PSC833, CyclosporinA, and Dexniguldipine Effects on Cellular Calcein Retention and Inhibition of the Multidrug Resistance Pump in Human Leukemic Lymphoblasts

Wigler, Paul W.

doi:10.1006/bbrc.1999.0475

Cited by 20 publications

(11 citation statements)

References 14 publications

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“…Our findings, however, are consistent with one report that used another P-gp-specific mAb (MRK16) (31). Moreover, our finding of functional inhibition of calcein-AM dye efflux from purified CD4 ϩ T cells and monocytes by specific (Hyb-241 mAb) and pharmacologic P-gp inhibitors, a well-described function of P-gp in other cell types (30,32), confirmed that P-gp is functional in CD4 ϩ T cells and monocytes.…”

Section: Discussionsupporting

confidence: 92%

Specific MDR1 P-Glycoprotein Blockade Inhibits Human Alloimmune T Cell Activation In Vitro

Frank

Denton

Alexander

et al. 2001

The Journal of Immunology

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MDR1 P-glycoprotein (P-gp), the multidrug resistance-associated transmembrane transporter, is physiologically expressed by human peripheral immune cells, but its role in cell-mediated immunity remains poorly understood. Here, we demonstrate a novel role for P-gp in alloantigen-dependent human T cell activation. The pharmacologic P-gp inhibitor tamoxifen (1–10 μM) and the MDR1 P-gp-specific mAb Hyb-241 (1–20 μg/ml), which detected surface P-gp on 21% of human CD3+ T cells and 84% of CD14+ APCs in our studies, inhibited alloantigen-dependent, but not mitogen-dependent, T cell proliferation in a dose-dependent manner from 40–90% (p < 0.01). The specific inhibitory effect on alloimmune T cell activation was associated with >85% inhibition (p < 0.01) of IL-2, IFN-γ, and TNF-α production in 48-h MLR coculture supernatants. Addition of recombinant human IL-2 (0.1–10 ng/ml) restored proliferation in tamoxifen-treated cocultures. Pretreatment of purified CD4+ T cells with Hyb-241 mAb before coculture resulted in inhibition of CD4+ T cellular IFN-γ secretion. Also, blockade of P-gp on allogeneic APCs inhibited IL-12 secretion. Taken together these results demonstrate that P-gp is functional on both CD4+ T cells and CD14+ APCs, and that P-gp blockade may attenuate both IFN-γ and IL-12 through a positive feedback loop. Our results define a novel role for P-gp in alloimmunity and thus raise the intriguing possibility that P-gp may represent a novel therapeutic target in allograft rejection.

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Section: Discussionsupporting

confidence: 92%

Specific MDR1 P-Glycoprotein Blockade Inhibits Human Alloimmune T Cell Activation In Vitro

Frank

Denton

Alexander

et al. 2001

The Journal of Immunology

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“…These include calcium channel blockers (Tsuruo et al, 1981), calmodulin inhibitors (Kamath et al, 1991), protein kinase C inhibitors (Gekeler et al, 1996), steroids (Aebi et al, 1999), immunosuppressants (Wigler, 1999;List et al, 2002), and various other agents (Bhat et al, 1995;Kruijtzer et al, 2002). Among these agents, calcium channel blockers may be the most extensively investigated class of multidrug resistance modulators.…”

mentioning

confidence: 99%

New 4-Aryl-1,4-Dihydropyridines and 4-Arylpyridines as P-Glycoprotein Inhibitors

Zhou

Zhang²,

Tseng³

et al. 2004

Drug Metab Dispos

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ABSTRACT:Efflux of cytotoxic agents mediated by P-glycoprotein is believed to be an important mechanism of multidrug resistance, which remains a serious limitation to successful chemotherapy in cancers such as metastatic breast cancer. A series of 4-aryl-1,4-dihydropyridines and corresponding aromatized 4-arylpyridines have been synthesized based on structure modifications of niguldipine to enhance multidrug resistance reversal activity, while minimizing calcium channel binding. Thirty new compounds were characterized.

