Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Doxorubicin- (OAW-dox, SK-OV-dox), taxol- (OAW-tax, SK-OV-tax) and cisplatin- (SK-OV-cis) resistant cells derived from the parental OAW-42 and SK-OV-3 cell lines were established. OAW-42 sublines showed high resistance, the SK-OV-3 sublines only low resistance. OAW-42 sublines showed a cross-resistance profile typical of multidrug resistance (MDR). The sublines of SK-OV-3 showed a cross-resistance profile different from the OAW-42 sublines. The mRNA expression of several resistance proteins and related factors was analyzed. An overexpression of P-glycoprotein 170 (P-170), glutathione-S-transferase-pi (GST-pi), thymidylate synthase (TS), glutathione peroxidase (GP) and c-jun was found in OAW-dox and OAW-tax cells. Additionally, OAW-tax cells expressed a higher mRNA level of protein kinase Cbeta2. DNA analysis revealed a 2-fold gene amplification of P-170, whereas the genes for GST-pi, TS and GP were not amplified. SK-OV-dox and SK-OV-tax cells showed a decreased level of histone 3 (H3) and TS mRNA. This shows that the sublines of OAW-42 developed resistance by co-expression of several resistance-related proteins and proto-oncogenes whereas the sublines of SK-OV-3 expressed resistance by decreased expression of the proliferation-dependent proteins H3 and TS.
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PMID:Messenger RNA expression of resistance proteins and related factors in human ovarian carcinoma cell lines resistant to doxorubicin, taxol and cisplatin. 907 15

Chemotherapy for adult T-cell leukemia (ATL) has been reported to fail to induce complete remission because of drug resistance in most patients. We have examined the expression of an ATL-derived factor (ADF)/thioredoxin in relation to resistance to adriamycin (ADM) in various T-cell leukemia cell lines including ATL cell lines. Immunoblot analysis demonstrated that ATL cell lines expressed ADF/thioredoxin at levels 2.8 to 12 times those of other T-cell acute lymphocytic leukemia (T-ALL) cell lines, and that ATL cell lines were 2 to 15 times more resistant to ADM than other T-ALL cell lines. Therefore, we established ADM-resistant cell lines from three different ATL cell lines, and examined the correlation between ADM resistance and expression of ADF/thioredoxin. ADM-resistant ATL cell lines were also found to be resistant to other drugs such as cisplatin and etoposide, and they expressed ADF/thioredoxin at levels 5 to 10 times those of parent ATL cell lines. Diamide and sodium selenite, which have been reported to inhibit ADF/thioredoxin, restored the sensitivity to ADM in ATL and ADM-resistant ATL cell lines. The MDR-1 gene product, a membrane P-glycoprotein (Pgp), was not expressed on ATL cell lines or ADM-resistant ATL cell lines. Topoisomerase II and glutathione peroxidase activities in T-cell leukemia cell lines were not correlated with ADM resistance. These results suggest that ADF/thioredoxin may play an important role in the drug resistance of ATL cells to ADM.
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PMID:Possible roles of an adult T-cell leukemia (ATL)-derived factor/thioredoxin in the drug resistance of ATL to adriamycin. 911 92

Resistance of tumor cells to chemotherapeutic drugs can not only be caused by treatment with antineoplastic agents but also by radiotherapy. The aim of this study was to analyze whether ionizing radiation can influence the mRNA expression of proteins which have been found to be involved in drug resistance of tumor cells. Human tumor cell lines (MCF-7, LXF and Sk-Mel) were treated with single doses of irradiation (5, 10 and 20 Gy). The expression of the resistance related proteins glutathione S-transferase-pi (GST-pi), topoisomerase II alpha (Topo II), thymidylate synthase (TS), O6-methylguanine-DNA-methyltransferase (MGMT), P-glycoprotein (Pgp), glutathione peroxidase (GPX) multidrug resistance-associated protein (MRP) and also of the heat-shock protein 70 (HSP 70) were determined at the mRNA level during the time interval from 1.5 to 72 h post-irradiation and compared with their corresponding controls. We also examined whether a relationship exists between these proteins and the proliferative activity (histone 3, Ki-67, statin) of the cells. We found that exposure of MCF-7, LXF and Sk-Mel cells to ionizing radiation increases the expression of the mRNA of GST-pi. Topo II, TS, HSP 70 and proliferation markers were also altered by exposure to ionizing radiation, but there was no common response of the three cell lines. No significant changes were observed in the expression of MGMT, Pgp, GPX and MRP after radiation treatment. Drug resistance tests revealed that irradiated MCF 7 cells were less sensitive to doxorubicin than non-irradiated control cells. Our results indicate that ionizing irradiation modifies the expression of some proteins involved in drug resistance and the response of MCF 7 cells to doxorubicin and may, therefore, play a role in clinical drug response.
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PMID:Messenger RNA expression of resistance factors in human tumor cell lines after single exposure to radiation. 941 87

