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)

Acquired drug resistance is a major factor in the failure of doxorubicin-based chemotherapy in breast cancer. We determined the ability of megestrol acetate and/or tamoxifen to reverse doxorubicin drug resistance in a doxorubicin-resistant breast cancer line (the human MCF-7/ADR). The cytotoxicity of doxorubicin, megestrol acetate, and/or tamoxifen was determined in the sensitive and resistant cell lines utilizing the sulphorhodamine B assay. Tamoxifen alone produced an IC50 (concentration resulting in 50% inhibition of control growth) of 10.6 microM, whereas megestrol acetate alone resulted in an IC50 of 48.7 microM in the MCF-7/ADR cell line. The IC50 of doxorubicin in MCF-7/ADR was 1.9 microM. Neither megestrol acetate alone nor tamoxifen alone at 1 or 5 microM altered the IC50 of doxorubicin. However, the combination of tamoxifen (1 or 5 microM) and megestrol acetate (1 or 5 microM) synergistically sensitized MCF-7/ADR cells. Additionally, megestrol acetate and tamoxifen inhibited iodoarylazidoprazosin binding to P-glycoprotein, and, in their presence, there was an increased doxorubicin accumulation in the MCF-7/ADR cells. Furthermore, the combination of tamoxifen and megestrol acetate had much less effect on the cytotoxicity of doxorubicin in MCF-7 wild-type cells. Clinically achievable concentrations of tamoxifen and megestrol acetate can largely sensitize MCF-7/ADR to doxorubicin. The combination of these three drugs in a clinical trial may be informative.
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PMID:Sensitization to doxorubicin resistance in breast cancer cell lines by tamoxifen and megestrol acetate. 883 29

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

MRP is an ATP-binding cassette family transporter that confers cellular resistance to a variety of natural product cytotoxic agents. However, the biochemical mechanism by which MRP confers resistance has not been established. To gain insight into its mechanism of action, the in vitro substrate specificity of MRP was examined by analyzing drug uptake into membrane vesicles prepared from MRP-overexpressing HL60/ADR cells. Compared to control HL60 membrane vesicles, HL60/ADR membrane vesicles exhibited markedly enhanced ATP-dependent transport of daunorubicin, etoposide, and vincristine. In contrast, little or no increased uptake was observed for vinblastine and Taxol. This pattern of in vitro substrate specificity was consistent with the analysis of the HL60/ADR drug resistance phenotype, which revealed substantial levels of resistance to anthracyclines, etoposide, and vincristine, but only slightly increased resistance to vinblastine and Taxol. Drug transport into HL60/ADR membrane vesicles was osmotically sensitive and dependent on ATP concentration, with a K(m) value of 45 microM for ATP. Lineweaver-Burk analysis indicated that substrate transport was concentration-dependent, with apparent K(m) values of 6.1, 5.7, and 5.5 microM for daunorubicin, etoposide, and vincristine, respectively. The P-glycoprotein-modulating agents cyclosporin A, PSC833, and verapamil, which have modest reversing effects on MRP-overexpressing cell lines, were weak competitive inhibitors of daunorubicin transport, with Ki values of 35, 84, and 95 microM, respectively. In addition, the glutathione analog azidophenacyl-glutathione, oxidized glutathione, and the LTD4 antagonist MK571 were competitive inhibitors of daunorubicin transport with Ki values of 69, 31, and 3.0 microM, respectively. Genistein, an MRP-specific modulating agent, and arsenate, a compound for which MRP has previously been reported to confer resistance, were also competitive inhibitors, with Ki values of 17 and 29 microM, respectively. These results are consistent with a previous report in which we demonstrated that HL60/ADR membrane vesicles transport azidophenacylglutathione and that transport of this agent is competitively inhibited by daunorubicin, vincristine, and etoposide [Shen et al., (1966) Biochemistry 35, 5719-5725]. Together, these uptake studies performed with HL60/ADR membrane vesicles constitute a consistent body of evidence that indicates that MRP transports both glutathione S conjugates and unaltered natural product drugs and support the idea that the direct transport of unaltered lipophilic cytotoxic drugs is the predominant biochemical mechanism whereby MRP confers multidrug resistance.
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PMID:ATP-dependent transport of lipophilic cytotoxic drugs by membrane vesicles prepared from MRP-overexpressing HL60/ADR cells. 954 8

