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)

We have examined the effect of FK506 on the Adriamycin sensitivity of the multidrug resistant human chronic myelocytic leukemia cell line (K562/ADM). In K562/ADM cells, 1.0 microgram/ml FK506 reversed the resistance of Adriamycin, and increased the IC50 value for Adriamycin up to 17 fold. However, IC50 value for the parent cells (K562) increased only 1.5 fold. By cell cycle analysis, the accumulation in late S-G2M phase was confirmed on K562/ADM cells, treated with 1.0 microgram/ml FK506 and low-dose of Adriamycin. Cyclosporin A (CsA) could also restored the Adriamycin sensitivity in the K562/ADM cells, as previously reported. 1.0 microgram/ml FK506 as well as CsA significantly increased radioactive Adriamycin accumulation in K562/ADM cells and blocked [3H]azidopien photoaffinity labeling of P-glycoprotein. These results suggest that 1.0 microgram/ml FK506 could reverse the Adriamycin resistance in a MDR human leukemia cells through the interaction with P-glycoprotein.
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PMID:FK506 reverses adriamycin resistance in a multidrug-resistant human leukemia cell line. 128 34

A human colon cancer cell line with acquired multidrug resistance (MDR) was assayed for the intracellular GSH level and the activity of GSH-S-transferase (GST), which catalyzes the conjugation reaction of electrophilic drugs with GSH. The GSH level and GST activity (as measured with 1-chloro-2,4-dinitrobenzene) were elevated in the resistant cells by 1.7-fold and 2-fold, respectively. This elevated catalytic activity of the resistant cells was reflected in a 2-fold increase in GST-pi mRNA, which was not the result of gene amplification. In addition, buthionine sulfoximine, a specific inhibitor of GSH synthesis, significantly increased Adriamycin sensitivity in both the MDR and the parental cells, affecting the former more than the latter. The effects seen with buthionine sulfoximine were not seen with puromycin and actinomycin D. A dramatic overexpression of mdr1, a P-glycoprotein gene responsible for the MDR phenotype, was also observed in the MDR cells. In contrast, none of these products (i.e., mdr P-glycoprotein, GSH level, total GST activity, GST-pi gene copy, and GST-pi mRNA level) was elevated in HeLa cells resistant to cisplatin and some alkylating agents, supporting the notion that the acquisition of cisplatin resistance differs from the mechanism of MDR. These results indicate that the intrinsic GSH level and GST-pi activity affect anthracycline resistance per se and not MDR in the human colon cancer cells.
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PMID:Overexpression of glutathione S-transferase and elevation of thiol pools in a multidrug-resistant human colon cancer cell line. 134 33

We have associated pharmacological studies to a semi-quantitative evaluation of P-glycoprotein(s) expression, to establish if classical multidrug resistance (MDR) could account for the complete resistance phenotype exhibited by progressively doxorubicin-resistant rat glioblastoma cells. Three resistant variants (C6 0.001, C6 0.1 and C6 0.5) of the C6 glioblastoma cell line (C6 S) were selected by long-term culture in the presence of three concentrations of doxorubicin (0.001, 0.1 and 0.5 microgram.ml-1 respectively). The degree of doxorubicin resistance was respectively 7, 33 and 400, and all the cell variants were cross-resistant to m-AMSA, etoposide and vincristine. Doxorubicin incorporation was reduced similarly in all resistant cells, irrespective of the level of resistance. When exposed to their respective doxorubicin IC50, the 7-fold resistant cells had the same intracellular drug incorporation as the sensitive cells, whereas the 33-fold and 400-fold resistant cells could incorporate respectively 3.7 and 17 times more drug. The ratio of doxorubicin exposures required for 50% DNA synthesis inhibition and 50% growth inhibition was dependent on the degree of resistance; this ratio was 12.8 in C6 S, 11.6 in C6 0.001, 6.3 in C6 0.1 and 1.8 in C6 0.5. P-glycoprotein(s) overexpression was of the same magnitude as the resistance factor in variants C6 0.001 and C6 0.1, but was lower than resistance factor in variant C6 0.5. Reversal of drug incorporation by verapamil was complete in all resistant cell lines; however, reversal of doxorubicin cytotoxicity was complete only in the 7-fold resistant line and was only partial in the most resistant lines, which remained 10-fold and 20-fold resistant to doxorubicin. These results suggest that classical MDR was the first phenotype selected by doxorubicin in C6 0.001, whereas mechanism(s) of doxorubicin resistance other than classical MDR are added in the most resistant lines.
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PMID:P-glycoprotein overexpression cannot explain the complete doxorubicin-resistance phenotype in rat glioblastoma cell lines. 134 23

