Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.3.44 (P-glycoprotein)
13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A homologue of the multidrug resistance (MDR) gene was obtained while screening a potato stolon tip cDNA expression library with 35S-labeled calmodulin. The mammalian MDR gene codes for a membrane-bound P-glycoprotein (170-180 kDa) which imparts multidrug resistance to cancerous cells. The potato cDNA (PMDR1) codes for a polypeptide of 1313 amino acid residues (ca. 144 kDa) and its structural features are very similar to the MDR P-glycoprotein. The N-terminal half of the PMDR1-encoded protein shares striking homology with its C-terminal half, and each half contains a conserved ATP-binding site and six putative transmembrane domains. Southern blot analysis indicated that potato has one or two MDR-like genes. PMDR1 mRNA is constitutively expressed in all organs studied with higher expression in the stem and stolon tip. The PMDR1 expression was highest during tuber initiation and decreased during tuber development.
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PMID:A potato cDNA encoding a homologue of mammalian multidrug resistant P-glycoprotein. 879 Mar

Iodide efflux, an index of anion permeability, has been monitored in cultured rat brain endothelial cells. Following hypotonicity-induced swelling, large, rapid increases in permeability occur, the extent of these increases depending on the degree of hypotonicity. Such large responses are not observed with rat aortic endothelial cells. Results of anion substitution experiments suggest that iodide efflux is via a chloride channel rather than an exchanger. The efflux increase is blocked by NPPB (100 microM) but not by DIDS or DPC at 100 microM. It is dependent on intracellular ATP but unaffected by removal of external calcium. Increasing internal calcium using A23187 does not produce a change in efflux, but depletion of calcium reduces or eliminates the response to hypotonicity. The response is reduced by pimozide (2-50 microM) that inhibits the actions of calmodulin and by pBPB (10 microM) that affects phospholipase A2 activity. It is eliminated by 5-lipoxygenase inhibitors (L-656,224 and ETH615, 10 microM) but is unaffected by cyclo-oxygenase inhibitors (indomethacin and piroxicam, 1-100 microM). It is blocked by some modulators of P-glycoprotein activity, e.g., verapamil (100 microM), tamoxifen (50 microM), and progesterone (100 microM) but not by others, e,g., forskolin (40 microM), dideoxyforskolin (40 microM), quinidine (100 microM) and cyclosporin A (10 microM).
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PMID:Hypotonicity-induced changes in anion permeability of cultured rat brain endothelial cells. 910 87

We have determined the kinetic parameters for stimulation and inhibition by 34 drugs of the P-glycoprotein ATPase in membranes derived from CR1R12 Chinese hamster ovary cells. The drugs chosen were sets of calmodulin antagonists, steroids, hydrophobic cations, hydrophobic peptides, chemotherapeutic substrates of P-glycoprotein, and some other drugs with lower affinity for P-glycoprotein. We studied how these kinetic parameters correlated with the partition coefficient and the Van der Waals surface area of the drugs. The maximum velocity of ATPase stimulation decreased with surface area and showed a suggestion of a maximum with increasing partition coefficient. The affinity of these drugs for P-glycoprotein showed no significant correlation with partition coefficient but was highly correlated with the surface area suggesting that binding between modulators and P-glycoprotein takes place across a wide interaction surface on the protein.
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PMID:Structure-activity relationships of P-glycoprotein interacting drugs: kinetic characterization of their effects on ATPase activity. 930 Jul 97

