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)

An increasing body of evidence appears to implicate the lipid bilayer of multidrug resistant (MDR) cells with P-glycoprotein activity. Several cationic amphiphilic drugs (CADs) have been extensively described as modulators of MDR. These same agents are also known to (1) inhibit lysosomal acid sphingomyelinase (ASmase), a phospholipid degrading enzyme, and/or (2) induce phospholipidosis in animal tissues or cultured cell lines. In this report, we randomly selected 17 CADs and evaluated their potency in modulating MDR in the murine MDR P388/ADR leukemia cell line. We compared these results with their ability to inhibit ASmase and observed a significant dose-dependent linear relationship (95% central confidence interval), between ASmase inhibition and MDR reversal. This approach permitted us to identify three new modestly potent chemosensitizers: trimipramine, desipramine, and mianserine. Modulation of MDR was not cell line specific, since CADs at 10 microM increased doxorubicin (DOX) and vinblastine (VBL) (but not methotrexate, MTX) cytotoxicity in both P388/ADR and the human MDR cell lines MES-SA/Dx5 and K562/R7, but not in the parental drug-sensitive cells. Although all chemosensitizing CADs at 10 microM significantly increased Rhodamine-123 (Rho-123) accumulation in the human leukemia MDR cell line K562/R7 and most presented significant displacement of the photoaffinity labelling probe iodoarylazidoprazosin, no correlation between these observations and the ability of CADs to sensitize MDR cells to DOX and VBL was found. In conclusion, our study strongly suggests that the chemosensitizing potency of agents such as CADs may be due to a dual mechanism of action: direct antagonism of P-gp activity and indirect modulation of P-gp activity through the disruption of cellular lipid metabolism.
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PMID:Inhibition of lysosomal acid sphingomyelinase by agents which reverse multidrug resistance. 771 13

Calcium channel inhibitors, such as verapamil, have been identified as having the ability to modulate the multidrug-resistant (MDR) phenotype due to overexpression of P-glycoprotein (Pgp). We have studied the effect of verapamil on Pgp expression levels in a cell line originating from acute myeloblastic leukemia and resistant to adriamycin, K562/ADR. In this line, the addition of 15 microM verapamil in the culture medium gives a 3-fold decrease of Pgp expression after 72 hours of treatment. Similar results have been obtained for two other MDR cell lines, which suggest that this phenomenon is not specific of a single model. The level of mdr1 mRNAs is decreased in the presence of verapamil (with a maximum effect obtained at the 24th hour), which suggests that the mechanism of action of verapamil is transcriptional and/or post-transcriptional. We have also studied the effect of verapamil on the level of expression of mdr1 mRNAs in non-drug selected cells such as the HEL line (human acute myeloblastic leukemia) and the parental K562 line, which present a very low level of expression of Pgp, detectable only by PCR. In these lines, verapamil treatment has no effect on the level of expression of mdr1 mRNAs. The effect of verapamil is therefore restricted to drug-selected lines presenting high levels of Pgp expression. The impact of the negative regulation of Pgp expression on the MDR phenotype has been studied in the K562/ADR line. When the cells are treated for 72 h by verapamil, there is a decrease of resistance and an increase of intracellular accumulation of anticancer agents such as daunorubicin or vinblastine. Negative regulation of Pgp expression appears therefore as a possible strategy for MDR phenotype reversal. The effect of verapamil, whose molecular mechanism of action is being studied, could constitute a basis for this strategy.
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PMID:[Pharmacological control of P-glycoprotein expression]. 774 15

The expression of protein kinase C (PKC) in 83 untreated solid human non-small cell lung carcinomas was determined and its correlation with inherent resistance to doxorubicin, with the expression of P-glycoprotein (P-170), and with the expression of glutathione S-transferase-pi (GST-pi) was analysed. Doxorubicin resistance was measured using an in vitro short-term test. The expression of PKC, P-170 and GST-pi was assessed immunohistochemically. Twenty-three tumors (= 28%) were PKC-positive, whereas 60 tumors (= 72%) were PKC-negative. Nineteen tumors (= 23%) were classified as sensitive and 64 tumors (= 77%) as resistant to doxorubicin. Thirty-nine tumors (= 47%) were P-170-positive and 51 tumors (= 61%) GST-pi-positive. Out of the PKC-positive tumors, 21 were resistant to doxorubicin and 2 were sensitive. Of the same 23 tumors, 18 were P-170-positive and 19 were GST-pi-positive. The correlations between the expression of PKC and the resistance to doxorubicin, the expression of P-170 and the expression of GST-pi were statistically significant. Corresponding results were obtained comparing the results of all tumors with the results of a subgroup of tumors having the same histology (squamous cell carcinomas). This supports the hypothesis that PKC is involved in the inherent doxorubicin-resistance of human lung cancer.
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PMID:Associated expression of protein kinase C with resistance to doxorubicin in human lung cancer. 776 22

