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Sample records for multidrug resistance p-glycoprotein

  1. Modulation of P-Glycoprotein Mediated Multidrug Resistance (Mdr in Cancer Using Chemosensitizers.

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    Velingkar V.S

    2010-03-01

    Full Text Available Multidrug resistance (MDR is one of the main obstacles in the chemotherapy of cancer. MDR is associated with the over expression of P-glycoprotein (P-gp, resulting in increased efflux of chemotherapy from cancer cells. Inhibiting P-gp as a method to reverse MDR in cancer patients has been studied extensively, but the results have generally been disappointing. First-generation agents were limited by unacceptable toxicity, whereas second-generation agents had bettertolerability but were confounded by unpredictable pharmacokinetic interactions and interactions with other transporter proteins. Third-generation inhibitors have high potency and specificity for P-gp. Furthermore, pharmacokinetic studies to date have shown no appreciable impact on drug metabolism and no clinically significant drug interactions with common chemotherapy agents. Third-generation P-gp inhibitors have shown promise in clinical trials. The continued development of these agents may establish the true therapeutic potential of P-gp-mediated MDR reversal.

  2. Is reduced accumulation of Hoechst 33342 in multidrug resistant cells related to P-glycoprotein activity?

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    Lahmy, S; Viallet, P; Salmon, J M

    1995-02-01

    Although bisbenzimidazole-DNA interactions have been studied in solution, little information has been available in living cells. The reduced accumulation of the nuclear dye Hoechst 33342 (H342) in cells with multidrug resistant (MDR) phenotype suggested its possible use in a functional test for detection of these cells. We performed experiments to elucidate the mechanisms involved in the H342-exclusion from resistant cells. As contradictory results have been reported in literature, we compared the entire fluorescence spectra of H342 in solution and in intact living cells under different experimental conditions. The study was performed by fluorescence image cytometry. This technique allow accurate quantification of the amount of H342 bound to DNA in living cells. The dye uptake was followed in sensitive and resistant cells, a lymphoblastoid cell line, CCRF-CEM, and its resistant variant selected with vinblastine CEM/VLB100 under conditions that could modulate H342-cell binding. Competition experiments with sodium azide, verapamil, and vinblastine indicated that resistant cells did not differ in the number of possible binding sites for H342. The obtained results ruled out the possibility of discriminating cells on the basis of a spectral shift. Two modes of binding, differing in their affinity for the dye, seem to co-exist in intact cells. Although it clearly appeared that the P-glycoprotein expressed in MDR cells was mainly responsible for the H342-exclusion, other mechanisms might also be involved. PMID:7743893

  3. Modulation of P-glycoprotein function and multidrug resistance in cancer cells by Thai plant extracts.

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    Takano, M; Kakizoe, S; Kawami, M; Nagai, J; Patanasethnont, D; Sripanidkulchai, B; Yumoto, R

    2014-11-01

    The effects of ethanol extracts from Thai plants belonging to the families of Annonaceae, Rutaceae, and Zingiberaceae on P-glycoprotein (P-gp) function and multidrug resistance were examined in paclitaxel-resistant HepG2 (PR-HepG2) cells. All the extracts tested, significantly increased the accumulation of [3H]paclitaxel, a P-gp substrate, in the cells. Among nine extracts, Z01 and Z02, extracts from Curcuma comosa and Kaempferia marginata (Zingiberaceae family), respectively, potently increased the accumulation. In addition, Z01 and Z02 increased the accumulation of other P-gp substrates, rhodamine 123 and doxorubicin, in PR-HepG2 cells in a concentration-dependent manner. Increased accumulation of rhodamine 123 and doxorubicin by Z01 and Z02 was also confirmed by confocal laser scanning microscopy. The effect of Z01 and Z02 pretreatment on the expression of MDR1 mRNA was also examined. The expression of MDR1 mRNA was not affected by the treatment of PR-HepG2 cells with these extracts for 48 hours. Cytotoxicity of paclitaxel was examined by XTT and protein assays in the absence and presence of Z02. Z02 potentiated the cytotoxicity of paclitaxel in PR-HepG2 cells. These results suggest that Curcuma comosa and Kaempferia marginata belonging to Zingiberaceae are useful sources to search for new P-gp modulator(s) that can be used to overcome multidrug resistance of cancer cells. PMID:25985578

  4. CD44 promotes multi-drug resistance by protecting P-glycoprotein from FBXO21-mediated ubiquitination

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    Ravindranath, Abhilash K.; Kaur, Swayamjot; Wernyj, Roman P.; Kumaran, Muthu N.; Miletti-Gonzalez, Karl E.; Chan, Rigel; Lim, Elaine; Madura, Kiran; Rodriguez-Rodriguez, Lorna

    2015-01-01

    Here we demonstrate that a ubiquitin E3-ligase, FBXO21, targets the multidrug resistance transporter, ABCB1, also known as P-glycoprotein (P-gp), for proteasomal degradation. We also show that the Ser291-phosphorylated form of the multifunctional protein and stem cell marker, CD44, inhibits FBXO21-directed degradation of P-gp. Thus, CD44 increases P-gp mediated drug resistance and represents a potential therapeutic target in P-gp-positive cells. PMID:26299618

  5. Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites

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    Cordon-Cardo, C.; O' Brien, J.P.; Casals, D.; Biedler, J.L.; Melamed, M.R.; Bertino, J.R. (Memorial Sloan-Kettering Cancer Center, New York, NY (USA)); Rittman-Grauer, L. (Hybritech, Inc., San Diego, CA (USA))

    1989-01-01

    Endothelial cells of human capillary blood vessels at the blood-brain and other blood-tissue barrier sites express P-glycoprotein as detected by mouse monoclonal antibodies against the human multidrug-resistance gene product. This pattern of endothelial cell expression may indicate a physiological role for P-glycoprotein in regulating the entry of certain molecules into the central nervous system and other anatomic compartments, such as the testes. These tissues, which limit the access of systemic drugs, are known pharmacologic sanctuaries for metastatic cancer. P-glycoprotein expression in capillary endothelium of brain and testes and not other tissues (i.e., kidney and placenta) may in part explain this phenomenon and could have important implications in cancer chemotherapy.

