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 multidrug resistance gene 1 encoding human P-glycoprotein (Pgp) is thought to play an important role in the multidrug resistance of lung cancer. The purpose of this study was to predict chemotherapy response by technetium-99m tetrofosmin (Tc-99m TF) lung single photon emission computed tomography (SPECT) and compare Pgp expression in patients with untreated small cell lung cancer (SCLC). Forty patients with untreated SCLC received Tc-99m TF lung SPECT prior to chemotherapy. The chemotherapy response was evaluated in the 3rd month after completion of treatment. Immunohistochemical staining of Pgp expression was performed on multiple nonconsecutive sections of biopsy specimens. By quantitative analyses, tumor to background ratios were 1.86 +/- 0.27 and 1.17 +/- 0.26 for patients with a good and poor response, respectively (p < 0.05). All of the 20 patients with a good chemotherapy response also had a positive Tc-99m TF lung SPECT and negative Pgp expression. In contrast, only 4 of the 20 patients with a poor chemotherapy response had a positive Tc-99m TF lung SPECT. Moreover, 10 of the 20 patients with a poor chemotherapy response also had negative Pgp expression (p < 0.05). Therefore, we concluded that Tc-99m TF lung SPECT can accurately predict the chemotherapy response, and Tc-99m TF lung SPECT findings can be partially compatible with Pgp expression in patients with untreated SCLC.
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PMID:Technetium-99m tetrofosmin SPECT predicts chemotherapy response in small cell lung cancer. 1461 Mar 19

In vitro studies demonstrated that the accumulation of 2-deoxy-D-glucose was reduced in multidrug resistant cell lines. In animal study, it has been suggested that 2-[18F]fluoro-2-deoxy-D-glucose (FDG) may be a marker for multidrug resistance (MDR). The aim of this clinical study was to compare MDR characteristics by immunohistochemical assay with FDG uptake and investigate whether FDG is a marker for MDR in patients with untreated lung cancer. Forty-seven patients with 49 untreated lung cancers, who had undergone both preoperative FDG PET imaging and thoracotomy, were enrolled in this study. Before surgery, FDG PET was performed 40 min after injection, and standardized uptake values (SUVs) were obtained. Patients were classified into low-SUV (< or = 5) and high-SUV (> 5) groups. After surgery, the expression of P-glycoprotein (Pgp) was investigated by immunohistochemistry, and the lung cancer FDG uptake was analysed for possible association with Pgp expression. The strong intensity of Pgp immunoreactivity was seen only in the low-SUV group. The percentage of the Pgp positive area was significantly lower in the high-SUV group (21.7 +/- 13.4%) than in the low-SUV group (44.1 +/- 29.7%) (P = 0.015). In the high-SUV group, the percentage of Pgp positive area did not exceed 50%. In lung adenocarcinoma, the intensity of Pgp immunoreactivity and the percentage of Pgp positive area increased with degree of cell differentiation, while FDG uptake decreased with degree of cell differentiation. Bronchioloalveolar carcinoma, in particular, showed overexpression of Pgp and modest uptake of FDG. In conclusion, Pgp expression was found to be inversely related to FDG uptake in untreated lung cancer. Pgp expression correlated with the degree of cell differentiation in adenocarcinomas, whilst FDG uptake was inversely related to cell differentiation. FDG may be an in vivo marker for MDR in patients with untreated lung cancer.
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PMID:P-glycoprotein expression is associated with FDG uptake and cell differentiation in patients with untreated lung cancer. 1506 Dec 61

MS-209, a quinolone-derived sphingomyelin synthase inhibitor that blocks P-glycoprotein and multidrug resistance-associated protein-1, is under development by Schering for the potential treatment of multidrug resistant tumors. By March 2003, phase II trials in breast cancer and non-small-cell lung cancer had been initiated.
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PMID:MS-209 Schering. 1564 56

