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

---

Query: EC:3.6.3.44 (P-glycoprotein)
13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The new lipophilic anthracycline N-benzyl-adriamycin-14-valerate (AD198) was evaluated for its activity in comparison to doxorubicin in P-glycoprotein (Pgp)-positive and -negative cell lines. AD198 and doxorubicin showed comparable antitumor activity in the Pgp-negative breast cancer cell line MCF-7 and the Pgp-negative ovarian carcinoma cell line A2780. By contrast, AD198 was significantly more active than doxorubicin in the Pgp-positive breast cancer cell line MCF7AD (IC50 values 2.5 and 0.15 microM for 96 h continuous exposure) and the Pgp-positive ovarian carcinoma cell line A2780 DX5 (IC50 values 0.6 and 0.07 microM, respectively). Unlike doxorubicin, the activity of AD198 was not increased by concommittant application of cyclosporin A in cell line MCF7AD. Flow cytometry studies showed that, in contrast to doxorubicin, AD198 was not transported by Pgp and that verapamil did not change the intracellular pharmacokinetics of this new anthracycline. These data provide evidence that AD198 possesses high activity in human solid tumor cell lines expressing the classical multidrug resistant phenotype. Its further clinical development appears to be warranted.
...
PMID:Activity of N-benzyl-adriamycin-14-valerate (AD198), a new anthracycline derivate, in multidrug resistant human ovarian and breast carcinoma cell lines. 884 78

In this study the ability of the new pure anti-estrogen ICI 182,780 to modulate the cytotoxic action of adriamycin (ADR) on parental and ADR-resistant MCF-7 (MCF-7 ADRr) human breast-cancer cells was investigated and compared with that of tamoxifen (TAM). TAM enhanced ADR cytotoxicity in MCF-7 ADRr cells in a dose-related manner, but this effect was slight or absent in MCF-7 WT. In contrast, ICI 182,780 was able to enhance ADR toxicity both in MCF-7 ADRr and in the parental cell line. ICI 182,780 was up to 2.5-fold more effective than TAM in reducing the IC50 of ADR in MCF-7 ADRr cells. Analysis of the data by the isobole method showed that the combination ADR/TAM and ADR/ICI 182,780 produced synergistic anti-proliferative activity in MCF-7 ADRr cells. Because ADR resistance in these cells is associated with the expression of high levels of P-glycoprotein (Pgp), we evaluated the effect of anti-estrogens on Pgp expression and activity. Both ICI 182,780 and TAM failed to modulate Pgp expression as assessed by flow cytometry and Western-blot analysis, performed using the monoclonal antibodies MM4.17 and C 219, which are specific for an external or an internal determinant respectively. Pgp activity was investigated by flow cytometry measuring the extrusion of ADR and the cationic dye Rhodamine 123 (Rh 123). ICI 182,780, but not TAM, reduced the activity of Pgp in MCF-7 ADRr cells. Flow cytometry was also used to investigate cell-cycle modifications induced by ADR in MCF-7 ADRr cells, both in the presence and in the absence of anti-estrogens. After 72 hr, higher doses induced an arrest of cells at the G2/M phase. The same effect was visible when lower doses of ADR were combined with ICI 182,780 or TAM. In terms of cell-cycle-blocking activity ICI 182,780 was largely more effective than TAM.
...
PMID:Modulatory effect of tamoxifen and ICI 182,780 on adriamycin resistance in MCF-7 human breast-cancer cells. 890 76

