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)

The interaction of etoposide (VP-16), Vinca alkaloids, and verapamil with the P-glycoprotein (P-gp) was studied in human breast (MCF-7) and Chinese hamster lung (DC3F) cell lines and the corresponding multidrug-resistant MCF-7/ADR and DC3F/ADX tumor cell lines, selected for resistance to Adriamycin and actinomycin D, respectively, and overexpressing P-gp. Verapamil (10 microM) markedly reversed resistance to vincristine (11-fold in DC3F/ADX and 125-fold in MCF-7/ADR; 1-hr exposure), but it had a very modest effect on resistance to VP-16 (3- to 4-fold; 1-hr exposure). Resistant cells accumulated 2- to 4-fold less VP-16 and vincristine than the parental cell lines. Verapamil (10 microM) significantly increased accumulation and retention of vincristine, but not of VP-16, in resistant cell lines. Photoaffinity labeling of resistant cell lines with radioactive analogs of verapamil [N(p-azido-3-125I-salicyl)-N'-beta-aminoethylverapamil (NASVP)] and vinblastine[N-(p-azido-3-125I-salicyl)-N'-beta-aminoethylvindesine (NASV)] showed distinctly labeled P-gp bands in both resistant cell lines, compared with wild-type cells. Excess nonradioactive vinblastine or verapamil effectively competed with the P-gp photolabeling by either NASVP or NASV, with IC50 levels of 0.6 and 10 microM, respectively. In contrast, nonradioactive VP-16 was 100- to 500-fold less potent than vinblastine in competing with P-gp photolabeling, suggesting that VP-16 has significantly lower affinity for P-gp than Vinca alkaloids have. Taken together, our data indicate that P-gp glycoprotein by itself may not be important in the transport/efflux of VP-16 and, thus, in the mechanism of resistance to VP-16 in these cells.
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PMID:P-glycoprotein-independent mechanism of resistance to VP-16 in multidrug-resistant tumor cell lines: pharmacokinetic and photoaffinity labeling studies. 197 71

The aim of this work is to evaluate the relationship between P-glycoprotein expression in circulating blasts and clinical response in patients suffering from acute lymphoblastic leukemia, acute non-lymphoblastic leukemia, and chronic myeloid leukemia in either lymphoid or myeloid blastic crisis. The results obtained show that: a) patients whose blasts express P-glycoprotein are resistant towards protocols including Doxorubicin, Daunorubicin, Etoposide, Mithramycin, Vincristine; b) P-glycoprotein can be expressed constitutively in some cases; c) P-glycoprotein does not appear to be the only mechanism responsible for resistance towards anthracyclines and Etoposide.
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PMID:P-glycoprotein and drug resistance in acute leukemias and in the blastic crisis of chronic myeloid leukemia. 198 99

We examined the distribution of RNA levels expressed by the multidrug-resistance gene (MDR1, also known as PGY1) in 42 renal cell carcinoma (RCC) samples (38 primary and four metastatic lesions). The median MDR1 RNA level for the 38 primary lesions, expressed relative to the level for KB-3-1 cells, was approximately one-half of the level in multidrug-resistant KB-8-5 cells. Elevated MDR1 RNA levels were also observed in three of the four metastatic lesions. The mean MDR1 RNA level was higher in well-differentiated RCCs than in those that were poorly differentiated, suggesting that the increased expression of the MDR1 gene in RCCs originates from the increased expression in renal proximal tubule cells. To clarify the association of the MDR1 protein product P-glycoprotein with natural resistance to doxorubicin (ADR) in RCCs, we evaluated the effects of quinidine on in vitro sensitivity to ADR in 16 RCC samples, using a [3H]thymidine incorporation assay. The enhancing effect of quinidine (7.5 micrograms/mL) on sensitivity to ADR was statistically significant only in the group with high MDR1 RNA levels. Similar enhancement by quinidine of sensitivity to ADR was also observed in the established RCC cell lines in which MDR1 RNA levels were high. These results suggest that P-glycoprotein is active in the natural resistance of RCCs to ADR.
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PMID:MDR1 RNA levels in human renal cell carcinomas: correlation with grade and prediction of reversal of doxorubicin resistance by quinidine in tumor explants. 272 49

The aim of this investigation was to find out whether resistant cells of different tumors can be detected immunocytochemically by the streptavidin-biotin-peroxidase-complex method using the monoclonal antibody 265/F4. This antibody was prepared against the membrane P-glycoprotein of Mr 170 kd from colchicine-resistant CHO cells. For this purpose the acquired resistance of tissue culture cells, ascites tumors and the acquired and inherent resistance of human lung carcinoma xenografts were analyzed. Doxorubicin-resistant S180 cells, daunorubicin-resistant L1210 cells and vincristine-resistant human epidermoid lung carcinoma xenografts showed an intense positive reaction with the monoclonal antibody. In contrast, no specific immunoreactivity was observed with parental (sensitive) tumor cells. These data could eventually provide a prognostic tool for the detection of resistant human tumor cells.
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PMID:Immunocytochemical detection of a resistance-associated glycoprotein in tissue culture cells, ascites tumors and human tumor xenografts by Mab 265/F4. 290 21