We studied the capacity of doxorubicin encapsulation in liposomes of various lipid compositions to circumvent multidrug resistance in several variants of the C6 rat glioblastoma cell line in culture, and to inhibit azidopine binding to membranes isolated from these cells. Three formulations of liposomes were prepared: (a) phosphatidylcholine (PC)/phosphatidylserine (PS)/cholesterol (cho) at a 9/24 ratio; (b) PC/cardiolipin (CL)/cho at 10/1/4 ratio; (c) dipalmitoylphosphatidylcholine (DPPC)/cho at 11/4 ratio. Unloaded liposomes presented no cytotoxicity against sensitive or resistant cells. Doxorubicin encapsulated in PC/PS/cho and PC/CL/cho liposomes had a cytotoxic activity close to that of free doxorubicin, whereas doxorubicin encapsulated in DPPC/cho liposomes was significantly less active than free doxorubicin in sensitive as well as in two of the three multidrug resistant cell lines, and as active as free doxorubicin in the third one. Free doxorubicin was able to decrease 50% of [3H]azidopine photolabelling to P-glycoprotein at a concentration of 40 microM; doxorubicin encapsulated in PC/CL/cho or PC/PS/cho liposomes was able to inhibit [3H]azidopine binding similarly as free drug, whereas doxorubicin encapsulated in DPPC/cho liposomes had no significant effect on this parameter. Unloaded liposomes of either lipid composition had no effect on [3H]azidopine binding. Together with physical studies performed in parallel on doxorubicin trapping in liposomes (J Liposome Res 1993, 3, 753-766), these results suggest that doxorubicin leaked out of fluid liposomes (PC/PS/cho or PC/CL/cho), whereas rigid liposomes (DPPC/cho) were able to sequester the drug more efficiently. In that case, however, no availability of the drug to the cells was possible and only a weak cytotoxicity was exhibited, especially without any favourable effect on multidrug resistance. In conclusion, no reversal of doxorubicin resistance was found to occur through liposomal encapsulation of the drug.
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PMID:Failure of liposomal encapsulation of doxorubicin to circumvent multidrug resistance in an in vitro model of rat glioblastoma cells. 778 7

The newly identified drug transporter MRP is functionally linked to a multiple drug resistance independent from P-glycoprotein. Resistance modifiers for this type of MDR are rare at present. We analyzed the modulating effect of the highly selective bisindolylmaleimide PKC inhibitor GF 109203X on the MRP overexpressing human MDR sublines HL60/AR and GLC4/ADR. Applying a 72 hour MTT-assay we demonstrate a complete reversal of the vincristine resistance of HL60/AR cells. Adriamycin resistance of HL60/AR, or vincristine resistance of GLC4/ADR were partially reversed. Furthermore, rhodamine 123 efflux from HL60/AR was strongly modulated by GF 109203X. Since the PKC inhibitor did not significantly influence MRP gene expression at the mRNA level which was examined by cDNA-PCR, our results suggest either a direct interaction of the compound with MRP or/and an indirect influence on MRP activity via altering the phosphorylation status of the transporter.
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PMID:The specific bisindolylmaleimide PKC-inhibitor GF 109203X efficiently modulates MRP-associated multiple drug resistance. 781 10

We have characterised sites of photodamage catalysed by the cationic photosensitiser tetrabromorhodamine 123, using P388 murine leukaemia cells and a subline (P388/ADR) which has a multidrug resistance phenotype and hyperexpresses mdr1 mRNA for P-glycoprotein. Fluorescence emission spectra were consistent with sensitiser localisation in hydrophobic regions of the P388 cell, and in more aqueous loci in P388/ADR. Subsequent irradiation resulted in photodamage to the P388 cells, resulting in loss of viability. In contrast, P388/ADR cells were unaffected except for an irreversible inhibition of P-glycoprotein, leading to enhanced accumulation of daunorubicin and rhodamine 123 and a corresponding increase in daunorubicin cytotoxicity. These results are consistent with the premise that substrates for P-glycoprotein are confined to membrane loci associated with the transporter, and indicate a very limited migration of cytotoxic photo-products in a cellular environment.
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PMID:Selective photodynamic inactivation of a multidrug transporter by a cationic photosensitising agent. 784 Oct 45

The effects of a novel porphyrin, tolyporphin, on P-glycoprotein-mediated multiple drug resistance in human ovarian and breast cell lines were characterized. Compared with parental SKOV3 and MCF-7 cells, the P-glycoprotein-overexpressing sublines SKVLB1 and MCF-7/ADR were 5- and 1.3-fold less sensitive to the cytotoxic effects of tolyporphin. Subtoxic doses of tolyporphin increased the sensitivity of the SKVLB1 and MCF-7/ADR cells to P-glycoprotein-transported drugs, but did not increase the antiproliferative effects of nontransported drugs. Tolyporphin also enhanced the accumulation of [3H]-vinblastine in SKVLB1 and MCF-7/ADR cells at doses approximately 10-fold lower than those required for similar responses to verapamil. In contrast, tolyporphin did not affect drug accumulation in SKOV3 or MCF-7 cells. Tolyporphin reduced [3H]-vinblastine efflux from SKVLB1 cells, reduced [3H]-vinblastine binding to membranes from SKVLB1 cells, and blocked the ability of [3H]-azidopine to photoaffinity-label P-glycoprotein in these membranes. These results indicate that tolyporphin binds to P-glycoprotein and inhibits the transport of cytotoxic natural product drugs. This novel natural product, and related compounds, may be useful for the reversal of multiple drug resistance and for further definition of the drug binding site(s) of P-glycoprotein.
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PMID:Reversal of multiple drug resistance by tolyporphin, a novel cyanobacterial natural product. 784 44

