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)

Malignant melanoma is considered to be a chemotherapy-refractory tumour and the commonly used anticancer drugs do not seem to modify the prognosis of metastatic disease. The cellular resistance mechanisms involved in melanoma chemoresistance have not yet been elucidated. Melanoma-derived cell lines are often markedly chemoresistant. Using the in vitro soft agar culture system to predict tumour cell sensitivity in well-established human melanoma cell lines, a high degree of resistance against all the cytostatic agents studied has been reported, suggesting the presence of intrinsic cellular resistance mechanisms. The relevance of the well-defined resistance mechanisms mediated by P-glycoprotein, multidrug resistance-associated protein (MRP), the glutathione/glutathione S-transferase system and topoisomerase II enzyme are reviewed. Mutated N-Ras oncogene has recently been implicated in melanoma resistance to cisplatin, both in vitro and in vivo, and the role of two other oncogenes, Bcl-2 and p53, which are already involved in the chemoresistance of haematological and solid malignancies, is beginning to be better elucidated. The finding that many chemotherapeutic agents can kill susceptible cells through the apoptosis pathway provides new molecular insight into chemoresistance mechanisms and suggests that apoptosis and/or resistance to apoptosis of melanoma cells should be investigated to better clarify the mechanism of melanoma chemoresistance.
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PMID:The chemoresistance of human malignant melanoma: an update. 1033 34

Glioblastoma is the most invasive form of primary brain tumors, and is often refractory to chemotherapy. Herein, we provide evidence that two highly invasive human glioma cell lines U-87 MG and U-373 MG, entered apoptosis after 48 hours following 24 h growth arrest induced by Doxorubicin (10 micrograms/2 x 10(5) cells/ml). Apoptosis depended solely on the level of intracellular drug accumulation, and it was not related to a functional p53 tumor suppressor factor. The multidrug resistance gene 1 (mdr-1) encoded P-glycoprotein (P-gp) was weakly expressed in these cells upon exposure to Doxorubicin, and exerted no influence on the extent of cellular drug efflux. Drug efflux occurred only in U-373 MG glioma cells subsequent to physical damage of the membrane upon exposure to Doxorubicin. Pretreatment of tumor cells with 10 micrograms/ml Doxorubicin precluded tumor formation on the chorioallantoic membrane (CAM) of embryonated hen eggs. Single-dose application of 0.4 microgram Doxorubicin on CAM/U-87 MG and CAM/U-373 MG tumor transplants inhibited tumor invasion in CAM tissue by 40 to 50%. These data suggest that highly invasive glioblastomas can be driven to apoptosis following growth arrest induced by Doxorubicin, providing that intracellular drug accumulation suffices cytotoxic levels.
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PMID:Doxorubicin-induced cell death in highly invasive human gliomas. 1036 37

Multidrug resistance-associated protein (MRP) is one of the major factors responsible for non-P-glycoprotein (Pgp)-mediated multidrug resistance of human tumour cells. In this study, we examined MRP and aberrant p53 expression in 54 colorectal cancers (CRC), 35 carcinoma in adenomas (CIA) and 40 adenomatous polyps by immunohistochemical procedures. 38 of 54 (70%) CRCs, 16 of 35 (46%) CIAs and 3 of 40 (8%) adenomatous polyps were MRP positive (chi 2 test, P < 0.0001). 36/54 (67%) CRCs, 10/35 (29%) CIAs and 0/40 adenomatous polyps were p53 positive. 30 of the 36 p53-positive CRCs were also MRP positive and 8/10 CIAs were both p53 and MRP positive. MRP overexpression correlated with aberrant p53 accumulation in CRCs and CIAs (chi 2 test, P < = or 0.01). Coexpression of MRP and p53 in the same cells was confirmed in the CRCs and CIAs by double staining procedures. These results suggested that MRP overexpression is related to aberrant p53 expression in CRC.
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PMID:Multidrug resistance-associated protein (MRP) expression is correlated with expression of aberrant p53 protein in colorectal cancer. 1074 Dec 88

