BackgroundRenal cell carcinoma patients respond poorly to conventional chemotherapy, this unresponsiveness may be attributable to multidrug resistance (MDR). The mechanisms of MDR in renal cancer are not fully understood and the specific contribution of ABC transporter proteins which have been implicated in the chemoresistance of various cancers has not been fully defined in this disease.MethodsIn ...
PubMed Central
The MDR1 (ABCB1) gene encodes a membrane-bound transporter that actively effluxes a wide range of compounds from cells. The overexpression of MDR1 by multidrug-resistant cancer cells is a serious impediment to chemotherapy. MDR1 is expressed in various tissues to protect them from the adverse ...
Using the doxorubicin-sensitive K562 cell line and the resistant derivative lines KD30 and KD225 as models, we found that acquisition of multidrug resistance (MDR) is associated with enhanced FOXO3a activity and expression of ABCB1 (MDR1), a plasma membrane P-glycoprotein that functions as an efflux pump for various anticancer agents. ...
PubMed
YM155, a novel small molecule that down-regulates survivin and exhibits potent antitumor activity, is hydrophilic and cationic. While previous studies have shown that influx transporters play important roles in the uptake of YM155 into hepatocytes and possibly into cancer cells, efflux transporters have yet to be investigated. Here, we assessed the interaction of YM155 with P-glycoprotein ...
Background and purpose:P-glycoprotein (Pgp) efflux assays are widely used to identify Pgp substrates. The kidney cell lines Madin-Darby canine kidney (MDCK)-II and LLC-PK1, transfected with human MDR1 (ABCB1) are used to provide recombinant models of drug transport. Endogenous transporters in these cells may ...
In vivo and in vitro studies have demonstrated that P-glycoprotein (P-gp) plays a very significant role in the ADME processes (absorption, distribution, metabolism, excretion) and drug-drug interaction (DDI) of drugs in humans. P-gp is the product of multidrug resistance gene (MDR1/ABCB1). Pharmacogenomics and ...
We have investigated the transcriptomic and/or proteomic patterns of 71 solute carrier (SLC) and organic solute (OST) transporters, 34 ATP-binding cassette (ABC) transporters, and 51 metabolizing enzymes in human brain microvessels. We used quantitative RT-PCR and LC-MS/MS to examine isolated brain microvessels and cortex biopsies from 12 patients with epilepsia or glioma. SLC2A1/GLUT1, ...
The caudal-related homeobox transcription factor CDX2 has a key role in intestinal development and differentiation. CDX2 heterozygous mutant mice develop colonic polyps, and loss of CDX2 expression is seen in a subset of colon carcinoma in man. Ectopic CDX2 expression in the stomach of transgenic mice promotes intestinal metaplasia, and CDX2 ...
P-glycoprotein (P-gp) is a membrane-bound transporter protein that is encoded by the human multidrug resistance gene MDR1 (ABCB1). P-gp recognizes a wide range of xenobiotics, is pivotal in mediating cancer drug resistance, and plays an important role in limiting drug penetration across the blood�brain barrier. ...
Cadmium (Cd(2+)) damages the kidney proximal tubule (PT) by ceramide-dependent apoptosis and is also a class I carcinogen. Multidrug resistance P-glycoprotein (MDR1, ABCB1) confers resistance to Cd(2+) apoptosis, and it has been hypothesized that ABCB1 can directly transport Cd(2+) as a mode of cellular protection. ...
... R. M. Herings, and B. H. Stricker. 1997. Neuro-psychiatric effects of antimalarials. European Journal of Clinical ... ...
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MDR1 (ABCB1 of P-glycoproteine), een menselijk MDR-transporteiwit. De aanwezigheid van verapamil, een verlaagde groeisnelheid (Hoofdstuk 4). Dit effect op de groeisnelheid wordt tenietgedaan door verapamil, wat
E-print Network
When cancer cells develop resistance to chemotherapeutics, it is frequently conferred by the ATP-dependent efflux pump P-glycoprotein (MDR1, P-gp, ABCB1). P-gp can efflux a wide range of cancer drugs; thus its expression confers cross-resistance, termed multidrug resistance (MDR), to a wide ...
Cancer multidrug resistance (MDR) mediated by ATP-binding cassette (ABC) transporters presents a significant unresolved clinical challenge. One strategy to resolve MDR is to develop compounds that selectively kill cells overexpressing the efflux transporter P-glycoprotein (MDR1, P-gp, ABCB1). We have previously ...
The efflux pumps ABCB1 (p-gp, MDR1) and ABCG2 (BCRP) are expressed to a high extent by endothelial cells at the blood-brain barrier (BBB) and other barrier tissues and are involved in drug resistance of tumor (stem) cells. Whereas numerous ABCB1 ...
Mutant p53 accumulation has been shown to induce multidrug resistance (MDR1) gene and ATP binding cassettes (ABCs)-based drug efflux in human breast cancer cells. In the present work we have found that transcriptional activation of the oxidative stress-responsive heat shock factor 1 (HSF-1) and expression of heat shock proteins, ...
RNA interference (RNAi) represents a high effective mechanism for specific inhibition of mRNA expression. Besides its potential as a powerful laboratory tool, the RNAi pathway appears to be promising for therapeutic utilization. For development of RNA interference (RNAi)-based therapies, delivery of RNAi-mediating agents to target cells is one of the major obstacles. A novel ...
Several transport proteins are constitutively expressed in skin cells, but the putative role of the ABC transporter P-glycoprotein (P-gp) in human skin is yet unknown. Therefore, we analysed mRNA and protein expression and localization of P-gp in human skin. Using qRT-PCR, we demonstrated a strong MDR1 mRNA ...
Background and purpose:Lopinavir is extensively metabolized by cytochrome P450 3A (CYP3A) and is considered to be a substrate for the drug transporters ABCB1 (P-glycoprotein) and ABCC2 (MRP2). Here, we have assessed the individual and combined effects of CYP3A, ABCB1 and ABCC2 on the pharmacokinetics of lopinavir ...
The human multidrug resistance (MDR1, ABCB1) gene encodes P-glycoprotein (P-gp), which affects the pharmacokinetics of many drugs. Here, we investigated whether common MDR1 single nucleotide polymorphisms (SNPs) (C1236T, C3435T, and G2677T/A) affect predisposition to ...
The impact of drug transporters on drug pharmacokinetics and pharmacodynamics has been increasingly recognized in recent years. P-glycoprotein (P-gp), the product of the ABCB1 (formerly MDR1) gene, is among the most well-characterized drug transporters, particularly in veterinary medicine. P-gp is expressed by a variety of normal ...
Neurovascular dysfunction is an important component of Alzheimer's disease, leading to reduced clearance across the blood-brain barrier and accumulation of neurotoxic ?-amyloid (A?) peptides in the brain. It has been shown that the ABC transport protein P-glycoprotein (P-gp, ABCB1) is involved in the export of A? from the brain into the blood. To determine ...
The major obstacle to tumor chemotherapy is drug resistance. In the present study, we investigated the characteristics of FaDu cells (a hypopharyngeal carcinoma cell line) with multidrug resistance (MDR) induced by Taxol. The resistant cell line, FaDu/T, was grown by exposing normal FaDu cells to escalating concentrations of Taxol stepwise for over 12 months. The multidrug resistant sensitivities ...
For detection of the nt230[del4] MDR1 mutation, a 4-bp deletion in the canine MDR1 (ABCB1) gene, a TaqMan allelic discrimination assay was designed that allows for MDR1 genotyping without post-PCR processing. Directly after completion of the PCR amplification, the MDR1 ...
