Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.1.3 (ATPase)
 65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Histochemical properties, muscle fiber cross-sectional area, muscle fiber length, and the oxidative capacity of masticatory muscles of female rhesus monkeys were assessed following alteration in functional length by an intraoral appliance or by detachment of the muscle. Experimental groups received the appliance only (A); the appliance and subsequent detachment of the masseter (AD); the appliance and detached masseter, but with surgical reattachment of the masseter to the pterygomasseteric sling (ADR); no appliance, but detachment and reattachment of masseter (DR); or an appliance which was removed after 24 weeks to study posttreatment responses (PT). Animals were sacrificed and the muscles were studied at intervals from 4 to 48 weeks after initiation of the experimental period. The results of these studies led to the following conclusions: (1) Stretching the masseter and temporalis muscles within physiological limits did not significantly alter the proportion of fiber types, although oxidative capacity of the fibers was reduced. (2) Fibers with "intermediate" myofibrillar ATPase activity were no more prevalent in experimental than control muscles. (3) The cross-sectional area of Type I fibers of masseter muscles decreased following some experimental procedures, indicating that recruitment of these fibers is the most sensitive to altered jaw function. (4) Minimal alteration of muscle capillarity was induced by any of the experimental procedures. (5) The lengths of masseter muscle fibers in Group PT and of temporalis muscle fibers in groups AD and ADR were greater than in control animals.
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PMID:Adaptation of the masseter and temporalis muscles following alteration in length, with or without surgical detachment. 645 41

In myotonic ADR mice that are homozygous for a defect in the muscular chloride channel gene adr/Clc-1, the hyperexcitability of fast muscles is associated with secondary changes in gene expression and fibre type composition. cDNA clones derived from a set of genes down regulated in fast muscles of the myotonic ADR mouse were isolated by a subtractive cloning procedure. A total of 1200 clones were analysed for high expression in fast muscle of wild type and low expression in mutant mouse. Differential transcript levels were verified by northern blot hybridizations. The identities of the corresponding transcripts were determined by sequencing as myosin heavy chain IIB, alpha-tropomyosin, troponin C, a Ca2+ ATPase and parvalbumin mRNAs. Of these, mRNAs for parvalbumin and myosin heavy chain IIB were drastically downregulated in myotonic muscle (to < 10% of control). A full length cDNA clone for skeletal muscle alpha-tropomyosin was homologous to the mouse fibroblast tropomyosin isoform 2, except for the portion encoding the alpha-tropomyosin specific amino acids 258-284. A cDNA derived from the 1100 nucleotide parvalbumin transcript was cloned and the sequence for the as yet unknown 3' extended trailer, generated by alternative polyadenylation, was determined.
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PMID:Subtractive cDNA cloning as a tool to analyse secondary effects of a muscle disease. Characterization of affected genes in the myotonic ADR mouse. 752 80

Cytochalasins are a family of structurally related natural product cytotoxins that selectively depolymerize microfilaments. In this study, the interaction between several cytochalasins and the drug transporter P-glycoprotein was investigated. Dihydrocytochalasin B and cytochalasin E consistently sensitized P-glycoprotein-overexpressing human breast carcinoma cells (MCF-7/ADR) to daunomycin, vinblastine, and actinomycin D without affecting the cytotoxicity of cisplatin. These compounds did not affect the sensitivities of the parental MCF-7 cells to anticancer drugs, indicating that their effects are due to P-glycoprotein inhibition. Effects of dihydrocytochalasin B and cytochalasin E were observed at concentrations as low as 2.5 and 5 microM, respectively. In contrast, cytochalasins A, B, C, D, H, and J did not sensitize MCF-7/ADR cells to any of the drugs. The accumulation of [3H]-vinblastine by MCF-7/ADR cells and by drug-resistant human ovarian carcinoma cells (SKVLB1) was increased to the greatest extent by verapamil, followed by dihydrocytochalasin B > cytochalasin E > cytochalasin B, whereas cytochalasins A, C, D, H, and J did not alter intracellular accumulation of the drug. Similarly to verapamil, dihydrocytochalasin B significantly stimulated the ATPase activity of P-glycoprotein, while other cytochalasins were ineffective. These results demonstrate that very closely related compounds can differentially interact with P-glycoprotein. For example, the only difference between cytochalasin B and dihydrocytochalasin B is the saturation of a carbon-carbon double bond in dihydrocytochalasin B. These structural differences may provide important insight into chemical determinants for drug interaction with P-glycoprotein.
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PMID:Differential interactions of cytochalasins with P-glycoprotein. 883 87