To develop new anticancer agents that are effective for treatment of chemoresistant tumors, we screened a chemical library for compounds that can effectively kill both paclitaxel-sensitive lung cancer cell H460 and P-glycoprotein-overexpressing paclitaxel-resistant cell H460/TaxR. A synthetic compound, MMPT (5-[(4-methylphenyl)methylene]-2-(phenylamino)-4(5H)-thiazolone), was identified to induce cytotoxic effects in both H460 and H460/TaxR cells but not in normal fibroblasts. MMPT effectively inhibited the growth of several human lung cancer cell lines in a dose-dependent manner, with 50% inhibitory concentrations ranging from 4.9 to 8.0 microM. The inhibitory effect on cancer cells is independent of the status of p53 and P-glycoprotein. Moreover, MMPT had no obvious toxic effects on normal human fibroblasts and mesenchymal stem cells at the 50% inhibitory concentration for lung cancer cell lines. Treating lung cancer cells with MMPT-induced apoptosis with caspase-3, -8, -9, and poly(ADP-ribose) polymerase cleavage and cytochrome c release from mitochondria. MMPT-induced apoptosis was abrogated when c-Jun N-terminal kinase (JNK) activation was blocked with a specific JNK inhibitor, SP600125. Furthermore, in vivo administration of MMPT suppressed human H460 xenograft tumor growth in nude mice. Our results suggest that MMPT may induce tumor-selective cell killing in both P-glycoprotein-negative and -positive cancer cells and could be a new anticancer agent for treatment of refractory tumors.
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PMID:P-glycoprotein-independent apoptosis induction by a novel synthetic compound, MMPT [5-[(4-methylphenyl)methylene]-2-(phenylamino)-4(5H)-thiazolone]. 1583 36

Gefitinib (Iressa) is a selective epidermal growth factor receptor tyrosine kinase inhibitor and is used for the treatment of lung cancer. Recently, we discovered that it inhibits the breast cancer resistance protein, which is an ATP-binding cassette transporter. P-glycoprotein (Pgp) also pumps multiple types of drugs out of the cell using energy generated from ATP, and confers multidrug resistance on cancer cells. This study was designed to examine whether gefitinib inhibits the function of Pgp. We used multidrug resistant PC-6/PTX lung cancer and MCF-7/Adr breast cancer cells which overexpress Pgp and measured their drug sensitivity and drug-efflux function by tetrazolium assay and flowcytometry, respectively. In addition, the drug-stimulated ATPase activity of Pgp was measured using insect membranes that express human Pgp. Epidermal growth factor receptor was expressed in MCF-7/Adr, but not in PC-6/PTX cells, and the overexpression of Pgp did not confer resistance to gefitinib to both cell types. However, clinically achievable levels of gefitinib moderately reversed the Pgp-mediated resistance to paclitaxel and docetaxel in Pgp overexpressing cells. In addition, gefitinib increased the intracellular accumulation of the Pgp substrate rhodamine-123 in resistant cells, and activated ATPase in a preparation of pure Pgp-expressing membrane. These findings suggest that gefitinib directly interacts with Pgp and inhibits its function. Gefitinib may clinically inhibit the excretion of Pgp substrate drugs including anticancer agents, and its drug-interaction should therefore be considered.
Lung Cancer 2005 Sep
PMID:Gefitinib, an EGFR tyrosine kinase inhibitor, directly inhibits the function of P-glycoprotein in multidrug resistant cancer cells. 1595 94

