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)

Defect in apoptotic signaling and up-regulation of drug transporters in cancer cells significantly limits the effectiveness of cancer chemotherapy. We propose that an agent inducing non-apoptotic cell death may overcome cancer drug resistance and showed that shikonin, a naturally occurring naphthoquinone, induced a cell death in MCF-7 and HEK293 distinct from apoptosis and characterized with (a) a morphology of necrotic cell death; (b) loss of plasma membrane integrity; (c) loss of mitochondrial membrane potentials; (d) activation of autophagy as a downstream consequence of cell death, but not a contributing factor; (e) elevation of reactive oxygen species with no critical roles contributing to cell death; and (f) that the cell death was prevented by a small molecule, necrostatin-1, that specifically prevents cells from necroptosis. The characteristics fully comply with those of necroptosis, a basic cell-death pathway recently identified by Degterev et al. with potential relevance to human pathology. Furthermore, we proved that shikonin showed a similar potency toward drug-sensitive cancer cell lines (MCF-7 and HEK293) and their drug-resistant lines overexpressing P-glycoprotein, Bcl-2, or Bcl-x(L), which account for most of the clinical cancer drug resistance. To our best knowledge, this is the first report to document the induction of necroptosis by a small molecular compound to circumvent cancer drug resistance.
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PMID:Shikonin circumvents cancer drug resistance by induction of a necroptotic death. 1751 12

Our previous study identified a vincristine-selected multidrug resistance (MDR) cell line, HOB1/VCR, derived from a lymphoblastoma HOB1. The HOB1/VCR cells are resistant to typical MDR drugs and are cross-resistant to P-glycoprotein-independent drugs such as cisplatin (cis-diamminedichloroplatinum [II]). The mechanism of this atypical MDR phenotype is uncertain. The present study provides evidence regarding the contribution of reactive oxygen species (ROS) to the resistance of cells in response to treatments (vincristine, cisplatin and H2O2). Notably, the HOB1/VCR cells were cross-resistant to H2O2. High levels of ROS formed in both sensitive and HOB1/VCR cells by H2O2, and moderate levels of ROS were generated by treatment with cisplatin and vincristine. The ROS level in HOB1/VCR cells was lower than that in sensitive cells following treatments. The ROS level was reduced markedly by a non-toxic concentration of N-acetyl-L-cysteine, a ROS scavenger, in drug-treated cells, and was correlated with reduced cytotoxicity. Furthermore, concentrations of glutathione and glutathione peroxidase, but not superoxide dismutase and catalase, increased in HOB/VCR cells. The DL-buthionine-[S,R]-sulfoximine inhibited formation of glutathione and sensitized both cell types to treatments. Therefore, overexpression of an H2O2-reducing system, glutathione-glutathione peroxidase, has a role in resistance. Experimental results further demonstrate that ROS is likely a primary signal in the acquisition of the MDR phenotype and therefore a potential target when designing drugs for chemoresistance.
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PMID:Involvement of reactive oxygen species in multidrug resistance of a vincristine-selected lymphoblastoma. 1751 54

The purpose of the study was to assess the suitability of the mouse endothelial cell line bEnd5 as a blood-brain barrier (BBB) model under normal or pathologic (stroke) conditions. In comparison to the well-established bovine brain endothelial cell (BBMEC) model, cultured bEnd5 monolayers reached a maximal transendothelial electrical resistance (TEER) of 121 Omega cm(2) on day 7, and possessed oval and spindle shape morphology. Structurally, confluent monolayers of bEnd5 cells and BBMECs exhibit peripheral band staining of the tight junction protein ZO-1 and occludin. Both bEnd5 and BBMECs express important tight junctional proteins, ZO-1, occludin and claudin-1, as well as the transporters P-glycoprotein (P-gp), NKCC, GLUT1, and most PKC isoforms. Marker permeability experiments suggest that bEnd5 cells form a tight barrier that compares to well-established in vitro BBB models, such as the BBMEC. After short durations of hypoxia/aglycemia (H/A), hyperpermeability was seen in the bEnd5 endothelial monolayer compared to later time periods for BBMECs, suggesting that bEnd5 cells are more sensitive to hypoxia/algycemia treatment than BBMECs. Taken together, bEnd5 cell culture model may provide a useful in vitro model of the BBB for drug delivery studies and modeling pathological states such as oxygen glucose deprivation associated with stroke.
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PMID:Evaluation of bEnd5 cell line as an in vitro model for the blood-brain barrier under normal and hypoxic/aglycemic conditions. 1782 43