The anthracycline doxorubicin has little activity against colorectal cancers. It is hypothesized that this is attributable to a multifactorial resistance mechanism in which the glutathione S-transferases (GST) may play a role. We studied the relationship between GST expression and doxorubicin resistance in four human colon adenocarcinoma cell lines (HT-29, LoVo, SW620, and Caco-2), with the goal of modulating GST activity to overcome resistance. Caco-2 cells were the most resistant to doxorubicin, showing an IC50 value approximately 80- to 90-fold higher than HT-29 or LoVo and 600-fold higher than SW620. Total GST catalytic activity was significantly higher in Caco-2 cells compared with the other lines. All four cell lines expressed GST-pi at the catalytic activity, protein, and mRNA levels; however, no significant differences were observed among the cell lines. GST-mu expression was not detectable at the protein and mRNA levels, and the four cell lines displayed very low catalytic activity toward a GST-mu-selective substrate. Caco-2 cells showed a unique, highly expressed GST-alpha-immunoreactive band that was not detected in the other lines; however, the glutathione peroxidase activity of Caco-2 cells was the lowest among the four cell lines. Neither ethacrynic acid nor glutathione analogues that function as GST class-selective inhibitors were able to potentiate the cytotoxic effects of doxorubicin in these colon cancer cell lines, as demonstrated in both microplate colorimetric and clonogenic assays. The multidrug resistance-associated protein and P-glycoprotein were either not detectable or expressed at such low levels that they are not likely to contribute to the differences in doxorubicin sensitivity observed among these cell lines.
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PMID:Role of glutathione S-transferases in the resistance of human colon cancer cell lines to doxorubicin. 950 Apr 55

It has been reported that several cis-unsaturated fatty acids (c-UFAs) could increase doxorubicin (DOX) accumulation in cancer cells and hence elevate its cytotoxicity. However, some researchers showed that c-UFA pretreatment did not affect its cytotoxicity in special cell lines. It is possible that the different results occurred due to different cellular characteristics. We hypothesized that c-UFA treatment might modulate the activities of some antioxidant enzymes to affect the resistance of cells to DOX. In the present study, we examined how c-UFA pretreatment affected DOX cytotoxicity on mouse leukemia cell line, P388, and its resistant subline, P388/DOX, which we found to have significantly higher glutathione peroxidase (GPx) activity as well as P-glycoprotein (p-gp) overexpression. We chose two c-UFAs, gamma-linolenic acid (GLA) (18:3n-6) and docosahexaenoic acid (DHA) (22:6n-3). Cytotoxicity was measured by MTT (3-(4.5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and trypan blue exclusion assays. DOX accumulation and p-gp expression were measured by flow cytometry. The activities of catalase (CAT), superoxide dismutase (SOD), glutathione S-transferase (GST), and GPx were determined for both cell lines with and without treatment with GLA or DHA. Significant DOX accumulation occurred in both cell lines with GLA or DHA pretreatment, but without any change in p-gp expression in either cell line. Sensitivity to DOX cytotoxicity was improved by GLA or DHA pretreatment in P388/DOX in which only SOD activity was significantly increased, but not in the parental cell line P388 in which both SOD and CAT were significantly increased by the pretreatment. However, combined pretreatment of GLA or DHA with antioxidants, pyrrolidinedithiocarbamate (PDTC) or Vitamin C, could sensitize not only P388/DOX but also P388 cells to DOX. We conclude that the effects of c-UFA pretreatment on the sensitivity of cancer cells to DOX not only depend on the change in drug accumulation but also the change in the levels of antioxidant enzyme activities, and suggest that combined administration of c-UFAs, antioxidants, and DOX may be more effective in treating leukemia.
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PMID:Effects of cis-unsaturated fatty acids on doxorubicin sensitivity in P388/DOX resistant and P388 parental cell lines. 1095 54

