P-Glycoprotein Substrates and Antagonists Cluster into Two Distinct Groups

Scala, Stefania; Akhmed, Nadia; Rao, U.S. Mahadeva; Paull, K.; Lan, Lu Bin; Dickstein, Bruce; Lee, Jong Seok; Elgemeie, Galal H.; Stein, Wilfred D.; Bates, Susan E.

doi:10.1124/mol.51.6.1024

Cited by 226 publications

(132 citation statements)

References 40 publications

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“…Many substrates and modulators of P-glycoprotein have been shown to stimulate or inhibit vanadate-sensitive associated ATPases (31,40,41). As a consequence we examined that characteristic for BPA over a wide concentration range (100 nM to 10 μM).…”

Section: Discussionmentioning

confidence: 99%

Effect of bisphenol A on drug efflux in BeWo, a human trophoblast-like cell line

Audus

2005

Placenta

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. (2005) Effect of bisphenol A on drug efflux in BeWo, a human trophoblast-like cell line. Placenta, 26 Suppl.A, S96-S103. PMID: 15837075. Publisher's official version: http://dx.doi.org/10.1016/j.placenta. Keywords:Bisphenol A (BPA), P-glycoprotein (P-gp), BeWo cells, Drug efflux and 17β-estradiol (E2) Abstract:Bisphenol A (BPA) is a monomer of polycarbonate plastics that has estrogenic activities and has been shown to be a substrate for multidrug resistant efflux mechanisms, specifically, P-glycoprotein. Since the natural hormone estrogen reverses multidrug resistance in some cell types, we hypothesized that BPA might have a similar activity in trophoblasts. We have used BeWo cells as an in vitro model for human trophoblasts and calcein AM as a substrate for drug efflux mechanism to characterize BPA interactions with placental P-glycoprotein. We found that chronic exposure of BeWo cells to BPA did not alter intracellular calcein accumulation in a fashion that would be reflective of changes in Pglycoprotein expression. However, BeWo cells acutely exposed to BPA pre-treatment were observed to have a significantly decreased calcein accumulation suggesting a direct stimulatory effect on P-gp. Addition of cyclosporin A, a P-glycoprotein inhibitor and substrate, completely reversed BPA's effects on calcein accumulation and resulted in a net increase, relative to controls, in calcein accumulation by the BeWo cells. BPA was found not stimulate P-gp ATPase. Therefore, our results suggested that BPA stimulated drug efflux by BeWo cells probably by direct effects on P-glycoprotein.

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Section: Discussionmentioning

confidence: 99%

Effect of bisphenol A on drug efflux in BeWo, a human trophoblast-like cell line

Audus

2005

Placenta

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“…The ability to inhibit photoaffinity labeling has frequently been used as an indicator of whether a particular drug interacts with Pglycoprotein (26,27). Therefore, to demonstrate the binding of the anthracycline derivatives to P-glycoprotein and to determine whether differences in azidopine competition could be identified between cytotoxic and noncytotoxic anthracycline derivatives, photolabeling experiments were performed on CH R B30 plasma membrane vesicles in which about 15% of the protein is P-glycoprotein.…”