The authors' experience studying the MDR1 gene prompted them to initiate work on a novel animal model to study MDR1/mdr1 gene expression under a variety of normal and breast cancer-related physiological conditions. With the advent of new bioimaging techno...
National Technical Information Service (NTIS)
Published reports implicate a variety of mechanisms that may contribute to drug resistance in ovarian cancer. The chief aim of this study is to understand the relationship between overexpression of drug resistance associated genes and multidrug resistance in ovarian cancer. Using lentiviral short hairpin RNA (shRNA) collections targeting 132 genes identified from transcriptional profiling of drug ...
IntroductionThe human multi-drug resistance gene (MDR1, ABCB1) codes for P-glycoprotein (P-gp), an important membrane-bound efflux transporter known to confer anti-cancer drug resistance as well as affect the pharmacokinetics of many drugs and xenobiotics. A number of single nucleotide polymorphisms (SNPs) have ...
Ixabepilone is the first epothilone to be approved for clinical use. Current data suggest the epothilones have a role in treating taxane-resistant cancers and ixabepilone is unaffected by at least some of the mechanisms underlying chemoresistance. Here, we report a series of cytotoxicity and transport studies to assess the potential role of P-glycoprotein (P-gp) and breast cancer resistance ...
Efflux proteins have been shown to greatly affect the uptake of antiretroviral drugs by cells and to hamper their access to the human immunodeficiency virus type 1 replication site. This study evaluated the factors that may lead to drug-drug interactions between emtricitabine (FTC), tenofovir (TFV), and efavirenz (EFV), including the modulation of efflux transporter expression ...
The study of eukaryotic membrane proteins has been hampered by a paucity of systems that achieve consistent high-level functional protein expression. We report the use of a modified membrane protein hyperexpression system to characterize three classes of fungal membrane proteins (ABC transporters Pdr5p, CaCdr1p, CaCdr2p, CgCdr1p, CgPdh1p, CkAbc1p, and CneMdr1p, the major ...
Hepatocytes are epithelial cells whose apical poles constitute the bile canaliculi. The establishment and maintenance of canalicular poles is a finely regulated process that dictates the efficiency of primary bile secretion. Protein kinase A (PKA) modulates this process at different levels. AKAP350 is an A-kinase anchoring protein that scaffolds protein complexes involved in modulating the dynamic ...
Multidrug resistance P-glycoprotein (Pgp), coded by the multidrug resistance type I (MDR1/ABCB1) gene, is an energy-dependent efflux pump and functions in systemic detoxification processes. In the present study, the expression and development of Pgp were evaluated in the porcine oocyte during ...
ATP-binding cassette (ABC) proteins include the best known mediators of resistance to anticancer drugs. In particular, ABCB1 (MDR1/P-gp) extrudes many types of drugs from cancer cells, thereby conferring resistance to those agents. Attempts to overcome P-gp-mediated drug resistance using specific inhibitors of P-gp ...
Standard chemotherapy fails in 40% to 50% of patients with diffuse large B-cell lymphoma (DLBCL). Some of these failures can be salvaged with high-dose regimens, suggesting a role for drug resistance in this disease. We examined the expression of genes in the glutathione (GSH) and ATP-dependent transporter (ABC) families in 2 independent tissue-based ...
Multidrug ABC transporters such as P-glycoprotein (P-gp/MDR1/ABCB1) and multidrug resistance protein 1 (MRP1/ABCC1) play an important role in the extrusion of drugs from the cell and their overexpression can be a cause of failure of anticancer and antimicrobial chemotherapy. Recently, the mouse ...
... expression in duodenal cells. The P-glycoprotein limits intestinal absorption and acts as a pump that removes its ... ...
Topical colchicine selection of keratinocytes transduced with the multidrug resistance gene (MDR1) can sustain and enhance transgene expression in vivo. Proc Natl Acad Sci U S A.
Cancer.gov
Tamoxifen is widely prescribed to patients with estrogen receptor-positive breast cancer, and it is a prodrug that requires bioactivation by cytochrome P450 enzymes CYP2D6 and 3A4 to generate the active metabolite, endoxifen. Large interpatient variability in endoxifen plasma levels has been reported, and polymorphisms in CYP2D6 have been implicated as a major determinant of such variability. ...
Imatinib is a tyrosine kinase inhibitor that is effective in the treatment of chronic myeloid leukemia (CML). Not all patients achieve cytogenetic response. Some patients even lose the initial cytogenetic response. In this study, we investigated the active cellular transport of imatinib to gain a better understanding of the possible mechanisms of imatinib resistance. We used the leukemic cell line ...
Multidrug resistance, the phenomenon by which cells treated with a drug become resistant to the cytotoxic effect of a variety of other structurally and functionally unrelated drugs, is often associated with the expression of P-glycoprotein, an efflux membrane pump coded by the MDR1 (ABCB1) gene. Transcription from ...
Some of the ATP-binding cassette (ABC) transporters like P-glycoprotein (P-gp; ABCB1, MDR1), BCRP (ABCG2) and MRPs (ABCCs) that are present at the blood-brain barrier (BBB) influence the brain pharmacokinetics (PK) of their substrates by restricting their uptake or enhancing their clearance from the brain into the ...
Purpose:? Antiepileptic drugs (AEDs) are widely used not only in the treatment of epilepsy but also as treatments for psychiatric disorders. Pharmacoresistance of AEDs in the treatment of epilepsy and psychiatric disorders is a serious problem. Transport of antiepileptic drugs by P-glycoprotein (Pgp, ABCB1, or MDR1), which is overexpressed in the ...
N,N-diethyl-2-[4-(phenylmethyl)phenoxyl]ethanamine (tesmilifene), a tamoxifen derivative with antihistamine activity, greatly enhanced the survival of doxorubicin-treated, advanced stage breast cancer patients in a phase III trial. However, the molecular basis of tesmilifene action is not firmly established. The effects of tesmilifene on activity of several anticancer drugs was investigated using ...
Herbal medicines, an important group of multicomponent therapeutics, are widely and increasignly used worldwide. Despite the popularitiy of herbal medicines, the clinical evidence that support the use of most herbal medicines is weak. Pharmacokinetic and absorption, distribution, metabolism and excretion (ADME) studies have been integrated into modern drug development, but ADME studies are ...
Resistance to the cytotoxic actions of antineoplastic drugs, whether intrinsic or acquired, remains a barrier to the establishment of curative chemotherapy regimens for advanced breast cancer. Over-expression of P-glycoprotein (P-gp), encoded by the MDR1 gene and known to mediate resistance to many antineoplastic drugs, may contribute to poor breast cancer treatment outcome. ...
The human multidrug resistance gene 1 (MDR1) encodes the plasma membrane P-glycoprotein (P-gp/ABCB1) that functions as an efflux pump for various anticancer agents. We recently reported that estrogens down-regulate the expression of breast cancer resistance protein (BCRP/ABCG2). In our present ...
OBJECTIVE:: CYP3A5, MDR1 (ABCB1), and OATP1 (SLCO1B1) polymorphisms have been associated with variability in the pharmacokinetics (PK) of protease inhibitors. The aim of this study was to investigate the influence of CYP3A5 A6986G, ABCB1 (C3435T and G2677T), and SLCO1B1 ...
P-glycoprotein (P-gp; abcb1) is one of the major ABC transport proteins that mediates multixenobiotic resistance (MXR) defense in fish. In order to offer a sound evaluation of its ecotoxicological relevance it is critical to characterize substrate specificity of fish P-gp. Measurement of the ATPase activity is a reliable approach often used to discern type ...