The multidrug resistance protein (MRP) is an ATP-dependent transport protein for organic anions, as well as neutral or positively charged anticancer agents. In this study we report that dinitrophenyl-S-glutathione increases ATPase activity in plasma membrane vesicles prepared from the MRP-overexpressing cell line GLC4/ADR. This ATPase stimulation parallels the uptake of DNP-SG in these vesicles. We also show that the (iso)flavonoids genistein, kaempferol and flavopiridol stimulate the ATPase activity of GLC4/ADR membranes, whereas genistin has no effect. The present data are consistent with the hypothesis that certain (iso)flavonoids affect MRP-mediated transport of anticancer drugs by a direct interaction with MRP.
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PMID:Modulation by (iso)flavonoids of the ATPase activity of the multidrug resistance protein. 928 Mar 10

Sphinxolides, a newly described family of cytotoxins from the New Caledonian sponge Neosiphonia superstes, bear structural resemblance to scytophycins. We now demonstrate that the cytotoxicity of sphinxolides is associated with cell cycle arrest in G2-M and induction of apoptosis. Like scytophycins and cytochalasins, sphinxolides caused rapid loss of microfilaments in cultured cells, without affecting microtubule organization. Microfilament reassembly was very slow after removal of the sphinxolide, consistent with the slow recovery of cellular proliferation. Sphinxolides potently inhibited actin polymerization in vitro and the microfilament-dependent ATPase activity of purified actomyosin, indicating a direct effect on actin. Importantly, sphinxolides were equally cytotoxic toward MCF-7 human breast carcinoma cells and a subline which overexpresses P-glycoprotein (MCF-7/ADR). Similarly, overexpression of the multidrug resistance-associated protein MRP by HL-60 cells did not confer resistance to the sphinxolides. These studies demonstrate that sphinxolides are potent new antimicrofilament compounds that circumvent multidrug resistance mediated by overexpression of either P-glycoprotein or MRP. Therefore, these agents may be useful in the treatment of drug-resistant tumors.
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PMID:Microfilament depletion and circumvention of multiple drug resistance by sphinxolides. 928 83

The thioether phospholipid ilmofosine (BM 41 440) is a new anti-cancer drug presently undergoing phase II clinical trials. Because resistance to anti-tumour drugs is a major problem in cancer treatment, we investigated the resistance of different cell lines to this compound. Here we report that the multidrug-resistant cell lines MCF7/ADR, CCRFNCR1000, CCRF/ADR500, CEM/VLB100 and HeLa cell lines transfected with a wild-type and mutated (gly/val185) multidrug resistance 1 gene (MDR1) are cross-resistant to ilmofosine compared with the sensitive parental cell lines. In CEMNM-1 cells, in which the resistance is associated with an altered topoisomerase II gene, no cross-resistance to ilmofosine was observed. Ilmofosine is not capable of modulating multidrug resistance and neither does it reduce the labelling of the P-glycoprotein (P-gp) by azidopine nor alter ATPase activity significantly. The resistance to ilmofosine in multidrug-resistant CCRF/VCR1000 cells cannot be reversed by the potent multidrug resistance modifier dexniguldipine-HCI (B8509-035). A tenfold excess of ilmofosine does not prevent the MDR-modulating effect of dexniguldipine-HCl. Treatment of cells with ilmofosine does not alter the levels of MDR1 mRNA. Long-term treatment of an ilmofosine-resistant Meth A subline with the drug does not induce multidrug resistance, indicating that ilmofosine does not increase the level of P-gp. Determination of the MDR2 mRNA levels in the cells revealed that the resistance pattern to ilmofosine is not correlated with the expression of this gene. It is concluded, therefore, that multidrug-resistant cells are cross-resistant to ilmofosine and that the compound is not a substrate of Pgp. No association between the expression of the MDR2-encoded P-gp and resistance to ilmofosine was observed. It is supposed that MDR1-associated alterations in membrane lipids cause resistance to ilmofosine.
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PMID:Resistance to the new anti-cancer phospholipid ilmofosine (BM 41 440). 932 44

Some multidrug-resistant cell lines efflux anticancer drugs but do not overexpress the well-known P-glycoprotein pump or Pgp. A 190 kDa or multidrug-resistant associated protein (MRP) has been identified and described as an MDR mediator. Many studies on cells overexpressing MRP and Pgp, show a concentration of the drug inside cytoplasmic vesicles followed by an exocytotic process. We studied daunorubicin (DNR) subcellular distribution in the presence of an H+-ATPase pump inhibitor 7-chloro-4-nitrobenz-2-oxa-1,3-diazole (NBD) and verapamil (VPL) in two human breast adenocarcinoma MCF7 etoposide-resistant and adriamycin-resistant cell lines, overexpressing respectively MRP (MCF7/VP) and Pgp (MCF7/ADR). Nucleo-cytoplasmic distribution of daunorubicin was carried out using scanning confocal microspectrofluorometry. This technique allows the determination of nuclear accumulation of anthracyclines. Our results show that NBD was able to increase the nuclear accumulation of DNR in MCF7/VP but not in MCF7/ADR cells. Similarly, NBD could reverse DNR resistance in MCF7/VP cells but had no effect on DNR cytotoxicity in MCF7/ADR cells. VPL caused a significant increase in nuclear accumulation of DNR in MCF7/VP and MCF7/ADR cells. Incubation of MCF7/VP and MCF7/ADR cells with VPL, increased the sensitivity of these cells. These data demonstrate clearly that even if vesicular sequestration can happen in cells overexpressing MRP and Pgp proteins, only the MRP protein is able to extrude the drug through intracellular vesicles and efflux. In cells overexpressing Pgp, drug efflux probably takes place directly at the membrane level.
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PMID:Role of the vacuolar H+-ATPase in daunorubicin distribution in etoposide-resistant MCF7 cells overexpressing the multidrug-resistance associated protein. 947 14