Section: Inhibition Of [ 3 H]azidopine Photolabeling Of P-glycoproteimentioning

confidence: 99%

Ligand-mediated Tertiary Structure Changes of Reconstituted P-glycoprotein

Sonveaux¹,

Vigano²,

Shapiro³

et al. 1999

Journal of Biological Chemistry

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Ligand-dependent changes in accessibility of purified P-glycoprotein, functionally reconstituted in liposomes, were investigated by fluorescence measurements. Trp quenching experiments provided evidence that P-glycoprotein adopts different tertiary structures upon binding of drug substrates in the absence and presence of MgATP and its nonhydrolyzable analog, MgATP␥S. Five anthracycline derivatives were tested as drug substrates: daunorubicin, 4-epi-doxorubicin, iododoxorubicin, 4-demethoxy-daunorubicin, and methoxy-morpholino-doxorubicin. Among them, daunorubicin and 4-epi-doxorubicin have been shown to be rejected outside the multidrug-resistant cells, whereas the three others have been shown to accumulate in multidrug-resistant cells overexpressing P-glycoprotein and therefore retain their cytotoxic activity. A small conformational change was associated with nucleotide binding and amplified after nucleotide hydrolysis. Different conformational states were adopted by P-glycoprotein upon the addition of the anthracycline derivatives in the absence and presence of MgATP or MgATP␥S. These conformational changes are shown to be related to the nature of the antitumor agents and more precisely to their capacity to accumulate in resistant cells. These data also suggest that the cytotoxicity of iododoxorubicin and 4-demethoxy-daunorubicin is related to the fact they are not transported by P-glycoprotein. On the contrary, methoxymorpholino-doxorubicin cytotoxicity may be explained in terms of its rapid reincorporation into the plasma membrane after being transported by P-glycoprotein.P-glycoprotein is a 170-kDa plasma membrane protein involved in the multidrug resistance phenomenon responsible for failure of many human cancer chemotherapies (1). A structural prediction based on its sequence predicts two homologous halves, each containing six putative membrane-spanning ␣ helices and a cytoplasmic nucleotide-binding domain (NBD) 1 with characteristic Walker motifs A and B. However, experimental studies concerning this proposed topology (2-5) remain controversial. According to its sequence, P-glycoprotein is classified as a member of a large family of membrane transporters known as the ATP-binding cassette superfamily that includes yeast, bacteria, and mammalian transporters (6, 7). P-glycoprotein is proposed to function as an ATP-driven efflux pump, transporting through the plasma membrane an unusually broad but well defined spectrum of structurally unrelated cytotoxic drugs, including the Vinca alkaloids, anthracyclines, epipodophyllotoxins, and taxanes (8 -10).A large body of evidence suggests that the transmembrane domains of the P-glycoprotein participate in the recognition of substrates, whereas the ATP hydrolysis necessary for transport is carried out by both NBD regions with a similar efficiency in an alternating fashion (11-16). The mechanism of coupling ATP hydrolysis at the two cytoplasmic nucleotidebinding sites to drug transport by the intramembrane drugbinding site(s) is likely to involve substantial conforma...

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“…After intracellular bioactivation (Furumai et al, 2002;Xiao et al, 2003), FK228 specifically inhibits class I HDAC enzymes (Furumai et al, 2002), and results in the induction (e.g., p21) or suppression (e.g., c-Myc) of various target genes (Sandor et al, 2000b). An in vitro screening conducted at the National Cancer Institute indicated that FK228 is an MDR1 (P-glycoprotein, ABCB1) substrate (Scala et al, 1997). Recently, we have shown that FK228 is a substrate of multidrug resistance-associated protein 1 (MRP1 or ABCC1) .…”

mentioning

confidence: 99%

Chemoresistance to Depsipeptide FK228 [(E)-(1S,4S,10S,21R)-7-[(Z)-Ethylidene]-4,21-diisopropyl-2-oxa-12,13-dithia-5,8,20,23-tetraazabicyclo[8,7,6]-tricos-16-ene-3,6,9,22-pentanone] Is Mediated by Reversible MDR1 Induction in Human Cancer Cell Lines

Xiao

Huang

Dai

et al. 2005

J Pharmacol Exp Ther

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Histone acetylation status, an epigenetic determinant of gene transcription, is controlled by histone acetyltransferases (HATs) and histone deacetylases (HDACs). The potent HDAC inhibitor -oxa-12,13-dithia-5,8,20,23-tetraazabicyclo[8,7,6]-tricos-16-ene-3,6,9,22-pentanone] is a substrate for multidrug resistance protein (MDR1) and multidrug resistance-associated protein 1 (MRP1), both of which mediate FK228 resistance. To determine the mechanisms underlying acquired FK228 resistance, we developed four FK228-resistant cell lines from HCT-15, IGROV1, MCF7, and K562 cells by stepwise increases in FK228 exposure. Parent and resistant cells were characterized using a 70-oligomer cDNA microarray, real-time reverse transcription-polymerase chain reaction (RT-PCR), Western blot, and cytotoxicity assays. At both mRNA and protein levels, MDR1, but not MRP1 or other potential resistance genes, was strongly up-regulated in all resistant cell lines. HAT or HDAC activities were unaffected in resistant cells, consistent with a lack of cross-resistance to HDAC inhibitors that are not MDR1 substrates. FK228 was found to reversibly induce MDR1 expression by HDAC inhibition and subsequent histone hyperacetylation at the MDR1 promoter, as shown by real-time RT-PCR, Western blot, and chromatin immunoprecipitation. This study reveals a significant role of histone acetylation in MDR1 transcription, which seems to mediate FK228 resistance.

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P-Glycoprotein Substrates and Antagonists Cluster into Two Distinct Groups

Cited by 226 publications

References 40 publications

Effect of bisphenol A on drug efflux in BeWo, a human trophoblast-like cell line

Effect of bisphenol A on drug efflux in BeWo, a human trophoblast-like cell line

Ligand-mediated Tertiary Structure Changes of Reconstituted P-glycoprotein

Chemoresistance to Depsipeptide FK228 [(E)-(1S,4S,10S,21R)-7-[(Z)-Ethylidene]-4,21-diisopropyl-2-oxa-12,13-dithia-5,8,20,23-tetraazabicyclo[8,7,6]-tricos-16-ene-3,6,9,22-pentanone] Is Mediated by Reversible MDR1 Induction in Human Cancer Cell Lines

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