Psychological distress reduces the efficacy of chemotherapy in breast cancer patients. The mechanism may be related to the altered neuronal or hormonal secretions during stress. Here, we reported that adrenaline, a hormone mediating the biological activities of stress, upregulates mdr1 gene expression in MCF-7 breast cancer cells via ...
BackgroundCorrelations of disease phenotypes with glycosylation changes have been analysed intensively in the tumor biology field. Glycoforms potentially associated with carcinogenesis, tumor progression and cancer metastasis have been identified. In cancer therapy, drug resistance is a severe problem, reducing therapeutic effect of drugs and adding to patient suffering. Although multiple ...
The human multidrug resistance gene (MDR1, ABCB1) codes for P-glycoprotein (P-gp) that affects the pharmacokinetics of many drugs. MDR1 single nucleotide polymorphisms (SNPs) are associated with drug clearance. Imatinib is a substrate of P-gp-mediated efflux. We ...
SUMMARY AT A GLANCE: The correlation between ABCB1 gene polymorphisms, ABCB1 mRNA expression and chemosensitivity to paclitaxel was assessed in a panel of 17 non-small cell lung cancer cell lines. The level of expression of the ABCB1 gene may be a predictive biomarker for ...
We evaluated the effect of spironolactone (SL), a well-known inducer of biotransformation and elimination pathways, on the expression and activity of P-glycoprotein (P-gp/ABCB1/MDR1), a major xenobiotic transporter, in HepG2 cells, as well as the potential mediation of pregnane X nuclear ...
Our data show that MDR1 gene expression is important in breast cancer resistance. The role of the MDR1 gene in breast cancer treatment will be further defined by sequentially determining MDR1 gene expression pre and post treatment with doxorubicin in the ...
Our data shows that MDR1 gene expression is important in breast cancer resistance. The role of the MDR1 gene in breast cancer treatment will be further defined by sequentially determining MDR1 gene expression pre and post treatment with doxorubicin in the...
BACKGROUND AND OBJECTIVES: Besides MDR1/P-glycoprotein (MDR1/P-gp), glucosylceramide synthase (GCS), an enzyme, which transfers UDP-glucose to ceramide to form glucosylceramide was also related with multidrug resistance (MDR) in breast cancer. Although many research showed that GCS could affect ...
The multidrug resistance gene-1 (MDR1, adenosine triphosphate-binding cassette transporter: ABCB1, P-glycoprotein) encodes membrane proteins that play a crucial role in protecting cells from xenobiotics, chemicals, and drugs. The TT genotype of 3435 codon in exon 26 of MDR1 gene causes overexpression of gene ...
The influence of P-glycoprotein (ABCB1) in drug resistance as well as drug absorption and disposition is an important factor to be considered during the development of new drugs. Thus, the early identification and exclusion of compounds showing a high affinity towards P-glycoprotein can help to select drug candidates. The aim of our study was to implement ...
Resistance to multiple antiepileptic drugs (AEDs) is a common problem in epilepsy, affecting at least 30% of patients. One prominent hypothesis to explain this resistance suggests an inadequate penetration or excess efflux of AEDs across the blood-brain barrier (BBB) as a result of overexpressed efflux transporters such as P-glycoprotein (Pgp), the encoded product of the multidrug resistance-1 ...
Multidrug resistance continues to be a major impediment to successful chemotherapy in cancer patients. One cause of multidrug resistance is enhanced expression of the mdr1 gene, but the precise factors and physiological conditions controlling mdr1 expression are not entirely known. To gain a better understanding of ...
Transgenic animals carrying and expressing human MDR1 gene have been produced. These transgenic animals serve as a useful model for testing the efficacy of high dosage chemotherapy and for the development of novel chemotherapeutic agents against cancers. ...
In the course of the past year, we have completed a meta-analysis of published studies, which confirms the expression and prognostic role of the MDR 1 mechanism of resistance in human breast cancer. In our effort to obtain effective inhibitors of this mec...
Metastasis of tumor cells to distant organs is the leading cause of death in melanoma. Yet, the mechanisms of metastasis remain poorly understood. One key question is whether all cells in a primary tumor are equally likely to metastasize or whether subpopulations of cells preferentially give rise to metastases. Here, we identified a subpopulation of uveal melanoma cells ...
Study ObjectiveThe purpose of this study was to determine if intermittent hypoxia that mimics obstructive sleep apnea would upregulate myocardial and hepatic p-glycoprotein protein and Abcb1a/Abcb1b mRNA expression.DesignProspective, randomized, blinded, parallel designed animal studySettingUniversity Research LaboratoryParticipantsThirty adult, male Sprague-Dawley ...
OBJECTIVE: Primer Express 2.0 software was used to design the primers and the MGB probe. With the plasmid pHaMDR1/A containing mdr1 cDNA as the template, we established a real-time fluorescent quantitative polymerase chain reaction system, which, at the template concentration of 3.061 x 10(3) ...
The ATP-binding cassette transporters P-glycoprotein (ABCB1, MDR1) and multidrug resistance protein 4 (MRP4) efflux irinotecan and its active metabolite SN-38 in vitro, and thus may contribute to system clearance of these compounds. Mdr1a/b(-/-), Mrp4(-/-), and wild-type ...
Multiple drug resistance protein 1 (MDR1) is composed of two homologous halves separated by an intracellular linker region. The linker has been reported to bind myosin regulatory light chain (RLC), but it is not clear how this can occur in the context of a myosin II complex. We characterized MDR1-RLC interactions ...
We investigated the mechanisms of MDR1 gene activation by CCAAT/enhancer binding protein beta (C/EBPbeta, or nuclear factor for interleukin 6) in human cancer cells. Transfection of the breast cancer cell line MCF-7 and its doxorubicin-selected variant MCF-7/ADR by either C/EBPbeta or C/EBPbeta-LIP (a dominant-negative form of C/EBPbeta) confirmed their roles in the activation or repression of the ...
Multidrug resistance (Mdr) transporters are ATP-binding cassette transporters that efflux amphipathic cations from cells and protect tissues from xenobiotics. Unfortunately, Mdr transporters also efflux anticancer drugs from some tumor cells, resulting in multidrug resistance. There are two groups of Mdrs in mice: group I includes Mdr1a and Mdr1b that ...
Intrinsic and acquired multidrug resistance (MDR) is an important problem in cancer therapy. MDR in human KB carcinoma cells selected for resistance to colchicine, vinblastine, or doxorubicin (former generic name adriamycin) is associated with overexpression of the MDR1 gene, which encodes P-glycoprotein. The authors previously have isolated an overlapping set of cDNA clones for the human ...
Energy Citations Database
Using an adenoviral system as a delivery mediator of therapeutic gene, we investigated the therapeutic effects of the use of combined MDR1 shRNA and human NIS (hNIS) radioiodine gene therapy in a mouse colon xenograft model. In vitro uptake of Tc-99m sestamibi was increased approximately two-fold in cells infected with an adenovirus vector that ...
MCF-7/ADR cells, a doxorubicin-resistant human breast cancer cell line, acquires resistance to several chemotherapeutic agents, such as anthracylines and taxol, via overexpression of the multidrug resistance1 (MDR1) gene. The present study was designed to clarify whether ginsenosides affect the expression of the MDR1 gene in MCF-7/ADR ...
BackgroundDrug resistance is the outcome of multiple-gene interactions in cancer cells under stress of anticancer agents. MDR1 overexpression is most commonly detected in drug-resistant cancers and accompanied with other gene alterations including enhanced glucosylceramide synthase (GCS). MDR1 encodes for ...