Chemoresistance remains the major obstacle to successful therapy of the lung cancer. The multi-drug resistance (MDR) is generally associated with altered expression of drug transporter proteins, such as P-glycoprotein (P-gp). So the distribution of P-gp on the membrane is of great importance to further study the interaction between drug and P-gp. In the present work, the P-gp of the H69/VP small-lung cancer cells was detected using monoclonal antibody UIC2. A secondary goat-anti mouse antibody coupled with biotin was used. The fluorescence emission was detected from a streptavidin-Texas Red. Results were investigated by a homemade scanning near-field optical microscope (SNOM) coupled to a confocal laser microspectrofluorometer (CLMF). Topographical images and localized spectra were obtained at the level of one cell membrane. It was found that the distribution of P-gp is not homogeneous and this observation is basically in accord with the fluorescent images obtained by classical microscopy. The distribution of P-gp would be localized in a higher region on a cell surface. This methodology would also enhance our understanding of MDR under physiological conditions.
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PMID:Imaging of P-glycoprotein of H69/VP small-cell lung cancer lines by scanning near-field optical microscopy and confocal laser microspectrofluorometer. 1607 26

The ganglioside patterns have been shown to dramatically change during cell proliferation and differentiation and in certain cell-cycle phases, brain development, and cancer malignancy. To investigate the significance of the ganglioside GM3 in cancer malignancy, we established GM3-reconstituted cells by transfecting the cDNA of GM3 synthase into a GM3-deficient subclone of the 3LL Lewis lung carcinoma cell line (Uemura, S. (2003) Glycobiology, 13, 207-216). The GM3-reconstituted cells were resistant to apoptosis induced by etoposide and doxorubicin. There were no changes in the expression levels of topoisomerase IIalpha or P-glycoprotein, or in the uptake of doxorubicin between the GM3-reconstituted cells and the mock-transfected cells. To understand the mechanism of the etoposide-resistant phenotype acquired in the GM3-reconstituted cells, we investigated their apoptotic signaling. Although no difference was observed in the phosphorylation of p53 at serine-15-residue site by etoposide between the GM3-reconstituted cells and mock-transfected cells, the activation of both caspase-3 and caspase-9 was specifically inhibited in the former. We found that the anti-apoptotic protein B-cell leukemia/lymphoma 2 (Bcl-2) was increased in the GM3-reconstituted cells. Moreover, wild-type 3LL Lewis lung carcinoma cells, which have an abundance of GM3, exhibited no DNA fragmentation following etoposide treatment and expressed higher levels of the Bcl-2 protein compared with the J5 subclone. Thus, these results support the conclusion that endogenously produced GM3 is involved in malignant phenotypes, including anticancer drug resistance through up-regulating the Bcl-2 protein in this lung cancer cell line.
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PMID:Endogenously produced ganglioside GM3 endows etoposide and doxorubicin resistance by up-regulating Bcl-2 expression in 3LL Lewis lung carcinoma cells. 1657 67

We recently identified two compounds of 5-benzylidene-2-phenylimino-1,3-thiazolidin-4-one (BPT) analog, 5-(4-methylbenzylidene)-2-phenylamino-1,3-thiazolidin-4-one (MMPT) and 5-(2,4-dihydroxybenzylidene)-2-phenylimino-1,3-thiazolidin-4-one (DBPT), that can effectively induce apoptosis in cancer cells but not in normal cells, independently of P-glycoprotein status. To further investigate the antitumor activity of BPT analogs, we obtained 18 commercially available analogs of BPT and synthesized 7 analogs in our lab, and analyzed their antitumor activity in various cancer cells, including paclitaxel- and vinorelbine-sensitive and -resistant human lung cancer cells. Two of the compounds were more potent than MMPT or DBPT in induction of apoptosis in certain cancer cell lines and remained tumor selective. Seven compounds did not induce any cytotoxic effects in any of the cell lines tested at the highest concentration tested (31 microM). The other compounds induced cytotoxic effects in some cancer cells but not in others or were less potent than MMPT and DBPT. Cell uptake studies showed that analogs that effectively induced cell killing in paclitaxel- and vinorelbine-resistant cells could be taken up easily by those cells despite their high levels of P-glycoprotein expression. These data further demonstrate that thiazolidinone analogs are not P-glycoprotein substrates and could be useful for treatment of P-glycoprotein overexpressing refractory cancers.
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PMID:Anticancer activity of 5-benzylidene-2-phenylimino-1, 3-thiazolidin-4-one (BPT) analogs. 1710 41

