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)

Alteration of the epidermal growth factor (EGF) signaling pathway occurs frequently in human cancer cells and may subsequently affect the cell survival towards anti-cancer agents. To elucidate the effect of long-term EGF treatment on the chemo-sensitivity of human cancer cells, human squamous carcinoma A431 cells (AP) were incubated continuously with 50 ng/ml EGF for 30 weeks and these cells were designated as the AC cells. The long-term EGF treatment did not alter the EGFR level and the EGF-induced protein tyrosine phosphorylation pattern in the AC cells. By MTT assay, the AC cells were shown to be more resistant than the AP cells to doxorubicin, etoposide and amsacrine but not to cisplatin. Among the drug-resistant proteins, topoisomerase IIalpha (topoII) was downregulated in the AC cells while there was no apparent change in the levels of P-glycoprotein, MRP-1 or glutathione- S-transferase-pi as compared to the AP cells. Furthermore, knockdown of topoII by antisense topoII oligonucleotide transfection decreased the sensitivity to doxorubicin, etoposide and amsacrine in the A431 cells. Results from the present study support an idea that long-term treatment with EGF may induce drug resistance in cells through the downregulation of topoII.
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PMID:Epidermal growth factor induction of resistance to topoisomerase II toxins in human squamous carcinoma A431 cells. 1696 95

We have previously shown that amphiphilic diblock copolymers composed of methoxypolyethylene glycol-b-polycaprolactone (MePEG-b-PCL) increased the cellular accumulation and reduced the basolateral to apical flux of the P-glycoprotein substrate, rhodamine 123 (R-123) in caco-2 cells. The purpose of this study was to investigate membrane perturbation effects of MePEG-b-PCL diblock copolymers with erythrocyte membranes and caco-2 cells and the effect on P-gp ATPase activity. The diblock copolymer MePEG(17)-b-PCL(5) induced increasing erythrocyte hemolysis at concentrations which correlated with increasing accumulation of R-123 into caco-2 cells. However, no increase in cellular accumulation of R-123 by non-P-gp expressing cells was observed, suggesting that diblock did not enhance the transmembrane passive diffusion of R-123, but that the accumulation enhancement effect of the diblock in caco-2 cells was likely mediated primarily via P-gp inhibition. Fluorescence anisotropy measurements of membrane fluidity and P-gp ATPase activity demonstrated that MePEG(17)-b-PCL(5) decreased caco-2 membrane fluidity while stimulating ATPase activity approximately threefold at concentrations that maximally enhanced R-123 caco-2 accumulation. These results suggest that inhibition of P-gp efflux by MePEG(17)-b-PCL(5) does not appear to be related to increases in membrane fluidity or through inhibition in P-gp ATPase activities, which are two commonly reported cellular effects for P-gp inhibition mediated by surfactants.
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PMID:Methoxypolyethylene glycol-block-polycaprolactone diblock copolymers reduce P-glycoprotein efflux in the absence of a membrane fluidization effect while stimulating P-glycoprotein ATPase activity. 1709 35

Silymarin consists of a family of flavonoids (silybin, isosilybin, silychristin, silydianin and taxifoline) commonly found in the dried fruit of the milk thistle plant Silybum marianum. Although silymarin's role as an antioxidant and hepatoprotective agent is well known, its role as an anticancer agent has begun to emerge. Extensive research within the last decade has shown that silymarin can suppress the proliferation of a variety of tumor cells (e.g., prostate, breast, ovary, colon, lung, bladder); this is accomplished through cell cycle arrest at the G1/S-phase, induction of cyclin-dependent kinase inhibitors (such as p15, p21 and p27), down-regulation of anti-apoptotic gene products (e.g., Bcl-2 and Bcl-xL), inhibition of cell-survival kinases (AKT, PKC and MAPK) and inhibition of inflammatory transcription factors (e.g., NF-kappaB). Silymarin can also down-regulate gene products involved in the proliferation of tumor cells (cyclin D1, EGFR, COX-2, TGF-beta, IGF-IR), invasion (MMP-9), angiogenesis (VEGF) and metastasis (adhesion molecules). The antiinflammatory effects of silymarin are mediated through suppression of NF-kappaB-regulated gene products, including COX-2, LOX, inducible iNOS, TNF and IL-1. Numerous studies have indicated that silymarin is a chemopreventive agent in vivo against a variety of carcinogens/tumor promoters, including UV light, 7,12-dimethylbenz(a)anthracene (DMBA), phorbol 12-myristate 13-acetate (PMA) and others. Silymarin has also been shown to sensitize tumors to chemotherapeutic agents through down-regulation of the MDR protein and other mechanisms. It binds to both estrogen and androgen receptors, and down-regulates PSA. In addition to its chemopreventive effects, silymarin exhibits antitumor activity against human tumors (e.g., prostate and ovary) in rodents. Various clinical trials have indicated that silymarin is bioavailable and pharmacologically safe. Studies are now in progress to demonstrate the clinical efficacy of silymarin against various cancers.
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PMID:Anticancer potential of silymarin: from bench to bed side. 1720 Nov 69

