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)

In an effort to develop a clinically useful approach to overcoming P-glycoprotein-mediated multidrug resistance (MDR1), we evaluated combined chemosensitization with verapamil and quinine in a multidrug-resistant (MDR) human myeloma cell line model. In clonogenic assay, verapamil was used at concentrations from 0.1 to 1.0 micrograms/mL, bracketing the plasma levels achieved by oral administration and high-dose intravenous (IV) infusion, respectively. The dose of quinine was held constant at 1.0 micrograms/mL, a plasma concentration readily achieved by oral administration. At each dose level of verapamil tested, the combination with quinine proved more effective than either drug individually in reversing resistance to doxorubicin and vinblastine and synergistic chemosensitizing interaction was observed. Verapamil at 0.1 microgram/mL combined with quinine was capable of restoring sensitivity to doxorubicin fully and reduced resistance to vinblastine as effectively as verapamil alone at 1.0 micrograms/mL. Furthermore, the combination of 1.0 mumol verapamil with 10 mumols quinine increased accumulation and retention of anthracycline in the resistant cells to a greater extent than did either drug individually (P less than .001) and inhibited drug efflux as effectively as verapamil alone at 10 mumols. Our findings suggest that combined chemosensitization with verapamil and quinine may prove useful for overcoming MDR1 in patients with drug-refractory B-cell neoplasms such as multiple myeloma or non-Hodgkin's lymphomas.
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PMID:Synergistic inhibition by verapamil and quinine of P-glycoprotein-mediated multidrug resistance in a human myeloma cell line model. 167 Jul 60

Resistance of human cancer cells to multiple cytotoxic hydrophobic agents (multidrug resistance) is due to overexpression of the MDR1 gene whose product is the ATP-dependent multidrug transporter, P-glycoprotein. We have previously reported that plasma membrane vesicles partially purified from multidrug-resistant human KB carcinoma cells, but not from drug-sensitive cells, accumulated [3H]vinblastine in an ATP-dependent manner (Horio, M., Gottesman, M.M. and Pastan, I. (1988) Proc. Natl. Acad. Sci. USA 85, 3580-3584). Certain calcium-channel blockers, quinidine, and phenothiazines are able to overcome multidrug resistance in cultured cells. In this work, the effect of these reversing agents on ATP-dependent vinblastine (VBL) transport by vesicles from drug-resistant KB cells has been characterized. Azidopine was the most potent inhibitor of ATP-dependent VBL uptake tested (ID50: concentration of inhibitor such that the transport of vinblastine is inhibited by 50%, less than 1 microM). Verapamil, quinidine, and the tiapamil analogue RO-11-2933 were potent but less effective inhibitors (ID50 less than 5 microM). Diltiazem, nifedipine and trifluoperazine were even less effective. These agents had no effect on Na(+)-dependent and Na(+)-independent L-leucine uptake by the vesicles, indicating that the inhibition of ATP dependent VBL transport by these agents is not a non-specific effect, as might result from leaks in the vesicle membrane. Verapamil, quinidine, azidopine and trifluoperazine increased the apparent Km value of vinblastine transport, suggesting that these agents may be competitive inhibitors of vinblastine transport.
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PMID:Agents which reverse multidrug-resistance are inhibitors of [3H]vinblastine transport by isolated vesicles. 167 42