Adriamycin (Adr), the single most active agent used in the treatment of breast cancer, may become ineffective as treatment progresses due to the development of multidrug resistant (MDR) tumors. A major mechanism associated with MDR is increased P-glycoprotein (Pgp) expression. This study examined the abilities of the anti-estrogen tamoxifen (TAM) and the progestin medroxyprogesterone acetate (MPA) as well as cyclosporin A (CsA), a known resistance modifier, to enhance the cytotoxic effects of Adr on human breast epithelial cells (HBEC) in primary culture. Pgp and estrogen receptor (ER) expression were determined in each of the cultures by immunocytochemical assays using the monoclonal antibodies C219 and H222 Sp gamma, respectively. The Adr-sensitive, Pgp-, ER+ MCF-7 cell line and the Adr-resistant, Pgp+, ER- MCF7-AdrR cell line were used as controls. Primary cultures were categorized as HBEC from tissues with or without previous chemotherapy. Pgp was detected in 1 of the 15 cell cultures from tissues without previous chemotherapy and in 5 of the 6 cell cultures from tissues previously exposed to chemotherapy. Incubation with either CsA or MPA plus Adr enhanced Adr toxicity in Pgp+ but not Pgp- cell cultures, whereas TAM had no effect on the sensitivity of any of the cultures. Of the 21 primary cultures of HBEC, 3 were ER+. There was no correlation between the enhancement of Adr cytotoxicity and ER status. The data suggest that MPA as well as CsA may be useful as modifying agents in overcoming Pgp-associated multidrug resistance.
...
PMID:The effects of cyclosporin A, tamoxifen, and medroxyprogesterone acetate on the enhancement of adriamycin cytotoxicity in primary cultures of human breast epithelial cells. 894 29

A series of new taxoids derived from 14 beta-hydroxy-10-deacetylbaccatin III was synthesized by means of the beta-lactam synthon method. Most of the new taxoids thus synthesized possess excellent cytotoxicity against human ovarian (A121), non-small-cell lung (A549), colon (HT-29), and breast (MCF-7) cancer cell lines, and several of these taxoids show subnanomolar IC50 values which are severalfold to 1 order of magnitude better than those of paclitaxel and docetaxel. Modifications at the 3'- and 3'-N-positions exert marked effects on the activity. For the substituents at C-3', the cytotoxicity decreases in the order 2-furyl approximately 2-methyl-1-propenyl > or = 2-methylpropyl > (E)-1-propenyl > or = n-propyl > phenyl > > 2,2-dimethylpropyl. For the 3'-N substituents, the activity decreases in the order t-BuOCO > Ph > n-hexanoyl. A significant increase in the cytotoxicity against the doxorubicin-resistant human breast cancer cell line MCF7-R that expresses the multidrug resistance (MDR) phenotype is observed by the proper modification of the substituent at C-10. The observed remarkable effects of the substituents at C-10 on the activity against MCF7-R can be ascribed to the effective inhibition of the binding of these new taxoids to P-glycoprotein that is responsible for MDR.
...
PMID:Syntheses and structure-activity relationships of taxoids derived from 14 beta-hydroxy-10-deacetylbaccatin III. 902 93

The multidrug resistance (MDR) phenotype of cancer cells often correlates with the level and activity of protein kinase C (PKC). We studied the ability of the staurosporine derivative PKC inhibitor CGP 41251 to reverse the MDR phenotype in MCF-7 human breast carcinoma and CT-26 murine colon adenocarcinoma cells and their doxorubicin (DXR)-selected MDR variants. Nontoxic concentrations of CGP 41251 significantly enhanced the cytotoxic properties of DXR, actinomycin D, vinblastine, and vincristine but not those of 5-fluorouracil. CGP 41251 increased intracellular concentrations of [14C]DXR but did not cause significant differences in P-glycoprotein (P-gp) expression. Pretreatment of MCF-7adr cells with phorbol 12-myristate 13-acetate reduced the CGP 41251 mediated intracellular accumulation of [14C]DXR. At concentrations that induced drug uptake, CGP 41251 significantly decreased the level of P-gp phosphorylation in the cells but did not compete with [3H]azidopine for photoaffinity labeling of P-gp. These data provide evidence that CGP 41251 reverses the MDR phenotype by modulating the phosphorylation of P-gp and/or other PKC substrates critical to the maintenance of the MDR phenotype.
...
PMID:Chemosensitization of cancer cells by the staurosporine derivative CGP 41251 in association with decreased P-glycoprotein phosphorylation. 903 58

