Inhibition of P-glycoprotein-mediated multidrug efflux by aminomethylene and ketomethylene analogs of reversins

Koubeissi, Ali; Raad, Imad; Ettouati, Laurent; Guilet, David; Dumontet, Charles; Pâris, J.

doi:10.1016/j.bmcl.2006.07.059

Cited by 12 publications

(13 citation statements)

References 17 publications

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“…CD4 + and CD8 + T cell proliferation to OVA-loaded BMDCs was strikingly decreased in the presence of a specific in vitro P-gp inhibitor (reversin 121; 200 nM; [24]) compared to its vehicle (Figure 5a,b). Secretion of IFN-γ and TNF-α (Th1 cytokines) was significantly decreased during P-gp inhibited T cell proliferation on different time points (5c–f).…”

Section: Resultsmentioning

confidence: 99%

P-Glycoprotein Acts as an Immunomodulator during Neuroinflammation

et al. 2009

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BackgroundMultiple sclerosis is an inflammatory demyelinating disease of the central nervous system in which autoreactive myelin-specific T cells cause extensive tissue damage, resulting in neurological deficits. In the disease process, T cells are primed in the periphery by antigen presenting dendritic cells (DCs). DCs are considered to be crucial regulators of specific immune responses and molecules or proteins that regulate DC function are therefore under extensive investigation. We here investigated the potential immunomodulatory capacity of the ATP binding cassette transporter P-glycoprotein (P-gp). P-gp generally drives cellular efflux of a variety of compounds and is thought to be involved in excretion of inflammatory agents from immune cells, like DCs. So far, the immunomodulatory role of these ABC transporters is unknown.Methods and FindingsHere we demonstrate that P-gp acts as a key modulator of adaptive immunity during an in vivo model for neuroinflammation. The function of the DC is severely impaired in P-gp knockout mice (Mdr1a/1b−/−), since both DC maturation and T cell stimulatory capacity is significantly decreased. Consequently, Mdr1a/1b −/− mice develop decreased clinical signs of experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. Reduced clinical signs coincided with impaired T cell responses and T cell-specific brain inflammation. We here describe the underlying molecular mechanism and demonstrate that P-gp is crucial for the secretion of pro-inflammatory cytokines such as TNF-α and IFN-γ. Importantly, the defect in DC function can be restored by exogenous addition of these cytokines.ConclusionsOur data demonstrate that P-gp downmodulates DC function through the regulation of pro-inflammatory cytokine secretion, resulting in an impaired immune response. Taken together, our work highlights a new physiological role for P-gp as an immunomodulatory molecule and reveals a possible new target for immunotherapy.

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Section: Resultsmentioning

confidence: 99%

P-Glycoprotein Acts as an Immunomodulator during Neuroinflammation

et al. 2009

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“…11 A similar sequence was observed as an undesired side reaction by Koubeissi et al 12 The Maryanoff protocol has since been extended to include 4-amino carboxylic acids by Mapes and Mani. 13 While this method is simple and robust, it necessitates the synthesis of the amino carboxylates or carboxylic acids.…”

Section: Resultsmentioning

confidence: 86%

Efficient Synthesis of γ-Lactams by a Tandem Reductive Amination/Lactamization Sequence

et al. 2008

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“…The effect of selective ABC transporter inhibitors (Reversin 121 against ABCB1, 28 MK-571 against ABCC1, 29 and FTC against ABCG2 30 ) on BLI intensity from HEK-293/ABC transporter reporter cells was also studied. Compared to vehicle treatment, Reversin 121 elevated BLI intensity 2.11 6 0.16-fold only in HEK-293/ABCB1/rLuc reporter cells, whereas FTC increased BLI intensity more than 2-fold in HEK-293/ABCG2/ cLuc, fLuc, and rLuc reporter cells (Figure 3).…”

Section: Resultsmentioning

confidence: 99%

ATP-Binding Cassette Transporters Modulate Both Coelenterazine- and D-Luciferin-Based Bioluminescence Imaging

et al. 2011

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Bioluminescence imaging (BLI) of luciferase reporters provides a cost-effective and sensitive means to image biological processes. However, transport of luciferase substrates across the cell membrane does affect BLI-readout-intensity from intact living cells. To investigate the effect of ATP-binding cassette (ABC) transporters on BLI readout, we generated Click Beetle-(cLuc), Firefly-(fLuc), Renilla-(rLuc), and Gaussia-(gLuc) luciferase HEK-293 reporter cells that overexpressed different ABC-transporters (ABCB1, ABCC1 and ABCG2). In vitro studies showed a significant BLI intensity decrease in intact-cells compared to cell-lysates, when ABCG2 was overexpressed in HEK-293/cLuc, fLuc, and rLuc cells. Selective ABC-transporter inhibitors were also applied. Inhibition of ABCG2 activity increased the BLI intensity >2-fold in HEK-293/cLuc, fLuc and rLuc cells; inhibition of ABCB1 elevated the BLI intensity 2-fold only in HEK-293/rLuc cells. BLI of xenografts derived from HEK-293/ABC-transporter/luciferase-reporter cells confirmed the results of inhibitor treatment in vivo. These findings demonstrate that coelenterazine-based rLuc-BLI intensity can be modulated by ABCB1 and ABCG2. ABCG2 modulates D-luciferin-based BLI in a luciferase-type-independent manner. Little ABC-transporter effect on gLuc-BLI intensity is observed since a large fraction of gLuc is secreted. The expression level of ABC-transporters is one key factor affecting BLI intensity, and this may be particularly important in luciferase-based applications in stem cell research.

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Inhibition of P-glycoprotein-mediated multidrug efflux by aminomethylene and ketomethylene analogs of reversins

Cited by 12 publications

References 17 publications

P-Glycoprotein Acts as an Immunomodulator during Neuroinflammation

P-Glycoprotein Acts as an Immunomodulator during Neuroinflammation

Efficient Synthesis of γ-Lactams by a Tandem Reductive Amination/Lactamization Sequence

ATP-Binding Cassette Transporters Modulate Both Coelenterazine- and D-Luciferin-Based Bioluminescence Imaging

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