The molecular chaperone heat shock protein 90 (HSP90) has emerged as an exciting molecular target. Derivatives of the natural product geldanamycin, such as 17-allylamino-17-demethoxy-geldanamycin (17-AAG), were the first HSP90 ATPase inhibitors to enter clinical trial. Synthetic small-molecule HSP90 inhibitors have potential advantages. Here, we describe the biological properties of the lead compound of a new class of 3,4-diaryl pyrazole resorcinol HSP90 inhibitor (CCT018159), which we identified by high-throughput screening. CCT018159 inhibited human HSP90beta with comparable potency to 17-AAG and with similar ATP-competitive kinetics. X-ray crystallographic structures of the NH(2)-terminal domain of yeast Hsp90 complexed with CCT018159 or its analogues showed binding properties similar to radicicol. The mean cellular GI(50) value of CCT018159 across a panel of human cancer cell lines, including melanoma, was 5.3 mumol/L. Unlike 17-AAG, the in vitro antitumor activity of the pyrazole resorcinol analogues is independent of NQO1/DT-diaphorase and P-glycoprotein expression. The molecular signature of HSP90 inhibition, comprising increased expression of HSP72 protein and depletion of ERBB2, CDK4, C-RAF, and mutant B-RAF, was shown by Western blotting and quantified by time-resolved fluorescent-Cellisa in human cancer cell lines treated with CCT018159. CCT018159 caused cell cytostasis associated with a G(1) arrest and induced apoptosis. CCT018159 also inhibited key endothelial and tumor cell functions implicated in invasion and angiogenesis. Overall, we have shown that diaryl pyrazole resorcinols exhibited similar cellular properties to 17-AAG with potential advantages (e.g., aqueous solubility, independence from NQO1 and P-glycoprotein). These compounds form the basis for further structure-based optimization to identify more potent inhibitors suitable for clinical development.
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PMID:In vitro biological characterization of a novel, synthetic diaryl pyrazole resorcinol class of heat shock protein 90 inhibitors. 3060 24

Acute myeloid leukaemia (AML) comprises 80% of acute adult leukaemias and the disease has mostly an unfavourable outcome. Diagnostic criteria rely primarily on morphological classification, while prognostic evaluation is determined by cytogenetic methods. Survival is highly variable and it is a matter of debate, whether alternative therapeutic approaches may improve the effectiveness of conventional cytotoxic drug treatment. Two transmembrane proteins undoubtedly contribute to worse prognosis: P-glycoprotein (Pgp) and FLT3. Pgp is a transmembrane, ATP-cassette binding efflux pump that efficiently removes structurally unrelated xenobiotics from leukaemic blasts. This leads to inefficiency towards several cytotoxic drugs, hence the phenomenon is called multidrug resistance. FLT3 is a transmembrane tyrosine kinase and an internal tandem duplication can considerably augment its kinase activity. Both mechanisms lead to chemotherapy resistance and significantly shorter survival; thus several studies have been designed to treat patients via therapeutic measures that neutralize these proteins. This review focuses on the pathophysiological phenomena and the detection methods of Pgp and FLT3 as well as on novel therapeutic strategies that are offered by their inhibition.
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PMID:Pgp and FLT3: identification and modulation of two proteins that lead to chemotherapy resistance in acute myeloid leukemia. 1734 44