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“…36 Briefly, the confluent MCF-7/PTX cells were treated with different blank formulations (MPEG-SS-2SA/TPGS, MPEG-2SA/TPGS, MPEG-SS-2SA, and blank medium) for 12 h and then washed three times with cold PBS. The trypsinized cells (5×10 5 ) were suspended in 500 μL of diluted JC-1 staining solution for 20 min. Then the cells were rinsed with physiological saline, subsequently, suspended in 500 μL of JC-1 staining buffer, and immediately the fluorescence intensities of FL1 (green fluorescence) and FL2 (red fluorescence) channels were measured by flow cytometry (BD FACSCalibur, Franklin Lakes, NJ, USA).…”

Section: Mitochondrial Membrane Potential Assaymentioning

confidence: 99%

“…[37][38][39] Specifically, MCF-7/PTX cells (1×10 5 per well) were seeded into a 12-well plate in RPMI-1640 complete medium containing one glass coverslip/well and incubated for 24 h. After that, the medium was removed and 2 mL growth medium (containing R123-loaded MPEG-SS-2SA/TPGS, MPEG-2SA/TPGS, MPEG-SS-2SA, and free R123) at a R123 concentration of 100 μg/mL was added into each well, respectively, and incubated for 4 h at 37°C. After incubation, coverslips were taken off, washed with PBS for three times, placed in empty wells, and treated with 1 mL of 4% paraformaldehyde for 15 min.…”

Section: In Vitro Cellular Uptake Qualitative Uptakementioning

confidence: 99%

“…Although many efforts have been made to overcome the MDR cancer, limited successful therapeutic regimens and antineoplastic agents have been applied. [4][5][6][7][8][9] The MDR of cancer cells results from many factors; one of the most important reasons is the reduction of drug accumulation caused by the superfamily of adenosine triphosphate (ATP)-binding cassette proteins, such as the P-glycoprotein (P-gp), MDR-associated protein (MRP), and breast cancer resistance protein (BCRP).…”

Section: Introductionmentioning

confidence: 99%

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Biodegradable mixed MPEG-SS-2SA/TPGS micelles for triggered intracellular release of paclitaxel and reversing multidrug resistance

Dong

Yan

Wang

et al. 2016

IJN

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In this study, a type of multifunctional mixed micelles were prepared by a novel biodegradable amphiphilic polymer (MPEG-SS-2SA) and a multidrug resistance (MDR) reversal agent ( d -α-tocopheryl polyethylene glycol succinate, TPGS). The mixed micelles could achieve rapid intracellular drug release and reversal of MDR. First, the amphiphilic polymer, MPEG-SS-2SA, was synthesized through disulfide bonds between poly (ethylene glycol) monomethyl ether (MPEG) and stearic acid (SA). The structure of the obtained polymer was similar to poly (ethylene glycol)-phosphatidylethanolamine (PEG-PE). Then the mixed micelles, MPEG-SS-2SA/TPGS, were prepared by MPEG-SS-2SA and TPGS through the thin film hydration method and loaded paclitaxel (PTX) as the model drug. The in vitro release study revealed that the mixed micelles could rapidly release PTX within 24 h under a reductive environment because of the breaking of disulfide bonds. In cell experiments, the mixed micelles significantly inhibited the activity of mitochondrial respiratory complex II, also reduced the mitochondrial membrane potential, and the content of adenosine triphosphate, thus effectively inhibiting the efflux of PTX from cells. Moreover, in the confocal laser scanning microscopy, cellular uptake and 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assays, the MPEG-SS-2SA/TPGS micelles achieved faster release and more uptake of PTX in Michigan Cancer Foundation-7/PTX cells and showed better antitumor effects as compared with the insensitive control. In conclusion, the biodegradable mixed micelles, MPEG-SS-2SA/TPGS, could be potential vehicles for delivering hydrophobic chemotherapeutic drugs in MDR cancer therapy.

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PSC833, CyclosporinA, and Dexniguldipine Effects on Cellular Calcein Retention and Inhibition of the Multidrug Resistance Pump in Human Leukemic Lymphoblasts

Cited by 20 publications

References 14 publications

Specific MDR1 P-Glycoprotein Blockade Inhibits Human Alloimmune T Cell Activation In Vitro

Specific MDR1 P-Glycoprotein Blockade Inhibits Human Alloimmune T Cell Activation In Vitro

New 4-Aryl-1,4-Dihydropyridines and 4-Arylpyridines as P-Glycoprotein Inhibitors

Biodegradable mixed MPEG-SS-2SA/TPGS micelles for triggered intracellular release of paclitaxel and reversing multidrug resistance

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