Research on multidrug resistance (MDR) has spread widely, with the emphasis on the development of therapeutic approaches. This line of research began in the early 1970s. In 1981 and 1982, calcium channel blockers such as verapamil and calmodulin inhibitors were found to enhance the intracellular levels of vincristine (VCR) and adriamycin (ADM) in resistant tumor cells by inhibiting their outward transport and to circumvent MDR in animal experiments. Since these results were noted for verapamil, various other compounds have been investigated to overcome drug resistance. Among these compounds, two compounds were evaluated in our laboratory. The non-immunosuppressive cyclosporin derivative SDZ PSC833 (PSC) has been shown to reverse MDR completely in vitro and in vivo. The second compound is MS-209, a novel quinoline derivative. MS209 completely reversed the resistance against VCR and ADM in vitro. MS209 enhanced the chemotherapeutic effects of VCR and ADM in P388/VCR- and P388/ADM-bearing mice. MS-209 has now started clinical trials in Japan. In addition to these chemical agents, monoclonal antibodies (moAb) against P-glycoprotein such as MRK16 could be useful tools for selective killing of MDR tumor cells. Furthermore another moAb MRK17 can be used against human MDR cells transfected with macrophage-colony stimulating factor (M-CSF) gene. M-CSF can act as an enhancer of antibody dependent cellular cytotoxicity (ADCC) in therapy of human MDR cancer with the anti-P-glycoprotein antibody.
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PMID:[Mechanism of multidrug resistant tumors and chemotherapeutic approaches against the resistant tumors]. 930 24

Multiple drug resistance (MDR) mechanisms are known to limit the effectiveness of some cancer chemotherapies, probably through enhancing P-glycoprotein-mediated drug efflux from mammalian cells. Similar mechanisms appear to act in other organisms, including bacteria, and may affect not only the toxicity but also the mutagenicity of certain chemicals. At least in some experimental situations, MDR can be overcome through concomitant treatment of the cells with various types of inhibitors. Two MDR inhibitors, verapamil, a calcium channel blocker, and trifluoperazine, a calmodulin inhibitor, were assayed for their ability to modulate the potency of nine mutagens with varying mechanisms of action in various Salmonella typhimurium his- strains. Neither verapamil nor trifluoperazine affected the direct mutagenicity of sodium dichromate and 2-methoxy-6-chloro-9[3-(2-chloroethyl)amino-propyl-amino] dihydrochloride (ICR 191) or the S9-mediated mutagenicity of benzo[a]pyrene and 2-amino-3,4-dimethyl-amidazo[4,5-f]quinoline (MeIQ). Both modulators enhanced the direct mutagenicity of doxorubicin. Moreover, trifluoperazine sharply increased the S9-mediated mutagenicity of cyclophosphamide and 2-aminofluorene, while it consistently decreased the mutagenicity of 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2). The contrasting effect towards the aromatic amine 2-aminofluorene and the heterocyclic amine Trp-P-2, representative of important chemical families responsible for the bacterial mutagenicity of cigarette smoke, may explain the observed lack of influence of trifluoperazine on the mutagenicity of a cigarette smoke condensate. These observations extend the known range of chemical types whose mutagenicity can be modulated by inhibitors of MDR and suggest that there may be value in adding MDR inhibitors, especially trifluoperazine, to optimize the detection of mutagenicity by certain types of chemicals in the Salmonella/mammalian microsome mutagenicity test.
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PMID:Modulation of the potency of promutagens and direct acting mutagens in bacteria by inhibitors of the multidrug resistance mechanism. 941 96

Purines can modify ciliary epithelial secretion of aqueous humor into the eye. The source of the purinergic agonists acting in the ciliary epithelium, as in many epithelial tissues, is unknown. We found that the fluorescent ATP marker quinacrine stained rabbit and bovine ciliary epithelia but not the nerve fibers in the ciliary bodies. Cultured bovine pigmented and nonpigmented ciliary epithelial cells also stained intensely when incubated with quinacrine. Hypotonic stimulation of cultured epithelial cells increased the extracellular ATP concentration by 3-fold; this measurement underestimates actual release as the cells also displayed ecto-ATPase activity. The hypotonically triggered increase in ATP was inhibited by the Cl--channel blocker 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB) in both cell types. In contrast, the P-glycoprotein inhibitors tamoxifen and verapamil and the cystic fibrosis transmembrane conductance regulator (CFTR) blockers glybenclamide and diphenylamine-2-carboxylate did not affect ATP release from either cell type. This pharmacological profile suggests that ATP release is not restricted to P-glycoprotein or the cystic fibrosis transmembrane conductance regulator, but can proceed through a route sensitive to NPPB. ATP release also was triggered by ionomycin through a different NPPB-insensitive mechanism, inhibitable by the calcium/calmodulin-activated kinase II inhibitor KN-62. Thus, both layers of the ciliary epithelium store and release ATP, and purines likely modulate aqueous humor flow by paracrine and/or autocrine mechanisms within the two cell layers of this epithelium.
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PMID:A release mechanism for stored ATP in ocular ciliary epithelial cells. 961 58

