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

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    • "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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    Experimental and therapeutic medicine 11/2014; 8(5):1611-1615. DOI:10.3892/etm.2014.1932 · 1.27 Impact Factor
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    • "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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