Overexpression of the multidrug resistance 1 (MDR1) gene, encoding P-glycoprotein (P-gp), facilitates resistance to diverse chemotherapeutic drugs and current P-gp inhibitors display high toxicity. We studied the effects of melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24), which exhibits cancer-specific apoptosis-inducing properties, in drug-sensitive (SW620) and drug-resistant (SW620/Dox) colorectal carcinoma cells. Adenovirus administered mda-7/IL-24, Ad.mda-7, effectively reversed resistance to doxorubicin-induced apoptosis in SW620/Dox cells by increased intracellular accumulation and decreased efflux of doxorubicin. Unexpectedly, P-gp-overexpressing cells (SW620/Dox) displayed increased apoptosis following Ad.mda-7 infection compared with parental SW620 cells, which correlated with more MDA-7/IL-24 protein in SW620/Dox than SW620 cell and potentially explains the increased sensitivity of P-gp-overexpressing cells to mda-7/IL-24. Transient overexpression of MDR1 in SW620 cells significantly increased apoptosis, decreased anchorage-independent growth, and increased MDA-7/IL-24 protein following Ad.mda-7 infection, whereas down-modulation of MDR1 in SW620/Dox cells by small interfering RNA decreased apoptosis following Ad.mda-7 infection. The increased mda-7/IL-24 sensitivity observed in SW620/Dox cells was partly due to increased reactive oxygen species generation and lower mitochondrial membrane potential. These findings confirm that mda-7/IL-24 is a potent MDR reversal agent, preferentially causing apoptosis in P-gp-overexpressing MDR cells, suggesting significant expanded clinical implications for the use of mda-7/IL-24 in treating neoplasms that have failed chemotherapy mediated by the P-gp MDR mechanism.
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PMID:Melanoma differentiation associated gene-7/interleukin-24 reverses multidrug resistance in human colorectal cancer cells. 1802 83

Salvicine, a novel diterpenoid quinone compound, displays potent antitumor activities in vitro and in vivo, which is under Phase II clinical trials for cancer therapy. Our previous studies have shown that salvicine effectively kills multidrug-resistant (MDR) cells and downregulates mdr-1 and P-glycoprotein (P-gp) levels by activation of transcription factor c-Jun in MDR K562/A02 cells. Recent studies have further demonstrated that salvicine-formed reactive oxygen species (ROS) contribute to its induction of cytotoxicity, DNA double strand breaks and apoptosis. In this study, we showed that salvicine induced equal ROS generation and glutathione depletion in both sensitive K562 and MDR K562/A02 cells. Pre-incubation with thiol antioxidants glutathione or N-acetyl-cysteine (NAC, precursor of intracellular glutathione) almost abolished the cytotoxicity of salvicine, which also could be attenuated by the H(2)O(2)-specific scavenger catalase. Moreover, NAC abrogated salvicine-induced DNA double strand breaks and apoptosis. Notably, both H(2)O(2) and vitamin C potentiated the cytotoxicity and apoptotic induction of salvicine in parental K562 and MDR K562/A02 cells, and catalase could remove such potentiation. Furthermore, pretreatment of K562/A02 cells with NAC eliminated P-gp downregulation, JNK phosphorylation and c-Jun activation induced by salvicine. Our data collectively indicate that salvicine-generated ROS contribute to both cell killing and P-gp downregulation in MDR K562/A02 cells, thus extending our prior related studies. This study also opens the possibility of the combination therapy of salvicine and vitamin C in the future.
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PMID:Reactive oxygen species contribute to cell killing and P-glycoprotein downregulation by salvicine in multidrug resistant K562/A02 cells. 1803 28

