Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P33527 (ABCC1)
 1,164 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have shown that multidrug resistance associated protein 1 (MRP1) mediates ATP-dependent extrusion of bilirubin, possibly limiting its potentially toxic accumulation in cells. To determine directly if Mrp1 protects cells against unconjugated bilirubin (UCB) toxicity, mouse embryo fibroblasts (MEF) were isolated from Mrp1 knockout (-/-) mice and their wild type (WT) (+/+) littermates. Compared to WT cells, cultured MEF (-/-) cells exposed to 40-140 nM unbound [H3]-bilirubin accumulated twice as much [H3]-bilirubin (P<0.01). This was associated with greater, dose-related cytotoxicity, assessed by the methylthiazoletetrazolium test, lactate dehydrogenase release and cellular ATP content. The data confirm that Mrp1 limits intracellular accumulation of UCB and thus decreases its cytotoxicity.
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PMID:Multidrug resistance associated protein 1 protects against bilirubin-induced cytotoxicity. 1645 8

Arsenic trioxide (arsenite, As(III)) has shown a remarkable clinical efficacy, whereas its side effects are still a serious concern. Therefore, it is critical to understand the effects of As(III) on human-derived normal cells for revealing the mechanisms underlying these side effects. We examined the effects of As(III) on primary cultured chorion (C) and amnion (A) cells prepared from human fetal membranes. A significant dose-dependent As(III)-mediated cytotoxicity was observed in the C-cells accompanied with an increase of lactate dehydrogenase (LDH) release. Higher concentrations of As(III) were required for the A-cells to show cytotoxicity and LDH release, suggesting that the C-cells were more sensitive to As(III) than the A-cells. The expression levels of aquaporin 9 (AQP9) were approximately 2 times higher in the C-cells than those in the A-cells. Both intracellular arsenic accumulation and its cytotoxicity in the C-cells were significantly abrogated by sorbitol, a competitive AQP9 inhibitor, in a dose-dependent manner. The protein expression levels of multidrug resistance-associated protein (MRP) 2 were downregulated by As(III) in the C-cells, but not in the A-cells. No significant differences in the expression levels of MRP1 were observed between C- and A-cells. The protein expression of P-glycoprotein (P-gp) was hardly detected in both cells, although a detectable amount of its mRNA was observed. Cyclosporine A, a broad-spectrum inhibitor for ABC transporters, and MK571, a MRP inhibitor, but not PGP-4008, a P-gp specific inhibitor, potently sensitized both cells to As(III)-mediated cytotoxicity. These results suggest that AQP9 and MRP2 are involved in controlling arsenic accumulation in these normal cells, which then contribute to differential sensitivity to As(III) cytotoxicity between these cells.
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PMID:Contribution of aquaporin 9 and multidrug resistance-associated protein 2 to differential sensitivity to arsenite between primary cultured chorion and amnion cells prepared from human fetal membranes. 2194 91

Multidrug resistance remains a major obstacle in the effective treatment of metastatic breast cancer. One mechanism by which multidrug resistance is conferred is the decreased intracellular drug accumulation due to the upregulation of the ATP-binding cassette (ABC) transporters. We have previously demonstrated that jadomycins, polyketide-derived natural products produced by Streptomyces venezuelae ISP5230, inhibit the growth of the human breast ductal carcinoma cell lines T47D and MDA-MB-435. To expand our understanding of jadomycin pharmacology, the goal of the present study was to determine whether the function of ABC efflux transporters affects the anticancer activity of jadomycins to MCF7 breast cancer cells. Seven jadomycin analogs (DNV, B, L, SPhG, F, S, and T) effectively reduced the viability of MCF7 control and ABCB1-, ABCC1-, or ABCG2-overexpressing drug-resistant MCF7 breast cancer cells as measured by methyltetrazolium cell viability assays and lactate dehydrogenase cytotoxicity assays. The inhibition of ABCB1, ABCC1, or ABCG2 with verapamil, MK-571, or Ko-143, respectively, did not augment the cytotoxicity of jadomycins DNV, B, L, SPhG, F, S, or T in drug-resistant MCF7 cells. Furthermore, jadomycins B, L, SPhG, F, S, and T did not increase the intracellular accumulation of ABCB1, ABCC1, or ABCG2 fluorescent substrates in HEK-293 cells stably transfected with ABCB1, ABCC1, or ABCG2. We conclude that jadomycins B, L, SPhG, F, S, and T are effective agents in the eradication of MCF7 breast cancer cells grown in culture, and that their cytotoxicities are minimally affected by ABCB1, ABCC1, and ABCG2 efflux transporter function.
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PMID:Jadomycins are cytotoxic to ABCB1-, ABCC1-, and ABCG2-overexpressing MCF7 breast cancer cells. 2423 27