Multidrug resistance (MDR) transporters have been termed the Phase III detoxification system because they not only export endogenous metabolites but provide protection from xenobiotic insult by actively secreting foreign compounds and their metabolites from tissues. However, MDR overexpression in tumors can lead to drug resistance, a major obstacle in the treatment of many cancers, including lung cancer. Isothiocyanates from cruciferous vegetables, such as sulforaphane (SF) and erucin (ER), are known to enhance the expression of Phase II detoxification enzymes. Here we evaluated the ability of SF and ER to modulate MDR mRNA and protein expressions, as well as transporter activity. The expression of P-glycoprotein (P-gp), multidrug resistance protein 1 (MRP1) and multidrug resistance protein 2 (MRP2) in liver (HepG2), colon (Caco-2) and lung (A549) cancer cells treated with ER or SF was analyzed by Western blotting. Neither SF nor ER affected P-gp expression in any of the cell lines tested. Both SF and ER increased the protein levels of MRP1 and MRP2 in HepG2 cells and of MRP2 in Caco-2 cells in a dose-dependent manner. In A549 lung cancer cells, SF increased MRP1 and MRP2 mRNA and protein levels; ER caused a similar yet smaller increase in MRP1 and MRP2 mRNA. In addition, SF and ER increased MRP1-dependent efflux of 5-carboxyfluorescein diacetate in A549 cells, although again the effect of SF was substantially greater than that of ER. The implication of these findings is that dietary components that modulate detoxification systems should be studied carefully before being recommended for use during chemotherapy, as these compounds may have additional influences on the disposition of chemotherapeutic drugs.
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PMID:Sulforaphane and erucin increase MRP1 and MRP2 in human carcinoma cell lines. 1761 9

Amrubicin is a completely synthetic 9-aminoanthracycline agent for the treatment of lung cancer in Japan. The cytotoxicity of C-13 hydroxy metabolite, amrubicinol, is 10 to 100 times greater than that of amrubicin. The transporters responsible for the intracellular pharmacokinetics of amrubicin and amrubicinol remains unclear. This study was aimed to determine whether P-glycoprotein (P-gp) plays functional and preventive role in cellular accumulation and cytotoxicity of amrubicin and its active metabolite amrubicinol by in vitro transport and toxicity experiments. Cytotoxicity and intracellular accumulation of amrubicin and amrubicinol were evaluated by LLC-PK1 cells, MDR1 gene-transfected LLC-PK1 (L-MDR1) cells overexpressing P-gp, and human A549 lung adenocarcinoma cells. L-MDR1 cells showed 6- and 12-fold greater resistance to amrubicin and amrubicinol, respectively, than the parental LLC-PK1 cells. The intracellular accumulation of both drugs in L-MDR1 cells was significantly reduced compared to the LLC-PK1 cells. The basal-to-apical transepithelial transport of both drugs markedly exceeded, whereas the apical-to-basal transport of both drugs was significantly lower in L-MDR1 cells than LLC-PK1 cells. Cyclosporin A (CyA) restored the sensitivity, intracellular accumulation and transport activity for both drugs in L-MDR1 cells. In A549 cells, CyA significantly increased the intracellular accumulation and cytotoxicity of both drugs. These findings indicated that P-gp is responsible for cellular accumulation and cytotoxicity of both amrubicin and amrubicinol, therefore suggesting that the antitumor effect of amrubicin could be affected by the expression level of P-gp in lung cancer cells in chemotherapeutic treatments.
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PMID:Role of P-glycoprotein in accumulation and cytotoxicity of amrubicin and amrubicinol in MDR1 gene-transfected LLC-PK1 cells and human A549 lung adenocarcinoma cells. 1805 47


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