To overcome multidrug resistance (MDR) existing in tumor chemotherapy, polymeric micelles encoded with folic acid on the micelle surface were prepared with the encapsulation of a potent MDR modulator, FG020326. The micelles were fabricated from diblock copolymers of poly(ethylene glycol) (PEG) and biodegradable poly(epsilon-caprolactone) (PCL) with folate attached to the distal ends of PEG chains. The folate-conjugated copolymers, folate-PEG-PCL, were synthesized by multistep chemical reactions. First, allyl-terminated copolymer (allyl-PEG-PCL) was synthesized through a ring-opening polymerization of epsilon-caprolactone in bulk employing monoallyl-PEG as a macroinitiator. Second, the allyl terminal groups of copolymers were converted into primary amino groups by a radical addition reaction, followed by conjugation of the carboxylic group of folic acid. In vitro studies at 37 degrees C demonstrated that FG020326 release from micelles at pH 5.0 was faster than that at pH 7.4. Cytotoxicity studies with MTT assays indicated that folate-functionalized and FG020326-loaded micelles resensitized the cells approximately five times more than their folate-free counterparts (p < 0.01) in human KB(v200) cells treated with vincristine (VCR). The in vitro Rhodamine 123 efflux experiment using MDR KB(v200) cells revealed that when cells were pretreated with folate-attached and FG020326-loaded micelles, the P-glycoprotein (P-gp) drug efflux function was significantly inhibited.
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PMID:Folate-functionalized polymeric micelles for tumor targeted delivery of a potent multidrug-resistance modulator FG020326. 1794 Oct 15

Chemotherapy plays a vital role in the treatment and management of breast cancer and is associated with significant improvements in survival. Regimens such as CMF (cyclophosphamide/methotrexate/5-fluorouracil) and, more recently, TAC (docetaxel/doxorubicin/cyclophosphamide) have been used with good response rates and complete remissions achieved in approximately 15% of cases. However, a significant proportion of women experience a recurrence of metastatic disease, with an average survival between 1-2 years. The monoclonal antibody trastuzumab is used in the treatment of HER2/neu-positive breast cancer. Although such targeted agents have heralded an exciting new era in cancer therapy, they are limited by the fact that only a subset of patients can benefit from treatment and by the emergence of resistance. Thus, the pursuit of a strategy that modulates resistance to standard chemotherapeutics remains valid. Accumulating evidence indicates that a number of mechanisms known to contribute to clinical drug resistance might be relevant to breast cancer. Tumor cell drug resistance might arise as a result of systemic pharmacologic factors, changes in the tumor microenvironment (eg, pH), cellular pharmacokinetics, drug metabolism and detoxification, drug target modifications, DNA repair, and apoptotic mechanisms. The adenotriphosphate-binding cassette membrane transporter family contributes to clinical drug resistance, especially in breast cancer. The most frequently described of this family is P-glycoprotein, followed by multidrug resistance protein-1. This review describes the factors thought to play a role in clinical breast cancer drug resistance and describes potential methods by which it might be circumvented.
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PMID:The role of efflux pumps in drug-resistant metastatic breast cancer: new insights and treatment strategies. 1802 75

Taxanes (e.g. paclitaxel, docetaxel) and epothilones (e.g. ixabepilone) are microtubule-targeting agents, which disrupt cellular processes and induce apoptosis. Although their mechanisms of action are similar, clinical data in breast cancer patients support at least partial non-cross resistance between the classes, and even between individual compounds. Several biomarkers might contribute to the identification of patient groups likely to derive benefit from one class of microtubule-targeting agent or even one agent. Overexpression of P-glycoprotein is associated with resistance to taxanes, but not ixabepilone, in vitro; its role in vivo remains unclear. Mutations in beta-tubulin linked to resistance to taxanes but not epothilones are observed in vitro; somatic mutations of beta-tubulin appear rare clinically. Overexpression of the betaIII-tubulin isoform is associated with taxane resistance in cell lines; some clinical studies support a relationship between poor response to taxanes and overexpression of betaIII-tubulin. BetaIII-tubulin overexpression seems not to affect sensitivity to ixabepilone. Estrogen receptor negativity, low expression of microtubule-associated protein tau, and perhaps HER2 amplification may define a subset of patients with higher than average sensitivity to paclitaxel. Large scale pharmacogenomic analysis has identified molecular markers potentially capable of distinguishing patients with differential sensitivity to paclitaxel and ixabepilone. These markers require validation in clinical trials.
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PMID:Markers predicting clinical benefit in breast cancer from microtubule-targeting agents. 1808 98