P-glycoprotein (P-gp) is a membranous ATPase responsible for the multidrug resistance phenotype. The effect on P-gp-mediated transport of anthracyclines of cell irradiation in the presence of 2,2-diphenyl-5-[N-1-(o-azidophenyl)ethylamino]valeronitrile (VP*), a photoactivable analogue of verapamil was studied in viable K562/ADR cells. The derivatives were daunorubicin (DNR), idarubicin (IDA), 8-(S)-fluoro-idarubicin (F-IDA), 2'-bromo-4'-epidaunorubicin (Br-DNR) and pirarubicin (PIRA). It was observed that the irradiation in the presence of the verapamil analogue was unable to completely inhibit the P-gp-mediated efflux of anthracyclines and we estimated that P-gp retained 10-20% of its ability to pump these toxins. The ability of verapamil, DNR, IDA, F-IDA, Br-DNR and PIRA to inhibit the effect of VP* was studied. For this purpose, cells were irradiated in the presence of VP* and various concentrations of either verapamil or of one of the anthracyclines and then the P-gp functionality was checked by its ability to pump pirarubicin. It was observed that (i) the effect observed, when cells were irradiated in the presence of VP*, was completely blocked by the presence of verapamil; (ii) that anthracyclines are able to partially inhibit the VP* effect. This inhibition occurs at low concentration of anthracycline and depends on the nature of the derivative used. With those used in that study, after the photoirradiation of K562 ADR cells in the presence of VP* and anthracycline, P-gp has retained 50 +/- 5% of its functionality. The anthracycline concentration required for this inhibition is rather low, the total drug concentration yielding 50% of the effect ranged from 0.5 (Br-DNR) to 4 microM (F-IDA). The corresponding cytosolic concentrations are highly correlated with the values of Km determined previously.
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PMID:Partial inhibition of the P-glycoprotein-mediated transport of anthracyclines in viable resistant K562 cells after irradiation in the presence of a verapamil analogue. 1041 60

The multidrug resistance protein 1 (MRP1) is an ATP-dependent transport protein for organic anions, as well as neutral or positively charged anticancer agents. In this study we show that flavopiridol, a synthetic flavonoid currently studied in phase 1 trials for its antiproliferative characteristics, interacts with MRP1 in a potent way. Flavopiridol, as well as other (iso)flavonoids stimulate the ATPase activity of MRP1 in a dose-dependent way at low micromolar concentrations. A new specific monoclonal antibody against MRP1 (MIB6) inhibits the (iso)flavonoid-induced ATPase activity of plasma membrane vesicles prepared from the MRP1 overexpressing cell line GLC4/ADR. The accumulation of daunorubicin in GLC4/ADR cells is increased by flavopiridol and by other non-glycosylated (iso)flavonoids that interact with MRP1 ATPase activity. However, flavopiridol is the only tested compound that affects the daunorubicin accumulation when present at concentrations below 1 microM. Glycosylated (iso)flavonoids do not affect MRP1-mediated transport or ATPase activity. Finally, MRP1 overexpressing and transfected cells are resistant to flavopiridol, but not to other (iso)flavonoids tested. These findings may be of relevance for the development of anticancer therapies with flavopiridol.
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PMID:Potent interaction of flavopiridol with MRP1. 1049 52

Studies have been carried out to examine in vitro drug transport in plasma membrane vesicles isolated from HL60/ADR cells that overexpress MRP. The results demonstrate that glutathione (GSH) enhances transport of daunomycin. A greater increase in transport activity occurs when the reaction is carried out in the presence of both GSH and sodium chloride. Sodium chloride alone has no effect on daunomycin transport. It has also been observed that GSH in the presence of sodium chloride induces a major increase in the transport level of LTC4. Thus far, no metal ion other than sodium chloride has been found to be active in the drug transport system. Kinetic analysis reveals that GSH in the presence of sodium chloride greatly reduces Km and increases Vmax, for daunomycin. Additional studies show that ATPase activity in isolated plasma membrane from HL60/ADR cells is greatly enhanced in the presence of both GSH and sodium chloride. These results suggest the possibility that GSH and sodium chloride stimulate MRP-mediated transport as a result of increased ATPase activity.
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PMID:Multidrug resistance-associated protein (MRP) mediated transport of daunomycin and leukotriene C4 (LTC4) in isolated plasma membrane vesicles. 1065 18


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