AbstractObjectiveGuanfacine has been shown to reduce hyperactive behaviors in children with attention-deficit/hyperactivity disorder (ADHD) and possibly in children with pervasive developmental disorder (PDD) and hyperactivity. The aim of this exploratory study was to examine whether gene variants encoding the multidrug resistance protein (MDR1 or ABCB1) , ...
Overexpression of human AP-endonuclease (APE1/Ref-1), a key enzyme in the DNA base excision repair (BER) pathway, is often associated with tumor cell resistance to various anticancer drugs. In this study, we examined the molecular basis of transcriptional regulatory (non repair) function of APE1 in promoting resistance to certain types of drugs. We have recently shown that APE1 stably interacts ...
Resistance to established drugs for cancer therapy is in many cases associated with overexpression of the multidrug resistance gene 1 (MDR-1). Regulation of basal expression of MDR-1 and mechanisms of induction as a result of exposure to cytotoxic substances are still not completely understood. Recent reports have suggested an ...
In this preliminary study, we report the cloning of the human MDR1 cDNA into a prokaryotic expression vector and the consequent functional expression of heterologous P-glycoprotein in Escherichia coli. We demonstrate increased resistance to the P-glycoprotein substrates TPA+, TPP+, and puromycin; reduced ...
1. P-glycoprotein, the protein product of the multidrug resistance (MDR1) gene, has ATP-dependent transporter activity. It has been suggested that P-glycoprotein may also function as a volume-regulated chloride channel or chloride channel regulator. To assess the chloride channel function of P-glycoprotein, we examined swelling-activated chloride ...
Functional expression of the multidrug resistance protein P-glycoprotein (P-gp) in Escherichia coli is providing an appropriate system for structure/function studies and might provide an invaluable tool to screen potential P-gp substrates and inhibitors. The major problem encountered in such studies, however, is the impermeability of the outer membrane of Gram-negative ...
Multidrug resistance (MDR) is a major obstacle in cancer chemotherapy and its inhibition is an effective way to reverse cancer drug resistance. In the present study, we investigated that puerarin, a natural isoflavonoid from Pueraria lobata, down-regulated MDR1 expression in MCF-7/adriamycin (MCF-7/adr), a human breast MDR cancer cell ...
The development of multidrug resistance (MDR) is associated with the overproduction of a plasma membrane glycoprotein, P glycoprotein. Here the authors report the functional expression of a member of the murine MDR family of proteins and show that Xenopus oocytes injected with RNA encoding the mouse mdr1b P glycoprotein develop a ...
To examine whether cisplatin affects the multidrug transporter MDR1/P-glycoprotein in the kidneys, the effects of cisplatin on cell sensitivity to an anticancer drug, MDR1 function and expression were examined by assessing the growth inhibition by the MDR1 substrate paclitaxel, the uptake and ...
ABC transporters are often found to be inherently expressed in a wide variety of stem cells, where they provide improved protection from toxins. We found a subpopulation of human melanoma cells expressing multidrug-resistance gene product 1 (MDR1). This fraction co-expresses the ABC ...
We measured intracellular accumulation of N-desmethyl imatinib (CGP 74588), the main pharmacologically active metabolite of imatinib (Gleevec or STI-571), in Bcr--Abl-positive cells. Using a sensitive and robust non-radioactive in vitro assay, we observed that CGP74588 accumulates in significantly higher amount than imatinib in sensitive K562 cells. In contrast, the intracellular level of CGP74588 ...
Murine norovirus (MNV) has recently been recognized as a widely prevalent viral pathogen in mouse colonies and causes disease and mortality in mice with impaired innate immunity. We tested the hypothesis that MNV infection would alter disease course and immune responses in mice with inflammatory bowel disease (IBD). ...
MDR1 (multidrug resistance) P-glycoprotein (Pgp; ABCB1) decreases intracellular concentrations of structurally diverse drugs. Although Pgp is generally thought to be an efflux transporter, the mechanism of action remains elusive. To determine whether Pgp confers drug resistance through changes in transmembrane ...
AIM: To explore the possibility of reversing multi-drug resistance (MDR) to HepG2/mdr1 in vitro and in vivo with RNA interference (RNAi).METHODS: HepG2/mdr1 was obtained by cloning the whole gene mdr1 into HepG2 cells. shRNA targeting sequence was designed to be homologous to the P-gp encoding ...
Membrane transporters and channels (collectively the transportome) govern cellular influx and efflux of ions, nutrients, and drugs. We used oligonucleotide arrays to analyze gene expression of the transportome in 60 human cancer cell lines used by the National Cancer Institute for drug screening. Correlating gene expression with the potencies of 119 ...
The use of the RNA interference (RNAi) through the expression of small hairpin RNA (shRNA) is a promising approach for efficient gene silencing for therapeutic applications. In this chapter, we describe the in vivo reversal of the classical MDR1/P-glycoprotein (MDR1/P-gp)-mediated multidrug ...
Aim:To investigate the changes of expression and function of P-glycoprotein (P-GP) in cerebral cortex, hippocampus, liver, intestinal mucosa and kidney of streptozocin-induced diabetic rats.Methods:Diabetic rats were prepared via a single dose of streptozocin (65 mg/kg, ip). Abcb1/P-GP mRNA and protein expression ...
P-glycoprotein (Pgp/ABCB1) and multidrug resistance related protein 1 (MRP1/ABCC1) were first described in multidrug resistant tumor cells. It is presently known that both proteins are also expressed in a variety of normal cells, including lymphocytes. ABCB1 activity has already been detected ...
The human multidrug resistance gene (MDR1) encodes a drug efflux pump glycoprotein (P-glycoprotein) responsible for resistance to multiple cytotoxic drugs. A plasmid carrying a human MDR1 cDNA under the control of a chicken beta-actin promoter was used to generate transgenic mice in which the transgene was mainly ...
Genetic variation in ABCB1, encoding P-glycoprotein (P-gp), is a potential cause of interindividual variation in drug response. Numerous studies have focused on the effects of coding region variants on P-gp expression and function, whereas few noncoding region variants have been investigated. The 3'-untranslated region (UTR) regulates mRNA levels or stability via RNA-protein ...
T2Rs (bitter taste-sensing type�2 receptors) are expressed in the oral cavity to prevent ingestion of dietary toxins through taste avoidance. They are also expressed in other cell types, including gut enteroendocrine cells, where their physiological role is enigmatic. Previously, we proposed that T2R-dependent CCK (cholecystokinin) secretion from ...
Loss of functional p53 paradoxically results in either increased or decreased resistance to chemotherapeutic drugs. The inconsistent relationship between p53 status and drug sensitivity may reflect p53�s selective regulation of genes important to cytotoxic response of chemotherapeutic agents. We reasoned that the discrepant effects of p53 on chemotherapeutic cytotoxicity is due to p53-dependent ...
PurposeThe role of adjuvant chemotherapy in patients with locally advanced bladder cancer still remains to be defined. We hypothesized that assessing the gene expression of the chemotherapy response modifiers multidrug resistance gene 1 (MDR1) and excision repair cross-complementing 1 (ERCC1) may help identify the group of patients ...
Patients with inflammatory bowel disease (IBD) are at increased risk for developing high-grade dysplasia and colorectal cancer. Animal IBD models that develop dysplasia and neoplasia may help elucidate the link between inflammation and colorectal cancer. Mdr1a?/? mice lack the membrane efflux pump p-glycoprotein and spontaneously ...
Mouse mitochondrial malic enzyme (L-malate:NADP/sup +/ oxidoreductase (oxaloacetate-decarboxylating), EC1.1.1.40) is a tetrameric protein. Two alleles of the structural gene (Mod-2) are known which code for electrophoretically distinct enzyme subunits: Mod-2/sup a/ and Mod-2/sup b/. A regulatory gene (Mdr-1), closely linked to Mod-2 on chromosome 7, ...