This long-term study includes up to 13 years of follow-up on 56 patients who underwent surgical resection of nonsmall cell lung cancers (NSCLC) at the University of Texas Medical Branch. The purpose of this study was to investigate whether p53 and P-glycoprotein expression in the tumor correlates with survival. The study included 35 men and 21 women with mean age at diagnosis of 63.6 years and 58.0 years, respectively. Follow-up ranged from four to 156 months (mean, 52 mo). Actual five-year survival was 50% and 10-year survival was 22%. There were 25 patients who survived more than 60 months. Commercially available antibodies, DO-7 monoclonal antibody to p53 protein, and NCL-PGLyp polyclonal antibody to P-glycoprotein were used. p53 expression was seen in 45%, and P-glycoprotein expression was seen in 61% of the tumors, using standard immunohistochemical techniques. Expression of p53 showed correlation with Caucasian race and a better, although nonsignificant, five-year survival. P-glycoprotein expression showed a highly significant association with squamous cell carcinoma. No association was found between P-glycoprotein expression and survival. A negative association was seen between p53 and P-glycoprotein expression. Using nonparametric analysis, significant correlations were found between female sex and younger age at diagnosis of lung cancer compared with males, adenocarcinoma, and Caucasian race. Using Kaplan-Meier survival tables, significantly better five-year survival was seen with stage I tumors, negative lymph nodes at surgery, Caucasian race, and well-differentiated tumors. Stage I and negative lymph nodes at surgery showed an independent significant association with long-term (>5-yr) survival. This study indicates that p53 and P-glycoprotein may not be useful as immunohistochemical markers for guiding therapy and predicting survival in NSCLC.
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PMID:p53 and P-glycoprotein expression do not correlate with survival in nonsmall cell lung cancer: a long-term study and literature review. 1061 70

Cutaneous malignant melanoma is a life-threatening cancer with poor prognosis due to a high metastasis potential. The main obstacle in treatment of metastatic melanoma is the resistance to chemotherapy. Recent studies indicated that apoptosis is a common mechanism of action for various cytotoxic agents. As p53 plays an important part in apoptosis, we investigated the role of p53 in chemosensitivity of melanoma cells. Previously, we found that melanoma cell lines containing wild-type p53 have significantly higher response rates to chemotherapy than cell lines with a mutant p53 gene. To confirm the role of p53 in melanoma chemosensitivity further, we transfected an expression vector, pED1, which carries a mutant p53 gene, into a wild-type p53 melanoma cell line, MMAN. We examined the effect of mutant p53 on camptothecin-induced apoptosis and the expression of genes which are known to be involved in apoptosis or drug resistance, such as bcl-2, bax, bak, p21waf1, and P-glycoprotein. Our results indicate that overexpression of the mutant p53 increased the growth rate of MMAN cells, reduced the sensitivity to camptothecin, and lowered drug-induced apoptosis by 2-3-fold. Flow cytometry indicated that the camptothecin-induced apoptosis is not associated with G1 arrest. Furthermore, camptothecin treatment reduced bcl-2 and P-glycoprotein expression in wild-type p53 MMAN cells, but not cells overexpressing mutant p53. These results demonstrate that p53 mutational status is a determinant of melanoma chemosensitivity. p53 may downregulate bcl-2 and P-glycoprotein to induce apoptosis in melanoma cells after chemotherapy.
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PMID:p53-dependent apoptosis in melanoma cells after treatment with camptothecin. 1069 11

Multidrug resistance (MDR) is the protection of a tumor cell population against numerous drugs differing in chemical structure and mechanisms of influence on the cells. MDR is one of the major causes of failures of chemotherapy of human malignancies. Recent studies show that the molecular mechanisms of MDR are numerous. Cellular drug resistance is mediated by different mechanisms operating at different steps of the cytotoxic action of the drug from a decrease of drug accumulation in the cell to the abrogation of apoptosis induced by the chemical substance. Often several different mechanisms are switched on in the cells, but usually one major mechanism is operating. The most investigated mechanisms with known clinical significance are: a) activation of transmembrane proteins effluxing different chemical substances from the cells (P-glycoprotein is the most known efflux pump); b) activation of the enzymes of the glutathione detoxification system; c) alterations of the genes and the proteins involved into the control of apoptosis (especially p53 and Bcl-2).
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PMID:Cellular mechanisms of multidrug resistance of tumor cells. 1070 44