Trimetrexate, a lipid-soluble analogue of methotrexate, appears to enter mammalian cells by passive diffusion, thus circumventing the methotrexate transport system which is frequently a subject for alterations leading to methotrexate resistance. Using a single-step selection protocol with trimetrexate, we have isolated 45 clonal variants and found the majority of them to be selectively resistant to lipophilic antifolates while retaining their sensitivity to methotrexate and drugs involved in multidrug resistance. The majority of spontaneously induced trimetrexate-resistant clones showed a change in neither the mRNA levels of dihydrofolate reductase (24 of 30) and P-glycoprotein (26 of 30) nor their gene copy numbers, whereas a small fraction of clones (4 of 30) showed multidrug resistance gene amplification and P-glycoprotein mRNA overexpression. gamma-Irradiation prior to selection markedly enhanced the frequency of trimetrexate resistance (100-fold after 1000 rads). None of the gamma-ray-induced trimetrexate-resistant clones (0 of 15) had evidence of dihydrofolate reductase and multidrug resistance gene amplification and/or overexpression. Flow cytometry data on trimetrexate-resistant clones showed no defect in the transport of trimetrexate. Verapamil, a modulator of the multidrug resistance phenotype, had no cytotoxic effect on parental and trimetrexate-resistant clones. However, when present with trimetrexate, verapamil (0.3-0.6 microM) reversed the lipophilic antifolate-resistant phenotype in clones that had invariant levels of P-glycoprotein and dihydrofolate reductase. This selective resistance to lipid-soluble antifolates was initially unstable but became stable after continued drug-selective growth. Two-dimensional gel electrophoresis showed some differences in protein(s) that may potentially be associated with this phenotype of selective resistance to lipophilic antifolates. We conclude that a gamma-radiation-enhanceable, verapamil-reversible, stable phenotype of selective resistance to lipid-soluble antifolates frequently emerges which requires neither the amplification nor the overexpression of dihydrofolate reductase or multidrug resistance genes.
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PMID:A phenotype conferring selective resistance to lipophilic antifolates in Chinese hamster ovary cells. 167 47

Drug resistance eventually limits the effectiveness of antiestrogens in breast cancer treatment. Pharmacological reversal of this refractoriness has been attempted with R-Verapamil, a well tolerated calcium channel blocker. This drug significantly decreased the incidence of lung foci after intravenous seeding of the R3230AC rat adenocarcinoma; this effect was correlated with reduction in the expression of P-glycoprotein. The simultaneous administration of antiestrogens with a non-toxic enantiomer of Verapamil was beneficial in the tumour model investigated.
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PMID:R-verapamil decreases anti-estrogen resistance in a breast cancer model. 167 80

The expression of the P-glycoprotein which is associated with the development of multidrug resistance in various cell lines was investigated in 87 fresh acute leukaemia and multiple myeloma samples using the specific mouse monoclonal antibody MRK16 in an indirect immunofluorescence assay. Considering a 10% positive cell cut-off value, a heterogeneous expression of P-glycoprotein was observed in 5/22 (22.7%) de novo acute leukaemias, 7/22 (31.8%) relapse or secondary acute leukaemias, 14/27 (51.8%) acute transformation of myeloproliferative or myelodysplastic syndromes and 5/16 (31.2%) multiple myelomas. This expression was not associated with specific cytogenetic abnormalities, especially alterations of chromosome 7q. Verapamil, a calcium channel blocker, has been demonstrated to circumvent the multidrug resistance in cell lines, possibly by interfering with P-glycoprotein function. Using the microculture tetrazolium assay, verapamil was demonstrated to increase the sensitivity of fresh leukaemic or myeloma cells to doxorubicin in 19/43 (43.1%) samples. The doxorubicin IC50 level and the capacity of verapamil to increase the sensitivity of blast cells to doxorubicin in vitro did not correlate with the expression of P-glycoprotein. We conclude that high non-cytotoxic concentrations of verapamil were able to increase the in vitro doxorubicin sensitivity of fresh acute leukaemia and myeloma cells without detectable expression of the P-glycoprotein.
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PMID:P-glycoprotein expression and in vitro reversion of doxorubicin resistance by verapamil in clinical specimens from acute leukaemia and myeloma. 167 57

