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)

The effects of cell cycle inhibition on the expression of the multidrug resistance transporter P-glycoprotein (P-gp) as well as of the cyclin-dependent kinase (CDK) inhibitors p27(Kip1) and p21(WAF-1) were investigated in DU-145 prostate tumor spheroids. With increasing spheroid size the number of cells in the G0/G1 phase augmented, whereas the number of cells in the G2/M phase and the S phase of the cell cycle declined. The number of G0/G1 cells was elevated after incubation with either mimosine, staurosporine or serum-free medium. Mitomycin C and roscovitine increased the number of S phase cells. Roscovitine additionally increased cells in the G2/M phase. Incubation in serum-free medium upregulated p21(WAF-1), p27(Kip1) and P-gp. Mimosine treatment resulted in upregulation of p27(Kip1) and P-gp, whereas p21(WAF-1) remained unchanged. Upon roscovitine treatment p27(Kip1) and p21(WAF-1) were downregulated, whereas P-gp was unaltered. Mitomycin C treatment resulted in downregulation of p27(Kip1) and p21(WAF-1); no significant change in P-gp levels was observed. Staurosporine induced upregulation of p21(WAF-1) whereas p27(Kip1) remained unaltered. P-gp was downregulated upon staurosporine treatment, which was owing to an elevation of intracellular reactive oxygen species by this compound. It is concluded that upregulation of P-gp in G0/G1 phase cells requires coexpression of the CDK inhibitor p27(Kip1) but not the CDK inhibitor p21(WAF-1).
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PMID:Modulation of intrinsic P-glycoprotein expression in multicellular prostate tumor spheroids by cell cycle inhibitors. 1190 40

Multidrug resistance (MDR) mediated by the ATP-dependent efflux protein P-glycoprotein (P-gp) is a major obstacle to the successful treatment of many cancers. In addition to effluxing toxins, P-gp has been shown to protect tumor cells against caspase-dependent apoptosis mediated by Fas and tumor necrosis factor receptor (TNFR) ligation, serum starvation and ultraviolet (UV) irradiation. However, P-gp does not protect against caspase-independent cell death mediated by granzyme B or pore-forming proteins (perforin, pneumolysin and activated complement). We examined the effects of the chemotherapeutic hybrid polar compound suberoylanilide hydroxamic acid (SAHA) on P-gp-expressing MDR human tumor cell lines. In the CEM T-cell line, SAHA, a histone deacetylase inhibitor, induced equivalent death in P-gp-positive cells compared with P-gp-negative cells. Cell death was marked by the caspase-independent release of cytochrome c, reactive oxygen species (ROS) production and Bid cleavage that was not affected by P-gp expression. However, consistent with our previous findings, SAHA-induced caspase activation was inhibited in P-gp-expressing cells. These data provide evidence that P-gp inhibits caspase activation after chemotherapeutic drug treatment and demonstrates that SAHA may be of value for the treatment of P-gp-expressing MDR cancers.
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PMID:Suberoylanilide hydroxamic acid (SAHA) overcomes multidrug resistance and induces cell death in P-glycoprotein-expressing cells. 1197 47

Multidrug resistance (MDR) in model systems is known to be conferred by two different integral proteins, the 170-kDa P-glycoprotein (P-gp) and the 190-kDa multidrug resistance-associated protein (MRP1), both of which pump drugs out of MDR cells. The presence of a nitrogen atom, charged at physiological pH, has frequently been considered to be a hallmark of P-gp substrates and inhibitors. The present study was aimed at investigating the role of nitrogen in the ability of the pump to recognise substrate. We measured the kinetics of active efflux of seven new anthracycline derivatives in P-gp-expressing K562/ADR cells and in MRP1-expressing GLC4/ADR cells. Six of these compounds represent analogues of daunorubicin in which the amino sugar nitrogen is bound to an amino- or a nitro-substituted benzyl moiety, the seventh is a doxorubicin derivative in which benzyl group is bound with 4'-oxygen. We found that the compounds with a nitro group on the benzyl ring were poor substrates for P-gp despite the presence of a secondary amine that can be protonated. In contrast, compounds that have a free amino group were very good substrates even though this amine is not protonated in the pH range studied (pK approximately 3). These results show that the nitrogen atom does not interact with P-gp in a charged form but rather as an electron donating group.
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PMID:Preferential efflux by P-glycoprotein, but not MRP1, of compounds containing a free electron donor amine. 1199 88

