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 studied the relationship between the chemical structure and multidrug resistance (MDR) reversal activity of racemic verapamil (VER) and 14 VER analogs (VAs). The LoVo-R human colon carcinoma cell line was used as an experimental model. This cell line exhibited a typical MDR phenotype and overexpressed the MDR1 gene products. Key structural features were identified as being related to MDR reversal and cytotoxic activity. In particular, we demonstrated that the methoxy groups in the VER molecule structure [1.7-Bis-(3.4-dimethoxyphenyl)-3-methylaza-7-cyan-8-methyl-n onane] prevented cytotoxicity when the VAs were used alone, whereas the 7-cyan-8-methyl groups were important for MDR reversal activity and interaction with P-glycoprotein (P-gp). Among the VAs tested, the most active compounds were gallopamil, R-isomer of VER (R-VER), and nor-VER, which potentiated doxorubicin (DOX) cytotoxicity by 52.3 +/- 7.2 (n = 3 +/- SD), 38.9 +/- 6.4 (n = 4 +/- SD), and 35.4 +/- 4.3 (n = 3 +/- SD) times, respectively. The reversal activity of these compounds was similar to that of VER, which enhanced DOX cytotoxicity by 41.3 +/- 5.0 (n = 3 +/- SD) times. The potentiation of DOX cytotoxicity was associated with an increase in DOX uptake in LoVo-R cells and with an increased [3H]azidopine P-gp photolabeling inhibition. Some compounds that had a high reversal potency (i.e. R-VER and nor-VER) showed a lower calcium antagonist activity than VER, and seem useful candidates for the treatment of MDR in cancer patients.
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PMID:Structure-activity relationship of verapamil analogs and reversal of multidrug resistance. 748 41

We compared the influence of exogenous N-ras oncogene and treatment with PKC agonist 12-O-tetradecanoylphorbol-13-acetate (TPA) on P-glycoprotein (Pgp) function in various human, rat and dog cell lines. Two approaches were used: (a) flow cytometry analysis of Rhodamine 123 (Rh123) exclusion; and (b) sensitivity to cytotoxic action of colchicine. We have found that in Rat1 fibroblasts, rat IAR2 epithelial cells and rat McA RH 7777 (hepatoma), ras activates Pgp function, while in MDCK (dog kidney), K562 (human chronic myelogenous leukaemia) and LIM1215 (human colon carcinoma) cells it either has no effect or even acts in opposite direction. TPA-induced Pgp function shows dissimilar pattern of cell specificity. It is assumed that PKC and ras oncogene regulate mdr1 gene expression through at least partially distinct signalling pathways.
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PMID:Cell-specific effects of RAS oncogene and protein kinase C agonist TPA on P-glycoprotein function. 762 41

A cDNA encoding the novel drug resistance gene, LRP (originally termed lung resistance-related protein), was isolated from HT1080/DR4, a 220-fold doxorubicin-resistant human fibrosarcoma cell line which displays a multidrug resistance phenotype and overexpresses the multidrug resistance protein (MRP) but does not overexpress P-glycoprotein encoded by the MDR1 gene. Using the full-length 2.8-kb cDNA probe, the gene for LRP was regionally localized to the 16p13.1-16p11.2 chromosomal segment in human metaphases. Dual color fluorescence in situ hybridization studies refined the localization of LRP to 16p11.2, a location approximately 27 cM proximal to MRP (16p13.1). Two color hybridization studies indicated that HT1080/DR4 fibrosarcoma cells contain amplification of both the MRP and LRP genes in a striking striped pattern in the homogeneously staining region, hsr(7)(p12p15). In contrast, only amplified MRP gene sequences were contained within the homogeneously staining region, hsr(18q). Amplification of LRP was not identified in any of seven other drug-resistant tumor cell lines characterized by 20-300-fold levels of doxorubicin resistance, including two cell lines known to overexpress LRP (SW1573/2R120 and GLC4/ADR). Amplified MRP gene sequences were identified in H69AR, GLC4/ADR, and HL-60/AR whereas only MDR1 gene amplification was observed in the S1B120 colon carcinoma cell line. These data indicate that although both the MRP and LRP genes map to the short arm of chromosome 16, they are rarely coamplified and are not normally located within the same amplicon. A key role for chromosome breakage in gene amplification is supported by the presence of non-random karyotypic anomalies near the MRP and LRP normal cellular loci.
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PMID:The LRP gene encoding a major vault protein associated with drug resistance maps proximal to MRP on chromosome 16: evidence that chromosome breakage plays a key role in MRP or LRP gene amplification. 767 Dec 23

