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

Resistance to chemotherapy is an obstacle to the successful treatment of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). The failure of therapeutic treatment may be due to the development of multidrug resistance (MDR), mechanisms of which include upregulation of membrane-resident transporters which efflux chemotherapeutic drugs from tumor cells, and failure of the cancer cell to undergo apoptosis in response to chemotherapy. Membrane transporter-based drug efflux transporters have been extensively studied, and agents that block drug efflux have been found and investigated. Presence of P-glycoprotein (Pgp, MDR1, ABCB1), a member of the ATP-binding cassette (ABC) transporter family, has been reported to correlate with poor prognosis in AML and MDS. In MDS, Pgp expression increases as the disease progresses. Overexpression of other transporters, such as the multidrug resistance protein (MRP1, ABCC1), and the vault-associated transporter lung resistance protein have been shown as well in both MDS and AML, but their prognostic relevance is not clear. Recently, a novel ABC half-transporter, the breast cancer resistance protein (ABCG2) has been found in approximately 30% of AML cases, and may play a role in resistance to chemotherapy. In clinical trials in MDS, first-generation Pgp blockers, such as cyclosporin-A and verapamil, were minimally effective, non-specific, and toxic. However, another first-generation blocker, quinine, was used in MDS and may specifically benefit MDS patients overexpressing Pgp. A second-generation drug, the non-immunosuppressive cyclosporine analog valspodar (PSC833), was studied in AML and MDS, and was highly toxic, resulting in the need to reduce the dosage of the chemotherapeutic drugs as a result of valspodar reducing the clearance of the chemotherapeutic agents. Third-generation drugs, which are highly specific for Pgp and which seem to have only modest effects on drug clearance, include tariquidar, zosuquidar, laniquidar, and ONT-093. These are all in phase I/II trials and show promise for future treatment.
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PMID:Modulation of drug resistance transporters as a strategy for treating myelodysplastic syndrome. 1549

Different mechanisms of drug resistance, including ATP-binding cassette (ABC) transporters, are responsible for treatment failure of tumors. We developed a low-density DNA microarray which contains 38 genes of the ABC transporter gene family. This tool has been validated with three different multidrug-resistant sublines (CEM/ADR5000, HL60/AR, and MCF7/CH1000) known to overexpress either the ABCB1 (MDR1), ABCC1 (MRP1), or ABCG2 (MXR and BCRP) genes. When compared with their drug-sensitive parental lines, we observed not only the overexpression of these genes in the multidrug-resistant cell lines but also of other ABC transporter genes pointing to their possible role in multidrug resistance. These results were corroborated by quantitative real-time reverse transcription-PCR. As the microarray allows the determination of the expression profile of many ABC transporters in a single hybridization experiment, it may be useful as a diagnostic tool to detect drug resistance in clinical samples.
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PMID:Microarray-based detection of multidrug resistance in human tumor cells by expression profiling of ATP-binding cassette transporter genes. 1560 63

The aim of the present study was to specifically silence the rat ATP-binding cassette transporter G2 (rABCG2) gene in brain capillary endothelial cells by transfection of short interfering RNA (siRNA). Four different siRNAs designed to target rABCG2 were each transfected into HEK293 cells with myc-tagged rABCG2 cDNA. Quantitative real-time PCR and western blot analyses revealed that three of the siRNAs were able to reduce exogenous rABCG2 mRNA and protein levels in HEK293 cells. Moreover, rABCG2-mediated mitoxantrone efflux transport was suppressed by the introduction of these three siRNAs into HEK293 cells. In contrast, the other siRNA and non-specific control siRNA did not significantly affect the mRNA expression, the protein level or the transport activity. Endogenous rABCG2 mRNA and protein expression in a conditionally immortalized rat brain capillary endothelial cell line (TR-BBB13) was suppressed by the most potent siRNA among the four siRNAs tested. Furthermore, this siRNA did not affect the mRNA levels of other ABC transporters, such as ABCB1, ABCC1 and ABCG1, and the protein level of ABCB1 in TR-BBB13 cells, suggesting that it can selectively silence rABCG2 at the blood-brain barrier. This should be a useful and novel strategy for clarifying the contribution of rABCG2 to brain-to-blood transport of substrate drugs and endogenous compounds across the blood-brain barrier.
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PMID:Selective gene silencing of rat ATP-binding cassette G2 transporter in an in vitro blood-brain barrier model by short interfering RNA. 1577 6