The iminoquinone is an important moiety of a large number of antineoplastic drugs and plays a significant role in the nucleus of actinomycins, powerful, highly toxic, natural antibiotics that target DNA as intercalating agents. A series of polycyclic iminoquinonic compounds, 2-amino-3H-phenoxazin-3-one (1), 2-amino-1,9-diacetyl-3H-phenoxazin-3-one (2), 2-acetylamino-3H-phenoxazin-3-one (3), 3H-phenoxazin-3-one (4), 5H-pyrido[3,2-a]phenoxazin-5-one (5), and 5H-pyrido[3,2-a]phenothiazin-5-one (6), strictly related to the actinomycin chromophore, were synthesized for developing new anticancer intercalating drugs. The antiproliferative activity of these compounds, evaluated against representative human liquid and solid neoplastic cell lines, showed that 5 and its isoster 6 were the most active compounds inhibiting cell proliferation in a submicromolar range. Compound 5 was also evaluated against KB subclones (KBMDR, KB7D, and KBV20C), which overexpress the MDR1/P-glycoprotein drug efflux pump responsible for drug resistance. All the above KB subclones did not show altered sensitivity to the antiproliferative activity of 5. UV-vis and (1)H NMR spectroscopy experiments support the phenoxazinone 5/DNA binding. Molecular mechanics methods were used to build a three-dimensional model of the 5/[d(GAAGCTTC)]2 complex. Electrostatic interactions between the hydrogen of the positively charged pyridine nitrogen of 5 and the negatively charged oxygen atoms (O4' and O5') of the cytosine C5 residue together with stacking forces contribute to the high antiproliferative activity. The metal(II)-assisted synthesis procedure of 5 is described, and the formation mechanism is proposed.
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PMID:Antitumor agents. 1. Synthesis, biological evaluation, and molecular modeling of 5H-pyrido[3,2-a]phenoxazin-5-one, a compound with potent antiproliferative activity. 1243 Oct 48

Imexon is an aziridine-containing iminopyrrolidone with selective growth-inhibitory potency for multiple myeloma. Our previous research indicates that imexon induces mitochondrial alterations, oxidative stress, and apoptosis. This drug represents an interesting model drug with a nonmyelosuppressive profile to study the basic mechanisms leading to antitumor activity and resistance. The major purpose of this study was to characterize an imexon-resistant RPMI8226/I cell line that was developed from RPMI8226 cells by continuous exposure to imexon. No significant differences were observed in the sensitivity to several cytotoxic drugs, including mitoxantrone, mitomycin C, melphalan, methotrexate, cytarabine, cisplatin, vincristine, and paclitaxel, in the imexon-resistant cells. However, RPMI8226/I cells were cross-resistant to arsenic trioxide, doxorubicin, fluorouracil, etoposide, irinotecan, and especially IFN-alpha. The data from DNA microarray and Western blot analyses indicated that the levels of antiapoptotic proteins Bcl-2 and thioredoxin-2, which reside mainly in the mitochondria, are increased in RPMI8226/I cells. In addition, increased levels of lung resistance protein were detected in imexon-resistant cells. Expression of P-glycoprotein was not detected in RPMI8226/I cells. No loss of mitochondrial membrane potential or increase in the levels of reactive oxygen species was observed in RPMI8226/I cells after exposure to imexon; however, the levels of glutathione are increased in the RPMI8226/I cells. Transmission electron microscopy revealed significant changes in the mitochondrial morphology of RPMI8226/I cells, whereas no ultrastructural changes were observed in other cellular compartments. Imexon-resistant RPMI8226/I myeloma cells appear to have a unique mechanism of resistance that is associated with morphological alterations of mitochondria, increased protection against oxidative stress, elevated levels of glutathione, and enhanced expression of antiapoptotic mitochondrial proteins.
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PMID:Molecular and cellular characterization of imexon-resistant RPMI8226/I myeloma cells. 1246 13