  6. The expression and significance of P-glycoprotein, lung resistance protein and multidrug resistance-associated protein in gastric cancer

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    Li Yan

    2009-11-01

    Full Text Available Abstract Background To detect the expression of multidrug resistance molecules P-glycoprotein (P-gp, Lung resistnce protein (LRP and Multidrug resistance-associated protein (MRP and analyze the relationship between them and the clinico-pathological features. Methods The expressions of P-gp, LRP and MRP in formalin-fixed paraffin-embedded tissue sections from 59 gastric cancer patients were determined by a labbelled Streptavidin-Peroxidase (SP immunohistochemical technique, and the results were analyzed in correlation with clinicopathological data. None of these patients received chemotherapy prior to surgery. Results The positive rates of P-gp, LRP, MRP were 86.4%, 84.7% and 27.1%, respectively. The difference between the positive rate of P-gp and MRP was significant statistically, as well as the difference between the expression of MRP and LRP. No significant difference was observed between P-gp and LRP, but the positively correlation between the expression of P-gp and LRP had been found. No significant correlation between the expression of P-gp, LRP, MRP and the grade of differentiation were observed. The expression of P-gp was correlated with clinical stages positively (r = 0.742, but the difference with the expression of P-gp in different stages was not significant. Conclusion The expressions of P-gp, LRP and MRP in patients with gastric cancer without prior chemotherapy are high, indicating that innate drug resistance may exist in gastric cancer.

  7. Expression of P-glycoprotein and multidrug resistance associated protein in Ehrlich ascites tumor cells after fractionated irradiation

    DEFF Research Database (Denmark)

    Nielsen, D; Maare, C; Eriksen, J; Litman, Thomas; Skovsgaard, T

    2001-01-01

    PURPOSE: To characterize irradiated murine tumor cells with respect to drug resistance, drug kinetics, and ATPase activity, and to evaluate the possible role of P-glycoprotein (PGP) and murine multidrug resistance associated protein (Mrp1) in the drug-resistant phenotype of these cells. METHODS AND...... MATERIALS: Sensitive Ehrlich ascites tumor cells (EHR2) were in vitro exposed to fractionated irradiation (60 Gy). Western blot analysis was performed for determination of PGP and Mrp1, reverse transcriptase-polymerase chain reaction (RT-PCR) for determination of mdr1a + b mRNA, and semiquantitative RT......-PCR for Mrp1 mRNA. The clonogenic assay was applied to investigate sensitivity, whereas the steady-state drug accumulation of daunorubicin (DNR), 3H-vincristine (VCR), and 3H-etoposide (VP16) was measured by spectrofluorometry and scintillation counting, respectively. For determining of ATPase activity...

  8. Phosphorylation of the multidrug resistant associated glycoprotein (p-glycoprotein): Preparation and characterization of 7-acetyltaxol

    International Nuclear Information System (INIS)

    To assess the role of phosphorylation in P-glycoprotein function, phosphorylation of P-glycoprotein in intact cells and in cell-free membrane fractions has been studied. Results obtained with cell-free membrane fractions indicate that P-glycoprotein is a substrate for a membrane-associated protein kinase A (PK-A). To assess whether P-glycoprotein was phosphorylated in vivo by PK-A, MDR cells were incubated with [32P]Pi in the presence or absence of 100 uM 8Br-cAMP. The tryptic phosphopeptides of six P-glycoproteins from five independently derived MDR cell lines were analyzed by HPLC. A similar analysis carried out with two other P-glycoproteins (from J7.V3-1 and the lower band of J7.T1-50) demonstrated a major phosphopeptide with a retention time of 26 min. Fraction 26 was resolved as a single phosphopeptide by 2-D mapping. The phosphorylation of fraction 26 which was derived from P-glycoprotein in J7.V3-1 or the J7.T1-50 lower band was enhanced when the cells were treated with 8BrcAMP

  9. Phosphorylation of the multidrug resistant associated glycoprotein (p-glycoprotein): Preparation and characterization of 7-acetyltaxol

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    Mellado, W.

    1988-01-01

    To assess the role of phosphorylation in P-glycoprotein function, phosphorylation of P-glycoprotein in intact cells and in cell-free membrane fractions has been studied. Results obtained with cell-free membrane fractions indicate that P-glycoprotein is a substrate for a membrane-associated protein kinase A (PK-A). To assess whether P-glycoprotein was phosphorylated in vivo by PK-A, MDR cells were incubated with ({sup 32}P)Pi in the presence or absence of 100 uM 8Br-cAMP. The tryptic phosphopeptides of six P-glycoproteins from five independently derived MDR cell lines were analyzed by HPLC. A similar analysis carried out with two other P-glycoproteins (from J7.V3-1 and the lower band of J7.T1-50) demonstrated a major phosphopeptide with a retention time of 26 min. Fraction 26 was resolved as a single phosphopeptide by 2-D mapping. The phosphorylation of fraction 26 which was derived from P-glycoprotein in J7.V3-1 or the J7.T1-50 lower band was enhanced when the cells were treated with 8BrcAMP.

  10. Modulation of P-glycoprotein-mediated multidrug resistance in K562 leukemic cells by indole-3-carbinol

    International Nuclear Information System (INIS)

    Resistance to chemotherapeutic drugs is one of the major problems in the treatment of cancer. P-glycoprotein (P-gp) encoded by the mdr gene is a highly conserved protein, acts as a multidrug transporter, and has a major role in multiple drug resistance (MDR). Targeting of P-gp by naturally occurring compounds is an effective strategy to overcome MDR. Indole-3-carbinol (I3C), a glucosinolates present in cruciferous vegetables, is a promising chemopreventive agent as it is reported to possess antimutagenic, antitumorigenic, and antiestrogenic properties in experimental studies. In the present investigation, the potential of I3C to modulate P-gp expression was evaluated in vinblastine (VBL)-resistant K562 human leukemic cells. The resistant K562 cells (K562/R10) were found to be cross-resistant to vincristine (VCR), doxorubicin (DXR), and other antineoplastic agents. I3C at a nontoxic dose (10 x 10-3 M) enhanced the cytotoxic effects of VBL time dependently in VBL-resistant human leukemia (K562/R10) cells but had no effect on parent-sensitive cells (K562/S). The Western blot analysis of K 562/R 10 cells showed that I3C downregulates the induced levels of P-gp in resistant cells near to normal levels. The quantitation of immunocytochemically stained K562/R10 cells showed 24%, 48%, and 80% decrease in the levels of P-gp by I3C for 24, 48, and 72 h of incubation. The above features thus indicate that I3C could be used as a novel modulator of P-gp-mediated multidrug resistance in vitro and may be effective as a dietary adjuvant in the treatment of MDR cancers

  11. Inhibition of multidrug resistance by immunisation with synthetic P-glycoprotein-derived peptides.

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    Pawlak-Roblin, C; Tosi, P-F; Perrin, L; Devy, J; Venteo, L; Albert, P; Nicolau, C; Madoulet, C