Multidrug resistance in MCF-7/Adr human breast cancer cells is mediated by several mechanisms including overexpression of the MDR1 gene product, P-glycoprotein and glutathione-related detoxifying enzymes. Mutations in the p53 tumor suppressor protein have been reported to play a role in the development of resistance to DNA damaging agents in several human cancer cells. In the present study we have assessed the mutational status of the p53 protein and its expression levels, degree of stability and cellular localization to investigate whether it is involved in modulating multidrug resistance in MCF-7/Adr cells compared to sensitive MCF-7 cells. As revealed by immunofluorescence microscopy using the anti-p53 mouse monoclonal antibody DO-1, wild-type p53 is sequestered in the cytoplasm of MCF-7 cells, whereas in MCF-7/Adr cells, the protein is localized in the nucleus. The sequencing of full-length p53 cDNA revealed a 21 bp deletion in its one of the four conserved regions within the conformational domain, spanning codons 126-133 at exon five, in MCF-7/Adr cells. Moreover, detection of ThaI polymorphism of codon 72 showed that MCF-7 cells predominantly express wild-type p53 with proline, while mutated p53 in MCF-7/Adr cells contains an arginine residue at codon 72. In addition, we demonstrate that the half-life of p53 in MCF-7 cells is less than 30 min while the mutated protein is more stable; its half-life is about 4 h in MCF-7/Adr cells. Thus, this study demonstrates that the deletion of codons 126-133 in p53 causes increased stability, overexpression and nuclear localization of the protein in multidrug resistant MCF-7/Adr cells, and further suggests that mutated p53 might be involved in the development of multidrug resistance in this cell line.
...
PMID:Expression of the mutated p53 tumor suppressor protein and its molecular and biochemical characterization in multidrug resistant MCF-7/Adr human breast cancer cells. 905 47

The taxanes are a promising family of anti-tumour drugs that block cell cycle replication by interfering with the microtubule network. The clinical use of these drugs involves some problems related to their low solubility and occurrence of resistance, which is mainly dependent on the multidrug-resistant (MDR) phenotype. To investigate the possible interaction between docetaxel and tamoxifen (TAM), three oestrogen receptor-negative cancer cell lines, MDR- MDA-MB 231, MDR + CEM-VBLr and MCF-7 ADRr, were used. In all three cell lines, the combination of docetaxel and TAM was more effective in terms of growth inhibition than single drug exposure. Isobolic analysis confirmed the presence of synergism in all cell lines when docetaxel was used at 0.2 microM and TAM at a dose equal to or higher than 1 microM. Flow cytometric DNA analysis performed on the three cell lines showed that TAM was able to increase the G2/M blocking activity of docetaxel. This blocking activity was followed by an increased flow cytometric DNA fragmentation suggestive of the presence of apoptosis, which was confirmed by DNA gel fragmentation and morphological analysis. While an antagonistic effect on P-glycoprotein (P-gp) activity may contribute to the synergistic effect of tamoxifen and docetaxel on CEM-VBLr and MCF-7 ADRr, other mechanisms must be involved, as the synergistic effect is also apparent with a P-gp-negative cell line.
...
PMID:Synergistic antiproliferative activity of tamoxifen and docetaxel on three oestrogen receptor-negative cancer cell lines is mediated by the induction of apoptosis. 906 11

