The power of the pump: Mechanisms of action of P-glycoprotein (ABCB1)

Ambudkar, Suresh V.; Kim, In‐Wha; Sauna, Zuben E.

doi:10.1016/j.ejps.2005.10.010

Cited by 191 publications

(155 citation statements)

References 82 publications

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“…Although RAL is not confined intracellularly as are NRTI-TPs, RAL-mediated export from cells can be caused by the efflux transporters p-glycoprotein/multidrug resistance transporter 1 (p-gp/MDR-1) (25). p-gp/MDR-1 are active at 37°C but inactive at 4°C (25)(26)(27). All washes were performed with ice-cold PBS at 4°C, taking care to ensure that RAL could not be effluxed by this mechanism.…”

Section: Discussionmentioning

confidence: 99%

Cellular Pharmacology and Potency of HIV-1 Nucleoside Analogs in Primary Human Macrophages

Gavegnano

Detorio

Bassit

et al. 2013

Antimicrob Agents Chemother

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Understanding the cellular pharmacology of antiretroviral agents in macrophages and subsequent correlation with antiviral potency provides a sentinel foundation for definition of the dynamics between antiretroviral agents and viral reservoirs across multiple cell types, with the goal of eradication of HIV-1 from these cells. Various clinically relevant nucleoside antiviral agents, and the integrase inhibitor raltegravir, were selected for this study. The intracellular concentrations of the active metabolites of the nucleoside analogs were found to be 5-to 140-fold lower in macrophages than in lymphocytes, and their antiviral potency was significantly lower in macrophages constitutively activated with macrophage colony-stimulating factor (M-CSF) during acute infection than in resting macrophages (EC 50 , 0.4 to 9.42 M versus 0.03 to 0.4 M, respectively). Although tenofovirtreated cells displayed significantly lower intracellular drug levels than cells treated with its prodrug, tenofovir disoproxil fumarate, the levels of tenofovir-diphosphate for tenofovir-treated cells were similar in lymphocytes and macrophages. Raltegravir also displayed significantly lower intracellular concentrations in macrophages than in lymphocytes, independent of the activation state, but had similar potencies in resting and activated macrophages. These data underscore the importance of delivering adequate levels of drug to macrophages to reduce and eradicate HIV-1 infection.

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Section: Discussionmentioning

confidence: 99%

Cellular Pharmacology and Potency of HIV-1 Nucleoside Analogs in Primary Human Macrophages

Gavegnano

Detorio

Bassit

et al. 2013

Antimicrob Agents Chemother

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“…The sipholane triterpenes are compounds that contain a perhydrobenzoxepin (rings A and B) and a [5,3,0] bicyclodecane ring systems (rings C and D) linked together by an ethylene group (Figure 1). This class of triterpenes consists of sipholenol A (1), sipholenone E (2), sipholenol L (3), and siphonellinol D (4), isolated from the Red Sea sponge Callyspongia siphonella [44,45], and semisynthetic derivatives of sipholenol A such as sipholenol A-4-O-acetate (5), sipholenol A-4-O-isonicotinate (6) [39], sipholenol A-4-O-3',4'-dichlorobenzoate (7) [46], sipholenol A 4-O-4'-chlorobenzoate (8), and 19,20-anhydrosipholenol A 4-O-4'-chlorobenzoate (9) [47] that were synthesized using a ligand-based design approach.…”

Section: Sipholane Triterpenoids and Derivativesmentioning

confidence: 99%

“…MDR to anticancer drugs is therefore a serious health problem that dramatically affects the efficacy of cancer treatments [4]. MDR is a phenomenon by which cancer cells develop broad resistance to a wide variety of structurally and functionally unrelated compounds which may arise from several mechanisms [5,6] including: (i) decreased cellular drug uptake; (ii) activation of detoxifying enzymes; (iii) alterations in the molecular targets of the drugs; (iv) defective apoptotic pathways; and (v) increased drug efflux [6][7][8][9]. One of the most prominent mechanisms of MDR to cytotoxic drugs is usually associated with the overexpression of ATP-binding cassette (ABC)-transporter proteins in the tumor cells.…”