Lapatinib [N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine, GW572016, Tykerb] is a tyrosine kinase inhibitor approved for use in combination with capecitabine to treat advanced or metastatic breast cancers overexpressing HER2 (ErbB2). In this work we investigated the role of efflux and uptake transporters in lapatinib disposition and drug interactions. In vitro studies evaluated whether lapatinib is a substrate for efflux transporters or an inhibitor of efflux/uptake transporters. In vivo studies included whole-body autoradiography and an evaluation of the role of efflux transporters on the intestinal absorption and brain penetration of lapatinib using chemical or genetic knockout animals. Lapatinib is a substrate for the efflux transporters P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP). Furthermore, lapatinib is an inhibitor (IC(50) values 0.025-5 muM) of Pgp, BCRP, and organic anion transporting polypeptide 1B1 (a hepatic uptake transporter). In contrast, lapatinib yielded little inhibition on renal transporters (organic anion transporters, organic cation transporters, and uric acid transporter). In vivo studies demonstrated that brain concentrations of lapatinib were low and influenced by efflux transporters at the blood-brain barrier. In contrast, systemic exposure of lapatinib after oral dosing was unchanged when efflux by Pgp and BCRP was absent from the gastrointestinal tract. These in vitro and in vivo preclinical investigations provide a mechanistic basis for elucidating clinical drug interactions.
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PMID:The role of efflux and uptake transporters in [N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine (GW572016, lapatinib) disposition and drug interactions. 1821 74

The utilization of surfactants to increase intestinal absorption of drugs is a viable strategy that benefits from increases in drug solubilization and the potential for inhibition of P-glycoprotein (P-gp) mediated efflux. However, the effective concentration range for P-gp inhibition of most surfactants is defined over a narrow concentration range, below the critical micelle concentration (CMC), as a result of significant micelle sequestration of drug. Therefore, the objectives of these studies were to assess if association of P-gp substrates differing in hydrophobicity will impact the effective concentration range for P-gp inhibition by amphiphilic diblock copolymers based on methoxypolyethylene glycol-block-polycaprolatone (MePEG-b-PCL). Comparisons between the micelle association and Caco-2 cellular accumulation were evaluated using two structurally homologous P-gp substrates, the relatively hydrophobic R-6G and the hydrophilic R-123, over concentrations above and below the CMC for MePEG-b-PCL diblock copolymers. An approximately 3.75-fold enhancement of R-123 accumulation occurred with 2 mM MePEG17-b-PCL5, compared to approximately 1.25-fold for R-6G. This decrease in the accumulation enhancement corresponds with the higher R-6G fraction (0.75) associated at 2 mM MePEG17-b-PCL5 compared with R-123 (0.25). Interestingly, R-6G accumulation was enhanced over a very broad range of MePEG17-b-PCL5 concentrations below the CMC. This was in contrast to R-123, which demonstrated no enhancement below the CMC. A similar concentration dependent accumulation profile was seen with other surfactants such as vitamin E TPGS and Cremophor EL and with two other P-gp substrates differing in hydrophobicity, the relatively hydrophobic paclitaxel and hydrophilic doxorubicin. In conclusion, the effective concentration range for surfactant mediated inhibition of P-gp appears to depend on the P-gp substrate hydrophobicity.
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PMID:P-glycoprotein efflux inhibition by amphiphilic diblock copolymers: relationship between copolymer concentration and substrate hydrophobicity. 1838 Apr 67


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