Overexpression of the multidrug resistance MDR1 gene product P-glycoprotein and/or the multidrug resistance-associated protein MRP confers multidrug resistance to cancer cells. The pipecolinate derivative VX-710 has previously been demonstrated to reverse MDR1-mediated multidrug resistance at concentrations of 0.5-2.5 microM by direct interaction with P-glycoprotein and inhibition of its drug efflux activity. In this study we investigated whether VX-710 as well as four other known MDR1 modulators could also reverse multidrug resistance mediated by MRP. VX-710 at 0.5-5 microM restored senstivity of MRP-expressing HL60/ADR promyelocytic leukemia cells to the cytotoxic action of doxorubicin, etoposide and vincristine. VX-710 was approximately 2-fold more effective than verapamil, MS-209 and CsA in modulating MRP-mediated multidrug resistance, whereas GF120918 had no significant effect. VX-710 was also more effective than verapamil, MS-209 and CsA in restoring the daunorubicin accumulation deficit in HL60/ADR cells and in increasing calcein uptake. A photoaffinity analog of VX-710, [3H]VF-13,159, specifically photo labeled the MRP protein and unlabeled VX-710 inhibited this binding in a concentration-dependent manner. These data suggest that VX-710 is not only a potent modulator of P-glycoprotein-mediated multidrug resistance, but also affects multidrug resistance in MRP-expressing cells and may exert its action, at least in part, by binding directly to MRP.
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PMID:Chemosensitization and drug accumulation effects of VX-710, verapamil, cyclosporin A, MS-209 and GF120918 in multidrug resistant HL60/ADR cells expressing the multidrug resistance-associated protein MRP. 907 10

Doxorubicin- (OAW-dox, SK-OV-dox), taxol- (OAW-tax, SK-OV-tax) and cisplatin- (SK-OV-cis) resistant cells derived from the parental OAW-42 and SK-OV-3 cell lines were established. OAW-42 sublines showed high resistance, the SK-OV-3 sublines only low resistance. OAW-42 sublines showed a cross-resistance profile typical of multidrug resistance (MDR). The sublines of SK-OV-3 showed a cross-resistance profile different from the OAW-42 sublines. The mRNA expression of several resistance proteins and related factors was analyzed. An overexpression of P-glycoprotein 170 (P-170), glutathione-S-transferase-pi (GST-pi), thymidylate synthase (TS), glutathione peroxidase (GP) and c-jun was found in OAW-dox and OAW-tax cells. Additionally, OAW-tax cells expressed a higher mRNA level of protein kinase Cbeta2. DNA analysis revealed a 2-fold gene amplification of P-170, whereas the genes for GST-pi, TS and GP were not amplified. SK-OV-dox and SK-OV-tax cells showed a decreased level of histone 3 (H3) and TS mRNA. This shows that the sublines of OAW-42 developed resistance by co-expression of several resistance-related proteins and proto-oncogenes whereas the sublines of SK-OV-3 expressed resistance by decreased expression of the proliferation-dependent proteins H3 and TS.
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PMID:Messenger RNA expression of resistance proteins and related factors in human ovarian carcinoma cell lines resistant to doxorubicin, taxol and cisplatin. 907 15

Expression of P-glycoprotein, a plasma-membrane glycoprotein involved in multidrug resistance and encoded by mdr genes, was investigated in cultured rat liver cells acutely exposed to doxorubicin. This anticancer drug was shown to increase mdr mRNA levels in a dose-dependent manner in both rat liver epithelial (RLE) cells and primary rat hepatocytes. This induction of mdr transcripts was detected as early as a 4-h exposure to doxorubicin used at 0.5 microg/ml. It occurred through increased expression of the mdr1 gene as assessed by northern blot analysis using rat mdr-gene-specific probes. In addition, RLE cells exposed to doxorubicin displayed an overexpression of a 140-kDa P-glycoprotein as demonstrated by western blotting. Moreover, doxorubicin-treated RLE cells displayed enhanced cellular efflux of the P-glycoprotein substrate rhodamine 123 that was inhibited by the P-glycoprotein blocker verapamil, thus providing evidence that doxorubicin-induced P-glycoprotein was functional in liver cells. Doxorubicin-mediated mdr mRNA induction was found to be fully inhibited by actinomycin D, thus indicating its dependence on RNA synthesis; it was demonstrated to be not associated with alteration of protein synthesis, suggesting it differed from the known mdr mRNA overexpression occurring in response to cycloheximide. In contrast to P-glycoprotein, other liver detoxification pathways such as cytochromes P-450 1A were not induced by doxorubicin treatment. These data indicate that doxorubicin can act as a potent acute inducer of functional P-glycoprotein in rat liver cells and therefore may modulate both chemosensitivity of hepatic cells and P-glycoprotein-mediated biliary secretion of xenobiotics.
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PMID:Up-regulation of P-glycoprotein expression in rat liver cells by acute doxorubicin treatment. 921 Apr 82

The relevance of MDR-1 gene expression to the multidrug resistance phenotype was investigated. Drug-resistant cells, KB-V1 and MCF7/ADR, constantly expressed mRNA of the MDR-1 gene and were more resistant to vinblastine and adriamycin than drug-sensitive cells, KB-3-1 and MCF7. The drug efflux rate of KB-V1 was the same as KB-3-1 although the MDR-1 gene was expressed in only the resistant cell. The higher intracellular drug concentration of KB-3-1 than KB-V1 was due to the large drug influx. In the case of MCF7 and MCF7/ADR, the influx and efflux of the drug had nearly the same pattern and drug efflux was not affected by verapamil. The amount of ATP, cofactor of drug pumping activity of P-glycoprotein, was not changed by the resistance. These observations suggested that drug efflux mediated by MDR-1 gene expression was not a major determining factor of drug resistance in the present cell systems, and that the drug resistance could be derived from the change in drug uptake and other mechanisms.
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PMID:MDR-1 gene expression is a minor factor in determining the multidrug resistance phenotype of MCF7/ADR and KB-V1 cells. 925 20