The transition from chemotherapy-responsive cancer cells to chemotherapy-resistant cancer cells is mainly accompanied by the increased expression of multi-drug resistance 1 (MDR1). We found that hepatitis-B-virus X protein (HBx) increases the transcriptional activity and protein level of MDR1 in a hepatoma cell line, H4IIE. In ...
Clopidogrel therapy to prevent atherothrombosis faces the challenge of reduced responsiveness. The absorption of clopidogrel is regulated by multidrug-resistance protein 1 (MDR1) in the intestinal epithelium. Given that aspirin induces MDR1 in cancer cells and peripheral blood cells, it may induce ...
Constitutive overexpression of the Mdr1 efflux pump is an important mechanism of acquired drug resistance in the yeast Candida albicans. The zinc cluster transcription factor Mrr1 is a central regulator of MDR1 expression, but other transcription factors have also been implicated in MDR1 regulation. To better understand how ...
BackgroundOver-expression of Aurora kinases promotes the tumorigenesis of cells. The aim of this study was to determine the preclinical profile of a novel pan-Aurora kinase inhibitor, BPR1K653, as a candidate for anti-cancer therapy. Since expression of the drug efflux pump, MDR1, reduces the effectiveness of ...
The patent application provides a full-length cDNA for the human MDR1 gene. This reconstructed cDNA, when inserted into a retroviral expression vector containing the long terminal repeats (LTRs) of Moloney leukemia virus or Harvey sarcoma virus, efficient...
IntroductionStudies using MDCKII and LLC-PK1 cells transfected with MDR1 cDNA indicate that ciprofloxacin is not a substrate of P-glycoprotein. However, our data has shown that transport studies done using different P-gp overexpressing cell lines (MDCKI-MDR1, MDCKII-MDR1 and L-MDR1), could lead to contradictory ...
When patients with cancers are treated with chemotherapeutic agents a long time, some of the cancer cells develop the multidrug resistance (MDR) phenotype. MDR cancer cells are characterized by the overexpression of multidrug resistance1(MDR1) gene which encodes P-glycoprotein (Pgp), a surface protein of tumor cells that functions to produce an excessive ...
Human AP-endonuclease (APE1/Ref-1), a central enzyme involved in the repair of oxidative base damage and DNA strand breaks, has a second activity as a transcriptional regulator that binds to several trans-acting factors. APE1 overexpression is often observed in tumor cells and confers resistance to various anticancer drugs; its downregulation sensitizes tumor cells to such agents. Because the ...
ToxCast chemicals were assessed for induction or suppression of xenobiotic metabolizing enzyme and transporter gene expression using primary human hepatocytes. The mRNA levels of 14 target and 2 control genes were measured: ABCB1, ABCB11, ABCG2, SLCO1B1, CYP1A1, CYP1A2, CYP2B6, C...
EPA Science Inventory
Multi-drug resistance (MDR) leads to impaired treatment efficacy in all forms of malignancy. The main forms of MDR are thought to be mediated by the substrate transporting actions of certain adenosine triphosphate binding cassette (ABC) transport proteins. The genes ABCB1, ABCB4, ABCC1, ABCG2 and LRP1 have been identified as the most prominent contributors ...
Intestinal xenobiotic transporters are a significant barrier to the absorption of many orally administered drugs. P-glycoprotein (PGP) is the best known, but several others, including members of the multidrug resistance-associated protein (MRP) family, are also expressed. Definitive information on their precise effect on intestinal drug permeability is scarce due to a lack of ...
Individual pharmacokinetic differences for herb-drug interaction have been associated with genetic variations of the multidrug resistance (MDR) gene. A high level expression of MDR protein increases cellular efflux and might decrease drug sensitivity. This study investigated the drug efflux activity difference of human MDR1 triallelic ...
Menopausal hormone therapy (HT) is associated with an increased breast cancer risk among postmenopausal women. In this study, we investigated genetic effect modification of HT associated breast cancer risk in 3,149 postmenopausal breast cancer patients and 5,489 controls from the two German population-based case-control studies MARIE and GENICA. Twenty-eight polymorphisms of 14 candidate genes ...
Infertility is a common problem affecting one in six couples, and in 30% of infertile couples, the male factor is a major cause due to defective sperm quality. P-glycoprotein (P-gp), a product of the MDR1 (ABCB1) gene, may be a link between genetic and environmental factors contributing to the development of male infertility because pesticides (P-gp ...
Hepatic transport protein expression can have a profound effect on the uptake and efflux of drugs in the overall process of drug management. Transporters located on the sinusoidal and canalicular membranes of hepatocytes regulate the efflux of drugs and metabolites into blood and bile, respectively. Changes in the expression or function of these ...
Background:Given that HIV-protease inhibitors (HIV-PIs) are substrates/inhibitors of the multidrug transporter ABCB1, can induce ABCB1 expression, and are used in combination with doxorubicin for AIDS-Kaposi's Sarcoma (KS) treatment, the role that ABCB1 plays in mediating multidrug resistance ...
In multidrug-resistant mouse J774.2 cells, the differential overproduction of functionally distinct phosphoglycoprotein isoforms reflects the amplification or transcriptional activation or both of two mdr gene family members, mdr1a and mdr1b. The mdr1a gene is a complex transcriptional unit whose expression is associated with multiple ...
P-glycoprotein (Pgp), encoded by the multidrug resistance 1 (MDR1) gene, is an efflux transporter and plays an important role in pharmacokinetics. In this study, we demonstrated that the pokemon promoter activity, the pokemon mRNA and protein expression can be significantly inhibited by Pgp. Chromatin immunoprecipitation assay showed ...
The screening of two different retroviral cDNA expression libraries to select genes that confer constitutive doxorubicin resistance has in both cases resulted in the isolation of the heat shock factor 1 (HSF1) transcription factor. We show that HSF1 induces a multidrug resistance phenotype that occurs in the absence of heat shock or cellular stress and is mediated at least in ...
Etravirine is a novel nonnucleoside reverse transcriptase inhibitor (NNRTI) for the treatment of HIV-1 infections. ABC transporters potentially mediate clinically relevant drug-drug interactions. We assessed substrate characteristics and the inhibitory and inductive potential of etravirine on ABC transporters. Etravirine did not inhibit P-gp/ABCB1 and was ...
Puromycin, hygromycin, and geneticin (G418) are antibiotics frequently used to select genetically engineered eukaryotic cells after transfection or transduction. Because intrinsic or acquired high expression of ATP-binding cassette (ABC) transporters, such as P-glycoprotein (Pgp/ABCB1) and multidrug resistance-associated proteins ...
This investigation describes the expression and interindividual variability in transcript levels of multiple drug efflux systems in the human jejunum and compares the expression profiles in these cells with that of the commonly used Caco-2 cell drug absorption model. Transcript levels of ten-drug efflux proteins of the ATP-binding cassette (ABC) ...
Overexpression of the MDR1 gene is one of the reasons for multidrug resistance (MDR). Some studies suggested that antioxidants could down-regulate MDR1 expression as a possible cancer treatment. In this report, we try to determine the effects of antioxidants (catalase or N-acetylcysteine [NAC]) on the regulation of intrinsic ...
ZAP-70 and CD38 expression can identify B-cell chronic lymphocytic leukemia with an inferior clinical outcome. Many groups have investigated the meaning of the expression of these two proteins and the correlation with the bad prognosis in B-CLL. But nobody has investigated the relation between the multidrug resistance mediated by Pgp overexpression ...
