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)

Cyclooxygenase-2 (Cox-2), an inducible form of the enzyme that catalyzes the first step in the synthesis of prostanoids, has been shown to be overexpressed in a wide range of tumors and possesses proangiogenic and antiapoptotic properties. To understand the molecular mechanism of Cox-2 action we used adenovirus-mediated transfer of rat Cox-2 cDNA into renal rat mesangial cells and determined the differential gene expression using cDNA microarrays. One of the several genes that were highly up-regulated by over expressed Cox-2 was MDR1. MDR1 or P-glycoprotein (P-gp), the product of the MDR1 gene, is implicated as the primary cause of multidrug resistance (MDR) in tumors where it acts as an efflux pump for chemotherapeutic agents. It is also expressed in normal tissues of the liver and kidney where it functions to actively transport lipophilic xenobiotics. Reverse transcriptase-PCR analysis confirmed the results of the microarray, showing increased mRNA levels for MDR1 in Cox-2 overexpressing cells. This increase in mRNA translated to an increase in MDR1 protein expression, which was dose-dependent on Cox-2 expression. Furthermore, using rhodamine 123 efflux assay we observed a significant increase in P-gp activity in Cox-2 overexpressing renal mesangial cells. The specific Cox-2 inhibitor NS398 was able to block the Cox-2-mediated increase in MDR1 expression and activity, suggesting that Cox-2 products may be implicated in this response. These results prove the existence of a causal link between Cox-2 and P-gp activity, which would have implications for kidney function and multidrug resistance in tumors where Cox-2 is overexpressed.
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PMID:Regulation of MDR-1 (P-glycoprotein) by cyclooxygenase-2. 1213 26

Multidrug resistance (MDR) of cancer cells to cytostatic agents is the major obstacle for the succesfull chemotherapy. One of the causes of the development of cellular resistance to a wide variety of drugs is the elevated expression of membrane transporter proteins such as members of ATP binding cassette (ABC) protein superfamily. Expression of the ABC transporter MDR1, also termed P-glycoprotein (P-gp), seems to correlate with drug resistance of tumors to chemotherapy. Cyclooxygenase-2, an inducible isoform of enzyme, responsible for generation of prostaglandins from arachidonic acid, is constitutively expressed in a number of cancer cells. Anti-cancer potency of cyclooxygenase inhibitors is established, but the mechanism of Cox-2-dependent potentiation of tumor growth is a subject of intense discussion. Here we focus on the discussion of potential link between Cox-2 expression and development of multidrug resistance phenotype. Our observation, that enforced expression of Cox-2 causes enhancement in MDR1 expression and functional activity suggests the existence of causal link between Cox-2 activity and MDR1 expression. The use of Cox-2 inhibitors to decrease function of MDR1 may enhance accumulation of chemotherapy agents and decrease resistance of tumors to chemotherapeutic drugs.
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PMID:Cyclooxygenase-2: potential role in regulation of drug efflux and multidrug resistance phenotype. 1496 27

The potential anti-tumour activity of non-steroidal anti-inflammatory drugs (NSAIDS) has been previously discussed. This study was undertaken to assess the possible anti-tumour activity of the cyclooxygenase-2 (COX-2) inhibitor; celecoxib in an animal model of mammary carcinoma; the solid Ehrlich carcinoma (SEC). The possibility that celecoxib may modulate the anti-tumour activity of doxorubicin on the SEC was also studied. Some of the possible mechanisms underlying such modulation were investigated. The anti-tumour activity of celecoxib (25 mg kg(-1)), diclofenac (12.5 mg kg(-1)) and doxorubicin (2 mg kg(-1)) either alone or in combination were investigated on SEC in vivo through the assessment of tumour growth delay (TGD) and tumour volume (TV), changes in tumour DNA content and nitric oxide (NO) levels, immunohistochemical staining of the tumour suppressor gene product; p53 histopathological examination and determination of apoptotic index of SEC. In addition, the influence of these drugs on the DNA fragmentation pattern of Ehrlich carcinoma cells (ECC) was studied. It was found that both celecoxib and diclofenac lack the anti-tumour activity on SEC. In addition there was a significant increase in doxorubicin anti-tumour activity when administered in combination with celecoxib. Moreover, it was found that both celecoxib and diclofenac have the potential to inhibit the function of P-glycoprotein (P-gp) in ECC using rhodamine uptake and efflux assays. Therefore, the current study suggested the chemosensitizing potential of celecoxib in the SEC animal model of mammary tumour, which could be explained in part on the basis of inhibition of P-gp function, with possible enhancement of doxorubicin anti-tumour activity.
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PMID:The potential role of cyclooxygenase-2 inhibitors in the treatment of experimentally-induced mammary tumour: does celecoxib enhance the anti-tumour activity of doxorubicin? 1545 69