Cyclosporin A (CsA) is a widely-used immunosuppressant drug whose therapeutic and toxic actions are mediated through inhibition of calcineurin (CN), a calcium- and calmodulin-dependent phosphatase. Inhibition of CN by CsA requires drug binding to its protein cofactor in the inhibition, cyclophilin. Because cyclophilin is a high affinity target for CsA it is expected that this protein can act as a reservoir for the drug in the cell and may be able to inhibit cellular efflux of CsA. P-glycoprotein (P-gp) is known to increase the rate of CsA efflux from CsA loaded cells but it is not clear if the P-gp drug efflux pump can compete effectively with cyclophilin at therapeutically relevant concentrations of CsA. To test the hypothesis that increased expression of P-gp confers protection against CsA-dependent inhibition of CN phosphatase activity, KB-V cells expressing varying levels of P-gp were analyzed to determine the potency of CsA as a CN inhibitor. When intact cells were treated with CsA, a positive correlation was observed between P-gp expression and resistance to CsA-dependent inhibition of CN: the IC50 is approximately 20-fold higher in the multidrug resistant epidermal carcinoma cell line, KB-V, which expresses P-gp at a high level than in the parental, KB, cell line expressing very low levels of P-gp. The resistance displayed by KB-V cells is abrogated by co-administration of the P-gp inhibitor verapamil, whereas verapamil has no effect on CsA potency in control KB cells. In cell lysates from KB-V cells with different amounts of P-gp CsA exhibits equivalent potency, indicating that the difference in sensitivity to CsA among the cell types requires maintenance of cell integrity. These observations support the view that resistance to CN inhibition by CsA occurs in cells with moderately elevated P-gp activity. Therefore, P-gp activity appears to be an important determinant of CsA cellular specificity for both therapeutic and toxic effects.
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PMID:Cyclosporin A has low potency as a calcineurin inhibitor in cells expressing high levels of P-glycoprotein. 965 Nov 11

Tumor cell resistance to inhibitors of topoisomerase II (topo II) is associated frequently with the overexpression of P-glycoprotein (PGP), and strategies to overcome resistance are focused on restoring defects in drug accumulation. Inhibitors of calcium-calmodulin-dependent enzymes sensitize resistant tumor cells to the topo II poison etoposide (VP-16) by enhancing DNA damage and an apoptotic response. In the present study, we have investigated the consequences of buffering intracellular calcium with 1,2-bis(o-aminophenoxy)ethane-N,N,N'N'-tetraacetic acid tetra(acetoxy-methyl) ester (BAPTA-AM) on the sensitizing effects of the calmodulin-dependent protein kinase II inhibitor 1-[N,O-bis(1,5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-piperazine (KN-62) in etoposide-resistant human leukemia HL-60 (HL-60/ADR0.05) cells. In cells pretreated with 20 microM BAPTA-AM for 2 hr, extracellular ATP failed to trigger intracellular calcium transients, and no effects on the accumulation of VP-16 were apparent. Also, the effect of KN-62 in significantly (P=0.002 to 0.042) enhancing the accumulation of VP-16 in HL-60/ADR0.05 cells was unaffected due to pretreatment with BAPTA-AM. In contrast, pretreatment with BAPTA-AM reduced the DNA damage induced by VP-16, and significantly (P=0.038) reversed the enhancement by KN-62 of VP-16-stabilized topo II-mediated DNA cleavable complex formation. The pretreatment of HL-60/ADR0.05 cells with BAPTA-AM was also associated with the hypophosphorylation of topo IIalpha. Consistent with the ability of BAPTA-AM to circumvent the potentiation by KN-62 of VP-16-induced DNA damage, survival of cells treated with 40 microM VP-16 in the absence of KN-62 and 10 microM VP-16 in the presence of KN-62 was significantly (P=0.026 to 0.031) higher due to BAPTA-AM pretreatment. Results demonstrate that intracellular calcium transients could play a key role in the sensitization of etoposide-resistant tumor cells by inhibitors of calcium-calmodulin-dependent enzymes.
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PMID:Tumor cell resistance to topoisomerase II poisons: role for intracellular free calcium in the sensitization by inhibitors or calcium-calmodulin-dependent enzymes. 974 72

