metabolites. The maternal uterus was the most sensitive tissue: Abcb1a, Abcb1b and Abcg2 mRNA and protein expressions were induced at both times, while Abcc1, Abcc3 and Esr1 mRNA and protein expressions were inhibited then induced 4 h and 24 h after exposure, respectively. In the fetal liver, Abcb1a and Esr1 protein expression was inhibited at both times, while mRNA expression was induced 24 h after the last exposure to ZEN. These results suggested that ZEN exposure could impact maternal and fetal exposure to ABC transporters substrates, and influence fetus development through nuclear receptor modulation.
Toxicology Letters 04/2012; 211(3):246-56. DOI:10.1016/j.toxlet.2012.04.001 · 3.26 Impact Factor
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ABSTRACT: The regulation of gene transcription is achieved through specific interactions between transcription factors and their binding sites in the upstream region of the gene being regulated. Correct identification of these binding sites represents a key challenging problem in computational biology. Our approach to the problem is to find a "clear" cluster in the space of all k-mers from the upstream regulatory regions of a set of genes that potentially share similar binding sites. The cluster identification is performed by using minimal spanning tree (MST) technique with a special distance between k-mers based on the chosen profile. It's shown that widely used "conservation" characteristic in position is a result of a "common sense" requirement for "conservation". The local convergence of algorithm for "conservation" maximization of profile has been proved and the method for statistical significance evaluation of results is presented. All ideas have been implemented in a form of software CUBIC.
Computational Systems Bioinformatics Conference, 2004. CSB 2004. Proceedings. 2004 IEEE; 09/2004
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