A multidrug-resistant murine lymphoid leukemia P388/ADR overexpresses P-glycoprotein (P-gp), an active transporter that pumps cytotoxic drugs out of cells and a product of mdr1 gene. Cytotoxic T lymphocytes (CTL) that showed cytotoxicity against P388/ADR were generated from mixed lymphocyte tumor cell culture. CTL do not kill drugsensitive parental P388 (P388/parent) that does not express P-gp. Monoclonal antibody against P-gp inhibited cytotoxic activity. Similar results were obtained in another multidrug-resistant cell line P388/VP-16. Cytotoxic activity was mediated by Thy1+ CD4- CD8+ T-cells. When P388/ADR was treated with murine IL-4, expression of P-gp was downregulated. Monoclonal antibody against interleukin-4 (IL-4) abrogated the IL-4-induced suppression of P-gp. Cytolytic activity of CTL against IL-4-treated P388/ADR was dose dependently inhibited. These results suggest that P-gp is immunogenic and can be a target of CTL in this murine leukemia model.
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PMID:Cytotoxic T-lymphocytes recognizing P-glycoprotein in murine multidrug-resistant leukemias. 926 May 76

Drug accumulation studies with the anticancer agents adriamycin and vincristine were carried out on the MDR variant of the human lung cell lines DLKP, DLKP-A10 which overexpresses the MDR associated P-glycoprotein efflux pump. Reduced cellular accumulation of both agents was observed in the resistant variant. The subsequent addition of verapamil and cyclosporin A resulted in partial restoration of cellular accumulation of both drugs in the DLKP-A10 resistant variant while complete restoration of cellular drug levels was observed in the SKMES-1/ADR cell line. These results suggested that the accumulation defect observed in the SKMES-1/ADR cell line was P-glycoprotein mediated and that accordingly, the cells exhibited characteristics consistent with the classical MDR phenotype. In contrast, while P-glycoprotein also appears to mediate a reduction in cellular drug accumulation in the DLKP-A10 cells, an alternative transport mechanism may also be present. No significant increase in the expression of either the MRP or LRP transport proteins was observed in the resistant cells. Metabolic inhibition by antimycin A (but not sodium azide or 2-deoxy-D-glucose) resulted in complete restoration of drug accumulation suggesting the presence of an alternative energy dependent transport mechanism. Fluorescent microscopy studies indicated different cellular localisation of the drug within the parental and resistant cells despite equivalent intracellular concentrations. These studies also revealed the presence of an ATP-dependent, vesicular sequestration mechanism which may be involved in the reduction of nuclear adriamycin accumulation in the DLKP-A10 cell line. This was indicated by observation of the disruption of cytoplasmic vesicles by antimycin A and also inhibition of cytoplasmic drug sequestration by the carboxylic ionophores, monensin and nigericin, accompanied by increased adriamycin accumulation and redistribution of the drug from the cytoplasm to the nucleus.
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PMID:The multidrug-resistant human lung tumour cell line, DLKP-A10, expresses novel drug accumulation and sequestration systems. 926 Aug 77

Multidrug resistance (MDR) is one of the major obstacles to long term successful cancer chemotherapy. The use of MDR reversal (MDRR) agents is a promising approach to overcome the undesired MDR phenotype. To design more effective MDRR agents that are urgently needed for clinical use, a data set of 609 diverse compounds tested for MDRR activity against P388/ADR-resistant cell lines was submitted to the MULTICASE computer program for structure-activity analysis. Some substructural features related to MDRR activity were identified. For example, the CH2-CH2-N-CH2-CH2 group was found in most of the active compounds, and the activity was further enhanced by the presence of (di)methoxylphenyl groups, whereas the presence of a stable quaternary ammonium salt, a carboxylic, a phenol, or an aniline group was found to be detrimental to activity. Possible explanations for these observations are proposed. Some physicochemical properties, e.g., the partition coefficient (log P) and the graph index (which in some sense measures the "complexity" of a molecule) were also found to be relevant to activity. Their role in MDRR was also rationalized. Based on our quantitative structure-activity relationship study of MDRR agents, some compounds with desired substructural features and activity were identified from the MACCS-II and National Cancer Institute DIS databases and tested experimentally. Our study may also help the rational design of anti-cancer drugs. Based on this study and on observations by other researchers, we postulate that P-glycoprotein-mediated resistance to paclitaxel could probably be eliminated by proper substitution of its benzamido and phenyl groups. Several novel compounds with the paclitaxel skeleton are proposed, which may lead to a new generation of paclitaxel anti-cancer drugs with less MDR potential.
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PMID:Quantitative structure-activity relationship of multidrug resistance reversal agents. 927 56


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