    2004-03-01

    Overexpression of the membrane glycoprotein (P170) represents the most common multidrug resistance (MDR) mechanism in cancer therapy. Specific auto-antibodies to extracellular loops 1, 2 and 4 of murine P170 were elicited in mice using palmitoylated synthetic peptides reconstituted in liposomes, with or without Lipid A, and resuspended in alum. IgM antibodies were detected 14 days following the first injection and IgG1 became predominant after the third challenge. Animals did not show any auto-immune symptoms or induced toxicity up to 18 months after the immunisation. Previous immunisations of mice using liposomes with MDR1 peptides increases the efficacy of chemotherapy treatments with doxorubicin and vinblastine against P388 R cells with increase of 77% in the survival half time in the immunised group. Sera from the immunised mice were also effective in reducing cellular resistance to vinblastine and doxorubicin in vitro. Taken together, these data suggest that this immunisation approach might have potential clinical applications. PMID:14962730

  12. Overexpression of P-glycoprotein but not its mRNA in multidrug resistant cells selected with hydroxyrubicin.

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    Zhao, J Y; Savaraj, N; Song, R; Priebe, W; Kuo, M T

    1994-01-01

    Previous studies have revealed that cultured cells treated with lipophilic natural products containing aromatic rings and basic amino group usually yielded multidrug resistant (MDR) variants. These MDR cells overexpress P-glycoprotein (P-gp), most often due to gene amplification or transcriptional activation of mdr/P-gp genes. Doxorubicin (Dox) is an anthracycline that belongs to this group of compounds. To explore the possible resistance mechanism(s) to anthracyclines that do not involve P-gp, we use a Dox analog, hydroxyrubicin (HyR) or WP159, which contains a C3' hydroxy group in replacement of the amino group in the sugar moiety of Dox thereby reducing basicity and eliminating positive charge in the parental compound to establish HyR-resistant cell lines. These resistant cells displayed the MDR phenotype and overexpressed P-gp as analyzed by Western blot analyses and immunohistochemical staining using two different anti-P-gp antibodies. Strikingly, the levels of P-gp mRNA in the majority of these MDR cells remained comparable to those in the drug-sensitive counterparts by slot blot hybridization. These results implicate that the basic center of the selecting agent is a critical determinant for generating diverse MDR variants, and that HyR may have a posttranscriptional effect on P-gp biosynthesis. This is the first report suggesting that cultured cells exposed to a particular selecting agent may give rise to particular subtype of MDR variants. PMID:7531410

  13. Natural lignans from Arctium lappa modulate P-glycoprotein efflux function in multidrug resistant cancer cells.

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    Su, Shan; Cheng, Xinlai; Wink, Michael

    2015-02-15

    Arctium lappa is a well-known traditional medicinal plant in China (TCM) and Europe that has been used for thousands of years to treat arthritis, baldness or cancer. The plant produces lignans as secondary metabolites which have a wide range of bioactivities. Yet, their ability to reverse multidrug resistance (MDR) in cancer cells has not been explored. In this study, we isolated six lignans from A. lappa seeds, namely arctigenin, matairesinol, arctiin, (iso)lappaol A, lappaol C, and lappaol F. The MDR reversal potential of the isolated lignans and the underlying mechanism of action were studied using two MDR cancer cell lines, CaCo2 and CEM/ADR 5000 which overexpress P-gp and other ABC transporters. In two-drug combinations of lignans with the cytotoxic doxorubicin, all lignans exhibited synergistic effects in CaCo2 cells and matairesinol, arctiin, lappaol C and lappaol F display synergistic activity in CEM/ADR 5000 cells. Additionally, in three-drug combinations of lignans with the saponin digitonin and doxorubicin MDR reversal activity was even stronger enhanced. The lignans can increase the retention of the P-gp substrate rhodamine 123 in CEM/ADR 5000 cells, indicating that lignans can inhibit the activity of P-gp. Our study provides a first insight into the potential chemosensitizing activity of a series of natural lignans, which might be candidates for developing novel adjuvant anticancer agents. PMID:25765837

  14. Progesterone interacts with P-glycoprotein in multidrug-resistant cells and in the endometrium of gravid uterus.

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    Yang, C P; DePinho, S G; Greenberger, L M; Arceci, R J; Horwitz, S B

    1989-01-15

    P-Glycoprotein (P-GP) plays a pivotal role in maintaining the multidrug-resistant (MDR) phenotype. This membrane glycoprotein is overproduced in MDR cells and the endometrium of the mouse gravid uterus (Arceci, R.J., Croop, J.M., Horwitz, S.B., and Housman, D. (1988) Proc. Natl. Acad. Sci. U.S.A. 85, 4350-4354). This latter observation and an interest in endogenous substrates for P-GP led to a study of the interaction of steroids with P-GP found in the endometrium of the mouse gravid uterus and in MDR cells derived from the murine macrophage-like cell J774.2. [3H]Azidopine labeling of P-GP from these two sources was inhibited by various steroids, particularly progesterone. Progesterone also markedly inhibited [3H]vinblastine binding to membrane vesicles prepared from MDR cells, enhanced vinblastine accumulation in MDR cells, and increased the sensitivity of MDR cells to vinblastine. In addition, we have demonstrated that the hydrophobicity of a steroid is important in determining its effect on inhibition of drug binding to P-GP. It is concluded that progesterone, a relatively nontoxic endogenous steroid, interacts with P-GP and is capable of reversing drug resistance in MDR cells. PMID:2562956

  15. Identification of the Interaction between P-Glycoprotein and Anxa2 in Multidrug-resistant Human Breast Cancer Cells

    International Nuclear Information System (INIS)

    To explore the interaction of Anxa2 with P-Glycoprotein (P-gp) in the migration and invasion of the multidrug-resistant (MDR) human breast cancer cell line MCF-7/ADR. A pair of short hairpin RNA (shRNA) targeting P-gp was transfected into MCF-7/ADR cells, and monoclonal cell strains were screened. The expression of P-gp was detected by Western blot. Transwell chambers were used to observe the cell migration capacity and invasion ability. The interaction between P-gp and Anxa2 was examined by immunoprecipitation and immunofluorescence confocal microscopy analyses. P-gp expression was significantly knocked down, and there were notable decreasing trends in the migration and invasion capability of MDR breast cancer cells (P<0.05). There was a close interaction between Anxa2 and P-gp. MCF-7/ADR is an MDR human breast cancer cell line with high migration and invasion abilities. The knockdown of P-gp notably impaired the migration and invasion abilities of the tumor cells. The interaction of Anxa2 with P-pg may play an important role in the enhanced invasiveness of MDR human breast cancer cells

  16. Directed evolution of P-glycoprotein cysteines reveals site-specific, non-conservative substitutions that preserve multidrug resistance