Drug resistance to cisplatin (CDDP) would represent a major obstacle for cancer therapy. The adenosine triphosphate (ATP) binding cassette (ABC) family of transport proteins, such as the 170 kDa P-glycoprotein (multidrug resistance gene-1; MDR-1) and the 190 kDa multidrug resistance-associated proteins (MRPs), are associated with multidrug resistance, including resistance to CDDP. The purpose of the present study was to investigate the relationship between cyclooxygenase-2 (COX-2) expression and the level of chemosensitivity to CDDP. We established the COX-2-overexpressed colon cancer cell line TR-5 from HCT-15 cells. We quantified the expression of m-RNA for MRP-1 and MDR-1 by a real-time PCR method, determining that the values of each gene/standardized GAPDH in HCT-15 and TR-5 were 23+/-0.4 and 6.1+/-0.5 in MRP-1 (p<0.02) and 9.0+/-4.8 and 3.6+/-0.5 in MDR-1, respectively. With respect to chemosensitivity, survival rates for 3 microg/ml and 10 microg/ml of CDDP were 81.5+/-12.2% and 26.1+/-11.7% (IC50=6.5 microg/ml) for HCT-15 and 96.6+/-1.7% and 77.4+/-4.9% (IC50=18.5 microg/ml) for TR-5, respectively, thus TR-5 showed higher resistance to CDDP than HCT-15 did with statistical differences. We also demonstrated a successful re-sensitization to CDDP toxicity in TR-5 by means of the COX-2 selective inhibitor JTE-522, 4-(4-cyclohexyl-2-methyl-1, 3-oxazol-5-yl)-2-fluorobenzene sulfonamide, which markedly decreased the IC50 of CDDP for TR-5 (from 17.3+/-2.6 microg/ml to 8.6+/-2.5 microg/ml). In conclusion, COX-2 overexpression induced increased MRP-1 expression in a colon cancer cell line, TR-5, resulting in chemoresistance to CDDP that was approximately triple the level of chemoresistance observed in the original HCT-15 cells line, as measured by calculation of the IC50. We also confirmed the efficacy of pretreatment of TR-5 cells with the COX-2 selective inhibitor JTE-522 in restoring chemosensitivity of these cells to CDDP, suggesting a strategy for overcoming drug resistance to CDDP.
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PMID:Cyclooxygenase-2 gene induction causes CDDP resistance in colon cancer cell line, HCT-15. 1551 78

P-glycoprotein, the product of the multidrug resistance protein 1 (MDR1) gene, is a xenobiotic transporter that may contribute to the physiology of the intestinal barrier. Twenty-five percent of mdr1a-deficient (mdr1a(-/-)) mice spontaneously develop colitis at variable ages when maintained under specific pathogen-free conditions. We hypothesized that this disease would result from epithelial dysfunction and that conventional housing would increase incidence and severity of the colitis phenotype. Wild-type congenic FVB (+/+) mice were maintained under the same conditions as controls. Knockout and wild-type mice were matched for age and gender and observed for signs of colitis. Colonic tissues from both groups of mice were examined for macroscopic and microscopic injury and for basal ion transport and transepithelial resistance (TER). Translocation of bacteria across the intestine was assessed by culturing the spleen and mesenteric lymph nodes. Protein analysis was performed by Western blot analysis. All mdr1a(-/-) mice developed weight loss and signs of colitis, whereas wild-type mice never showed such signs. Within the mdr1a(-/-) group, males consistently developed severe colitis earlier than females. Knockout mice showed increased basal colonic ion transport (females, 162.7 +/- 4.6 vs. 49.7 +/- 3.8 muA/cm(2); males, 172.6 +/- 5.6 vs. 54.2 +/- 3.1 muA/cm(2); P < 0.01) and decreased TER (females, 25.4 +/- 0.3 vs. 36.4 +/- 0.8 Omega.cm(2); males, 23.1 +/- 1.0 vs. 38.3 +/- 0.2 Omega.cm(2); P < 0.01) compared with wild-type mice. Barrier dysfunction was accompanied by decreased phosphorylation of tight junction proteins. Expression of cyclooxygenase-2 and inducible nitric oxide synthase in intestinal tissues was increased in the mdr1a(-/-) group (P < 0.01) and correlated with disease severity. Bacterial translocation was greater both in incidence (P < 0.01) and severity (P < 0.001) for the knockout group. With respect to all indexes studied, mdr1a(-/-) males performed worse than females. Our data support the hypothesis that alterations in the intestinal barrier alone, in the absence of immune dysfunction, may rapidly lead to colitis in the setting of a normal colonic flora.
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PMID:Epithelial dysfunction associated with the development of colitis in conventionally housed mdr1a-/- mice. 1577 38