A variant, MS23, of murine thymoma W7 cells, previously selected for its resistance to low concentrations of dexamethasone, is cross-resistant to unrelated drugs such as puromycin and colchicine. We report here that transcription of the mouse mdr1 gene is activated and P-glycoprotein is expressed in MS23 cells. Moreover, additional ...
A full-length cDNA for the human multidrug resistance gene 1 (MDR1) has been inserted into a retroviral vector containing a murine Harvey sarcoma virus from which the viral oncogene was deleted. Ecotropic and amphotropic virus was produced after transfection of this vector into psi-2 and PA-12 packaging cell lines. This virus conferred the full phenotype ...
P-glycoprotein (Pgp; ABCB1), a member of the ATP-binding cassette (ABC) superfamily, exports structurally diverse hydrophobic compounds from the cell, driven by ATP hydrolysis. Pgp expression has been linked to the efflux of chemotherapeutic drugs in human cancers, leading to multidrug resistance (MDR). The protein also plays an ...
Euphorbia factor L1 (EFL1) belongs to diterpenoids of genus Euphorbia. In this article, its reversal activity against ABCB1-mediated MDR in KBv200 and MCF-7/adr cells was reported. However, EFL1 did not alter the sensitivity of KB and MCF-7 cells to chemotherapeutic agents. Meanwhile, EFL1 significantly increased accumulation of doxorubicin and rhodamine ...
Genotyping of putative determinants of temozolomide (TMZ)-induced life-threatening bone marrow suppression was performed in two patients with glioma treated with adjuvant TMZ and radiation therapy. DNA was extracted from the patients' mononuclear cells and genotyping of O-methylguanine-DNA-methyltransferase (MGMT), multidrug resistance (MDR1; also known as ...
This study provides evidence that quinidine can be used as a probe substrate for ABCB1 in multiple experimental systems both in vitro and in vivo relevant to the blood-brain barrier (BBB). The combination of quinidine and PSC-833 (valspodar) is an effective tool to assess investigational drugs for interactions on ABCB1. Effects of quinidine and substrate-inhibitor interactions were tested in a ...
Twenty years of genetic studies have not contributed to improvement in the clinical management of primary arterial hypertension. Genetic heterogeneity, epistatic-environmental-biological interactions, and the pathophysiological complexity of hypertension have hampered the clinical application of genetic findings. In the companion article, we furnished data from rodents and human cells ...
In the present study we used human breast cancer cell lines to assess the influence of ceramide and glucosylceramide (GC) on expression of MDR1, the multidrug resistance gene that codes for P-glycoprotein (P-gp), because GC has been shown to be a substrate for P-gp. Acute exposure (72 h) to C8-ceramide (5 microg/ml culture medium), a cell-permeable ceramide, increased ...
The development of multidrug resistance 1 (MDR1) can be mediated by a number of different mechanisms but elevated gene expression of MDR1 (P-glycoprotein) has often been a major cause of chemoresistance in many cancer cells. Therefore, the present study aimed to investigate the role of forkhead box-containing protein, O subfamily ...
Ovarian cancer patients frequently develop resistance to chemotherapy regiments utilizing Taxol and carboplatin. One of the resistance factors that protects cancer cells from Taxol-based therapy is multi-drug resistance 1 (MDR1). micro(mi)RNAs are small noncoding RNAs that negatively regulate protein expression. Members of the let-7 ...
The aim of this study was to determine whether primary human tubular cell monolayers could provide a powerful tool with which to investigate the renal proximal tubular handling of xenobiotics. Human proximal and distal tubule/collecting duct cells were grown as monolayers on permeable filter supports. After 10 days in culture, proximal tubule cells remained differentiated and ...
Clinical resistance to chemotherapy in acute myeloid leukemia (AML) is associated with the expression of the multidrug resistance (MDR) proteins P-glycoprotein, encoded by the MDR1/ABCB1 gene, multidrug resistant-related protein (MRP/ABCC1), the lung resistance-related protein (LRP), or major vault protein (MVP), and the breast cancer resistance protein (BCRP/ABCG2). The ...
IntroductionDuctal carcinoma in situ (DCIS) is a non-invasive lesion of the breast that is frequently detected by mammography and subsequently removed by surgery. However, it is estimated that about half of the detected lesions would never have progressed into invasive cancer. Identifying DCIS and invasive cancer specific epigenetic lesions and understanding how these epigenetic changes are ...
BACKGROUND: To evaluate risk factors that predict brain metastasis in epithelial ovarian, fallopian tube, and peritoneal cancer. METHODS: All patients with FIGO stage I to IV who underwent initial cytoreductive surgery between January 1995 and January 2009 were evaluated. The tumor samples were evaluated for 7 markers including multidrug resistance gene ...
The aim of this study was to investigate the link between protein kinase C (PKC) and multidrug resistance (mdr) phenotype. The expression of both was studied in doxorubicin-resistant MCF-7/Adr cells as they reverted to the wild-type phenotype when cultured in the absence of drug. The following parameters were measured in cells 4, 10, 15, 20 and 24 weeks after removal of ...
The natural product austocystin D was identified as a potent cytotoxic agent with in vivo antitumor activity and selectivity for cells expressing the multidrug resistance transporter MDR1. We sought to elucidate the mechanism of austocystin D's selective cytotoxic activity. Here we show that the selective cytotoxic action of ...
The natural product austocystin D was identified as a potent cytotoxic agent with in vivo antitumor activity and selectivity for cells expressing the multidrug resistance transporter MDR1. We sought to elucidate the mechanism of austocystin D�s selective cytotoxic activity. Here we show that the selective cytotoxic action of ...
P-glycoprotein (Pgp), a product of the multi-drug resistance gene MDR1a, is a broad specificity efflux ATP cassette transmembrane transporter that is predominantly expressed in epithelial tissues. Because mdr1a(-/-) mice tend to develop spontaneous colitis in bacteria-dependent manner, Pgp is ...
Breast cancers are either primarily resistant to chemotherapy (intrinsic resistance), or respond to chemotherapy but later recur with a multidrug-resistant phenotype because of overexpression of the multidrug transporter P-glycoprotein. The MDR1 gene encoding P-glycoprotein may be transcriptionally regulated by a Y-box transcription factor. We now report that, in multidrug-resistant MCF-7 breast ...
In order to determine the role of multidrug resistance proteins in mercury and zinc resistance, human MDR1, Lactococcus lactis lmrA, and Oenococcus oeni omrA genes were expressed in an Escherichia coli tolC mutant which is hypersensitive to metals. The three transporters conferred an increased mercury and zinc resistance to E. coli as ...
Multidrug resistance (MDR) caused by overexpression of p-glycoprotein is a major obstacle in chemotherapy of malignant cancer, which usually is characterized by constitutive activation of signal transducer and activator of transcription 3 (STAT3), but their relation between MDR and STAT3 remains unclear. Here, we showed that STAT3 was overexpressed and highly activated in adriamycin-resistant ...
One of the many obstacles to effective drug treatment is the efflux transporter P-glycoprotein (P-gp), which can restrict the plasma and intracellular concentrations of numerous xenobiotics. Variable drug response to P-gp substrates suggests that genetic differences in ABCB1 may affect P-gp transport. The current study examined how ABCB1 variants alter the ...
One of the many obstacles to effective drug treatment is the efflux transporter P-glycoprotein (P-gp), which can restrict the plasma and intracellular concentrations of numerous xenobiotics. Variable drug response to P-gp substrates suggests that genetic differences in ABCB1 may impact P-gp transport. The current study examined how ABCB1 variants alter the ...