Doxorubicin (adriamycin) preconditioned S180 cells were more resistant to doxorubicin. The resistance was detected by three different methods (short-term test, colony assay, tissue culture assay). The doxorubicin-resistant S180 cells express the pleitrop drug resistance phenotype. There exists a multidrug resistance to doxorubicin, dactinomycin (actinomycin D), vincristine and colchicine. In addition, collateral sensitivity was found to fluorouracil (5-fluorouracil) and methotrexate. This multidrug phenotype is in accordance with the pleiotropic phenotype of colchicine-resistant CHO cells. Resistant S180 cells express a glycoprotein of Mr 170 kd determined by indirect immunofluorescence using a monoclonal antibody (Mab 265/F4) to the P-glycoprotein of colchicine-resistant CHO-cells. The P-glycoprotein could be an important prognostic factors for tumors with multidrug resistance.
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PMID:Detection of murine S180 cells expressing a multidrug resistance phenotype using different in vitro test systems and a monoclonal antibody. 331 82

Using four cell lines including drug-sensitive K562/Parent cells, P-glycoprotein (Pgp)-mediated multidrug resistant (MDR) K562/VCR, K562/ADR and revertant K562/ADR-R cells, two fluorescent agents, Fluo-3 and rhodamine-123 (Rh-123), were compared as indicators in a functional assay of MDR. Cells were incubated with 4 microM Fluo-3 or 1 microM Rh-123 for 45 min and then the intracellular accumulation of the agent was measured using a flow cytometer. Verapamil (20 microM) or cepharanthine (biscoclaurine alkaloid, 10 microM) was added just before the fluorescent agents. Efflux patterns were also studied 60 min after incubation with or without verapamil and cepharanthine. Increased intracellular accumulation and a delayed efflux pattern of Fluo-3 by verapamil and cepharanthine were demonstrated in multidrug resistant K562/VCR and K562/ADR cells, indicating that Fluo-3 is another good indicator of MDR. However, a similar, but lower, increase in uptake and a delayed efflux pattern of Fluo-3 by verapamil and cepharanthine were also demonstrated even in Pgp-non-overexpressed K562/Parent cells. In contrast, accumulation of Rh-123 was not affected by verapamil and cepharanthine. To further study the Pgp dependency of Fluo-3, another cell line, K562/NC16 expressing minimum MDR1 mRNA, was cloned. Increased uptake and a delayed efflux pattern of Fluo-3, but not Rh-123, with verapamil or cepharanthine were again demonstrated in K562/NC16 cells, indicating that intracellular accumulation of Fluo-3 may be non-specifically influenced by verapamil and cepharanthine at very low levels of Pgp-related MDR, while the influx and efflux patterns of Rh-123 may be specifically affected by Pgp overexpression.
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PMID:Flow cytometric functional analysis of multidrug resistance by Fluo-3: a comparison with rhodamine-123. 748 25

Expression of P-glycoprotein by tumor cells confers resistance to multiple natural product drugs because of its ability to export these compounds. This transporter is a substrate for several protein kinases; however, the functional significance of its phosphorylation is not defined. We examined the effects of many activators and inhibitors of protein kinases on the activity of P-glycoprotein in drug-resistant human breast carcinoma cells (MCF-7/ADR). Several phorbol esters sensitized these cells to P-glycoprotein substrate drugs; however, there was no correlation with activation of protein kinase C. The 4 alpha- and 4 beta-isomers of phorbol 12-myristate 13-acetate were equally potent in sensitizing the cells to actinomycin D and daunomycin and in increasing the intracellular accumulation of [3H]vinblastine. These effects of 4 beta-phorbol myristate acetate required much higher concentrations than were needed to increase P-glycoprotein phosphorylation and were not antagonized by staurosporine. Similar to verapamil, the phorbol esters did not sensitize MCF-7/ADR cells to cisplatin, nor parental MCF-7 cells to any of the anticancer drugs. Mezerein, K-252a, and H-89 sensitized MCF-7/ADR cells, increased intracellular accumulation of [3H]vinblastine, and antagonized photolabeling of P-glycoprotein by [3H]azidopine. Therefore, phosphorylation does not appear to play a significant role in regulating P-glycoprotein activity in MCF-7/ADR cells.
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PMID:Circumvention of P-glycoprotein-mediated multiple drug resistance by phosphorylation modulators is independent of protein kinases. 749 4