In tumor cell lines, multidrug resistance is often associated with an ATP-dependent decrease in cellular drug accumulation which is attributed to the overexpression of certain ATP-binding cassette (ABC) transporter proteins. ABC proteins that confer drug resistance include (but are not limited to) P-glycoprotein (gene symbol ABCB1), the multidrug resistance protein 1 (MRP1, gene symbol ABCC1), MRP2 (gene symbol ABCC2), and the breast cancer resistance protein (BCRP, gene symbol ABCG2). In addition to their role in drug resistance, there is substantial evidence that these efflux pumps have overlapping functions in tissue defense. Collectively, these proteins are capable of transporting a vast and chemically diverse array of toxicants including bulky lipophilic cationic, anionic, and neutrally charged drugs and toxins as well as conjugated organic anions that encompass dietary and environmental carcinogens, pesticides, metals, metalloids, and lipid peroxidation products. P-glycoprotein, MRP1, MRP2, and BCRP/ABCG2 are expressed in tissues important for absorption (e.g., lung and gut) and metabolism and elimination (liver and kidney). In addition, these transporters have an important role in maintaining the barrier function of sanctuary site tissues (e.g., blood-brain barrier, blood-cerebral spinal fluid barrier, blood-testis barrier and the maternal-fetal barrier or placenta). Thus, these ABC transporters are increasingly recognized for their ability to modulate the absorption, distribution, metabolism, excretion, and toxicity of xenobiotics. In this review, the role of these four ABC transporter proteins in protecting tissues from a variety of toxicants is discussed. Species variations in substrate specificity and tissue distribution of these transporters are also addressed since these properties have implications for in vivo models of toxicity used for drug discovery and development.
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PMID:Multidrug resistance proteins: role of P-glycoprotein, MRP1, MRP2, and BCRP (ABCG2) in tissue defense. 1584 15

ATP-binding cassette (ABC) membrane proteins comprise a superfamily of transporters with a wide variety of substrates. Humans have 49 members in this superfamily. Several human ABC transporters, such as ABCB1 and ABCC1, have been attributed to cause multidrug resistance (MDR) in cancer treatment when over-expressed. In the past, an MDR cancer cell line MCF7/AdVp3000 has been selected, and overexpression of ABCG2 was thought to cause MDR in this cell line. However, ectopic overexpression of ABCG2 in MCF7 cells could not explain the high drug resistance level observed with the selected cell line. In this study, we designed an AmpArray analysis to profile whether other ABC transporters were also selected to contribute to the increased drug resistance in MCF7/AdVp3000 cells. We found that 16 ABC transporters, including ABCG2, had >/=1.5-fold altered expression in MCF7/AdVp3000 compared with the parental MCF7 cells. In particular, the expression of ABCA4 and ABCC3 was increased by 132- and 459-fold, respectively, whereas ABCG2 was increased by approximately 3000-fold. Furthermore, the elevated expression of these three transporters reversed with the reversed drug resistance phenotype, and silencing ABCC3 expression in MCF7/AdVp3000 cells significantly reduced doxorubicin resistance. Thus, other ABC transporters in addition to ABCG2 are likely to contribute to the MDR selected in MCF7/AdVp3000 cells. This study also shows that AmpArray can be used as a quick and easy tool to profile the expression of ABC transporters in resistant cell lines and tumor samples for potential use in individualized design of therapy.
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PMID:Expression profiling of ABC transporters in a drug-resistant breast cancer cell line using AmpArray. 1590 50

Resistance to mitoxantrone is often associated with enhanced drug efflux mediated by members of the superfamily of adenosinetriphosphate-binding cassette (ABC) transporters, i.e. MDR1/P-gp (ABCB1), MRP1 (ABCC1), or BCRP (ABCG2). So far it is unclear whether the same ABC-transporter is always activated from the beginning of mitoxantrone treatment to the end of drug exposure. Here, we demonstrate that the expression of all three extrusion pumps is induced by increasing levels of mitoxantrone resistance, but in the end, merely the overexpression of a dominant single drug transporter, i.e. Mdr1/P-gp, is realized. This upregulation of Mdr1/P-gp was reflected by amplification of the Mdr1/P-gp encoding gene. Short mitoxantrone exposure demonstrated that upregulation of two different transporters, Mdr1/P-gp and Bcrp, was induced. The data indicate that mitoxantrone treatment influences the expression of several ABC-transporters, but in the end, merely a single extrusion pump will be dominant.
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PMID:Induction of the ABC-transporters Mdr1/P-gp (Abcb1), mrpl (Abcc1), and bcrp (Abcg2) during establishment of multidrug resistance following exposure to mitoxantrone. 1592 Sep 9