Hypoxia in tumors is generally associated with chemoresistance and radioresistance. However, the correlation between the heterodimeric hypoxia-inducible factor-1 (HIF-1) and the multidrug resistance transporter P-glycoprotein (P-gp) has not been investigated. Herein, we demonstrate that with increasing size of DU-145 prostate multicellular tumor spheroids the pericellular oxygen pressure and the generation of reactive oxygen species decreased, whereas the alpha-subunit of HIF-1 (HIF-1alpha) and P-gp were up-regulated. Furthermore, P-gp was up-regulated under experimental physiological hypoxia and chemical hypoxia induced by either cobalt chloride or desferrioxamine. The pro-oxidants H2O2 and buthionine sulfoximine down-regulated HIF-1alpha and P-gp, whereas up-regulation was achieved with the radical scavengers dehydroascorbate, N-acetylcysteine, and vitamin E. The correlation of HIF-1alpha and P-gp expression was validated by the use of hepatoma tumor spheroids that were either wild type (Hepa1) or mutant (Hepa1C4) for aryl hydrocarbon receptor nuclear translocator (ARNT), i.e., HIF-1beta. Chemical hypoxia robustly increased HIF-1alpha as well as P-gp expression in Hepa1 tumor spheroids, whereas no changes were observed in Hepa1C4 spheroids. Hence, our data demonstrate that expression of P-gp in multicellular tumor spheroids is under the control of HIF-1.
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PMID:Regulation of the multidrug resistance transporter P-glycoprotein in multicellular tumor spheroids by hypoxia-inducible factor (HIF-1) and reactive oxygen species. 1251 19

Cadmium (Cd(2+)) is a non-essential heavy metal, which is taken up from the environment into the body through pulmonary and enteral pathways. The S1 segment of the kidney proximal tubule (PT) is a major target of chronic Cd(2+) toxicity. Renal dysfunction develops in up to 7% of the general population and in its most severe form displays major features of Fanconi syndrome, such as a defective protein, amino acid, glucose, bicarbonate and phosphate reabsorption. The major pathway for Cd(2+) uptake by PT cells (PTCs) in vivo is apical endocytosis of Cd(2+) complexed to the high-affinity metal-binding protein metallothionein (MT), which may be receptor-mediated. MT is subsequently degraded in endo-lysosomes, and Cd(2+) is liberated for translocation into the cytosolic compartment, possibly using transporters for Fe(2+), Zn(2+) or Cu(2+), such as the divalent metal transporter DMT1. Free Cd(2+) ions in the extracellular space are translocated across apical and/or basolateral PTC membranes into the cytosol via transporters, whose identity remains unknown. Cytosolic Cd(2+) generates reactive oxygen species (ROS), which deplete endogenous radical scavengers. ROS also damage a variety of transport proteins, including the Na(+)/K(+)-ATPase, which are subsequently degraded by the proteasome and endo-lysosomal proteases. Cd(2+) causes mitochondrial swelling and release of cytochrome C. If these ROS-mediated stress events are not balanced by repair processes, affected cells undergo apoptosis. But Cd(2+) also induces the upregulation of cytoprotective stress and metal-scavenging proteins, such as MT. In addition, Cd(2+) upregulates the detoxifying pump multidrug resistance P-glycoprotein, which appears to protect PTCs against Cd(2+)-induced apoptosis. Thus, Cd(2+) interferes with various cellular events ranging from mechanisms of induction of programmed cell death to activation of cell survival genes. A better understanding of the cellular mechanisms involved in Cd(2+) nephrotoxicity should provide insights into other heavy metal (e.g. Pb(2+), Hg(2+)) nephropathies and various forms of acquired Fanconi syndrome.
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PMID:Nephrotoxicity and the proximal tubule. Insights from cadmium. 1275 69