To characterize the P-glycoprotein (Pgp) expression in human hepatocellular carcinoma (HCC), we studied 101 cases of HCC treated with surgical resection without prior treatment. Pgp expression was detected immunohistochemically using 2 monoclonal antibodies (C494, C219) and correlated with pathologic features, survival, and p53 expression. Chemotherapy response was analyzed in a separate group of patients with inoperable HCC treated with systemic chemotherapy. Positive immunostaining was seen in 92% and 80% of the tumors with C494 and C219, respectively; bile canalicular type staining was seen in all positive tumors. Pgp expression was less extensive in the tumors than in the corresponding nontumorous liver tissue. Tumor Pgp expression with either antibody had no association with cellular differentiation, aggressive pathologic features, survival, or p53 overexpression. In patients with inoperable HCC, the chemotherapy response was significantly inversely related to Pgp expression with C494 and C219. Pgp was expressed in human HCC but was patchy and less extensive than in the nontumorous tissue. Response to systemic chemotherapy was inversely related to the level of Pgp expression in patients with inoperable tumors. Pgp expression in tumors not treated with chemotherapy was not associated with a more aggressive tumor phenotype or p53 overexpression and did not influence survival.
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PMID:Expression of P-glycoprotein in hepatocellular carcinoma. A determinant of chemotherapy response. 1070 15

The development of biological markers of response to chemo- and radiotherapy to judge benefit to risk ratios for toxic treatments is still at an experimental stage. Tumour cell death is largely by apoptosis and the p53 gene has a major influence on this. P-glycoprotein (P-gp) accumulation has been correlated with treatment failure in several types of cancer. p53 and P-gp expression were studied in 111 advanced head and neck cancers treated with radiotherapy and up to four courses of synchronous or sequential chemotherapy. The probability of survival at 5 years for patients in the trial as a whole was 27.7%, while the cohort used for this marker project was 29.4%. Among the subjects used for the marker study at the time of analysis, 13 remained disease-free and 18 were alive. Immunohistochemistry was used to assess p53 and P-gp expression; 27/111 (24%) head and neck cancers demonstrated p53/P-gp expression and 33/111 (30%) were both p53- and P-gp- negative. In univariate analysis, both p53 and P-gp expression were associated with reduced disease-free and overall survival. Multivariate analysis revealed tumour size, p53, and P-gp expression as the most powerful pretreatment prognosticators in the study cohort. Long-term follow-up results suggest that p53 and P-gp co-expression predicts the biological behaviour or the outcome following chemo/radiotherapy in advanced head and neck cancer.
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PMID:p53 and P-glycoprotein expression are significant prognostic markers in advanced head and neck cancer treated with chemo/radiotherapy. 1076 16

