The Experts below are selected from a list of 10491 Experts worldwide ranked by ideXlab platform

Damir Janigro - One of the best experts on this subject based on the ideXlab platform.

  • Significance of MDR1 and Multiple Drug Resistance in refractory human epileptic brain
    BMC medicine, 2004
    Co-Authors: Nicola Marchi, Kelly Kight, Kerri Hallene, Luca Cucullo, William Bingaman, Gabriel Möddel, Gabriele Dini, Annamaria Vezzani, Damir Janigro
    Abstract:

    Background The Multiple Drug Resistance protein (MDR1/P-glycoprotein) is overexpressed in glia and blood-brain barrier (BBB) endothelium in Drug refractory human epileptic tissue. Since various antiepileptic Drugs (AEDs) can act as substrates for MDR1, the enhanced expression/function of this protein may increase their active extrusion from the brain, resulting in decreased responsiveness to AEDs.

  • Vascular and Parenchymal Mechanisms in Multiple Drug Resistance: a Lesson from Human Epilepsy
    Current drug targets, 2003
    Co-Authors: Matteo Marroni, Luca Cucullo, Nicola Marchi, N. Joan Abbott, Kathy Signorelli, Damir Janigro
    Abstract:

    Long term treatment with antiepileptic Drugs (AEDs) is the standard therapeutic approach to eradicate seizures. However, a small but significant number of patients fail AED treatment. Intrinsic Drug Resistance may depend on two main and not necessarily mutually exclusive mechanisms: 1) Loss of pharmacological target (e.g., GABAA receptors); 2) poor penetration of the Drug into the central nervous system (CNS). The latter is due to the action of Multiple Drug Resistance proteins capable of active CNS extrusion of Drugs. These include MDR1 (P-glycoprotein, PgP), the multiDrug Resistance related proteins MRP1-5, and lung-Resistance protein (LRP). Overexpression of MDR1 occurs in human epileptic brain. It has therefore been proposed that MDR1/PgP may contribute to Multiple Drug Resistance in epilepsy. In addition to MDR1/PgP, other genes such as MRP2, MRP5, and human cisplatin Resistance-associated protein are also overexpressed in Drug-resistant epilepsy. In normal brain tissue MDR1/PgP is expressed almost exclusively by endothelial cells (EC), while in epileptic cortex both EC and perivascular astrocytes express MDR1/PgP. The underlying causes for tissue differences may be genomic (i.e., at the DNA level), or MDR1/PgP could be induced by seizures, previous Drug treatment, or a combination of the above. We will present evidence showing that expression of Multiple Drug Resistance genes in epilepsy is a complex phenomenon and that glial cells are involved. This second line of defense for xenobiotics may have profound implications for the pharmacokinetic properties of antiepileptic Drugs and their capacity to reach neuronal targets.

  • Relationship between expression of Multiple Drug Resistance proteins and p53 tumor suppressor gene proteins in human brain astrocytes
    Neuroscience, 2003
    Co-Authors: Matteo Marroni, M. L. Agrawal, Kelly Kight, Kerri Hallene, Mohammed Hossain, Luca Cucullo, K. Signorelli, Shobu Namura, William Bingaman, Damir Janigro
    Abstract:

    Multiple Drug Resistance occurs when cells fail to respond to chemotherapy. Although it has been established that the Drug efflux protein P-glycoprotein protects the brain from xenobiotics, the mechanisms involved in the regulation of expression of Multiple Drug Resistance genes and proteins are not fully understood. Re-entry into the cell cycle and integrity of the p53 signaling pathway have been proposed as triggers of Multiple Drug Resistance expression in tumor cells. Whether this regulation occurs in non-tumor CNS tissue is not known. Since Multiple Drug Resistance overexpression has been reported in glia and blood vessels from epileptic brain, we investigated the level of expression of multiDrug Resistance protein, multiDrug Resistance-associated proteins and lung Resistance protein in endothelial cells and astrocytes isolated from epileptic patients or studied in situ in surgical tissue samples by double label immunocytochemistry. Reverse transcriptase-polymerase chain reaction and Western blot analyses revealed that Multiple Drug Resistance, multiDrug Resistance protein, and lung Resistance protein are expressed in these cells. Given that lung Resistance proteins have been reported to be preferentially expressed by tumors, we investigated expression of tumor suppressor genes in epileptic cortices. The pro-apoptotic proteins p53 and p21 could not be detected in "epileptic" astrocytes, while endothelial cells from the same samples readily expressed these proteins, as did normal brain astroglia and normal endothelial cells. Other apoptotic markers were also absent in epileptic glia. Our results suggest a possible link between loss of p53 function and expression of Multiple Drug Resistance in non-tumor CNS cells.