Camptothecin (CPT) analogues are powerful anticancer agents but are chemically unstable due to their alpha-hydroxylactone six-membered E-ring structure, which is essential for trapping topoisomerase I (Top1)-DNA cleavage complexes. To stabilize the E-ring, CPT keto analogues with a five-membered E-ring lacking the oxygen of the lactone ring (S38809 and S39625) have been synthesized. S39625 has been selected for advanced preclinical development based on its promising activity in tumor models. Here, we show that both keto analogues are active against purified Top1 and selective against Top1 in yeast and human cancer cells. The keto analogues show improved cytotoxicity toward colon, breast, and prostate cancer cells and leukemia cells compared with CPT. The drug-induced Top1-DNA cleavage complexes induced by the keto analogues show remarkable persistence both with purified Top1 and in cells following 1-h drug treatments. Moreover, we find that S39625 is not a substrate for either the ABCB1 (multidrug resistance-1/P-glycoprotein) or ABCG2 (mitoxantrone resistance/breast cancer resistance protein) drug efflux transporters, which sets S39625 apart from the clinically used CPT analogues topotecan or SN-38 (active metabolite of irinotecan). Finally, we show that nanomolar concentrations of S38809 or S39625 induce intense and persistent histone gamma-H2AX. The chemical stability of the keto analogues and the ability of S39625 to produce high levels of persistent Top1-DNA cleavage complex and its potent antiproliferative activity against human cancer cell lines make S39625 a promising new anticancer drug candidate. Histone gamma-H2AX could be used as a biomarker for the upcoming clinical trials of S39625.
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PMID:Novel E-ring camptothecin keto analogues (S38809 and S39625) are stable, potent, and selective topoisomerase I inhibitors without being substrates of drug efflux transporters. 1808 16

Cells lacking mitochondrial genome (defined as rho(0)) are useful models in studies on cancer, aging, mitochondrial diseases and apoptosis, but several of their functional aspects have been poorly characterized. Using different clones of rho(0) cells derived from the human osteosarcoma line 143B, we have tested the effects of different apoptogenic molecules such as staurosporine (STS), doxorubicin, daunomycin and quercetin, and have analyzed apoptosis, mitochondrial membrane potential (MMP), levels of oxygen free radicals, reduced glutathione (GSH) content, and expression of P-glycoprotein (P-gp). When compared to parental cells, rho(0) cells resulted much less sensitive to apoptosis. MMP was well maintained in rho(0) cells, and remained unchanged after adding apoptogenic agents, and did not change after treatment with molecules able to depolarize mitochondria such as valinomycin. After adding STS, the production of reactive oxygen species was similar in both cell types, but rho(0) cells maintained higher levels of GSH. In rho(0) cells, P-gp was strongly over-expressed both at mRNA and protein level, and its functionality was higher. The resistance to apoptosis of rho(0) cells could be not only due to an increased scavenger capacity of GSH, but also due to a selection of multidrug resistant cells that hyperexpress P-gp.
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PMID:Resistance of mtDNA-depleted cells to apoptosis. 1830 87

Human malignant mesothelioma (HMM), which is strongly related to asbestos exposure, exhibits high resistance to many anticancer drugs. Asbestos fibre deposition in the lung may cause hypoxia and iron chelation at the fibre surface. Hypoxia-inducible factor (HIF)-1alpha, which is upregulated by a decreased availability of oxygen and iron, controls the expression of membrane transporters, such as P-glycoprotein (Pgp), which actively extrude the anticancer drugs. The present study aimed to assess whether asbestos may play a role in the induction of doxorubicin resistance in HMM cells through the activation of HIF-1alpha and an increased expression of Pgp. After 24-h incubation with crocidolite asbestos or with the iron chelator dexrazoxane, or under hypoxia, HMM cells were tested for HIF-1alpha activation, Pgp expression, accumulation of doxorubicin and sensitivity to its toxic effect. Crocidolite, dexrazoxane and hypoxia caused HIF-1alpha activation, Pgp overexpression and increased resistance to doxorubicin accumulation and toxicity. These effects were prevented by the co-incubation with the cell-permeating iron salt ferric nitrilotriacetate, which caused an increase of intracellular iron bioavailability, measured as increased activity of the iron regulatory protein-1. Crocidolite, dexrazoxane and hypoxia induce doxorubicin resistance in human malignant mesothelioma cells by increasing hypoxia-inducible factor-1alpha activity, through an iron-sensitive mechanism.
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PMID:Asbestos induces doxorubicin resistance in MM98 mesothelioma cells via HIF-1alpha. 1838 76