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    Douglas J. Swartz

    2014-06-01

    Full Text Available Pgp (P-glycoprotein is a prototype ABC (ATP-binding-cassette transporter involved in multidrug resistance of cancer. We used directed evolution to replace six cytoplasmic Cys (cysteine residues in Pgp with all 20 standard amino acids and selected for active mutants. From a pool of 75000 transformants for each block of three Cys, we identified multiple mutants that preserved drug resistance and yeast mating activity. The most frequent substitutions were glycine and serine for Cys427 (24 and 20%, respectively and Cys1070 (37 and 25% of the Walker A motifs in the NBDs (nucleotide-binding domains, Cys1223 in NBD2 (25 and 8% and Cys638 in the linker region (24 and 16%, whereas close-by Cys669 tolerated glycine (16% and alanine (14%, but not serine (absent. Cys1121 in NBD2 showed a clear preference for positively charged arginine (38% suggesting a salt bridge with Glu269 in the ICL2 (intracellular loop 2 may stabilize domain interactions. In contrast, three Cys residues in transmembrane α-helices could be successfully replaced by alanine. The resulting CL (Cys-less Pgp was fully active in yeast cells, and purified proteins displayed drug-stimulated ATPase activities indistinguishable from WT (wild-type Pgp. Overall, directed evolution identified site-specific, non-conservative Cys substitutions that allowed building of a robust CL Pgp, an invaluable new tool for future functional and structural studies, and that may guide the construction of other CL proteins where alanine and serine have proven unsuccessful.

  17. Membrane transport of camptothecin: facilitation by human P-glycoprotein (ABCB1 and multidrug resistance protein 2 (ABCC2

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    Lee Sung-Hack

    2004-05-01

    Full Text Available Abstract Background The purpose of the present study was to continue the investigation of the membrane transport mechanisms of 20-(S-camptothecin (CPT in order to understand the possible role of membrane transporters on its oral bioavailability and disposition. Methods The intestinal transport kinetics of CPT were characterized using Caco-2 cells, MDCKII wild-type cells and MDCKII cells transfected with human P-glycoprotein (PGP (ABCB1 or human multidrug resistance protein 2 (MRP2 (ABCC2. The effects of drug concentration, inhibitors and temperature on CPT directional permeability were determined. Results The absorptive (apical to basolateral and secretory (basolateral to apical permeabilities of CPT were found to be saturable. Reduced secretory CPT permeabilities with decreasing temperatures suggests the involvement of an active, transporter-mediated secretory pathway. In the presence of etoposide, the CPT secretory permeability decreased 25.6%. However, inhibition was greater in the presence of PGP and of the breast cancer resistant protein inhibitor, GF120918 (52.5%. The involvement of additional secretory transporters was suggested since the basolateral to apical permeability of CPT was not further reduced in the presence of increasing concentrations of GF120918. To investigate the involvement of specific apically-located secretory membrane transporters, CPT transport studies were conducted using MDCKII/PGP cells and MDCKII/MRP2 cells. CPT carrier-mediated permeability was approximately twofold greater in MDCKII/PGP cells and MDCKII/MRP2 cells than in MDCKII/wild-type cells, while the apparent Km values were comparable in all three cell lines. The efflux ratio of CPT in MDCKII/PGP in the presence of 0.2 ?M GF120918 was not completely reversed (3.36 to 1.49. However, the decrease in the efflux ratio of CPT in MDCKII/MRP2 cells (2.31 to 1.03 suggests that CPT efflux was completely inhibited by MK571, a potent inhibitor of the Multidrug Resistance Protein transporter family. Conclusions The current results provide evidence that PGP and MRP2 mediate the secretory transport of CPT in vitro. However, the involvement of other transporters cannot be ruled out based on these studies. Since these transporters are expressed in the intestine, liver and kidney variations in their expression levels and/or regulation may be responsible for the erratic oral absorption and biliary excretion of CPT observed in human subjects.

  18. Technetium-99m methoxyisobutylisonitrile imaging for parathyroid adenoma: relationship to P-glycoprotein or multidrug resistance-related protein expression

    International Nuclear Information System (INIS)

    Gland size has been reported to have a major influence on localisation of parathyroid adenomas by technetium-99m methoxyisobutylisonitrile (99mTc-MIBI) imaging. It has also been suggested that P-glycoprotein (Pgp) expression in parathyroid adenomas may influence localisation because false negative studies have been reported with large tumours and true positives with very small tumours. Therefore, the purpose of this study was to retrospectively evaluate the relationship between 99mTc-MIBI parathyroid imaging results and Pgp or multidrug resistance-related protein (MRP) expression in parathyroid adenomas. Before surgery, 47 patients with large parathyroid adenomas (larger than 1.5 g) underwent early and delayed parathyroid imaging, 10 min and 2 h after intravenous injection of 99mTc-MIBI. Immunohistochemical analyses (IHA) were performed, using multiple non-consecutive sections of the operative specimens, to detect Pgp or MRP expression. According to the results of IHA, the 34 parathyroid adenomas were separated into four groups: (1) three adenomas positive for both Pgp and MRP expression, (2) one adenoma positive for Pgp but negative for MRP expression, (3) four adenomas negative for Pgp but positive for MRP expression and (4) 39 adenomas with negative for both Pgp and MRP expression. All 39 adenomas in group 4 could be detected by 99mTc-MIBI parathyroid imaging. None of the eight adenomas in groups 1-3 could be detected by 99mTc-MIBI parathyroid imaging (P99mTc-MIBI imaging in localising parathyroid adenomas preoperatively. (orig.)

  19. Reversal of P-glycoprotein-mediated multidrug resistance by the murine double minute 2 antagonist nutlin-3.

    Science.gov (United States)

    Michaelis, Martin; Rothweiler, Florian; Klassert, Denise; von Deimling, Andreas; Weber, Kristoffer; Fehse, Boris; Kammerer, Bernd; Doerr, Hans Wilhelm; Cinatl, Jindrich

    2009-01-15

    Murine double minute 2 (MDM2) negatively regulates the activity of the tumor suppressor protein p53. Nutlin-3 is a MDM2 inhibitor under preclinical investigation as nongenotoxic activator of the p53 pathway for cancer therapy. Here, nutlin-3 was evaluated for its activity alone or in combination with established chemotherapeutic drugs for antitumor action in chemosensitive and chemoresistant neuroblastoma and rhabdomyosarcoma cell lines. Effects of nutlin-3 single treatment were much more pronounced in p53 wild-type cell lines (IC(50)s 17 micromol/L). In sharp contrast to the expectations, nutlin-3 concentrations that did not affect viability of p53-mutated cell lines strongly increased the efficacy of vincristine in p53-mutated, P-glycoprotein (P-gp)-overexpressing cell lines (decrease in IC(50)s 92- to 3,434-fold). Similar results were obtained for other P-gp substrates. Moreover, nutlin-3 reduced efflux of rhodamine 123 and other fluorescence dyes that are effluxed by P-gp. Investigation of Madin-Darby canine kidney (MDCK) II cells stably transfected with plasmids encoding for P-gp (MDCKII MDR1) or multidrug resistance protein 1 (MRP-1, MDCKII MRP1) revealed that nutlin-3 not only interferes with P-gp but also affects MRP-1-mediated efflux. Kinetic studies and investigation of P-gp-ATPase activity showed that nutlin-3 is likely to act as a P-gp transport substrate. Examination of the nutlin-3 enantiomers nutlin-3a and nutlin-3b revealed that, in contrast to MDM2-inhibitory activity that is limited to nutlin-3a, both enantiomers similarly interfere with P-gp-mediated drug efflux. In conclusion, nutlin-3-induced inhibition of P-gp and MRP-1 was discovered as a novel anticancer mechanism of the substance in this report. PMID:19147553