Welwitindolinones are a family of novel alkaloids recently isolated from the blue-green alga Hapalosiphon welwitschii as a part of our effort to identify new compounds that overcome multiple drug resistance. The abilities of three structurally similar members of this family to interact with P-glycoprotein have been compared. Similarly to the effects of verapamil, N-methylwelwitindolinone C isothiocyanate (compound 1) attenuated the resistance of MCF-7/ADR cells to natural product anticancer drugs, including vinblastine, taxol, actinomycin D, daunomycin, and colchicine, without affecting the cytotoxicity of cisplatin. These effects of compound 1 were apparent at doses as low as 0.1 microM, indicating that it is considerably more potent than verapamil for reversal of resistance. Welwitindolinone C isothiocyanate (compound 3) demonstrated weaker reversing activity, whereas an analogue of compound 1 in which the isothiocyanate group is replaced by an isonitrile group (compound 2) was inactive. The accumulation of [3H]vinblastine in SK-VLB-1 cells was increased by compound 1 > compound 3 > verapamil >> compound 2. Interestingly, only compound 1 and verapamil enhanced [3H]taxol accumulation by these cells. Photoaffinity labeling of P-glycoprotein with [3H]azidopine in membranes from SK-VLB-1 cells was inhibited by compounds 1 and 3, but not by compound 2. Therefore, the differences in the size and/or the electronegativity of the isothiocyanate and isonitrile moieties appear to dramatically affect the abilities of the compounds to interact with P-glycoprotein.
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PMID:Welwitindolinone analogues that reverse P-glycoprotein-mediated multiple drug resistance. 787 31

The expression of drug resistance-associated mdr-1, GST pi, and topoisomerase II genes was analyzed in cell cycle phase enriched populations of doxorubicin-resistant murine leukemic P388/R-84 cells. Flow cytometric analysis of bromodeoxyuridine (BrdU) incorporation and staining with anti-BrdU antibodies was used to confirm the purity of cell cycle phase enriched populations obtained by centrifugal elutriation. Doxorubicin (DOX) and daunorubicin (DNR) accumulation was significantly lower in S-phase cells, and coincubation with verapamil (VPL) or chlorpromazine (CPZ) enhanced DOX and DNR accumulation more in S-phase than in G1- and G2/M-phase cells. While the cellular content of mdr-1 and topoisomerase II mRNAs changed, GST pi mRNA content remained constant during the cell cycle. S-phase cells had about 3-fold higher mdr-1 mRNA content than G1- and G2/M-phase cells. In G1 cells, P-glycoprotein expression, as determined by C219 monoclonal antibody, was 12% less than that of S and G2/M cells. Topoisomerase II mRNA content increased with the progression of cell cycle and peaked in G2/M cells. These observations suggest that cell cycle stage related changes in expression of drug resistance markers may have a major bearing on chemosensitivity of drug-resistant cells.
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PMID:Expression of drug resistance-associated mdr-1, GST pi, and topoisomerase II genes during cell cycle traverse. 787 60

Drugs used in anti-cancer chemotherapy are thought to exert their cytotoxic action by induction of apoptosis. Genes have been identified which can mediate or modulate this drug-induced apoptosis, among which are c-myc, p53 and bcl-2. Since expression of oncogenic ras genes is a frequent observation in human cancer, we investigated the effects of the c-H-ras oncogene on anti-cancer drug-induced apoptosis. Apoptosis induced by a 2 h doxorubicin exposure was measured by in situ nick translation and flow cytometry in a rat cell line (R2T24) stably transfected with the c-H-ras oncogene and in a control cell line (R2NEO) transfected only with the antibiotic resistance gene neo. Both cell lines (R2T24 and R2NEO) had nearly identical growth characteristics, including cell doubling time, distribution over the cell cycle phases and plating efficiency in soft agar. Doxorubicin exposure of the R2NEO cells led to massive induction of apoptosis. In contrast, R2T24 cells, expressing the c-H-ras oncogene, showed significantly less apoptosis after doxorubicin incubation. Doxorubicin induced approximately 3- to 5-fold less cytotoxicity in the R2T24 cells than in the R2NEO cells, as determined by clonogenic assay in soft agar. No difference was observed in intracellular doxorubicin accumulation between the two cell lines, indicating that the classical, P-glycoprotein-mediated multidrug resistance phenotype is not involved in the observed differences in drug sensitivity. In conclusion, our data show that constitutive expression of the c-H-ras oncogene suppresses doxorubicin-induced apoptosis and promotes cell survival, suggesting that human tumours with ras oncogene expression might be less susceptible to doxorubicin treatment.
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PMID:Constitutive expression of the c-H-ras oncogene inhibits doxorubicin-induced apoptosis and promotes cell survival in a rhabdomyosarcoma cell line. 788 Jul 39


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