Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We studied the restoration of doxorubicin accumulation and sensitivity by verapamil and quinine in a variant of the human erythroleukemia cell line K562 selected for resistance to doxorubicin and presenting a multidrug-resistance (MDR) phenotype. Verapamil was able to completely restore doxorubicin accumulation in the resistant cells to the level obtained in sensitive cells, but only partially reversed doxorubicin resistance. Quinine, in contrast, had a relatively weak effect on doxorubicin accumulation but was able to completely restore doxorubicin sensitivity in the resistant cells. In addition, verapamil was able to decrease azidopine binding to P-glycoprotein, whereas quinine was not. Quinine also modified the intracellular tolerance to doxorubicin, which suggests that it is able to modify drug distribution within the cells. Confocal microscopy revealed that verapamil and quinine were able to restore nuclear fluorescence staining of doxorubicin in resistant cells; since this was obtained for quinine without significant increase of doxorubicin accumulation, this observation confirms that quinine acts principally on doxorubicin redistribution within the cells, allowing the drug to reach its nuclear targets. When used in association, verapamil and quinine reversed doxorubicin resistance in a synergistic fashion. We conclude that verapamil and quinine do not share the same targets for reversal of MDR in this cell line; whereas verapamil directly interferes with P-glycoprotein and mainly governs drug accumulation, quinine has essentially intracellular targets involved in drug redistribution from sequestration compartments.
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PMID:Differential effects of verapamil and quinine on the reversal of doxorubicin resistance in a human leukemia cell line. 762 69

Effectiveness of chemotherapeutic treatment is limited by multidrug resistance (MDR) phenomenon mediated by the overexpression of P-glycoprotein 170 termed Pgp which serves as an efflux pump removing several types of cytostatic drugs from the MDR cells. Several small molecules, frequently lipophilic cations and weak bases, are able to reverse in vitro this resistance. Several studies have shown that MDR modulators interact with Pgp. However, some molecules do not interact with Pgp but are able to completely restore drug sensitivity (e.g., quinine). Bennis et al. (1995) have shown recently that in contrast to verapamil and S9788, quinine increases nuclear doxorubicin accumulation without modifying its intracellular concentration. From this work, the authors concluded that quinine has essentially intracellular targets involved in drug distribution (cytoplasm to nucleus) from sequestration compartments. Their results have been obtained using spectrofluorometry on cell populations and fluorescence microscopy. By using confocal laser microspectrofluorometry, we investigated restoration of nuclear THP-DOX accumulation and sensitivity by verapamil, S9788 and quinine in 2 variants of the Chinese hamster ovary cells LR73, selected for resistance to doxorubicin (LR73D) and transfected with the mdr1 gene (LR73R), as well as in the sensitive ones (LR73S). Results show that verapamil and S9788 were able to restore THP-DOX sensitivity in resistant cells by increasing nuclear THP-DOX accumulation. This restoration is the consequence of Pgp inhibition and redistribution of the anticancer drug from the cytoplasm to nucleus. Quinine, in contrast, restores the sensitivity of MDR cells to THP-DOX and decreased their resistance index, but has no effect on THP-DOX nuclear accumulation. This suggests that quinine modifies the molecular environment of anthracyclines and/or their binding to cytoplasmic targets involved in another mechanism of anthracycline action.
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PMID:[Effect of quinine on the multiple drug resistance and intracellular distribution of pirarubicin in LR73 tumor cells: a comparative study with verapamil and S9788 by confocal laser microspectrofluorometry]. 923 56

The potential inhibitory effect on P-glycoprotein (Pgp) by antiparasitic drugs and natural compounds was investigated. Compounds were screened for Pgp interaction based on inhibition of Pgp mediated [3H]-taxol transport in Caco-2 cells. Bidirectional transport of selected inhibitors was further evaluated to identify potential Pgp substrates using the Caco-2 cells. Of 21 antiparasitics tested, 14 were found to inhibit Pgp mediated [3H]-taxol with K(iapp) values in the range 4-2000 microM. The antimalarial quinine was the most potent inhibitor with a K(iapp) of 4 microM. Of the 12 natural compounds tested, 3 inhibited [3H]-taxol transport with K(iapp) values in the range 50-400 microM. Quinine, amodiaquine, chloroquine, flavone, genistein, praziquantel, quercetin and thiabendazole were further investigated in bidirectional transport assays to determine whether they were substrates for Pgp. Transport of quinine in the secretory direction exceeded that in the absorptive direction and was saturable, suggesting quinine being a Pgp substrate. The rest of the compounds inhibiting Pgp showed no evidence of being Pgp substrates. In conclusion, we have demonstrated that a substantial number of antiparasitic and natural compounds, in a range of concentrations, are capable of inhibiting Pgp mediated [3H]-taxol efflux in Caco-2 cells, without being substrates and this may have implications for drug interactions with Pgp.
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PMID:The potential inhibitory effect of antiparasitic drugs and natural products on P-glycoprotein mediated efflux. 1684 20