We have previously shown that the multidrug-resistant EHR2/DNR+ cells, which overexpress P-glycoprotein, accumulate only about 20-30% of daunorubicin at steady state compared to the sensitive cells. These cells have been thought to be a "pure" P-glycoprotein cell line. We now report that the EHR2/DNR+ cells exhibit decreased DNA topoisomerase II catalytic activity. We also found that the amount of immunoreactive DNA topoisomerase II from these cells is about one-third that seen in the drug-sensitive cell line. In agreement with the decreased activity and amount of topoisomerase II, the number of DNA-protein complexes stabilized by teniposide (VM-26) was reduced by about 50% in nuclear extracts from EHR2/DNR+ cells. Furthermore, using an intact cell assay for DNA protein complexes, we found that the VM-26-stimulated complexes formed in the drug-resistant cells never reached the level seen in the drug-sensitive cells. Verapamil and Cremophor EL block P-glycoprotein-mediated efflux of "natural product" drugs and increase their accumulation in resistant cells. Coincubation of the EHR2/DNR+ cells with VM-26 and either of these modulators increased the number of complexes formed in the resistant cells. However, neither modulator increased the number of topoisomerase II-DNA complexes in the drug-resistant cells to the level seen in the EHR2 cells. We conclude that the resistance of EHR2/DNR+ cells is due in part to reduced amounts of DNA topoisomerase II. Furthermore, we note that a single cell line can express features of both P-glycoprotein-associated multidrug resistance and altered topoisomerase II-associated multidrug resistance.
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PMID:Decreased DNA topoisomerase II in daunorubicin-resistant Ehrlich ascites tumor cells. 167 12

Four human colon cancer cell lines (SW620, LS 180, DLD-I, and HCT-15) and sub-lines isolated in vitro by selection with Adriamycin were studied for reversal of intrinsic and acquired Adriamycin resistance, using buthionine sulfoximine (BSO) to deplete cellular glutathione alone and in combination with the P-glycoprotein antagonist verapamil. GSH levels varied among the parental cell lines but did not increase with resistance. In the parental SW620, DLD-I and HCT-15 and their drug-resistant derivatives, there was no relation between the effect of the glutathione-depleting agent BSO, the mRNA expression of both selenium-dependent glutathione peroxidase (GPx) and glutathione S-transferase pi (GST pi), bulk glutathione S-transferase (GST) activity, and the degree of resistance. However, in LS 180 and its derivative sub-lines, which do not principally rely on P-glycoprotein (Pgp) for Adriamycin resistance, treatment with BSO demonstrated a relatively diminished GSH depletion and enhanced recovery. In comparison with the other acquired cell lines, BSO specifically reversed acquired resistance in the LS 180 Adriamycin-resistant subline (LS 180 Ad150) after short-term drug exposure. Furthermore, the LS 180 Ad150 cells demonstrated an increase in both GPx and GST pi mRNA expression. These observations suggest that glutathione-mediated detoxification of Adriamycin may play a role in the resistance of this sub-line. Verapamil enhanced Adriamycin cytotoxicity 1.2- to 12-fold in the intrinsically resistant cells and as much as 15-fold in cell lines with acquired resistance. Combination of BSO with verapamil resulted in additive, but not synergistic, reversal of resistance. The results underscore the complex nature of Adriamycin resistance, and suggest a role for drug-resistance-modulating agents in the treatment of colon carcinoma.
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PMID:Contribution of glutathione and glutathione-dependent enzymes in the reversal of adriamycin resistance in colon carcinoma cell lines. 168 79