  • overexpression of Multiple Drug Resistance genes in endothelial cells from patients with refractory epilepsy
    Epilepsia, 2001
    Co-Authors: Stephen M Dombrowski, Matteo Marroni, Luca Cucullo, William Bingaman, Shailesh Y Desai, Kris Goodrich, Marc R Mayberg, Ljiljana Bengez, Damir Janigro
    Abstract:

    Summary:  Purpose: It has been suggested that altered Drug permeability across the blood–brain barrier (BBB) may be involved in pharmacoResistance to antiepileptic Drugs (AEDs). To test this hypothesis further, we measured Multiple Drug Resistance (MDR) gene expression in endothelial cells (ECs) isolated from temporal lobe blood vessels of patients with refractory epilepsy. ECs from umbilical cord or temporal lobe vessels obtained from aneurysm surgeries were used as comparison tissue. Methods: cDNA arrays were used to determine MDR expression. MDR protein (MRP1) immunocytochemistry and Western blot analysis were used to confirm cDNA array data. Results: We found overexpression of selected MDR and significantly higher P-glycoprotein levels in “epileptic” versus “control” ECs. Specifically, MDR1, cMRP/MRP2, and MRP5 were upregulated in epileptic tissue, whereas Pgp3/MDR3 levels were comparable to those measured in comparison tissue. The gene encoding cisplatin Resistance–associated protein (hCRA-α) also was overexpressed in epileptic tissue. Immunocytochemical analysis revealed that MDR1 immunoreactivity was localized primarily in ECs; MRP1 protein levels also were significantly higher in epileptic tissue. Conclusions: Complex MDR expression changes may play a role in AEDs pharmacoResistance by altering the permeability of AEDs across the BBB.

Albert D Donnenberg - One of the best experts on this subject based on the ideXlab platform.

  • measurement of Multiple Drug Resistance transporter activity in putative cancer stem progenitor cells
    Methods of Molecular Biology, 2009
    Co-Authors: Vera S Donnenberg, Michael E Meyer, Albert D Donnenberg
    Abstract:

    Multiple Drug Resistance, mediated by the expression and activity of ABC-transporters, is a major obstacle to antineoplastic therapy. Normal tissue stem cells and their malignant counterparts share MDR transporter activity as a major mechanism of self-protection. Although MDR activity is upregulated in response to substrate chemotherapeutic agents, it is also constitutively expressed on both normal tissue stem cells and a subset of tumor cells prior to the initiation of therapy, representing a built-in obstacle to therapeutic ratio. Constitutive and induced MDR activity can be detected in cellular subsets of disaggregated tissues, using the fluorescent substrates Rhodamine 123 and Hoechst 33342 for ABCB1 (also known as P-gp and MDR1) and ABCG2 (BCRP1). In this chapter, we will describe the complete procedure for the detection of MDR activity, including: (1) Preparing single-cell suspensions from tumor and normal tissue specimens; (2) An efficient method to perform cell surface marker staining on large numbers of cells; (3) Flow cytometer setup and controls; (4) Simultaneous measurement of Hoechst 33342 and Rhodamine123 transport; and (5) Data acquisition and analysis.