The aim of the study is to test the prognostic value of cyclooxygenase-2 (COX-2) and P-glycoprotein in relation to responsiveness to chemotherapy in ovarian carcinoma patients with "shorter and longer" survival. We evaluated 52 ovarian carcinomas homogeneous for stage, histologic type, grade of differentiation, and surgical and chemotherapeutic treatment. Twenty-eight of the patients had died of progression of disease no later than 2 years after primary surgical treatment, while 24 patients were alive with no evident disease 5 years after primary surgical treatment. In logistic regression analysis, COX-2 and P-glycoprotein, when analyzed one by one, are significant (P= 0.017 and P < 0.0005, respectively). P-glycoprotein is correlated with COX-2 (P= 0.008, Fisher's exact test); moreover, both COX-2 and the P-glycoprotein are correlated with clinical response to chemotherapy (P= 0.022 and P < 0.0005, respectively, Chi-square test). Our data suggest that COX-2 and P-glycoprotein may have prognostic significance in advanced ovarian serous carcinoma. The COX-2 and the P-glycoprotein overexpressions are correlated to one another and both with a progression of disease during the first-line chemotherapy. The administration of a COX-2 inhibitor in association with chemotherapy in ovarian carcinoma patients may improve the tumor chemosensibility and the overall survival.
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PMID:Increased cyclooxygenase-2 (COX-2) and P-glycoprotein-170 (MDR1) expression is associated with chemotherapy resistance and poor prognosis. Analysis in ovarian carcinoma patients with low and high survival. 1582 8

Irinotecan (CPT-11, 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin) has exhibited clinical activities against a broad spectrum of carcinomas by inhibiting DNA topoisomerase I (Topo I). However, severe and unpredictable dosing-limiting toxicities (mainly myelosuppression and severe diarrhea) hinder its clinical use. The latter consists of early and late-onset diarrhea, occurring within 24 hr or > or = 24 hr after CPT-11 administration, respectively. This review highlights novel agents potentially inhibiting CPT-11-induced diarrhea, which are designed and tested under guidance of disposition pathways and potential toxicity mechanisms. Early-onset diarrhea is observed immediately after CPT-11 infusion and probably due to the inhibition of acetylcholinesterase activity, which can be eliminated by administration of atropine. Late-onset diarrhea appears to be associated with intestinal exposure to SN-38 (7-ethyl-10-hydroxycamptothecin), the major active metabolite of CPT-11, which may bind to Topo I and induce apoptosis of intestinal epithelia, leading to the disturbance in the absorptive and secretory functions of mucosa. CPT-11 and SN-38 may also stimulate the production of pro-inflammatory cytokines and prostaglandins (PGs), thus inducing the secretion of Na(+) and Cl(-). Early treatment of severe late-onset diarrhea with oral high-dose loperamide has decreased patient morbidity. Extensive studies have been conducted to identify other potential agents to ameliorate diarrhea in preclinical and clinical models. These include intestinal alkalizing agents, oral antibiotics, enzyme inducers, P-glycoprotein (PgP) inhibitors, cyclooxygenase-2 (COX-2) inhibitors, tumor necrosis factor-alpha (TNF-alpha) inhibitors, or blockers of biliary excretion of SN-38. Further studies are needed to identify the molecular targets associated with CPT-11 toxicity and safe and effective agents for alleviating CPT-11-induced diarrhea.
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PMID:Novel agents that potentially inhibit irinotecan-induced diarrhea. 1597 2