Sublines from the small cell lung cancer (SCLC) cell lines U1285 and U1690, denoted U1285-100, U1285-250, U1690-40 and U1690-150, were adapted to grow in the continuous presence of 100, 250, 40 and 150 ng ml-1 doxorubicin (Dox), respectively. The Dox resistance was accompanied by cross-resistance to vincristine (Vcr), Vp-16 and for U1285-100 also to cisplatinum. Sublines of U1690-40 and U1285-100, cultured in absence of Dox for 4 months were only partially reversed with respect to Dox resistance. Neither the parental nor the most Dox resistance sublines had detectable levels of mdr 1 RNA but a small fraction of cells in all cell lines stained weakly positive for P-glycoprotein (P-gp). Verapamil (Ver) at 5 microM reversed the Dox resistance completely and partly in the U1690 and U1285 sublines, respectively, but did not increase the cellular accumulation of Dox. The cytoplasmic free Ca2+ concentration (Ca2+i) was close to 100 nM in both parental cell lines but elevated in the U1285-100 and U1690-40 sublines by 21 and 44%, respectively, and in U1285-250 and U1690-150 by 51 and 91%, respectively. The partly reverted sublines still showed significant but smaller elevations in Ca2+i of 10-30%. Ver was without acute or long term effects of Ca2+i in the U1285-100 and U1690-40 sublines. Selection for Dox resistance in SCLC may thus result in atypical multidrug-resistance characterised by absence of P-gp overexpression and atypical cross-resistance. Although Ver did not seem to affect Dox accumulation it may still work as a resistance modulator.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Doxorubicin selected multidrug-resistant small cell lung cancer cell lines characterised by elevated cytoplasmic Ca2+ and resistance modulation by verapamil in absence of P-glycoprotein overexpression. 168 6

Considering the possibility to overcome drug resistance by other treatment strategies than chemotherapy we investigated the susceptibility of three independently selected multidrug-resistant sublines of the T-lymphoblastoid leukemic cell line CCRF-CEM to lymphokine-activated killer (LAK) cells. We found that two of the multidrug-resistant sublines were significantly less susceptible targets to LAK cells. A third one, however, was as susceptible as the parental CCRF-CEM cell line. Moreover, a multidrug-resistant subline that reverted to an almost drug-sensitive phenotype was observed to be also revertant for resistance against LAK cells. We found an inverse relationship between the expression of the mdr1 gene (P-glycoprotein) and the susceptibility to LAK cells. Verapamil, a calcium channel blocker, while increasing the drug sensitivity of a multidrug-resistant subline, did not induce a reversal of the suppression of LAK susceptibility. The possibility of enhanced resistance to LAK cells of multidrug-resistant cells should be taken into account when one is looking for therapy strategies to overcome multidrug resistance.
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PMID:Susceptibility of multidrug-resistant human leukemia cell lines to human interleukin 2-activated killer cells. 169 43

The uptake and efflux of doxorubicin (Dox) were investigated in a human bladder cancer cell line (UM-UC-6) and in a multi-drug resistant (mdr) subline (UM-UC-6Dox). Unlike previous reports, the initial uptake kinetics of Dox, and its accumulation and retention to steady-state were modelled mathematically. Cells were incubated with Dox and the amount of Dox in the cellular and medium phases was measured by a specific HPLC method. When monitored for 1 min from 0.02 microM to 25 microM Dox, the uptake was very rapid but was significantly faster in the resistant cell line. The initial rate of uptake at t = 0 followed Michaelis-Menten kinetics yielding Vmax values (the maximal rate of uptake) of 15.0 +/- 1.7 and 12.9 +/- 1.2 nmol/10(6)/min and Km (rate at Vmax/2) of 25.2 +/- 4.7 and 16.4 +/- 2.9 microM for UM-UC-6 and UM-UC-6Dox, respectively. There was no metabolism of Dox by keto-reduction or reductive hydrolysis. At 1.0 microM the uptake of Dox to steady-state was biexponential but there was no difference in total cellular Dox concentration between the two cell lines at equilibrium. A 3 compartment sequential closed model was fitted yielding significantly different values for the intercompartmental and hybrid rate constants, indicating altered intracellular distribution in resistant cells. Verapamil (10 microM), trifluoperazine (10 microM) or Tween 80 (0.005%) had no effect on the uptake or efflux of Dox. The UM-UC-6Dox line appeared to show atypical mdr characteristics since net drug accumulation was not lowered and classic P-glycoprotein inhibitors were not effective. The primary mechanism of Dox resistance is not enhanced metabolism or lowered intracellular concentrations.
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PMID:The uptake and efflux of doxorubicin by a sensitive human bladder cancer cell line and its doxorubicin-resistant subline. 182 1


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