Previous studies of P-glycoprotein have demonstrated that its function can be modulated by phosphorylation. In the present study, inhibition of protein kinase C with calphostin C or stauroporine or prolonged treatment with the phorbol ester TPA decreased phosphorylation of P-glycoprotein, and impaired transport of vinblastine. Calphostin C also inhibited transport of actinomycin D, vincristine, rhodamine, and azidopine in SW620 Ad300 multidrug-resistant human colon carcinoma cells. Photoaffinity labeling of P-glycoprotein with azidopine was decreased by calphostin C, suggesting that dephosphorylation alters the affinity of P-glycoprotein for its substrates. Impaired transport of rhodamine in normal T lymphocytes treated with staurosporine demonstrates that modulation of P-glycoprotein function is not limited to cells selected for drug resistance in vitro. Transport of P-glycoprotein antagonists in SW620 Ad300 cells was also affected by calphostin C. Cyclosporin A transport decreased, while verapamil transport increased. Cyclosporin A in calphostin C-treated cells resulted in additive P-glycoprotein antagonism, while no additive effect could be demonstrated with verapamil, suggesting that the increase in verapamil transport makes it a poorer P-glycoprotein antagonist. These studies suggest that transport by P-glycoprotein is a dynamic process which can be modulated by phosphorylation, and that antagonists may block P-glycoprotein differently in different phosphorylation states.
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PMID:Differential modulation of P-glycoprotein transport by protein kinase inhibition. 769 Feb 50

To study the mechanisms of the acute induction of drug resistance in cancer cells, we have established a model system in which adriamycin (ADM) induces immediate drug resistance. In this system, human colon carcinoma HT-29 cells were pretreated for 1 h with a subtoxic dose of ADM (0.3 micrograms/ml) and incubated for 24 h in drug-free medium. Then the cells were treated for 1 h with ADM, and the cell survival was determined in terms of colony-forming ability. The survival of the pretreated cells was increased up to 100-fold, as compared with that of untreated cells. Such increased survival, however, was observed only after high doses of ADM (2 to 8 micrograms/ml); more than 99% of the cells were killed. These results indicate that only a small fraction of ADM-pretreated cells acquire the ADM-resistant phenotype. Similar induced resistance was observed in five of seven subclones isolated from HT-29 cells by limiting dilution, suggesting that the majority of cells in the parental HT-29 population could acquire the ADM-resistant phenotype. In the subclone HT-29T9, the ADM pretreatment induced concomitant resistance to daunomycin, VP-16, and VM-26 but not to agents other than topoisomerase II inhibitors. The ADM-induced drug resistance did not accompany MDR1 gene expression and could not be overcome by verapamil, a P-glycoprotein inhibitor. The present system could be useful to study the acute induction mechanism(s) of ADM-resistance, which could be relevant to clinical resistance in patients.
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PMID:Acute induction of adriamycin-resistance in human colon carcinoma HT-29 cells exposed to a sublethal dose of adriamycin. 773 Jan 48

Bisantrene, mitoxantrone, and anthracyclines are anthracene derivatives that interact with DNA and are used for the treatment of cancers. The mechanisms of resistance to bisantrene are unknown. Here we show that cells that overexpress low levels of P-glycoprotein or are transfected with human MDR1 have approximately 10-fold greater resistance to bisantrene compared to vinblastine, doxorubicin, or colchicine. Furthermore, bisantrene can be used to select for high-level P-glycoprotein-mediated multiple drug resistance in a human colon carcinoma cell line, LS 174T, and the drug blocks photoaffinity labeling of P-glycoprotein. The data suggest that bisantrene is an excellent substrate for P-glycoprotein. These findings could influence subsequent clinical evaluation of bisantrene for the treatment of cancer.
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PMID:P-glycoprotein mediates profound resistance to bisantrene. 786 4