Section: Introductionmentioning

confidence: 99%

Marine Natural Products as Models to Circumvent Multidrug Resistance

et al. 2016

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Multidrug resistance (MDR) to anticancer drugs is a serious health problem that in many cases leads to cancer treatment failure. The ATP binding cassette (ABC) transporter P-glycoprotein (P-gp), which leads to premature efflux of drugs from cancer cells, is often responsible for MDR. On the other hand, a strategy to search for modulators from natural products to overcome MDR had been in place during the last decades. However, Nature limits the amount of some natural products, which has led to the development of synthetic strategies to increase their availability. This review summarizes the research findings on marine natural products and derivatives, mainly alkaloids, polyoxygenated sterols, polyketides, terpenoids, diketopiperazines, and peptides, with P-gp inhibitory activity highlighting the established structure-activity relationships. The synthetic pathways for the total synthesis of the most promising members and analogs are also presented. It is expected that the data gathered during the last decades concerning their synthesis and MDR-inhibiting activities will help medicinal chemists develop potential drug candidates using marine natural products as models which can deliver new ABC transporter inhibitor scaffolds.

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“…The current view is that overexpression of a membrane associated efflux transporter called P-glycoprotein (P-gp; 170 kDa), a member of the ATP-binding cassette (ABC) superfamily of transporters, is the primary mechanism involved in multidrug resistance (MDR) formation (1). Previous studies of P-gp have mainly focused on the expression of plasma membrane P-gp.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial localization of P-glycoprotein in the human breast cancer cell line MCF-7/ADM and its functional characterization

et al. 2012

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Abstract. The current view of multidrug resisitance is that overexpression of membrane P-glycoprotein (P-gp) is a major causative factor. However, the controversial presence of subcellular P-gp may also participate in the drug resistance. In this study, we sought to investigate the localization and functional characterization of P-gp in mitochondria isolated from MCF-7 and doxorubicin-resistant MCF-7 (MCF-7/ ADM) cells. Mitochondria were isolated and purified from the MCF-7 cell line and its resistant cells MCF-7/ADM. We used electron microscopy, western blot analysis and confocal microscopy to demonstrate the localization of P-gp in the mitochondria of MCF-7/ADM cells. Flow cytometry was used to evaluated the efflux function of mitochondrial P-gp in the presence or absence of the P-gp inhibitor cyclosporine A (CsA). Mitochondria were isolated and purified successfully and were analyzed by electron microscopy. Western blotting demonstrated the expression of P-gp in the cell membrane and purified mitochondria from MCF-7/ADM cells but not from sensitive MCF-7 cells. Immunofluorescence analysis using confocal microscopy demonstrated the localization of P-gp [labeled with green fluorescence (FITC)] to the mitochondria [labeled with red fluorescence (Mitotracker Deep Red 633)] of MCF-7/ADM cells and that was absent in MCF-7 cells. Rho123 (a mitochondrial fluorescent probe) accumulation was largely reduced and efflux was strongly increased in the mitochondria of MCF-7/ADM cells compared to those of MCF-7 cells (P<0.01), and these were completely reversed in the presence of the P-gp inhibitor CsA (P<0.01). No significant changes were observed in the mitochondria of MCF-7 cells (P>0.05). P-gp is expressed in the mitochondria of doxorubicin-resistant MCF-7 cells and has an efflux function. It could be involved in multidrug resistance at the subcellular site by pumping out anticancer drugs from mitochondria to protect the function of mitochondria.

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The power of the pump: Mechanisms of action of P-glycoprotein (ABCB1)

Cited by 191 publications

References 82 publications

Cellular Pharmacology and Potency of HIV-1 Nucleoside Analogs in Primary Human Macrophages

Cellular Pharmacology and Potency of HIV-1 Nucleoside Analogs in Primary Human Macrophages

Marine Natural Products as Models to Circumvent Multidrug Resistance

Mitochondrial localization of P-glycoprotein in the human breast cancer cell line MCF-7/ADM and its functional characterization

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