A major obstacle to successful cancer chemotherapy is the development of multidrug resistance (MDR). The previous study revealed that a doxorubicin-resistant AML subline (AML-2/DX100) overexpressed an MDR-associated protein (MRP) but not P-glycoprotein. The AML-2/DX100 also showed various levels of resistance to daunorubicin and vincristine but was paradoxically sensitive to hydrogen peroxide (5-fold), t-butyl hydroperoxide (3-fold), and paraquat (2-fold) when compared to the drug-sensitive parental AML-2 cells (AML-2/WT). We compared the activities of antioxidant enzymes to detoxify reactive oxygen species (ROS), including superoxide dismutases, glutathione S-transferase, catalase, glutathione reductase, glutathione peroxidase, and glucose-6-phosphate dehydrogenase in both AML-2/WT and AML-2/DX100. Interestingly, of these antioxidant enzymes, catalase activity of AML-2/DX100 decreased significantly to about one-third that of AML-2/WT (P < 0.000005). The decreased activity of catalase was due to reduced expression of the catalase gene; confirmed by Western blot and reverse transcription-polymerase chain reaction (RT-PCR) analyses. The decreased activity of catalase was maintained even in the absence of doxorubicin for 3 months as well as by the treatment of probenecid, an MRP inhibitor. In addition, there was no difference in catalase activity between HL-60 and another MRP-overexpressing subline HL-60/Adr. Taken together, the paradoxical increase in the sensitivity of an MRP-overexpressing AML-2/DX100 in response to peroxides and paraquat is due to the down-regulation of catalase gene expression, which totally independent of overexpression of MRP. It is therefore possible that decreased catalase activity could be exploited as an Achilles' heel in resistant cells such as this.
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PMID:Down-regulation of catalase gene expression in the doxorubicin-resistant AML subline AML-2/DX100. 1117 67

The confluence-dependent resistance of human larynx carcinoma HEp-2 cells to hydrogen peroxide and a new antitumor drug based on the combination of vitamins C and B12b was studied. It was found that this resistance in growing cells is suppressed by the disruption of intercellular contacts by EGTA and is related neither to the activity of P-glycoprotein nor to the content of intracellular glutathione and the activities of glutathione S-transferases, glutathione peroxidase and glutathionine reductase. Here we showed that the level of expression of the small heat shock protein hsp27, which is known to protect cells from a variety of stresses associated with apoptosis, in growing confluent cells both in the presence and absence of the vitamins B12b and C is much higher (about 20-25 times) than in non-confluent cells. Taken together, the results suggest that the confluence-dependent resistance of cells to the combination of vitamins C and B12b and to hydrogen peroxide is mediated by hsp27 overexpression, which is activated via cell-cell adhesion.
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PMID:Small heat shock protein hsp27 as a possible mediator of intercellular adhesion-induced drug resistance in human larynx carcinoma HEp-2 cells. 1474 39

Cepharanthin (CEP) is a biscoclaurine alkaloid extracted from Stephania cepharantha Hayata. CEP is reported to inhibit drug resistance by inhibiting P-glycoprotein, a drug efflux pump, and recently to induce apoptosis. In the present study, we examined the effects of CEP as an inhibitor of adriamycin (ADR) resistance on ADR-induced apoptosis and necrosis. First, we established p53-deficient ADR-resistant osteosarcoma cell lines, SaOS2-AR and SaOS2 F-AR. Resistant cells showed a higher level of intracellular glutathione peroxidase activity than parent cells. P-glycoprotein was overexpressed in resistant cells. The intracellular ADR level of resistant cells was lower than that of parent cells. One micro g/ml CEP eliminated the degradation of intracellular ADR of resistant cells; that is, to a level equivalent to that of the parent cells. CEP of 0.5 micro g/ml, which was not cytotoxic when used alone, significantly increased the ADR sensitivity of resistant cells, to a level similar to the parent cell level. Isosorbide 5-mononitrate, a potential nitric oxide-generation agent, combined with CEP further increased the ADR sensitivity of resistant cells, indicating a synergistic effect of CEP and isosorbide 5-mononitrate on ADR cytotoxicity. Time-lapse microscopic observation revealed that ADR dominantly induced apoptosis much more than necrosis for both parent and resistant cells, and that the use of 0.5 micro g/ml CEP with ADR synergistically accelerated apoptosis in resistant cells. Finally, we clarified the property by which CEP synergistically accelerates ADR-induced apoptosis. This property might be a new mechanism that explains how CEP overcomes ADR resistance.
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PMID:Cepharanthin enhances adriamycin sensitivity by synergistically accelerating apoptosis for adriamycin-resistant osteosarcoma cell lines, SaOS2-AR and SaOS2 F-AR. 1520 88