A specific type of myelodysplastic syndrome (MDS) is associated with isolated deletion on the long arm of chromosome 5, i.e., 5q-syndrome (del(5q)). The treatment approaches for MDS del(5q) include the immunomodulating drug lenalidomide (LEN). Thirteen MDS del(5q) patients were included in this study. We found elevated activities of lactate dehydrogenase (LDH) and matrix metalloproteinase 9 (MMP-9) in the blood plasma of MDS del(5q) patients as compared with healthy controls. This was stabilized to control values after LEN treatment. Similar behavior we registered also for the thioredoxin and calnexin contents in BP. Peripheral blood mononuclear cells (PBMC) from patients with MDS del(5q) prior to and after treatment with LEN did not exhibit any detectable amount of P-glycoprotein (P-gp) gene transcript. However, we detected a measurable amount of multidrug resistance associated protein 1 (MRP1) mRNA in PBMCs from three patients prior to LEN treatment and in one patient during LEN treatment but it was not present prior to treatment. These data indicated on usefulness of applied protein markers estimation for monitoring of MDS del(5q) patient treatment effectiveness by LEN. Expression of MRP1 seems to be independent on LEN treatment and reflects probably the molecular variability in the ethiopathogenesis of MDS del(5q).
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PMID:Lenalidomide treatment induced the normalization of marker protein levels in blood plasma of patients with 5q-myelodysplastic syndrome. 2600 Dec 89

The aim of the present study is to discover multidrug resistance-associated protein (MRP) inhibitors with neuroblastoma-selective cytotoxicity by means of fluorescence assay with a membrane-permeable fluorescent dye, Fluo-8 AM, based on our observation that gene expression of Mrp3 in neuroblastoma Neuro2a cells was remarkably higher than that in primary cultured cortical neurons, as determined by real-time PCR. Neuro2a cells showed minimal fluorescence upon incubation with Fluo-8 AM. However, blocking of Mrp3 efflux function by small interfering RNA (siRNA) transfection or inhibition with probenecid resulted in significant dye accumulation, observed as an increase of fluorescence. Interestingly, Mrp3 siRNA or probenecid treatment also resulted in increased cytotoxicity, as evidenced by decreased 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)-reducing activity of Neuro2a, with a concomitant increase in release of lactate dehydrogenase. On the other hand, primary cultured neurons exhibited higher fluorescence intensity after incubation with Fluo-8 AM regardless of addition of probenecid. Also, probenecid only minimally affected MTT-reducing activity. Thus, probenecid showed selective cytotoxicity towards Neuro2a cells. Based on these findings, we screened a series of established therapeutic agents for ability to induce Fluo-8 accumulation in Neuro2a cells. Several uricosuric and nonsteroidal anti-inflammatory drugs were identified, and these drugs were confirmed to decrease MTT-reducing activity selectively in Neuro2a. There was a negative linear correlation between Fluo-8 accumulation and cytotoxicity of these agents. Although the compounds identified here are insufficiently potent for practical application, further screening to discover higher-affinity MRP3 inhibitors using larger chemical libraries may uncover drug candidates with potent neuroblastoma-selective cytotoxicity.
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PMID:Screening to Identify Multidrug Resistance-Associated Protein Inhibitors with Neuroblastoma-Selective Cytotoxicity. 2772 40