The in vitro cytotoxic effects of docetaxel (Taxotere; RP56976, NSC688503) proved both time and concentration dependent. Amongst thirteen human cell lines from various tumor types, exposure to increasing concentrations of docetaxel over 24 hrs resulted in a plateau-shaped dose response curve, suggesting that increased cell kill becomes more dependent on increased exposure duration than on concentration. IC50 concentrations (reducing survival by 50%) ranged from 0.13-3.3 ng/ml, with three neuroblastoma lines proving most sensitive and three breast and two colon carcinoma lines showing least sensitivity. There was significant cross-resistance to docetaxel in the classic multidrug resistant (MDR) Chinese hamster ovarian (CHO) CHRC5 line and the human lymphoblastoid CCRF-CEMVLB1000 line, as well as in two vincristine (VCR)-selected MDR MCF-7 sublines. All four of these MDR sublines overexpress P-glycoprotein (Pgp), as did a 6-fold docetaxel-selected resistant CHO subline. As an apparent corollary, in two human teratoma lines selected for etoposide resistance and showing some cross-resistance to VCR and in two CHO sublines expressing low levels of VCR resistance, yet all proving Pgp positive, no docetaxel cross-resistance was identified. Verapamil modulated docetaxel resistance only in sublines expressing resistance to the drug and overexpressing Pgp. Four other human tumor sublines selected for resistance to 5-fluorouracil, cisplatin or teniposide, showed a lack of cross-resistance to docetaxel. Furthermore, cross-resistance to docetaxel was not apparant in four epipodophyllotoxin-selected resistant sublines with alterations in topoisomerase II, indicating its effectiveness against tumor cells expressing the topoisomerase II-related MDR phenotype. Our observation that docetaxel cross-resistance was not automatically expressed by classic MDR tumour cells appears of interest and of potential clinical relevance.
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PMID:Differential cytotoxic effects of docetaxel in a range of mammalian tumor cell lines and certain drug resistant sublines in vitro. 789 35

A rat colon carcinoma cell line, CC531, was exposed to stepwise increasing concentrations of colchicine. A cell line, CC531mdr+, which grows in the presence of 0.2 microM of colchicine was obtained. A revertant cell line, CC531rev was isolated upon colchicine withdrawal. The CC531mdr+ displayed a multidrug-resistant phenotype. Marked resistance to the selecting agent colchicine, was found (RF = 37.5) as well as to vinblastine (RF = 11.3) and actinomycin D (RF = 2.6). Cross resistance to doxorubicin (RF = 8) and daunorubicin (RF = 13.3) was demonstrated. Verapamil was able to reverse drug resistance to colchicine and daunorubicin. The revertant cell line, CC531rev, showed increased sensitivity to colchicine (RF = 0.43), vinblastine (RF = 0.13), doxorubicin (RF = 0.28) and daunorubicin (RF = 0.56). Marked cross resistance to cis-platinum (RF = 6.9) was also induced in CC531mdr+ and was maintained in CC531rev. We conclude that CC531 displays an intrinsic low-level multidrug-resistant phenotype, which was amplified in the CC531mdr+ variant. This correlates with a higher level of expression of P-glycoprotein. CC531rev lacks the multidrug-resistant phenotype and can be used as the drug-sensitive counterpart of the latter two cell lines. Furthermore, it has been shown that in these cell lines cis-platinum resistance is mediated through a mechanism independent of the multidrug-resistant phenotype, since the revertant cell line CC531rev has lost the multidrug-resistant phenotype while retaining the concomitantly induced cis-platinum resistance of the multidrug-resistant variant CC531mdr+.
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PMID:Multidrug resistance in rat colon carcinoma cell lines CC531, CC531mdr+ and CC531rev. 790 65