Accumulating evidence suggests the concept that epirubicin and lymphokine-activated killer (LAK) cells cytotoxicity may be mediated by free radicals generation and P-glycoprotein-positive (Pg-p+) cancer cells are more sensitive for LAK cells than their drug-sensitive parental lines. We tested this hypothesis further by exposing drug-sensitive (WT) and epirubicin-resistant MCF-7 human breast tumor cells to epirubicin and LAK cells. Subsequently, we monitored cell proliferation as a measure of cytotoxicity. The cytotoxicity of epirubicin, LAK, and LAK + epirubicin (1/10 of IC50) was evaluated in 400-fold epirubicin resistant MCF-7 EPI(R) (P-glycoprotein overexpressing) and drug-sensitive MCF-7 WT cells. IC50 values were measured using the MTT cytotoxicity test. The MCF-7 EPI(R) cells exhibited an increased susceptibility to LAK cells than did the MCF-7 WT cells. P-gp+ MCF-7 EPI(R) cells were lysed by human LAK cells to a greater extend than were their drug-sensitive counterparts. LAK + epirubicin combined treatment increased susceptibility of MCF-7 WT and MCF-7 EPI(R) cells to LAK cells cytotoxicity. For both cell lines, cytotoxicity was dependent upon the concentration of the epirubicin and effector cell/target cell (E/T) ratio. The resistance of MCF-7 EPI(R) cells to epirubicin appears to be associated with a developed tolerance to superoxide, most likely because of a tree-fold increase in superoxide dismutase (SOD) activity and 13-fold augmented selenium dependent glutathione peroxidase (GSH-Px) activity. Acting in concert, these two enzymes would decrease the formation of hydroxyl radical from reduced molecular oxygen intermediates. The addition of SOD decreased cytotoxicity of epirubicin and LAK cells. Taken together, these observations support the role of oxygen radicals in the cytotoxicity mechanism of epirubicin and suggest further that the development of resistance to this drug by the MCF-7 EPI(R) tumor cells may have a component linked to oxygen free radicals. It is proposed that production of reactive oxygen species by the treatment of epirubicin and LAK cells can cause cytotoxicity of MCF-7 WT and MCF-7 EPI(R) cells. SOD, catalase, GSH-Px, GST (glutathione S-transferase), and GSH (reduced glutathione) must be considered as part of the intracellular antioxidant defense mechanism of MCF-7 WT and MCF-7 EPI(R) cells against reactive oxygen species.
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PMID:Combined effect of epirubicin and lymphokine-activated killer cells on the resistant human breast cancer cells. 1568 29

Zinc, at low levels, has several basic housekeeping functions in metalloenzymes, transcription factors, immunoregulation, growth, and cytoprotection, displaying antioxidant, anti-apoptotic, and anti-inflammatory roles. At high levels, however, the metal can be highly toxic. The aim of this work is to investigate the toxic effect of zinc on antioxidant status and stress proteins in the gills of the brown mussel Perna perna exposed for 48 h to zinc chloride (zinc) at 10, 30 and 100 microM. Glutathione reductase (GR) activity was drastically reduced at 30 and 100 microM zinc. At the lower levels, i.e. 10 microM zinc, antioxidant defenses were up-regulated, as were glutathione levels and the activities of glutathione peroxidase and catalase, in spite of the absence of effect on glutathione S-transferase and glucose 6-phosphate dehydrogenase activity. At the higher tested concentration of 100 microM zinc, oxidative stress was apparent as reflected by the increased lipid peroxidation end products and decreased protein thiol and glutathione levels, associated with an inability to up regulate antioxidant defenses. Using 30 microM zinc, higher gill rhodamine B efflux was observed, indicating an activation of multixenobiotic resistance (MXR) activity, which is reinforced by increased immunoreactive P-glycoprotein detection. Zinc also increased the HSP60-immunoreactive protein, whereas the HSP70-immunoreactive protein remained unchanged. Overall, the results indicate that zinc toxicity -- at higher levels -- may be connected to a strong inhibition of GR activity, and related to the pro-oxidative state found. Mussels showed an adaptive-like response to 10 microM zinc by increasing antioxidant defenses. Increased P-glycoprotein and HSP60 expression, and rhodamine B efflux were also remarkable features in the gill response to zinc.
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PMID:Antioxidant status and stress proteins in the gills of the brown mussel Perna perna exposed to zinc. 1656 39


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