  20. Impact of BCRP/MXR, MRP1 and MDR1/P-Glycoprotein on thermoresistant variants of atypical and classical multidrug resistant cancer cells

    DEFF Research Database (Denmark)

    Stein, Ulrike; Lage, Hermann; Jordan, Andreas; Walther, Wolfgang; Bates, Susan E; Litman, Thomas; Hohenberger, Peter; Dietel, Manfred

    2002-01-01

    The impact of the ABC transporters breast cancer resistance protein/mitoxantrone resistance associated transporter (BCRP/MXR), multidrug resistance-associated protein 1 (MRP1) and multidrug resistance gene-1/P-glycoprotein (MDR1/PGP) on the multidrug resistance (MDR) phenotype in chemoresistance...... EPG85-257RNOV expression of BCRP/MXR and of MRP1 were clearly enhanced (vs. parental and classical MDR lines). MDR1/PGP expression was distinctly elevated in the classical MDR subline EPG85-257RDB (vs. parental and atypical MDR sublines). In all thermoresistant counterparts basal expression of BCRP....../MXR, MRP1 and MDR1/PGP was increased relative to thermosensitive sublines. Although it could be shown that the overexpressed ABC transporters were functionally active, however, no decreased drug accumulations of doxorubicin, mitoxantrone and rhodamine 123 were observed. Thus, expression of BCRP/MXR, MRP1...

  1. Non-alkaloids extract from Stemona sessilifolia enhances the activity of chemotherapeutic agents through P-glycoprotein-mediated multidrug-resistant cancer cells.

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    Han, Lu; Ma, Yang-Mei; An, Li; Zhang, Qiao; Wang, Chang-Li; Zhao, Qing-Chun

    2016-05-01

    One of the major impediments to the successful treatment of cancer is the development of resistant cancer cells, which could cause multidrug resistance (MDR), and overexpression of ABCB1/P-glycoprotein (P-gp) is one of the most common causes of MDR in cancer cells. Recently, natural products or plant-derived chemicals have been investigated more and more widely as potential multidrug-resistant (MDR) reversing agents. The current study demonstrated for the first time that non-alkaloids extract from Stemona sessilifolia significantly reversed the resistance of chemotherapeutic agents, adriamycin, paclitaxel and vincristine to MCF-7/ADR cells compared with MCF-7/S cells in a dose-dependent manner. The results obtained from these studies indicated that the non-alkaloids extract from S. sessilifolia plays an important role in reversing MDR of cancer as a P-gp modulator in vitro and may be effective in the treatment of multidrug-resistant cancers. PMID:26190165

  2. Expression and function of P-glycoprotein and absence of multidrug resistance-related protein in rat and beige mouse peritoneal mast cells.

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    Candussio, L; Crivellato, E; Rosati, A M; Klugmann, F B; Granzotto, M; Giraldi, T; Decorti, G

    2001-05-01

    To clarify the function of the multidrug transporter P-glycoprotein in mast cells we used the green fluorescent compound Bodipy-FL-verapamil, which is a substrate of P-glycoprotein. This compound is also transported by Multidrug Resistance-related Protein (MRP), another membrane transport protein expressed in many tumour resistant cells as well as in normal cells. When rat peritoneal mast cells were incubated with Bodipy-verapamil, a rapid uptake of this compound was observed. Pretreatment with modulators of P-glycoprotein activity, such as verapamil and vinblastine, increased Bodipy-verapamil intracellular concentrations. In addition, Bodipy-verapamil efflux from these cells was rapid and also inhibited by verapamil and vinblastine. In contrast, no effect was observed when cells were treated with agents, such as probenecid and indomethacin, that are known inhibitors of MRP. Methylamine and monensin, substances that modify the pH values in the granules, were able to lower the concentrations of Bodipy-verapamil. Microscopical observations, conducted in both rat and beige mouse mast cells, demonstrated that the fluorochrome accumulated in the cytoplasmic secretory granules. RT-PCR performed on rat peritoneal mast cells revealed the presence of MDR1a and MDR1b mRNAs; on the contrary, MRP mRNA was not expressed. Mast cells were further treated with the fluorescent probe LysoSensor Blue, a weak base that becomes fluorescent when inside acidic organelles. This substance accumulated in mast cell granular structures and its fluorescence was reduced either by treatment with P-glycoprotein modulators or with agents that disrupt pH gradients. In conclusion, these data further confirm the presence of an active P-glycoprotein, but not of MRP, in rat peritoneal mast cells. These findings, coupled with previous ultrastructural data, lend further support to the assumption that this protein is located on the mast cell perigranular membrane. The functional role of P-glycoprotein in these cells is at present unclear, but a possible involvement in the transport of molecules from the granules to the cytosol can be hypothesized. Alternatively, this protein might be indirectly implicated in changes of pH values inside secretory granules. PMID:11563538

  3. P-glycoprotein, but not Multidrug Resistance Protein 4, Plays a Role in the Systemic Clearance of Irinotecan and SN-38 in Mice

    OpenAIRE

    Tagen, Michael; Zhuang, Yanli; Zhang, Fan; Harstead, K. Elaine; Shen, Jun; Schaiquevich, Paula; Fraga, Charles H.; Panetta, John C; Waters, Christopher M.; Stewart, Clinton F.

    2010-01-01

    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 mice were administered 20 or 40 mg/kg irinotecan, and plasma samples were collected for 6 hours. Irinotecan and SN-38 lactone and carboxylate were quantitated and data were analyzed with nonlinear mixed-effects modeling. Mdr1a/b ...