In this study we have investigated the effects of the multidrug-resistance (MDR) modifiers verapamil (VPM), cyclosporin A (CsA) and tamoxifen (TMX) on the intracellular pH(pHi) of four colon carcinoma-derived cell lines with low P-glycoprotein expression (CaCo-2, HT-29, SW 620 and SW 480). Addition of VPM (1 mu M), CsA (1 microgram/ml) or TMX (2 microM) in HEPES- or bicarbonate/CO2-buffered Ringer's solution was followed by dose-dependent and reversible decreases of the pHi (0.1-0.3 units) of all cell lines, as measured ratiometrically by the changes in the pH-dependent fluorescence of bis(carboxyethyl)carboxyfluorescein (BCECF). Testing the effects of the resistance modifiers on the Na+/H+ antiporter and bicarbonate trans-porters under appropriate buffer conditions and addition of inhibitors (amiloride, DIDS) revealed that the chemomodulator-induced acidification does not interfere with the function of these major pHi-regulating acid-base transporters. The induction of changes in pHi shows no correlation with MDR-reversing activity of the drugs and our data do not support the P-gp-inhibition-mediated accumulation of acidic substrates as underlying mechanism. In addition to the P-gp-directed MDR-reversal, chemomodulator-induced intracellular acidification may enhance the chemosensitivity of the cells especially under alkaline extracellular conditions, and contribute to the decreased efficacy of MDR-modifiers in acidic extracellular environments and to the chemosensitising effect of VPM in P-gp-negative cell lines.
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PMID:The multidrug-resistance modifiers verapamil, cyclosporine A and tamoxifen induce an intracellular acidification in colon carcinoma cell lines in vitro. 790 52

Diarylsulfonylurea (DSU) antitumor agents represent a new class of oncolytic compounds with an unknown, potentially novel, mechanism of action. At high concentrations of several of these agents, cytotoxicity appears to be a consequence of uncoupling of mitochondria. However, the mechanism of action at pharmacologically achievable concentrations is unknown. To further study these agents a subline of human colon carcinoma, GC3/c1, was selected for resistance to N-(5-indanylsulfonyl)-N'-(4-chlorophenyl)urea (ISCU) (Sulofenur). This clone (designated LYC5) was stably resistant for 2 years in the absence of selection pressure and was characterized for cross-resistance to other antitumor DSU and therapeutically used oncolytic agents. LYC5 was cross-resistant to six of seven DSU analogues examined when cells were exposed to drugs for 7 days. However, the degree of resistance was inversely related to the potency of the individual DSU against the parental GC3/c1 clone. Consequently, against LYC5 cells there was a relatively narrow range for concentrations inhibiting colony formation by 50% (4-fold), compared with that in GC3/c1 cells (12-fold range). With a single exception, each DSU examined caused uncoupling of oxidative phosphorylation in isolated mitochondria at 50 microM, and data suggest that cytotoxicity in LYC5 cells may be a consequence of mitochondrial impairment. In contrast, LYC5 cells were collaterally sensitive to the mitochondrial toxins rotenone, antimycin, and oligomycin, by 11.4-, 7.2-, and 36.9-fold respectively. LYC5 cells were also collaterally sensitive to vincristine (7.7-fold), Actinomycin D (5.9-fold), and rhodamine-123 (10.5-fold), agents associated with P-glycoprotein (Pgp)-mediated multidrug resistance (MDR). LYC5 cells were slightly more sensitive to Melphalan and doxorubicin (2.8- and 2.3-fold, respectively) but not to cisplatin or dideazatetrahydrofolic acid. Collateral sensitivity to vincristine and Actinomycin D was consistent with decreased Pgp levels in LYC5 cells. Immunohistochemical staining and Western blotting with anti-Pgp antibodies indicated an 8-fold reduction in Pgp levels in LYC5 cells, relative to expression in parental GC3/c1 cells. Consequently, association of mitochondrial toxins with resistance in MDR KB8-5 cells was examined in the presence or absence of the MDR-reversing agent verapamil. KB8-5 cells had equal or greater sensitivity, compared with parental KB3-1 cells, to rotenone, antimycin, and oligomycin and also to each DSU analogue examined. In addition, verapamil tended to have a protective effect against these mitochondrial toxins.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Cross-resistance to antitumor diarylsulfonylureas and collateral sensitivity to mitochondrial toxins in a human cell line selected for resistance to the antitumor agent N-(5-indanylsulfonyl)-N'-(4-chlorophenyl)urea. 791 Jun 60


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