The anti-drug resistance effect of three derivatives (AR-1, AR-2 and AR-3) of [1,2,5-trimethyl-4-phenyl-4-beta-(N,N-disubstituted-ethylamino)] piperidines, that were evaluated as calcium and calmodulin antagonists, was studied on doxorubicin (ADM) and vincristine (VCR) resistant Sarcoma-45 inoculated rats. Treatment with ADM (5 mg/kg) or VCR (3 mg/kg) alone, as well as with AR-1, AR-2 or AR-3 (50 mg/kg) alone, had no effect on tumor growth. However, AR-2 in dose 50 mg/kg (calmodulin antagonist), but not AR-1 and AR-3 (calcium channel blocker), administered with ADM (5 mg/kg) or VCR (3 mg/kg), significantly suppressed tumor growth 80% and 70%, respectively. Two rats treated with ADM/AR-2 and one treated with VCR/AR-2 were cured. 170 kDa protein was purified from sarcoma-45 tumor cells to apparent homogeneity by successive steps of phosphocellulose, DEAE-cellulose, and AR-2-coupled sepharose chromatography. The protein proved to be immunopositive with the P-glycoprotein-specific monoclonal antibody. It is concluded that the effect of AR-2 can be explained by both hydrophobic and electrostatic interaction with a protein target (170 kDa P-glycoprotein) in resistant sarcoma-45 tumor cell's membrane.
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PMID:Reversal of drug resistance in sarcoma-45 by the new calmodulin antagonist--trihydrochloride of [1,2,5-trimethyl-4-phenyl-4-beta-[N-(beta-ethylamino)-N-4'-methoxybe nzy l]-ethylamino] piperidine (AR-2). 1063 81

The overexpression of P-glycoprotein (P-gp) is associated with multidrug resistance (MDR) of tumor cells to a number of chemotherapeutic drugs. P-gp inhibitors have been shown to effectively reverse P-gp-mediated MDR in both in vitro and in vivo. Our previous studies demonstrated that E6, a novel synthetic calmodulin inhibitor, exhibited potent inhibitory effect on P-gp in rat brain microvessel endothelial cells (RBMECs). In the present study, the effect of E6 on MDR in a K562 MDR cell line (K562/DOX) highly expressing P-gp was studied and compared with that of a conventional P-gp inhibitor, verapamil (VER). E6 at concentrations of 1, 3, 10, 30 microM reduced the IC50 value of doxorubicin in K562/DOX cells from 79.19 microM to 35.18, 21.86, 6.31 and 1.97 microM, respectively. However, the IC50 value of doxorubicin in K562 sensitive subline was not significantly changed by E6. Using a DNA content analysis and an annexin V binding assay, the effects of E6 on doxorubicin-induced apoptosis were also examined. The results indicated that E6 effectively reversed the resistance to doxorubicin-induced apoptosis in K562/DOX cells. In addition, co-treatment of E6 and doxorubicin resulted in a remarkably G2/M blocking effect in K562/DOX cells. Furthermore, the treatment of K562/DOX cells with 10 microM E6 led to increased intracellular accumulation and decreased efflux of doxorubicin. Overall, the pharmacological effects of E6 on P-gp-mediated MDR is much stronger than that of positive control drug VER. These results suggested that E6 is a novel and potent MDR reversal agent and may be a potential adjunctive agent for tumor chemotherapy.
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PMID:Reversal of P-glycoprotein mediated multidrug resistance in K562 cell line by a novel synthetic calmodulin inhibitor, E6. 1620 58


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