PANC02 is a ductal adenocarcinoma of the pancreas that is resistant to every known class of clinically active antitumor agent. To study the mechanism(s) underlying the intrinsic drug resistance of this tumor, a mammary adenocarcinoma (CA-755) that also grows in C57/BL mice and is known to be drug sensitive was used for comparison. PANC02 resistance and CA-755 sensitivity to several antitumor agents and to X-ray therapy was confirmed in mice, and PANC02 also demonstrated relative resistance in tissue culture. Relative to Chinese hamster ovary (CHO) and CA-755 cells, PANC02 did not appear to show a higher rate of mutation to drug resistance in culture as based on the 6-thioguanine resistance marker. Although P-glycoprotein characteristic of the multidrug resistance (MDR) phenomenon could be demonstrated at the mRNA level using a sensitive RNAse protection assay, the level of expression found was several orders of magnitude lower than that observed in phenotypic MDR cell lines. Furthermore, quinidine failed to increase the sensitivity of PANC02 cells to Adriamycin under conditions that clearly potentiated the toxicity of the drug to a CHO cell line exhibiting classic MDR traits. The heterogeneity in the distribution of drugs was inferred as being significantly greater in PANC02 versus CA-755 cells in vivo as based on measurements of within-animal, within-tumor variance in the distribution of the marker compounds inulin and antipyrine. Although it may not be the only mechanism involved, this greater intratumor heterogeneity in drug distribution could theoretically play a major role in the intrinsic drug resistance of PANC02 in vivo.
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PMID:Intrinsic resistance to anticancer agents in the murine pancreatic adenocarcinoma PANC02. 134 74

To investigate the possible role of the multidrug resistance phenotype to chemoresistance in human ovarian carcinoma, we have analyzed human multidrug resistance gene (mdr 1) expression in 8 human ovarian adenocarcinoma cell lines. An increase in P-glycoprotein level specific to multidrug-resistant tumor cells was not apparently associated with the increase in resistance to vincristine (VCR) or doxorubicin (Adriamycin). Mdr 1 transcripts (4.5 kilobases) were observed in the RNA preparation obtained from only one cell line (SHIN-3) that showed the highest resistance to both drugs in vitro and in vivo. No cell lines showed mdr 1 DNA amplification. These results suggest that the insensitivity of human ovarian carcinoma to chemotherapy could be partly explained by the expression of mdr 1.
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PMID:Expression of a human multidrug resistance gene in human ovarian carcinoma cell lines. 134 3

It has been shown previously that verapamil and other calcium antagonists and calmodulin inhibitors can reverse multidrug resistance. We compared the potency of the dihydropyridine derivatives (4R)-3-[3-(4,4-diphenyl-1-piperadinyl)-propyl]-5-methyl-1,4-dihydr o-2,6- dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate-hydrochloride (B859-35), a metabolite of B859-35, niguldipine and (R)-nitrendipine to that of (RS)-verapamil in reversing multidrug resistance. The accumulation of the fluorescent dye rhodamine 123, which is transported by the P-glycoprotein, was determined by a flow cytometer. Multidrug-resistant human HeLa KB-8-5 and Walker rat carcinoma cells were incubated in the presence and in absence of the drugs indicated above. We found that 0.1 microM B859-35 increases the accumulation of rhodamine 123 in multidrug-resistant KB-8-5 and Walker cells more effectively than 1 microM (RS)-verapamil. In sensitive KB-3-1 cells addition of the drugs had no significant influence on the accumulation of rhodamine 123. IN KB-8-5 cells, 10 nM Adriamycin caused a reduction of cell growth to 85% compared to untreated controls (= 100%). If 1 microM B859-35, B859-35 metabolite, niguldipine, verapamil or (R)-nitrendipine was added to 10 nM Adriamycin, growth reduction compared with untreated controls increased to 12%, 11%, 23%, 63%, and 82% respectively. The effect of 0.1 microM B859-35 was a reduction in proliferation to 38%, that of 0.1 microM verapamil to 72%. These data illustrate that B859-35, a compound with antitumor activity in several tumors, is at least ten times more potent than racemic verapamil in reversing multidrug resistance.
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PMID:Reversal of multidrug resistance by B859-35, a metabolite of B859-35, niguldipine, verapamil and nitrendipine. 134 91

N-Benzyladriamycin-14-valerate (AD 198) is a highly lipophilic analogue of Adriamycin with novel cytotoxic mechanisms, greater in vivo antitumor activity, and the ability to circumvent multidrug resistance due to P-glycoprotein-mediated drug efflux or decreased topoisomerase II activity. To identify the mechanism(s) which may confer AD 198 resistance, J774.2 mouse macrophage-like cells were selected for growth in cytotoxic levels of AD 198 (AD 198R). AD 198R cells exhibited over-expression of the mdr1b (P-glycoprotein) gene, cross-resistance to Adriamycin and vinblastine, and potentiation of drug cytotoxicity by verapamil. However, net intracellular accumulation of AD 198 in AD 198R cells was unchanged compared to parental cells, while Adriamycin and vinblastine accumulations were reduced 40% and 95%, respectively. AD 198 was localized in the perinuclear region of the cytoplasm in both parental and AD 198R cells, with additional vesicular compartmentalization in AD 198R cells. Verapamil-induced reversal of AD 198 resistance coincided with some drug redistribution from cytoplasmic vesicles, but without redistribution of AD 198 into the nucleus. These results suggest that AD 198 resistance was not conferred through a P-glycoprotein-mediated reduction in intracellular drug accumulation but through other cytoplasmic mechanisms, including, but not limited to, drug compartmentalization.
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PMID:Resistance to N-benzyladriamycin-14-valerate in mouse J774.2 cells: P-glycoprotein expression without reduced N-benzyladriamycin-14-valerate accumulation. 135 Jul 53