The major limitation of treatment with antimetabolite drugs is that they produce resistant clones both in vitro and in patients who either do not respond to treatment or relapse soon after response has been documented. To better understand the phenomenon of cross-resistance, we developed seven CEM/ara-C-resistant leukemic clones from the CEM/0 (wt) cell line. These clones ranged from 4- to 3.5 x 10(8)-fold more resistant to ara-C than the wt CEM/0 cell line. Using this model, we determined IC50 concentrations to several chemotherapeutic agents and gamma radiation, and we also studied pro- (p53) and anti-apoptotic (bcl-2) proteins, as well as P-glycoprotein (P-gp) and multidrug resistance related protein (MRP). The cell viability assays showed that these clones were cross-resistant to 6-thioguanine (6-TG) or 6-mercaptoguanosine (6-TGuo) from 1.1- to 8.8-fold with ara-C; cross-resistance to vincristine (VCR) was from 200- to 1 x 10(4)-fold with ara-C. Taxotere (TXR) showed cross-resistance with ara-C from 1.39- to 3.03 x 10(3)-fold; dexamethasone (DEX) also showed a significant degree of cross-resistance from 27.4- to 3.87 x 10(7)-fold. Gamma radiation treatments from 0.77 Gy to 12.3 Gy showed a radiation dose-dependent cross-resistance with ara-C from 1.43- to 2.93-fold. Idarubicin was collaterally sensitive with ara-C from 4.6- to 1 x 10(9)-fold in these cell lines. The CEM/ara-C/G resistant cell line was 3-fold more sensitive to 6-TG or VCR than CEM/0 (wt), and 5-fold more sensitive to 6-TGuo. This cell clone expressed p53 and did not overexpress bcl-2 protein. All of the cell lines studied, CEM/0 (wt) and the ara-C resistant clones, showed functional p53 protein. The cell treatment with 0.1, 1 and 10 microM ara-C for 48 hours showed increased p53 protein expression in most of these lines. No increase in bcl-2 protein expression was seen in the wt cell line after ara-C treatment for 48 hours. Three cell lines resistant to ara-C (CEM/ara-C/B, CEM/ara-C/D and CEM/ara-C/I) showed an important increased expression of bcl-2 protein after treatment with 1 microM ara-C, but not after 10 microM. This alteration may lead to resistance to apoptosis and enhanced cell survival. The ratio of bcl-2 to p53 was increased significantly in these three clones, thus favoring an anti-apoptotic drive. All of the cell lines examined were negative for MRP expression and only two, CEM/ara-C/B and CEM/ara-C/J, were positive for MRP functional activity. However, three ara-C resistant cell clones, CEM/ara-C/7A, CEM/ara-C/B and CEM/ara-C/G, were positive for P-gp expression and functional activity. It is apparent that selection for ara-C resistance confers cross-resistance to many other classes of drugs and gamma radiation, probably due to bcl-2 protein overexpression or P-gp and MRP expression, as independent mechanisms.
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PMID:Cytosine arabinoside (ara-C) resistance confers cross-resistance or collateral sensitivity to other classes of anti-leukemic drugs. 1076 46

Paclitaxel (Taxol) kills tumor cells by inducing both cellular necrosis and apoptosis. A major impediment to paclitaxel cytotoxicity is the establishment of multidrug resistance whereby exposure to one chemotherapeutic agent results in cross-resistance to a wide variety of other drugs. For example, selection of MCF-7 breast cancer cells for resistance to doxorubicin (MCF-7ADR cells) results in cross-resistance to paclitaxel. This appears to involve the overexpression of the drug transporter P-glycoprotein which can efflux both drugs from tumor cells. However, MCF-7ADR cells possess a deletion mutation in p53 and have considerably reduced levels of the Fas receptor, Fas ligand, caspase-2, caspase-6, and caspase-8, suggesting that paclitaxel resistance may also stem from a bona fide block in paclitaxel-induced apoptosis in these cells. To address this issue, we examined the ability of the P-glycoprotein inhibitor valspodar to restore paclitaxel accumulation, paclitaxel cytotoxicity, and paclitaxel-induced apoptosis. Compared to drug sensitive MCF-7 cells, MCF-7ADR cells accumulated >6-fold less paclitaxel, were approximately 100-fold more resistant to killing by the drug, and were highly resistant to paclitaxel-induced apoptosis. In contrast, MCF-7ADR cells pretreated with valspodar were indistinguishable from drug-sensitive cells in their ability to accumulate paclitaxel, in their chemosensitivity to the drug, and in their ability to undergo paclitaxel-induced apoptosis. Valspodar, by itself, did not affect these parameters. This suggests that the enhancement of paclitaxel toxicity in MCF-7ADR cells involves a restoration of apoptosis and not solely through enhanced drug-induced necrosis. Morever, it appears that changes in the levels/activity of p53, the Fas receptor, Fas ligand, caspase-2, caspase-6, or caspase-8 activity have little effect on paclitaxel-induced cytotoxicity and apoptosis in human breast cancer cells.
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PMID:Role of specific apoptotic pathways in the restoration of paclitaxel-induced apoptosis by valspodar in doxorubicin-resistant MCF-7 breast cancer cells. 1083 93


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