Cyclosporine A (CsA) is a substrate for cytochrome P450 3A and the efflux transporter P-glycoprotein (P-gp; ABCB1), both abundantly expressed in the kidney. We retrospectively investigated the role of polymorphisms in CYP3A4, CYP3A5 and ABCB1 kidney graft donors on recipient renal function and subsequent graft loss, in a long-term ...
Dwarfism traits in Zea mays are regulated by multiple factors including the hormone auxin. Dwarf brachytic2 (br2) mutants harbour lesions in the gene encoding an orthologue of Arabidopsis thaliana ABCB1 which functions in auxin efflux out of meristematic regions in the shoot and root. br2 mesocotyls and coleoptiles exhibit reduced auxin transport. However, ...
The ATP-binding cassette, sub-family B, member 1 (ABCB1) gene encoding the protein P-glycoprotein (P-gp) has been implicated in the pathophysiology of Parkinson's disease (PD) due to its role in regulating transport of endogenous molecules and exogenous toxins. In the present study, we analyzed the ABCB1 single nucleotide polymorphisms (SNPs) 1236C/T (exon ...
Specific inhibition of P-glycoprotein (Pgp) expression, which is encoded by multidrug resistance gene-1 (MDR1), is considered a well-respected strategy to overcome multidrug resistance (MDR). Deoxyribozymes (DRz) are catalytic nucleic acids that could cleave a target RNA in sequence-specific manner. However, it is difficult to select ...
Lopinavir is the preferred HIV protease inhibitor in pregnancy but it is unknown if gestational diabetes mellitus (GDM) affects its disposition. Hepatic protein expression and plasma protein binding is altered in rodent models of GDM. Because lopinavir is influenced by hepatic transporters and metabolic enzymes and is highly protein bound, it was hypothesized that ...
Development of agents to overcome multidrug resistance (MDR) is important in cancer chemotherapy. Up to date, few chemicals have been reported to down-regulate MDR1 gene expression. We evaluated the effect of tryptanthrin on P-glycoprotein (P-gp)-mediated MDR in a breast cancer cell line MCF-7. Tryptanthrin could depress overexpression ...
We have recently identified a new class of compounds that selectively kill cells that express P-glycoprotein (P-gp, MDR1), the ATPase efflux pump that confers multidrug resistance on cancer cells. Several isatin-?-thiosemicarbazones from our initial study have been validated, and a range of analogs synthesized and tested. A number ...
Drug resistance, both primary and acquired, is a major obstacle to advances in cancer chemotherapy. In vitro, multidrug resistance can be mediated by P-glycoprotein (PGY1), a cell surface phosphoglycoprotein that acts to efflux natural products from cells. PGY1 is encoded by the MDR1 gene located at 7q21.1. Overexpression of MDR1 has been demonstrated in many cancers, both in patient tumors and in ...
Multidrug resistance following initial chemotherapy is commonly associated with MDR1 gene encoding for P-glycoprotein (P-gp). RNA interference of MDR1 gene expression was used as a strategy to reverse MDR1-mediated multidrug resistance phenotypes. Here we report that endonuclease-prepared small interfering RNA (esiRNA) at ...
Tumor radiotherapy with large-field irradiation results in an increase in apoptosis of the radiosensitive hematopoietic stem cells (CD34(+)). The aim of this study was to demonstrate the radioprotective potential of MDR1 overexpression in human CD34(+) cells using a lentiviral self-inactivating vector. Transduced human undifferentiated CD34(+) cells were irradiated with 0-8 Gy and held in liquid ...
Human CD4+ T cells express P-glycoprotein (P-gp), the ATP binding cassette efflux transporter encoded by MDR1. A common MDR1 single-nucleotide polymorphism in exon 26 (C3435T), which is linked to an exon 21 polymorphism (G2677T/A) and reportedly alters expression, has been associated with greater CD4+ T-cell ...
Previous studies have demonstrated leukemic complications in mice after high-copy retroviral gene transfer of the multidrug resistance 1 (MDR1) cDNA, encoding a membrane-located efflux pump expressed in hematopoietic stem cells. In contrast, no such complications or MDR1-associated alterations of hematopoiesis were observed in numerous ...
1,1-Bis(4-chlorophenyl)-2,2,2-trichloroethane (DDT) is an organochlorine pesticide. Its metabolite, 1,1-dichloro-2,2-bis(p-chlorophenyl)-ethene (p,p'-DDE) is a persistent environmental contaminant and both compounds accumulate in animals. Because multidrug resistance transporters, such as p-glycoprotein, function as a defense against xenobiotic exposure, we analyzed the ability of DDT and ...
PURPOSE: Cumulative data support the role of TAp73 variants in tumorigenic processes such as drug resistance. We evaluate the impact of TP73 isoforms and their putative target genes ABCB1, HMGB1 and CASP1 on colon cancer patient's survival and the correlation between their expressions.EXPERIMENTAL DESIGN: We determined in 77 patients ...
The identification and cloning of a segment of a human multidrug resistance gene (mdr1) was reported recently. To examine, the molecular basis of one type of multidrug resistance, the authors have prepared RNA from human tumors and normal tissues and measured their content of mdr1 RNA. They find that the mdr1 gene is expressed at a ...
Stroke is a major human health problem inducing long-term disability without any efficient therapeutic option being currently available. Under hypoxia, hypoxia-inducible factor-1? (HIF-1?) activates several genes as erythropoietin receptor (Epo-R) related with O(2) supply, and the multidrug-resistance gene (MDR-1) related with drug-refractory phenotype. ...
PURPOSE: To characterize resistance mechanisms to the nucleoside analog 9-?-D-arabinofuranosylguanine (AraG) in the T-cell acute lymphoblastic leukemia cell line MOLT-4 and its AraG-resistant variant. METHODS: A gene expression microarray analysis was performed, as well as gene expression and enzyme activity measurements of key enzymes in the activation of ...
Recent studies have shown that the histone-modifying enzymes histone acetyltransferase (HAT) and histone deacetylase (HDAC) are involved in transcriptional activation and repression, respectively. However, little is known about the endogenous genes that are regulated by these enzymes or how specificity is achieved. In the present report, we demonstrate that HAT and HDAC activities modulate ...
Amrubicin is a completely synthetic 9-aminoanthracycline agent for the treatment of lung cancer in Japan. The cytotoxicity of C-13 hydroxy metabolite, amrubicinol, is 10 to 100 times greater than that of amrubicin. The transporters responsible for the intracellular pharmacokinetics of amrubicin and amrubicinol remains unclear. This study was aimed to determine whether P-glycoprotein (P-gp) plays ...
BackgroundThe aim of this study is to examine the safety and distribution of Ad-EGFP-MDR1, an adenovirus encoding human multidurg resistance gene (human MDR1), in the mice colon carcinoma model.MethodsAfter bone marrow cells (BMCs) were infected with Ad-EGFP-MDR1, they were administered by intra bone marrow-bone marrow transplantation (IBM-BMT). Total ...
The human multidrug resistance (MDR1) gene product P-glycoprotein is highly expressed in intestinal epithelial cells, where it constitutes a barrier against xenobiotics, bacterial toxins, drugs and other biologically active compounds, possibly carcinogens. In this study, an association of MDR1 gene polymorphism and the occurrence of ...
Dielectrophoresis (DEP) was used to examine a panel of MCF-7 cell lines comprising parental MCF-7 cells and MDR derivatives: MCF-7TaxR (paclitaxel-resistant, P-glycoprotein (P-gp) positive), MCF-7DoxR (doxorubicin-resistant MRP2 positive) plus MCF-7MDR1 (MDR1 transfected, P-gp positive). MCF-7DoxR and MCF-7MDR1 ...