Calphostin C is a potent and specific inhibitor of protein kinase C (PKC). In this investigation we examined the effect of Calphostin C (without prior exposure to light) on daunorubicin (DNR) accumulation and sensitivity to DNR in multidrug-resistant (MDR) murine leukemia P388/ADR and human myeloid leukemia HL60/AR cells. P388/ADR cells overexpress P-glycoprotein, whereas HL60/AR cells lack any expression of P-glycoprotein (both at mRNA and protein levels). Calphostin C, in a concentration-dependent manner, increased the accumulation of DNR in P388/ADR cells and partially reversed (threefold) the DNR resistance in P388/ADR cells but had no effect on either of the parameters in HL60/AR cells. Calphostin C-induced increased accumulation of DNR in P388/ADR cells was due to increased uptake and decreased efflux of DNR. Furthermore, Calphostin C increased the uptake and decreased the efflux of rhodamine 123 (a substrate for P-gp) in P388/ADR cells but had no such effect in P388 cells. In addition, Calphostin C without exposure to light did not inhibit PKC activity in any of the cell lines studied. Taken together, these data suggest that Calphostin C may reverse drug resistance via P-glycoprotein independently of its effect on PKC activity. Therefore, any data regarding the effect of Calphostin C on the reversal of MDR should be interpreted in the light of these findings.
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PMID:Effect of Calphostin C (PKC inhibitor) on daunorubicin resistance in P388/ADR and HL60/AR cells: reversal of drug resistance possibly via P-glycoprotein. 751 83

Previous studies have revealed that cultured cells treated with lipophilic natural products containing aromatic rings and basic amino group usually yielded multidrug resistant (MDR) variants. These MDR cells overexpress P-glycoprotein (P-gp), most often due to gene amplification or transcriptional activation of mdr/P-gp genes. Doxorubicin (Dox) is an anthracycline that belongs to this group of compounds. To explore the possible resistance mechanism(s) to anthracyclines that do not involve P-gp, we use a Dox analog, hydroxyrubicin (HyR) or WP159, which contains a C3' hydroxy group in replacement of the amino group in the sugar moiety of Dox thereby reducing basicity and eliminating positive charge in the parental compound to establish HyR-resistant cell lines. These resistant cells displayed the MDR phenotype and overexpressed P-gp as analyzed by Western blot analyses and immunohistochemical staining using two different anti-P-gp antibodies. Strikingly, the levels of P-gp mRNA in the majority of these MDR cells remained comparable to those in the drug-sensitive counterparts by slot blot hybridization. These results implicate that the basic center of the selecting agent is a critical determinant for generating diverse MDR variants, and that HyR may have a posttranscriptional effect on P-gp biosynthesis. This is the first report suggesting that cultured cells exposed to a particular selecting agent may give rise to particular subtype of MDR variants.
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PMID:Overexpression of P-glycoprotein but not its mRNA in multidrug resistant cells selected with hydroxyrubicin. 753 10

A multidrug-resistant (MDR) subline of the immunoblastic B lymphoma cell line was established by sequentially selecting in increasing concentrations of adriamycin. The adriamycin-resistant cell line (HOB1/ADR) demonstrated resistance to a wide spectrum of chemotherapeutic agents including MDR drugs (Vinca alkaloids and anthracycline), antimicrotubule drug (colchicine), and DNA-damaging agents (cisplatin and mitomycin C). The expression of human mdr1 gene, as analyzed by RT-PCR and Western blotting, revealed a 13-15-fold increase in resistant cells. Unexpectedly, HOB1/ADR cells demonstrated a lack of reduced accumulation and of enhanced efflux of adriamycin. More than 60% adriamycin was effluxed at the same rate in both cell lines within 10 min. In contrast, the initial rate of vincristine accumulation was reduced by 3 fold in this resistant cell line. The maximal level of vincristine accumulation was 50% lower in the resistant cells than the parental cells. The maximal efflux rate was enhanced by 5 fold in the resistant cells. Inhibition of vincristine resistance by verapamil associated with restoration of drug accumulation, suggesting that acquired resistance in these cells is due to P-glycoprotein. These studies demonstrated that immunoblastic B lymphoma cells selected for adriamycin resistance preferentially developed P-glycoprotein-mediated vincristine efflux which plays an important role in vincristine resistance. In contrast, the resistant cells did not elevate adriamycin efflux, suggesting an additional mechanism responsible for adriamycin resistance.
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PMID:Lack of elevated drug efflux in adriamycin-resistant immunoblastic B lymphoma cells with mdr1 overexpression. 758 84


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