Heavy metal pollution is a worldwide problem, and cadmium (Cd) is one of the most noxious pollutants in aquatic environments. We studied P-glycoprotein (P-gp) expression and function in control and Cd exposed (50microgL(-1) Cd, 30-40 days) oysters Crassostrea virginica as a possible mechanism of cell protection against Cd. Our data show that P-gp is expressed on cell membrane and in mitochondria of oyster gills and hepatopancreas. Inhibitor studies with verapamil, cyclosporine A and JS-2190 suggest that in the gills, mitochondrial P-gp pumps substrates from cytosol into the mitochondria, while cell membrane P-gp pumps substrates from cytosol out of the cell. Cd exposure resulted in a 2-2.5-fold increase in P-gp protein expression in cell membranes and a 3.5-7-fold increase in transport activity measured as the inhibitor-sensitive rhodamine B extrusion rate. In contrast, p-gp mRNA levels were similar in control and Cd-exposed oysters. No difference in P-gp protein expression was observed between mitochondria of control and Cd-exposed oysters but the apparent transport activity was higher in mitochondria from Cd-exposed oysters. Overall, a stronger increase in substrate transport activity in Cd-exposed oysters compared to a relatively weaker change in P-gp protein levels suggests that P-gp activity is post-translationally regulated. Our data show that direct determination of P-gp transport activity may be the best measure of the xenobiotic-resistant phenotype, whereas p-gp mRNA levels are not a good marker due to the likely involvement of multiple post-transcriptional regulatory steps. Cd exposure resulted in a significantly elevated rate of oxygen consumption of isolated oyster gills by 46%. Specific inhibitors of ATPase function of P-gp (cyclosporine A and JS-2190) had no significant effect on tissue oxygen consumption indicating that P-gp contribution to energy budget is negligible and supporting indirect estimates based on the ATP stoichiometry of substrate transport that also suggest low energy demand for P-gp function.
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PMID:Effects of cadmium exposure on expression and activity of P-glycoprotein in eastern oysters, Crassostrea virginica Gmelin. 1845 12

Here, we report that diesel exhaust particles (DEPs), a major constituent of urban air pollution, affect blood-brain barrier function at the tissue, cellular, and molecular levels. Isolated rat brain capillaries exposed to DEPs showed increased expression and transport activity of the key drug efflux transporter, P-glycoprotein (6 h EC(50) was approximately 5 microg/ml). Up-regulation of P-glycoprotein was abolished by blocking transcription or protein synthesis. Inhibition of NADPH oxidase or pretreatment of capillaries with radical scavengers ameliorated DEP-induced P-glycoprotein up-regulation, indicating a role for reactive oxygen species in signaling. DEP exposure also increased brain capillary tumor necrosis factor-alpha (TNF-alpha) levels. DEP-induced P-glycoprotein up-regulation was abolished when TNF-receptor 1 (TNF-R1) was blocked and was not evident in experiments with capillaries from TNF-R1 knockout mice. Inhibition of JNK, but not NF-kappaB, blocked DEP-induced P-glycoprotein up-regulation, indicating a role for AP-1 in the signaling pathway. Consistent with this, DEPs increased phosphorylation of c-jun. Together, our results show for the first time that a component of air pollution, DEPs, alters blood-brain barrier function through oxidative stress and proinflammatory cytokine production. These experiments disclose a novel blood-brain barrier signaling pathway, with clear implications for environmental toxicology, CNS pathology, and the pharmacotherapy of CNS disorders.
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PMID:Diesel exhaust particles induce oxidative stress, proinflammatory signaling, and P-glycoprotein up-regulation at the blood-brain barrier. 1847 46


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