The blood-brain barrier (BBB) plays an important role in controlling the passage of molecules from blood to brain extracellular fluid. The multidrug efflux pump P-glycoprotein (P-gp) is highly expressed in the luminal membrane of brain endothelium and contributes to the formation of a functional barrier to lipid-soluble drugs such as anticancer agents. The mdr1a P-gp-encoding ...
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 ...
P-glycoprotein, a transmembrane protein associated with multidrug resistance in cancer cells, is also expressed in normal tissues. To get more insight into the physiologic role of mdr1/P-glycoprotein, we investigated its expression in human fetal tissues after 7 to 38 weeks of gestation by an immunohistochemical technique, using three different monoclonal ...
BackgroundPrevious results showed that over-expression of the WTH3 gene in MDR cells reduced MDR1 gene expression and converted their resistance to sensitivity to various anticancer drugs. In addition, the WTH3 gene promoter was hypermethylated in the MCF7/AdrR cell line and primary drug resistant breast cancer ...
Accumulation of unconjugated bilirubin (UCB) in the brain causes bilirubin encephalopathy. Pgp (ABCb1) and Mrp1 (ABCc1), highly expressed in the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB) respectively, may modulate the accumulation of UCB in brain. We examined the effect of prolonged exposure to elevated ...
The ability of the polymerase chain reaction (PCR) to quantitate expression of mRNA was examined in the present study. The model chosen was expression of the multidrug resistance gene mdr-1/Pgp in two colon carcinoma cell lines which express mdr-1/Pgp ...
Biofilm formation is a major virulence attribute of Candida albicans and is directly associated with therapeutic failure. One method by which Candida acquires antifungal resistance is the expression of drug-resistance genes. This study aimed to evaluate the transcriptional regulation of several genes associated with antifungal resistance of C. albicans under planktonic, ...
Hypoxia inducible factor-1 (HIF-1) has been considered as a critical transcriptional factor in response to hypoxia. It can increase P-glycoprotein (P-Gp) thus generating the resistant effect to chemotherapy. At present, the mechanism regulating HIF-1? is still not fully clear in hypoxic tumor cells. Intracellular redox status is closely correlated with hypoxic micro-environment, so we investigate ...
Cynomolgus monkey has been used as a model for the prediction of drug disposition in human brain. The purpose of this study was to clarify protein expression levels of membrane proteins affecting drug distribution to brain, such as transporters, receptors, and junctional proteins, in cynomolgus monkey brain microvessels by using liquid chromatography tandem mass spectrometory. ...
The possibility of interactions between natural products/supplements and conventional prescription medicines is one of the most important issues in pharmacotherapeutic safety. Recently, we reported that some terpenoids such as (R)-(+)-citronellal and glycyrrhetic acid, which are present in herbal medicines, can act as inhibitors of P-glycoprotein ...
Multidrug resistance resulting from expression of an energy-dependent drug efflux pump encoded by the human MDR1 gene is a major impediment to effective cancer therapy. Pharmacologic intervention aimed at inhibiting this multidrug transporter should improve existing chemotherapy of human cancer, but drug development has been delayed by ...
Abstract There are three currently identified secondary resistance mechanisms observed in patients with chronic myeloid leukemia (CML) receiving tyrosine kinase inhibitors (TKIs). These are BCR-ABL kinase domain (KD) mutations, increased BCR-ABL expression, and overexpression of drug-efflux proteins (ABCB1 and ABCG2). To investigate ...
P-glycoprotein (P-gp) mediates efflux of xenobiotics and bacterial toxins from the intestinal mucosa into the lumen. Dysregulation of P-gp has been implicated in inflammatory bowel disease. Certain probiotics have been shown to be effective in treating inflammatory bowel disease. However, direct effects of probiotics on P-gp are not known. Current studies examined the effects of Lactobacilli on ...
Increased levels of the protein kinase C (PKC) isoenzymes alpha and theta occur in conjunction with MDR1 gene expression in cells and tissues that have acquired a multidrug resistance (MDR) phenotype. Studies using PKC activators or antisense strategies against PKC suggest that activation of PKC engenders MDR1 gene transcription. In ...
Hyaluronan (HA) is a major glycosaminoglycan in the extracellular matrix whose expression is tightly linked to multidrug resistance and tumor progression. In this study we investigated HA-induced interaction between CD44 (a HA receptor) and Nanog (an embryonic stem cell transcription factor) in both human breast tumor cells (MCF-7 cells) and human ovarian tumor cells ...
Background:Malignant melanoma, generally described as incurable, is notoriously refractory to chemotherapy. The mechanisms contributing to this have not yet been defined and the contributions of drug efflux pumps, implicated in chemo-resistance of many other cancer types, have not been extensively investigated in melanoma.Methods:In this study, expression of multi-drug ...
The drug transporter P-glycoprotein (P-gp) appears to play an important role in the ability of tumor cells to evade killing by chemotherapeutic agents. Using pharmacological inhibitors of cAMP-dependent protein kinase (PKA), it has been suggested that, similar to rodent model systems, the human P-gp gene (MDR1) is also under PKA-dependent control and that ...
OBJECTIVE: Multidrug resistance-related protein 2 (Mrp2) is expressed in apical membranes of renal proximal tubular cells and contributes to the renal secretion of cyclosporine A (CsA). Mrp2 deficiency may lead to local renal CsA accumulation. We investigated whether kidney-specific Mrp2 deficiency enhances acute CsA nephrotoxicity in rats. METHODS: Kidney-specific Mrp2 ...
Except for hereditary disease, genetic factors that contribute to the development of renal epithelial tumors are unknown. There is a possibility that the MDR1 encoded plasma membrane transporter P-glycoprotein (PGP) influences the risk of development of renal neoplasms. PGP is known to be involved in uptake, binding, transport, and distribution of xenobiotics. There is evidence that the ...
Since solute carrier (SLC) and ATP-binding cassette (ABC) transporters play pivotal roles in the transport of both nutrients and drugs into breast milk, drug-nutrient transport interactions at the lactating mammary gland are possible. Our purpose was to characterize lactation stage-dependent changes in transporter expression in rat mammary gland and isolated mammary epithelial ...
The plasma membrane associated human multidrug resistance (MDR1) gene product, known as the 170-kDa P-glycoprotein or the multidrug transporter, acts as an ATP-dependent efflux pump for various cytotoxic agents. The authors expressed recombinant human multidrug transporter in a baculovirus expression system to ...
2-Methoxyestradiol (2ME), a natural derivative of estradiol, is currently evaluated in clinical trials for breast cancer. The current study aims to evaluate the modulatory effects of 2ME on regulation of multidrug resistance (MDR) in doxorubicin (Dox) resistant breast cancer cells (MCF-7/Dox) and its underlying mechanisms. The chemosensitizing effect of 2ME on Dox cytotoxicity is tested by MTT ...
Increasing evidence has shown that the immunological reaction of leukocytes plays a crucial role in the development of neurodegenerative disorders. We conducted transcriptome analysis of leukocytes from patients of mild cognitive impairment (MCI), Alzheimer's disease (AD), as well as normal controls (NC) by oligonucleotide microarray. The differentially expressed genes of ...
ATP-binding cassette (ABC) transporters are able to efflux their substrate drugs from the cells. We compared expression of efflux proteins in normal human corneal epithelial tissue, primary human corneal epithelial cells (HCEpiC), and corneal epithelial cell culture model (HCE model) based on human immortal cell line. Expression of multidrug resistance ...