Breast cancers are either primarily resistant to chemotherapy (intrinsic resistance), or respond to chemotherapy but later recur with a multidrug-resistant phenotype because of overexpression of the multidrug transporter P-glycoprotein. The MDR1 gene encoding P-glycoprotein may be transcriptionally regulated by a Y-box transcription factor. We now report that, in multidrug-resistant MCF-7 breast cancer cells, nuclear localization of YB-1 is associated with MDR-1 gene expression. In drug-sensitive MCF-7 cells, however, YB-1 was localized to the cytoplasm. Regulated overexpression of YB-1 in drug-sensitive diploid breast epithelial cells induced MDR-1 gene expression and multidrug resistance. In 27 out of 27 untreated primary breast cancers, YB-1 protein was expressed in the cytoplasm although it was undetectable in normal breast tissue of these patients. In a subgroup of tumors (9/27), however, YB-1 was also localized to the nucleus and, in these cases, high levels of P-glycoprotein were present. These results show that in a subset of untreated primary breast cancers, nuclear localization of YB-1 protein is associated with intrinsic multidrug resistance. Our data show that YB-1 has an important role in controlling MDR1 gene transcription and this finding provides a basis for the analysis of molecular mechanisms responsible for intrinsic multidrug resistance in human breast cancer.
...
PMID:Nuclear localization and increased levels of transcription factor YB-1 in primary human breast cancers are associated with intrinsic MDR1 gene expression. 909 65

The aim of this study was to investigate the link between protein kinase C (PKC) and multidrug resistance (mdr) phenotype. The expression of both was studied in doxorubicin-resistant MCF-7/Adr cells as they reverted to the wild-type phenotype when cultured in the absence of drug. The following parameters were measured in cells 4, 10, 15, 20 and 24 weeks after removal of doxorubicin; (1) sensitivity of the cells towards doxorubicin; (2) levels of P-glycoprotein (P-gp) and MDR1 mRNA; (3) levels and cellular localization of PKC isoenzyme proteins alpha, theta and epsilon; and (4) gene copy number of PKC-alpha and MDR1 genes. Cells lost their resistance gradually with time, so that by week 24 they had almost completely regained the drug sensitivity seen in wild-type MCF-7 cells. P-gp levels measured by Western blot mirrored the change in doxorubicin sensitivity. By week 20, P-gp had decreased to 18% of P-gp protein levels at the outset, and P-gp was not detectable at week 24. Similarly, MDR1 mRNA levels had disappeared by week 24. MCF-7/Adr cells expressed more PKCs-alpha and -theta than wild-type cells and possessed a different cellular localization of PKC-epsilon. The expression and distribution pattern of these PKCs did not change for up to 20 weeks, but reverted back to that seen in wild-type cells by week 24. MDR1 gene amplification remained unchanged until week 20, but then was lost precipitously between weeks 20 and 24. The PKC-alpha gene was not amplified in MCF-7/Adr cells. The results suggest that MCF-7/Adr cells lose MDR1 gene expression and PKC activity in a co-ordinate fashion, consistent with the existence of a mechanistic link between MDR1 and certain PKC isoenzymes.
...
PMID:Co-ordinate loss of protein kinase C and multidrug resistance gene expression in revertant MCF-7/Adr breast carcinoma cells. 915 54

The use of anticancer drugs in the chemotherapeutic treatment of cancer patients frequently results in the emergence of drug resistant tumors. Selection of tumor cell lines in vitro has led to the identification of several proteins that mediate drug resistance to anticancer drugs. In this study, an immuno-dot blot method was used to isolate a monoclonal antibody (IPM96) which recognized a 40 kDa protein (or P-40) co-expressed with P-glycoprotein and MRP in several multidrug resistant cell lines (MCF-7/Adr, SKOV/VLB1.0, H69/Adr, and HL60/AR). Furthermore, P-40 levels dropped significantly in one revertant cell line (H69/PR) derived from H69/AR cells. Interestingly, the expression of P-40 was also higher in two tumor cell lines (SKTax6a and A2780CP) that were selected with paclitaxel or cisplatin but do not express P-gp or MRP. Immuno-fluorescence staining of cells with IPM96 showed both membrane and cytoplasmic staining. These results were confirmed by Western blot analysis of different subcellular fractions from MCF-7/Adr cells. The membrane bound P-40 was resistant to extraction with high salt, chelating agents, and denaturing agents, but was solubilized with 10 mM CHAPS. Taken together, the overexpression of P-40 in multidrug resistant cells has not been previously determined and therefore could be important in the expression of the drug resistance phenotype.
...
PMID:Overexpression of a 40-kDa protein in human multidrug resistant cells. 924 Apr 65


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---