  4. Photodynamic therapy inhibits p-glycoprotein mediated multidrug resistance via JNK activation in human hepatocellular carcinoma using the photosensitizer pheophorbide a

    Directory of Open Access Journals (Sweden)

    Kong Siu-Kai

    2009-07-01

    Full Text Available Abstract Background Multidrug resistance (MDR is frequently observed after prolonged treatment in human hepatoma with conventional anti-tumor drugs, and photodynamic therapy (PDT is a recently suggested alternative to overcome MDR. The therapeutic potential of PDT was evaluated in a multidrug resistance (MDR human hepatoma cell line R-HepG2 with photosensitizer pheophorbide a (Pa. Results Our results demonstrated that intracellular accumulation of Pa was not reduced by the overexpression of P-glycoprotein. Pa-based PDT (Pa-PDT significantly inhibited the growth of R-HepG2 cells with an IC50 value of 0.6 ?M. Mechanistic study demonstrated that genomic DNA fragmentation and phosphatidylserine externalization occurred where increase of intracellular singlet oxygen level triggers the phosphorylation of c-Jun N-terminal Kinase (JNK and leads to activation of intrinsic apoptotic caspases cascade during the Pa-PDT treatment. The cytotoxicity of Pa-PDT, accumulation of sub-G1 population, and depolarization of mitochondrial membrane could be inhibited by JNK inhibitor in the Pa-PDT treated cells. Interestingly, the Pa-PDT induced JNK activation showed inhibitory effect on MDR by the down-regulation of P-glycoprotein in R-HepG2 cells in a dose-dependent manner. In addition, significant reduction of tumor size was obtained in Pa-PDT treated R-HepG2-bearing nude mice with no significant damages in liver and heart. Conclusion In summary, our findings provided the first evidence that PDT could inhibit the MDR activity by down-regulating the expression of P-glycoprotein via JNK activation using pheophorbide a as the photosensitizer, and our work proved that Pa-PDT inhibited the growth of MDR hepatoma cells by mitochondrial-mediated apoptosis induction.

  5. In vitro transport of gimatecan (7-t-butoxyiminomethylcamptothecin) by breast cancer resistance protein, P-glycoprotein, and multidrug resistance protein 2.

    Science.gov (United States)

    Marchetti, Serena; Oostendorp, Roos L; Pluim, Dick; van Eijndhoven, Monique; van Tellingen, Olaf; Schinkel, Alfred H; Versace, Richard; Beijnen, Jos H; Mazzanti, Roberto; Schellens, Jan H

    2007-12-01

    Lipophilic camptothecin derivatives are considered to have negligible affinity for breast cancer resistance protein (BCRP; ABCG2). Gimatecan, a new orally available 7-t-butoxyiminomethyl-substituted lipophilic camptothecin derivative, has been previously reported to be not a substrate for BCRP. Using a panel of in vitro models, we tested whether gimatecan is a substrate for BCRP as well as for P-glycoprotein (MDR1) or multidrug resistance protein 2 (MRP2; ABCC2), ATP-binding cassette drug efflux transporters involved in anticancer drug resistance, and able to affect the pharmacokinetics of substrate drugs. Cell survival, drug transport, accumulation, and efflux were studied in IGROV1 and (human BCRP overexpressing) T8 cells, Madin-Darby canine kidney II (MDCKII-WT, MDCKII-Bcrp1, MDCKII-MDR1, and MDCKII-MRP2), and LLCPK (LLCPK-WT and LLCPK-MDR1) cells. Competition with methotrexate uptake was studied in Sf9-BCRP membrane vesicles. In vitro, expression of BCRP resulted in 8- to 10-fold resistance to gimatecan. In Transwell experiments, gimatecan was transported by Bcrp1 and transport was inhibited by the BCRP/P-glycoprotein inhibitors elacridar and pantoprazole. Efflux of gimatecan from MDCKII-Bcrp1 cells was faster than in WT cells. In Sf9-BCRP membrane vesicles, gimatecan significantly inhibited BCRP-mediated transport of methotrexate. In contrast, gimatecan was not transported by MDR1 or MRP2. Gimatecan is transported by BCRP/Bcrp1 in vitro, although to a lesser extent than the camptothecin analogue topotecan. Implications of BCRP expression in the gut for the oral development of gimatecan and the interaction between gimatecan and other BCRP substrate drugs and/or inhibitors warrant further clinical investigation. PMID:18089724

  6. Multi-drug resistance in a canine lymphoid cell line due to increased P-glycoprotein expression, a potential model for drug-resistant canine lymphoma.

    Science.gov (United States)

    Zandvliet, M; Teske, E; Schrickx, J A

    2014-12-01

    Canine lymphoma is routinely treated with a doxorubicin-based multidrug chemotherapy protocol, and although treatment is initially successful, tumor recurrence is common and associated with therapy resistance. Active efflux of chemotherapeutic agents by transporter proteins of the ATP-Binding Cassette superfamily forms an effective cellular defense mechanism and a high expression of these transporters is frequently observed in chemotherapy-resistant tumors in both humans and dogs. In this study we describe the ABC-transporter expression in a canine lymphoid cell line and a sub-cell line with acquired drug resistance following prolonged exposure to doxorubicin. This sub-cell line was more resistant to doxorubicin and vincristine, but not to prednisolone, and had a highly increased P-glycoprotein (P-gp/abcb1) expression and transport capacity for the P-gp model-substrate rhodamine123. Both resistance to doxorubicin and vincristine, and rhodamine123 transport capacity were fully reversed by the P-gp inhibitor PSC833. No changes were observed in the expression and function of the ABC-transporters MRP-1 and BCRP. It is concluded that GL-40 cells represent a useful model for studying P-gp dependent drug resistance in canine lymphoid neoplasia, and that this model can be used for screening substances as potential P-gp substrates and their capacity to modulate P-gp mediated drug resistance. PMID:24975508

  7. Effect of P-glycoprotein and multidrug resistance associated protein gene expression on Tc-99m MIBI imaging in hepatocellular carcinoma

    International Nuclear Information System (INIS)

    P-glycoprotein (Pgp) and multidrug resistance-associated protein (MRP) expressions as well as Tc-99m methoxisobutylisonitrile (MIBI) images were assessed in 25 patients hepatocellular carcinoma (HCC). Tc-99m MIBI imaging was performed 10 minutes after intravenous injection of 20 mCi Tc-99m MIBI. Using immunohistochemical staining, 60% of the HCC lesions showed positive for Pgp and 64% showed positive for MRP. In 3 patients with MIBI uptake, immunohistochemical study of tumor tissue showed no Pgp stained cells. Nevertheless, they were all positive for MRP. The result of Tc-99m MIBI imaging is more related to the expression of Pgp than MRP gene. It is possible that other membrane transporters as well as Pgp and MRP are involved in the efflux of Tc-99m MIBI

  8. Selecting surfactants for the maximum inhibition of the activity of the multidrug resistance efflux pump transporter, P-glycoprotein: conceptual development.

