Mechanisms of resistance to xenobiotics in human therapy

Saves, Isabelle; Masson, Jean-Michel

doi:10.1007/s000180050170

Cited by 12 publications

(5 citation statements)

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“…29) Briefly, luciferase produces light by ATP-dependent oxidation of luciferin enhances the emission maximum at 560 nm at pH 7.8. Cells (5ϫ10 5 ) were incubated in the presence or absence of qinghaosu or oligomycin at 37°C for 10 min to 1 h. The cells were pelleted and then permeabilized by 500 ml lysis solution containing 0.1% Triton X-100, 20 mM Tris, 0.1 mM EDTA, and 5 mM MgSO 4 . The intensity of light was recorded by Perkin Elmer LS50B spectrofluorometer after the addition of 50 ml luciferin-luciferase (20 mg/ml).…”

Section: Measurement Of Atp In Cell Extractsmentioning

confidence: 99%

“…MDR phenomena are intensively studied in anti-cancer, anti-bacterial, anti-paludism, and human immunodeficiency virus-1. [1][2][3][4][5] The MDR phenotype is characterized by a low free intracellular cytotoxic drug concentration in comparison with their corresponding drugsensitive cells. This is frequently associated with protein membrane transporters, such as P-glycoprotein and MRP1-protein, which ATP-dependently extrude cytotoxic agents out of cells, thus reducing their efficacy.…”

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confidence: 99%

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Modulation of Multidrug Resistance by Artemisinin, Artesunate and Dihydroartemisinin in K562/adr and GLC4/adr Resistant Cell Lines.

Reungpatthanaphong

Mankhetkorn

2002

Biological & Pharmaceutical Bulletin

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Multidrug resistance (MDR) is a principle cause of failure in human drug treatment. MDR phenomena are intensively studied in anti-cancer, anti-bacterial, anti-paludism, and human immunodeficiency virus-1. [1][2][3][4][5] The MDR phenotype is characterized by a low free intracellular cytotoxic drug concentration in comparison with their corresponding drugsensitive cells. This is frequently associated with protein membrane transporters, such as P-glycoprotein and MRP1-protein, which ATP-dependently extrude cytotoxic agents out of cells, thus reducing their efficacy. To overcome MDR phenomena, the direct interaction between inhibitors and proteins has been researched by many groups. A variety of small molecules, such as verapamil, dihydropyridines, forskolin and cyclosporin were found to bind to P-glycoprotein and inhibit its ability to pump out antitumor drugs. 6-9) All compounds cited are difficult to use in vivo due to their toxicity. As a consequence, the clinical utility of non-toxic derivatives of these and other molecules as chemosensitizing agents has been extensively studied. 10,11) It was reported that in MDR plasmodium falciparum strains, the pfmdr-1 gene and pgh-1 were characterized, which has about 54% homology to mdr-1 gene of MDR cancer cells. [12][13][14][15] However, its function is still not clear. Recently, it was reported that qinghaosu is an effective compound against MDR plasmodium falciparum strains, 16,17) but studies regarding its effect on protein transporters have not been performed, neither in erythrocytes infected by MDR plasmodium falciparum strains nor in cancer MDR cells. Qinghaosu drugs such as artemisinin and artesunate are now in widespread use, particularly in Southast Asia, and are used as a prophylaxis in China. 18,19) In this study we have demonstrated that artemisinin, artesunate and dihydroartemisinin poorly inhibited P-glycoprotein and did not inhibit MRP1 protein function in multidrug resistant K562/adr cells, overexpression P-glycoprotein, or in GLC4/adr cells overexpression of MRP1-protein, respectively. However, they increased in cytotoxic effect induced by pirarubicin or doxorubicin only in MDR cell lines. We also demonstrated that these qinghaosu modulate mitochondrial function, leading to a decrease in intracellular ATP content in all cell lines tested. MATERIALS AND METHODS Cell Culture and Cytotoxicity AssayThe erythromyelogenous leukemic, K562, and its P-glycoprotein-overexpressing K562/adr, 20,21) and the human small cell lung cancer, GLC4 and its MRP1-overexpressing GLC4/adr, [22][23][24] were kindly provided by Professor Arlette Garnier-Suillerot, Laboratoire de Chimie Physique, Biomoleculaire et Cellulaire, UFR Sante Medecine Biologie Humaine, Universite de Paris Nord, France. These cells were routinely cultured in RPMI 1640 medium supplemented with 10% fetal calf serum (Gibco Biocult, Ltd.). The resistant K562/adr and GLC4/adr cells were cultured with 100 nM doxorubicin two weeks before the experiments. For the assays, a culture was initiated at 5ϫ10 5 cells ...