  • Multiple Drug Resistance in cancer revisited the cancer stem cell hypothesis
    The Journal of Clinical Pharmacology, 2005
    Co-Authors: Vera S Donnenberg, Albert D Donnenberg
    Abstract:

    The failure to eradicate cancer may be as fundamental as a misidentification of the target. Current therapies succeed at eliminating bulky disease but often miss a tumor reservoir that is the source of disease recurrence and metastasis. Recent advances in the understanding of tissue development and repair cause us to revisit the process of Drug Resistance as it applies to oncogenesis and tumor heterogeneity. The cancer stem cell hypothesis states that the cancer-initiating cell is a transformed tissue stem cell, which retains the essential property of self-protection through the activity of Multiple Drug Resistance (MDR) transporters. This resting constitutively Drug-resistant cell remains at low frequency among a heterogeneous tumor mass. In the context of this hypothesis, the authors review the discovery of MDR transporters in cancer and normal stem cells and the failure of MDR reversal agents to increase the therapeutic index of substrate antineoplastic agents.

  • Constitutive Multiple Drug Resistance in tumor stem cells
    Cancer Research, 2005
    Co-Authors: Vera S Donnenberg, James D. Luketich, Julie A. Deloia, Adam Brufsky, Neil A. Christie, Jeffrey A. Romoff, Albert D Donnenberg
    Abstract:

    2047 Failure to eradicate cancer may be as fundamental as a misidentification of the target. Current therapies succeed at eliminating bulky disease and proliferating cells, but miss a tumor reservoir that leads to disease recurrence and metastasis. Advances in the understanding of normal tissue development and repair provide a basis for revisiting oncogenesis, tumor heterogeneity, and Drug Resistance. In order to test the hypothesis that tumor stem cells, small resting cells with the stem cell-like properties of self-renewal, protection, and apoptosis Resistance, exist as rare populations in heterogeneous tumors, we used flow cytometry to simultaneously measure tumor and stem cell markers, and constitutive Multiple Drug Resistance transporter expression and activity ( side population ) in cancer specimens (breast, ovarian, lung, colon, renal, prostate). We concentrated on pleural effusions and ascites, where analysis is not confounded by the presence of normal tissue stem cells. In all cases (n=28) we have succeeded in detecting cytokeratin+, ESA+, CD45-, MDR+ tumor cells of small resting morphology. Building on the findings of the Clarke laboratory, we have shown that these cells are contained within the tumorigenic CD44+/CD24 negative or dim population. Small resting tumor cells are cytokeratin dim, exclusively display P-gp (ABCC1) activity (rhodamine 123 transport) and also express the classical stem cell markers c-kit (CD117), Thy-1 (CD90) and the MDR transporter ABCG2 (BCRP1). This population represents the best candidate for the resting tumor stem cell and is present in pleural effusions at a frequency of ∼1/100,000 cells. In ovarian and breast cancer we have isolated this subset and demonstrated long-term in vitro clonogenicity at frequencies

Fedor F. Severin - One of the best experts on this subject based on the ideXlab platform.

  • Dodecyltriphenylphosphonium inhibits Multiple Drug Resistance in the yeast Saccharomyces cerevisiae
    Biochemical and biophysical research communications, 2014
    Co-Authors: Dmitry A. Knorre, Olga V. Markova, Ekaterina A. Smirnova, Iuliia E. Karavaeva, Svyatoslav S. Sokolov, Fedor F. Severin
    Abstract:

    Abstract Multiple Drug Resistance pumps are potential Drug targets. Here we asked whether the lipophilic cation dodecyltriphenylphosphonium (C12TPP) can interfere with their functioning. First, we found that suppression of ABC transporter gene PDR5 increases the toxicity of C12TPP in yeast. Second, C12TPP appeared to prevent the efflux of rhodamine 6G – a fluorescent substrate of Pdr5p. Moreover, C12TPP increased the cytostatic effects of some other known Pdr5p substrates. The chemical nature of C12TPP suggests that after Pdr5p-driven extrusion the molecules return to the plasma membrane and then into the cytosol, thus effectively competing with other substrates of the pump.