    Directory of Open Access Journals (Sweden)

    Apte Shireesh Prakash

    2010-12-01

    Full Text Available Amphiphilic excipients, such as surfactants, have been shown to be inhibitors of the multidrug resistance (MDR efflux pump transporter protein, P-glycoprotein (Pgp. In vitro studies using manysurfactants have demonstrated that those with an optimum hydrophilic-lipophilic balance (HLB exhibit greater efflux pump inhibition than those that are either very hydrophobic, or very hydrophilic, although the correlation of HLB to Pgp inhibition activity remains weak. Using the data from multiple in vitro studies, a model has been conceptualized that underscores the attributes of both the HLB and the critical micellar concentration (CMC, occurring in tandem, and unable of being varied independently, as key determinants toward prediction of surfactant Pgp inhibition activity. The algorithm that formalizes this concept provides a ‘semi-rational’ method of choosingsurfactants for a specific type of cancer for maximum inhibition of MDR.

  9. Differential overexpression of three mdr gene family members in multidrug-resistant J774.2 mouse cells. Evidence that distinct P-glycoprotein precursors are encoded by unique mdr genes.

    Science.gov (United States)

    Hsu, S I; Lothstein, L; Horwitz, S B

    1989-07-15

    A hallmark of the multidrug-resistant phenotype is the overproduction of a family of 130-180-kDa integral membrane phosphoglycoproteins collectively called P-glycoprotein. Gene-specific hybridization probes were derived from three classes of mouse P-glycoprotein cDNAs. These probes revealed the differential amplification and/or transcriptional activation of three distinct but closely related mdr genes (mdr1a, mdr1b, and mdr2) in independently selected multidrug-resistant J774.2 mouse cell lines. Overexpression of mdr1a and mdr1b was found to correlate, in general, with the differential overproduction of either a 120- or 125-kDa P-glycoprotein precursor, respectively. This same correlation was observed in a single cell line during the course of stepwise selection for resistance to vinblastine in which a switch in gene expression from mdr1b to mdr1a resulted in a switch from the 125- to 120-kDa P-glycoprotein precursor. These findings suggest that differential overexpression of distinct mdr genes which encode unique P-glycoprotein isoforms is a possible mechanism for generating diversity in the multidrug-resistant phenotype. PMID:2473069

  10. Regulation of Multidrug Resistance P-Glycoprotein in the Developing Blood-Brain Barrier: Interplay between Glucocorticoids and Cytokines.

    Science.gov (United States)

    Iqbal, M; Baello, S; Javam, M; Audette, M C; Gibb, W; Matthews, S G

    2016-03-01

    P-glycoprotein (P-gp) encoded by Abcb1 provides protection to the developing brain from xenobiotics. P-gp in brain endothelial cells (BECs) derived from the developing brain microvasculature is up-regulated by glucocorticoids and inhibited by pro-inflammatory cytokines in vitro. However, little is known about how prenatal maternal glucocorticoid treatment can affect Abcb1/P-gp function and subsequent cytokine regulation in foetal BECs. We hypothesised that glucocorticoid exposure increases Abcb1/P-gp in the foetal brain microvasculature and enhances the sensitivity of Abcb1/P-gp in BECs to the inhibitory effects of cytokines. BECs isolated from dexamethasone- or vehicle-exposed foetal guinea pigs were cultured and treated with interleukin-1β, interleukin-6 or tumour necrosis factor-α, and Abcb1/P-gp expression and function were assessed. Prenatal dexamethasone exposure significantly increased Abcb1/P-gp expression/activity and cytokine receptor levels in BECs of the foetal brain microvasculature. Foetal dexamethasone exposure in vivo also increased the subsequent responsiveness of BECs to pro-inflammatory cytokines in vitro. In conclusion, maternal treatment with synthetic glucocorticoids appears to prematurely mature P-gp mediated drug resistance at the foetal BBB in vivo and profoundly impact the subsequent responsiveness of P-gp to pro-inflammatory cytokines in the foetal BEC. The significance of these findings to foetal brain protection against xenobiotics and other P-gp substrates in vivo requires further elaboration. However, the results of the present study may have implications for human pregnancy and foetal brain protection, particularly in cases of preterm birth combined with infection. PMID:26718627

  11. Expression of P-glycoprotein, multidrug resistance-associated protein, glutathione-S-transferase pi and p53 in canine transmissible venereal tumor

    Directory of Open Access Journals (Sweden)

    Daniel G. Gerardi

    2014-01-01

    Full Text Available The overexpression of proteins P-glycoprotein (P-gp, multidrug resistance-associated protein (MRP1, mutant p53, and the enzyme glutathione-S-transferase (GSTpi are related to resistance to chemotherapy in neoplasms. This study evaluated the expression of these markers by immunohistochemistry in two groups of canine TVT, without history of prior chemotherapy (TVT1, n=9 and in TVTs presented unsatisfactory clinical response to vincristine sulfate (TVT2, n=5. The percentage of specimens positively stained for P-gp, MRP1, GSTpi and p53 were, respectively 88.8%, 0%, 44.5% and 22.2% in TVT1 and 80%, 0%, 80% and 0% in TVT2. In TVT1, one specimen presented positive expression for three markers and four specimens for two markers. In TVT2, three specimens expressed P-gp and GSTpi. In conclusion, the canine TVTs studied expressed the four markers evaluated, but just P-gp and GSTpi were significantly expressed, mainly at cytoplasm and cytoplasm and nuclei, respectively, either before chemotherapy as after vincristine sulfate exposure. Future studies are needed to demonstrate the function of these two markers in conferring multidrug resistance (MDR or predict the response to chemotherapy in canine TVT.

  12. Characterisation of non-P-glycoprotein multidrug-resistant Ehrlich ascites tumour cells selected for resistance to mitoxantrone

    DEFF Research Database (Denmark)

    Nielsen, D; Eriksen, J; Maare, C; Litman, Thomas; Kjaersgaard, E; Plesner, T; Friche, E; Skovsgaard, T

    2000-01-01

    An Ehrlich ascites tumour cell line (EHR2) was selected in vivo for resistance to mitoxantrone (MITOX). The resistant cell line (EHR2/MITOX) was 6123-, 33-, and 30-fold-resistant to mitoxantrone, daunorubicin, and etoposide, respectively, but retained sensitivity to vincristine. The resistant cel...... to be associated with: 1) a quantitative reduction in topoisomerase IIalpha and beta protein; 2) reduced drug accumulation, probably as a result of increased expression of a novel transport protein with ATPase activity; and 3) increased expression of MRP mRNA....