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Section: Measurement Of Atp In Cell Extractsmentioning

confidence: 99%

mentioning

confidence: 99%

Modulation of Multidrug Resistance by Artemisinin, Artesunate and Dihydroartemisinin in K562/adr and GLC4/adr Resistant Cell Lines.

Reungpatthanaphong

Mankhetkorn

2002

Biological & Pharmaceutical Bulletin

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“…The resistance of tumor cells is often the result of the enhanced ability of these cells to impair efficacy of cytostatics through increased elimination by phase II and III metabolism [drug conjugation and drug efflux, respectively, mediated by, for instance, P-glycoprotein and multidrug resistance protein 1 (MRP1)] (Saves and Masson, 1998;Litman et al, 2001;Borst and Oude Elferink, 2002).…”

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confidence: 99%

Inhibition of the Multidrug Resistance Protein 1 (MRP1) by Peptidomimetic Glutathione-Conjugate Analogs

et al. 2002

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Inhibition of multidrug resistance protein 1 (MRP1) mediated cytostatic drug efflux might be useful in the treatment of drug resistant tumors. Because the glutathione (GSH) conjugate of ethacrynic acid (EA), GS-EA, is a good substrate of MRP1, GS-EA derivatives are expected to be good inhibitors of MRP1. To study structure-activity relationships of MRP1 inhibition, a series of novel GS-EA analogs was synthesized in which peptide bonds of the GSH backbone were replaced by isosteric groups [Bioorg Med Chem 10:195-205, 2002]. Several of these compounds were effective inhibitors of MRP1-mediated [ 3 H]GS-EA and [ 3 H]E 2 17␤G transport, as studied in membrane vesicles prepared from MRP1-overproducing Sf9 cells. The modifications of the peptide backbone have distinct implications for recognition by MRP1: the ␥-glutamyl-cysteine peptide bond is important for binding, whereas the cysteinyl-glycine amide does not seem essential. When the ␥-glutamyl-cysteine peptide bond (C-CO-N) is replaced by a urethane isostere (O-CO-N), an effective competitive MRP1-inhibitor (K i ϭ 11 M) is obtained. After esterification of this compound to improve its cellular uptake, it inhibited MRP1-mediated efflux of calcein from 2008 ovarian carcinoma cells overexpressing MRP1. This compound also partially reversed the resistance of these cells to methotrexate. Because the urethane isostere is stable toward ␥-glutamyl transpeptidase-mediated breakdown, it is an interesting lead-compound for the development of in vivo active MRP1 inhibitors.

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“…Drug efflux The cerebral cells express P glycoprotein 1 and 2 which can efflux the anti epileptic drugs 5 .…”

Section: Resistance To Anti Epileptic Drugsmentioning

confidence: 99%

Non Microbial Drug Resistance

Ruckmani¹

2013

CHCMJ

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Mechanisms of resistance to xenobiotics in human therapy

Cited by 12 publications

References 182 publications

Modulation of Multidrug Resistance by Artemisinin, Artesunate and Dihydroartemisinin in K562/adr and GLC4/adr Resistant Cell Lines.

Modulation of Multidrug Resistance by Artemisinin, Artesunate and Dihydroartemisinin in K562/adr and GLC4/adr Resistant Cell Lines.

Inhibition of the Multidrug Resistance Protein 1 (MRP1) by Peptidomimetic Glutathione-Conjugate Analogs

Non Microbial Drug Resistance

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