Multidrug resistance (MDR) of neoplastic tissues is a major obstacle in cancer chemotherapy. The predominant cause of MDR is the overexpression and drug transport activity of P-glycoprotein (P-gp, a product of the MDR gene). P-gp is a member of the ATP binding cassette (ABC) transporters family, with broad substrate specificity for several substances including anticancer drugs, linear and cyclic peptides, inhibitors of HIV protease, and several other substances. The development of P-gp-mediated MDR is often associated with several changes in cell structure and metabolism of resistant cells. In the present review are discussed the relations between glucosylceramide synthase activity, Pregnane X receptor and development of P-gp mediated MDR phenotype. Attention is also focused on the changes in protein kinase systems (mitogen-activated protein kinases, protein kinase C, Akt kinase) that are associated with the development of MDR phenotype and to the possible role of these kinase cascades in modulation of P-gp expression and function. The overexpression of P-gp may be associated with changes in metabolism of sugars as well as energy production. Structural and ultrastructural characteristics of multidrug resistant cells expressing P-gp are typical for cells engaged in a metabolically demanding process of protein synthesis and transport. P-gp mediated MDR phenotype is often also associated with alterations in cytoskeletal elements, microtubule and mitochondria distribution, Golgi apparatus, chromatin texture, vacuoles and caveolae formation. The current review also aims at bringing some state-of-the-art information on interactions of P-glycoprotein with various substances. To capture and transport the numerous unrelated substances, P-gp should contain site(s) able to bind compounds with a molecular weight of several hundreds and comprising hydrophobic and/or base regions that are protonated under physiological conditions. Drug binding sites that are able to recognize substances with different chemical structures may have a complex architecture in which different parts are responsible for binding of different drugs. For P-gp substrates and inhibitors, a pharmacophore-based model has been described. The pharmacophores have to contain parts with hydrophobic and aromatic characteristics and functional groups that can act as hydrogen-bond donors and/or acceptors. Several drugs are known to be P-glycoprotein antagonizing agents. They represent a large group of structurally unrelated substances that can act via direct interaction with P-gp and inhibition of its transport activity, or via possible modulation of processes (such as phosphorylation) regulating P-gp transport activity. Effects of MDR reversal agents on the P-gp expression have also been reported. Function and expression of P-gp can be affected indirectly as well, e.g. through cyclooxygenase-2 or carbonic anhydrase-IX expression and effects.
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PMID:P-glycoprotein--implications of metabolism of neoplastic cells and cancer therapy. 1617 19

Cyclooxygenase-2 (COX-2), P-glycoprotein (P-gp) and multi-drug resistance-associated protein (MRP) are considered important tumor-associated proteins in humans and dogs. In the present study, we immunohistochemically evaluated the expression of these proteins in canine patients with transitional cell carcinoma (TCC). Of 52 cases, 30 (57.7%) were positive for COX-2, 40 (76.9%) for P-gp, and only 10 (19.2%) for MRP. In addition, 27 samples (27/52, 51.9%) were positive for two markers, while 3 (5.7%) and 5 (9.6%) cases were positive and negative, respectively, for all three markers. No significant correlations were seen for COX-2 and P-gp on Fisher's exact test and Mann-Whitney's test, but a significance was seen on Spearman's rank correlation analysis using the IHC scoring system (P=0.043). These results suggest that P-gp expression is induced by overexpression of COX-2 in canine patients with TCC.
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PMID:Expression of cyclooxygenase-2, P-glycoprotein and multi-drug resistance-associated protein in canine transitional cell carcinoma. 1731 22

In several neoplastic diseases, including hepatocellular carcinoma, the expression of P-glycoprotein and cyclooxygenase-2 (COX-2) are often increased and involved in drug resistance and poor prognosis. P-glycoprotein, in addition to drug resistance, blocks cytochrome c release, preventing apoptosis in tumor cells. Because COX-2 induces P-glycoprotein expression, we evaluated the effect of celecoxib, a specific inhibitor of COX-2 activity, on P-glycoprotein-mediated resistance to apoptosis in cell lines expressing multidrug resistant (MDR) phenotype. Experiments were done using MDR-positive and parental cell lines at basal conditions and after exposure to 10 or 50 micromol/L celecoxib. We found that 10 micromol/L celecoxib reduced P-glycoprotein, Bcl-x(L), and Bcl-2 expression, and induced translocation of Bax from cytosol to mitochondria and cytochrome c release into cytosol in MDR-positive hepatocellular carcinoma cells. This causes the activation of caspase-3 and increases the number of cells going into apoptosis. No effect was shown on parental drug-sensitive or on MDR-positive hepatocellular carcinoma cells after transfection with MDR1 small interfering RNA. Interestingly, although inhibiting COX-2 activity, 50 micromol/L celecoxib weakly increased the expression of COX-2 and P-glycoprotein and did not alter Bcl-x(L) and Bcl-2 expression. In conclusion, these results show that relatively low concentrations of celecoxib induce cell apoptosis in MDR cell lines. This effect is mediated by P-glycoprotein and suggests that the efficacy of celecoxib in the treatment of different types of cancer may depend on celecoxib concentration and P-glycoprotein expression.
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PMID:P-glycoprotein mediates celecoxib-induced apoptosis in multiple drug-resistant cell lines. 1751 Apr 21


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