The major function of the placenta is to transfer nutrients and oxygen from the mother to the foetus and to assist in the removal of waste products from the foetus to the mother. In addition, it plays an important role in the synthesis of hormones, peptides and steroids that are vital for a successful pregnancy. The placenta provides a link between the circulations of two distinct individuals but also acts as a barrier to protect the foetus from xenobiotics in the maternal blood. However, the impression that the placenta forms an impenetrable obstacle against most drugs is now widely regarded as false. It has been shown that that nearly all drugs that are administered during pregnancy will enter, to some degree, the circulation of the foetus via passive diffusion. In addition, some drugs are pumped across the placenta by various active transporters located on both the fetal and maternal side of the trophoblast layer. It is only in recent years that the impact of active transporters such as P-glycoprotein on the disposition of drugs has been demonstrated. Facilitated diffusion appears to be a minor transfer mechanism for some drugs, and pinocytosis and phagocytosis are considered too slow to have any significant effect on fetal drug concentrations. The extent to which drugs cross the placenta is also modulated by the actions of placental phase I and II drug-metabolising enzymes, which are present at levels that fluctuate throughout gestation. Cytochrome P450 (CYP) enzymes in particular have been well characterised in the placenta at the level of mRNA, protein, and enzyme activity. CYP1A1, 2E1, 3A4, 3A5, 3A7 and 4B1 have been detected in the term placenta. While much less is known about phase II enzymes in the placenta, some enzymes, in particular uridine diphosphate glucuronosyltransferases, have been detected and shown to have specific activity towards marker substrates, suggesting a significant role of this enzyme in placental drug detoxification. The increasing experimental data on placental drug transfer has enabled clinicians to make better informed decisions about which drugs significantly cross the placenta and develop dosage regimens that minimise fetal exposure to potentially toxic concentrations. Indeed, the foetus has now become the object of intended drug treatment. Extensive research on the placental transfer of drugs such as digoxin and zidovudine has assisted with the safe treatment of the foetus with these drugs in utero. Improved knowledge regarding transplacental drug transfer and metabolism will result in further expansion of pharmacological treatment of fetal conditions.
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PMID:Drug transfer and metabolism by the human placenta. 1517 Mar 65

Marine organisms and especially those living in tidal zones are confronted with dramatic changes in their environment such as temperature fluctuations on a daily and/or seasonal basis. In the present study, we investigated whether these parameters affect expression of multixenobiotic resistance (MXR)-related genes that serve as a first line of defense against a broad spectrum of natural and man-made toxicants. Expression of MXR-related genes seems to be an appropriate biomarker to determine hazardous effects of chemicals in contaminated marine habitats. The interference of natural environmental factors in the expression of biomarkers is an important issue with respect to the use of biomarkers in monitoring biological effects of pollutants, making interpretations difficult. We studied the effects of temperature, salinity and oxygen supply (anaerobiosis) on expression of MXR-related genes in gills and digestive gland of the blue mussel Mytilus edulis in order to differentiate between pollution-induced stress and responses to natural environmental variations. We found changes in expression levels of P-glycoprotein (pgp), major vault protein (mvp), topoisomerase II (topoII), heat shock protein 70 (hsp70), but not of the multidrug resistance-related protein (mrp2) genes, in laboratory experiments in relation to high temperature, low salinity and anaerobiosis but not low temperature. These effects of environmental factors have to be considered in sampling strategies for monitoring programmes to prevent false interpretation of results.
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PMID:Regulation of expression of multixenobiotic resistance (MXR) genes by environmental factors in the blue mussel Mytilus edulis. 1521 Feb 93

The accumulation of glutamate in the extracellular space in the central nervous system (CNS) plays a major part in ischemic and anoxic damage. In this study, we examined the effect of glutamate on the expression and activity of P-glycoprotein (P-gp) in rat brain microvessel endothelial cells (RBMECs) making up the blood-brain barrier (BBB). The level of P-gp expression significantly increased in RBMECs after the treatment of 100 microM glutamate. At this concentration, glutamate also enhanced rat mdr1a and mdr1b mRNA levels determined by RT-PCR analysis. Flow cytometry was used to study P-gp activity by analysis of intracellular rhodamine123 (Rh123) accumulation. Overexpression of P-gp resulted in a decreased intracellular accumulation of Rh123 in RBMECs. Glutamate-induced increase of intracellular reactive oxygen species (ROS) was observed by using the 2',7'-dichlorofluorescein (2',7'-DCF) assay. MK-801, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, and ROS scavenger N-acetylcysteine obviously blocked ROS generation and attenuated the changes of both expression and activity of P-gp induced by glutamate in RBMECs. These data suggested that glutamate up-regulated P-gp expression in RBMECs by an NMDA receptor-mediated mechanism and that glutamate-induced generation of ROS was linked to the regulation of P-gp expression. Therefore, transport of P-gp substrates in BBB appears to be affected during ischemic and anoxic injury.
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PMID:Glutamate up-regulates P-glycoprotein expression in rat brain microvessel endothelial cells by an NMDA receptor-mediated mechanism. 1523 89


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