Imatinib mesylate is a selective tyrosine kinase inhibitor that is successfully used in the treatment of Philadelphia-positive chronic and acute leukaemia's, and gastrointestinal stromal tumors. We investigated whether the intended chronic oral administration of imatinib might lead to the induction of the intestinal ABC transport proteins ABCB1, ABCC1 (MRP1), ABCC2 (MRP2) and ABCG2. Using Caco2 cells as an in vitro model for intestinal drug transport, we found that continuous exposure (up to 100 days) with imatinib (10 microM) specifically upregulates the expression of ABCG2 (maximal approximately 17-fold) and ABCB1 (maximal approximately 5-fold). The induction of gene expression appeared to be biphasic in time, with a significant increase in ABCG2 and ABCB1 at day 3 and day 25, respectively, and was not mediated through activation of the human orphan nuclear receptor SXR/NR1I2. Importantly, chronic imatinib exposure of Caco2 cells resulted in a approximately 50% decrease in intracellular accumulation of imatinib, probably by enhanced ABCG2- and ABCB1-mediated efflux, as a result of upregulated expression of these drug pumps. Both ABCG2 and ABCB1 are normally expressed in the gastrointestinal tract and it might be anticipated that drug-induced upregulation of these intestinal pumps could reduce the oral bioavailability of imatinib, representing a novel mechanism of acquired pharmacokinetic drug resistance in cancer patients that are chronically treated with imatinib.
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PMID:Chronic imatinib mesylate exposure leads to reduced intracellular drug accumulation by induction of the ABCG2 (BCRP) and ABCB1 (MDR1) drug transport pumps. 1597 Jun 68

ATP binding cassette (ABC)-transporters like P-glycoprotein (multidrug resistance (MDR)1/ABCB1), the multidrug resistance associated proteins 1 and 2 (MRP1/ABCC1 and MRP2/ABCC2), and the breast cancer resistance protein (BCRP/ABCG2) have a large impact on the pharmacokinetics of numerous drugs and may also modulate the effectiveness of drug therapy. Prediction of a patient's susceptibility to xenobiotics and individualization of drug therapy would become possible, if a simple test were available for an easy screening of transporter expression. This study quantified the mRNA expression of the four ABC-transporters and of the pregnane X receptor (PXR), a key regulator in drug metabolism and efflux, in peripheral blood mononuclear cells (PBMCs), and corresponding liver or small intestine samples of humans by real-time reverse transcription-polymerase chain reaction (RT-PCR). The results obtained prove the absence of a correlation between the expression of four major ABC-transporters in PBMCs and in the intestine or liver. For all transporters (except MRP1/ABCC1 in the intestine), mRNA amount of the ABC-transporters was positively correlated with PXR expression in PBMCs and intestine. In conclusion, the study suggests that basal expression levels of the transporters are directly influenced by PXR expression in liver and PBMCs and demonstrates that PBMCs do not qualify as surrogate tissue for the expression of the four ABC-transporters in small intestine and liver. However, the transporter status in PBMCs remains important for drugs, whose primary site of therapeutic action is the lymphocyte and which are known substrates of the transporters.
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PMID:Expression of the drug transporters MDR1/ABCB1, MRP1/ABCC1, MRP2/ABCC2, BCRP/ABCG2, and PXR in peripheral blood mononuclear cells and their relationship with the expression in intestine and liver. 1605 95

Membrane transporters play important roles in mediating chemosensitivity and -resistance of tumor cells. ABC transporters, such as ABCB1/MDR1, ABCC1/MRP1 and ABCG2/BCRP, are frequently associated with decreased cellular accumulation of anticancer drugs and multidrug resistance of tumors. SLC transporters, such as folate, nucleoside, and amino acid transporters, commonly increase chemosensitivity by mediating the cellular uptake of hydrophilic drugs. Ion channels and pumps variably affect sensitivity to anticancer therapy by modulating viability of tumor cells. A pharmacogenomic approach, using correlations between drug potency and transporter gene expression in multiple cancer cell lines, has shown promise for identifying potential drug-transporter relationships and predicting anticancer drug response, in an effort to optimize chemotherapy for individual patients.
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PMID:Membrane transporters and channels in chemoresistance and -sensitivity of tumor cells. 1616 62

Gastrointestinal stromal tumors (GIST) are the most frequent mesenchymal tumors of the digestive tract and respond poorly to chemotherapy. A tyrosine kinase inhibitor treatment, imatinib mesylate, was recently shown to have antitumor effects in metastatic patients. However, this drug is a substrate for multidrug resistance (MDR) proteins. Therefore, we investigated the expression of ABCB1 (P-glycoprotein), ABCC1 (MRP1), and ABCG2 (BCRP) by Western blotting in 21 GISTs and 3 leiomyosarcomas. All the GISTs were positive for either ABCB1 (86% of cases) or ABCC1 expression (62%), but negative for ABCG2. ABCB1 was expressed in all gastric GISTs, but in only 67% of nongastric GISTs. By contrast, ABCC1 expression was more common in nongastric tumors (78% versus 42%). The levels of these MDR proteins in gastric GISTs were higher for ABCB1 (P = 0.007) and lower for ABCC1 (P = 0.004) compared with nongastric GISTs. We found no correlation between MDR protein expression and the risk assessment. None of the six patients treated with imatinib was resistant, although all were positive for at least one MDR protein. These results confirm that gastric and nongastric GISTs have different biological characteristics and suggest that MDR proteins do not impair the initial response of the tumor to imatinib.
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PMID:Multidrug resistance proteins in gastrointestinal stromal tumors: site-dependent expression and initial response to imatinib. 1627 76


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