Activities of a newly synthesized compound, N-ethoxycarbonyl-7-oxo-staurosporine (NA-382), on cyclic AMP-dependent protein kinase (A-kinase), Ca2+/phospholipid dependent protein kinase (C-kinase), and drug resistance were investigated and compared with those of staurosporine. Protein kinase-inhibitory activity of NA-382 was lower but more selective to C-kinase than that of staurosporine. NA-382 was less toxic to P388 cells and at a non-cytotoxic concentration completely reversed the vinblastine (VBL) resistance of Adriamycin-resistant P388 (P388/ADR) cells without influence on the effect of VBL on the parental P388/S cells. However, the cytotoxicity of staurosporine was too high to give the combination effect with VBL. NA-382 dose-dependently increased VBL-accumulation and inhibited VBL-efflux in P388/ADR with higher potency than staurosporine. Both compounds inhibited the photolabeling of [3H]azidopine on 140-kDa P-glycoprotein in the plasma membrane from the resistant cells. These results suggest that a staurosporine analog, NA-382, reverses multidrug resistance by inhibiting the drug-efflux system or P-glycoprotein.
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PMID:Reversal of vinblastine resistance by a new staurosporine derivative, NA-382, in P388/ADR cells. 135 92

In both mouse sarcoma 180 and human KB cells selected for the multiple drug resistance (MDR) phenotype, there is an elevation in the steady state mRNA level of c-fos. There is no detectable gene amplification for c-fos, nor is there any significant change in the rate of mRNA transcription or degradation, suggesting that other factors are responsible for the increased expression level in resistance. Cells selected for resistance to methotrexate, a drug not in the MDR group, do not have an increase in c-fos mRNA expression. When drug-sensitive cells are exposed for 30 min to an ED50 concentration of vinblastine, Adriamycin, colchicine, or VP-16, but not to methotrexate or cisplatin, there is a 3-6-fold induction in the level of c-fos message. Because the former drugs are members of the MDR class and the latter are not, the results are consistent with the hypothesis that induction of c-fos by low levels of cytotoxic drugs may be an early event in the acquisition of the MDR phenotype. If this were the case, then c-fos would be expected to act in concert with c-jun to control transcription by binding to a specific DNA regulatory site. Consistent with this explanation is the existence of an AP-1 sequence in the promotor region for the P-glycoprotein gene (mdr1), as well as the fact that c-jun is also overexpressed in MDR cells.
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PMID:Expression of c-fos in human and murine multidrug-resistant cells. 135 51

Multidrug resistance can be induced in mammalian cells by selection with a single cytotoxic agent. Overproduction of the energy-dependent drug efflux pump P-glycoprotein, encoded by the mdr1 gene, has been identified as the cause of one form of multidrug resistance. The molecular basis of other forms of multidrug resistance is unknown. Doxorubicin selection of the human squamous lung cancer cell line SW-1573 resulted in multidrug-resistant sublines in which a non-P-glycoprotein-mediated form of multidrug resistance precedes mdr1 expression. Here we present a cytogenetic analysis of both non-P-glycoprotein-mediated multidrug-resistant and P-glycoprotein-mediated multidrug-resistant sublines derived from SW-1573. Three independently derived non-P-glycoprotein-mediated multidrug-resistant sublines showed a heterozygous deletion of the short arm of chromosome 2 (p23-pter), whereas alterations of chromosome 7 were present in the P-glycoprotein-mediated multidrug-resistant cell lines. In one series of clonally derived P-glycoprotein-mediated multidrug-resistant sublines, mdr1 overexpression was accompanied by various markers of chromosome 7 with breakpoints at 7q22, the mdr1 gene being known to be located at 7q21.1. Our data suggest that in SW-1573 cells acquisition of non-P-glycoprotein-mediated multidrug resistance is accompanied by a specific deletion or a translocation involving the short arm of chromosome 2, whereas in the emergence of P-glycoprotein-mediated multidrug resistance a rearrangement of the long arm of chromosome 7 is a critical event.
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PMID:Cytogenetic alterations associated with P-glycoprotein- and non-P-glycoprotein-mediated multidrug resistance in SW-1573 human lung tumor cell lines. 135 3


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