  • Amiodarone inhibits Multiple Drug Resistance in yeast Saccharomyces cerevisiae
    Archives of microbiology, 2009
    Co-Authors: Dmitry A. Knorre, Tatiana N. Krivonosova, Olga V. Markova, Fedor F. Severin
    Abstract:

    Amiodarone is a widely used antiarrhythmic Drug. There is also evidence that amiodarone decreases multiDrug Resistance in human cell lines. In this paper, we have shown that amiodarone has similar effect on yeast, Saccharomyces cerevisiae, decreasing Multiple Drug Resistance. Amiodarone stimulates the accumulation of ethidium bromide by inhibiting its efflux from the cells. The effect of amiodarone is much stronger on wild-type cells compared to the mutant with inactivated ABC-transporters. Interestingly, the action of amiodarone is additive with the one of chloroquine, a known inhibitor of ABC-transporters. We speculate that these findings could help in the development of antifungal Drug mixes.

Engelbert Buxbaum - One of the best experts on this subject based on the ideXlab platform.

  • Co-operating ATP sites in the Multiple Drug Resistance transporter Mdr1.
    European journal of biochemistry, 1999
    Co-Authors: Engelbert Buxbaum
    Abstract:

    The ATPase activity of the Multiple Drug Resistance transporter Mdr1 (P-glycoprotein, gp170) depended on the concentration of ATP with both positive and negative co-operativity both in the absence and in the presence of verapamil. Four co-operating binding sites for ATP were required to adequately model the experimental findings. The activation energy for the ATPase activity increased from ≈ 385 kJ·mol−1 at 10 µm ATP to 512 kJ·mol−1 at 1600 µm, while changes in verapamil concentration had little effect. This indicates that the reaction mechanism of ATP hydrolysis depends on ATP concentration and is further evidence for co-operation of ATP binding sites. Free ATP in higher concentration was inhibitory; however, this inhibition could be reduced by complexing the ATP with Mg2+. Free Mg2+ had little effect on Mdr1 apart from complexing ATP.

  • Co-operative binding sites for transported substrates in the Multiple Drug Resistance transporter Mdr1.
    European journal of biochemistry, 1999
    Co-Authors: Engelbert Buxbaum
    Abstract:

    Suramin, a known inhibitor of ATP binding enzymes with six negatively charged sulfonic acid groups, stimulated the ATPase activity of the Multiple Drug Resistance transporter Mdr1 in low concentrations by acting as a substrate and by increasing the affinity for both verapamil and ATP. At higher concentrations suramin inhibited the ATPase activity competitively with respect to ATP and noncompetitively with respect to verapamil. This indicates an interaction of suramin with the ATP site. Verapamil itself activated the ATPase activity of Mdr1 only at moderate concentrations, but showed substrate inhibition at higher concentrations. This was also observed for progesterone, which decreased the Ki of Mdr1 for verapamil but increased the Km. Additionally, verapamil increased the Hill coefficient of Mdr1 for progesterone from 1.1 to 3.2. These results indicate the existence of Multiple binding sites (at least four for progesterone) for transported substrate in Mdr1 and a complicated mode of interactions between them.

Yoshifumi Takeda - One of the best experts on this subject based on the ideXlab platform.

  • Emergence of tetracycline Resistance due to a Multiple Drug Resistance plasmid in Vibrio cholerae O139.
    FEMS immunology and medical microbiology, 1995
    Co-Authors: Tatsuo Yamamoto, G. Balakrish Nair, Yoshifumi Takeda
    Abstract:

    Of the 173 clinical strains of Vibrio cholerae O139 isolated from India, Bangladesh, and Thailand tested, six strains from India were resistant to tetracycline, ampicillin, chloramphenicol, kanamycin, and gentamicin. These six strains harbored a self-transmissible plasmid that mediated Resistance to tetracycline, ampicillin, chloramphenicol, kanamycin, gentamicin, sulfamethoxazole, trimethoprim, and O/129. The Multiple Drug Resistance plasmids were 200 kb in size and belonged to the incompatibility group C. Although a majority of the O139 strains (94.8%) were highly resistant to streptomycin, sulfamethoxazole, trimethoprim, and O/129, the tetracycline-susceptible strains so far tested were plasmid-negative. The data suggest the existence of two distinct Multiple antimicrobial agent Resistance (MAR) patterns in V. cholerae O139.