  13. Glicoproteína-P, resistência a múltiplas drogas (MDR) e relação estrutura-atividade de moduladores P-glycoprotein and multidrug resistance: structure-activity relationships of modulators

    OpenAIRE

    Paula C. Huber; Cintia H. Maruiama; Wanda P. Almeida

    2010-01-01

    Multidrug resistance, MDR is a major obstacle for cancer chemotherapy. MDR can be reversed by drugs that vary in their chemical structure and main biological activity. Many efforts have been done to overcome MDR based on studies of structure-activity relationships and in this review we summarize some aspects of MDR mediated by P-glycoprotein (P-gp), as the most experimentally and clinically tested form of drug resistance. The most significant MDR mechanisms revealed until now are shortly disc...

  14. Multi-drug resistance (MDR1 gene and P-glycoprotein influence on pharmacokinetic and pharmacodymanic of therapeutic drugs

    Directory of Open Access Journals (Sweden)

    Linardi Renata Lehn

    2006-01-01

    Full Text Available (MDR1 gene expressed in tumor cells and also in several normal tissues, such as intestine, liver, kidney, blood-brain barrier, spinal cord, and placenta. P-gp has been identified in mice, rat, bovine, monkey, rodents, and human beings and has been receiving a particular clinical relevance because this protein expression limits brain access and intestinal absorption of many drugs. This protein plays a role as a protective barrier against a wide variety of substrates, avoiding drug entry into the central nervous system. P-glycoprotein also interferes with drug bioavailability and disposition, including absorption, distribution, metabolization, and excretion, influencing pharmacokinetic and pharmacodynamic of drugs. Modulation of P-gp may help the efficacy of treatment of several diseases and can explain some adverse central nervous system effects induced by drugs after intravenous administration and the poor response of oral administration in patients. Alteration in P-gp expression or function has been associated with several diseases susceptibility in humans and animals. Furthermore, additional studies relating MDR1 and P-gp expression has an important clinical implication also in terms of treatment efficacy.

  15. Detecting parathyroid adenoma using technetium-99m tetrofosmin: comparison with P-glycoprotein and multidrug resistance related protein expression--a preliminary report

    International Nuclear Information System (INIS)

    The aim of this study was to investigate the relationships among technetium-99m tetrofosmin (Tc-TF) accumulation in parathyroid adenoma and the expression of P-glycoprotein (Pgp) or multidrug resistance related protein (MRP). Before operation, 33 patients with parathyroid adenomas (larger than 1.5 gm) were studied with parathyroid scintigraphy 10 minutes and 2 hours after intravenous injection of Tc-TF before operation. Immunohistochemical analyses (IHA) were performed on multiple nonconsecutive sections of operative parathyroid specimens to detect Pgp or MRP expression. According to the results of IHA, the 33 parathyroid adenomas were separated into four groups: (1) 2 adenomas with both positive Pgp and positive MRP expression, (2) 1 adenomas with positive Pgp but negative MRP expression, (3) 2 adenomas with negative Pgp but positive MRP expression, and (4) 28 adenomas with both negative Pgp and negative MRP expression. All of 28 adenomas in the group 4 could be detected by Tc-TF parathyroid imaging. All of 5 adenomas in the groups 1 to 3 could not be detected by TcTF parathyroid imaging (p < 0.05). Not only the size of parathyroid adenomas, but also significant Pgp or MRP expression limited the sensitivity of Tc-TF parathyroid imaging to localize parathyroid adenomas before operation

  16. Comparative uptake of Tc-99m sestamibi and Tc-99m tetrofosmin in cancer cells and tissue expressing P-Glycoprotein or multidrug resistance associated protein

    International Nuclear Information System (INIS)

    99mTc-sestamibi(MIBI) and 99mTc-tetrofosmin have been used as substrates for P-glycoprotein (Pgp) and multidrug resistance associated protein (MRP), which are closely associated with multidrug resistance of the tumors. To understand different handling of radiotracers in cancer cell lines expressing Pgp and MRP, we compared cellular uptakes of 99mTc-MIBI and 99mTc-tetrofosmin. The effects of cyclosporin A (CsA), well-known multidrug resistant reversing agent, on the uptake of both tracers were also compared. HCT15/CL02 human colorectal cancer cells for Pgp expressing cells, and human non-small cell lung cancer A549 cells for MRP expressing cells, were used for in vitro and in vivo studies. RT-PCR, western blot analysis and immunohistochemistry were used for detection of Pgp and MRP. MDR-reversal effect with CsA was evaluated at different drug concentrations after incubation with MIBI or tetrofosmin. Radioactivities of supernatant and pellet were measured with gamma well counter. Tumoral uptake of the tracers were measured from tumor bearing nude mice treated with or without CsA. RT-PCR, western blot analysis of the cells and immunochemical staining revealed selective expression of Pgp and MRP for HCT15/CL02 and A549 cells, respectively. There were no significant difference in cellular uptakes of both tracers in HCT15/CL02 cells, but MIBI uptake was slightly higher than that of tetrofosmin in A549 cells. Co-incubation with CsA resulted in a increase in cellular uptakes of MIBI and tetrofosmin. Uptake of MIBI or tetrofosmin in HCT15/CL02 cells was increased by 10-and 2.4-fold, and by 7.5 and 6.3-fold in A549 cells, respectively. Percentage increase of MIBI was higher than that of tetrofosmin with CsA for both cells (ρ < 0.05). In vivo biodistribution study showed that MIBI (114% at 10 min, 257% at 60 min, 396% at 24C min) and tetrofosmin uptake (110% at 10 min, 205% at 60 min, 410% at 240 min) were progressively increased by the time, up to 240 min with CsA. But increases in tumoral uptake were not significantly different between MIBI and tetrofosmin for both tumors. MIBI seems to be a better tracer than tetrofosmin for evaluating MDR reversal effect of the modulators in vitro, but these differences were not evident in vivo tumoral uptake. Both MIBI and tetrofosmin seem to be suitable tracers for imaging Pgp-and MRP=mediated drug resistance in tumors

  17. Interaction of forskolin with the P-glycoprotein multidrug transporter

    Energy Technology Data Exchange (ETDEWEB)

    Ming s, D.I.; Seamon, K.B. (Food and Drug Administration, Bethesda, MD (United States)); Speicher, L.A.; Tew, K.D. (Fox Chase Cancer Research Center, Philadelphia, PA (United States)); Ruoho, A.E. (Univ. of Wisconsin, Madison (United States))

    1991-08-27

    Forskolin and 1,9-dideoxyforskolin, an analogue that does not activate adenylyl cyclase, were tested for their ability to enhance the cytotoxic effects of adriamycin in human ovarian carcinoma cells, SKOV3, which are sensitive to adriamycin and express low levels of P-glycoprotein, and a variant cell line, SKVLB, which overexpresses the P-glycoprotein and has the multidrug reing ance (MDR) phenotype. Forskolin and 1,9-dideoxyforskolin both increased the cytotoxic effects of adriamycin in SKVLB cells, yet had no effect on SKOV3 cells. Two photoactive derivatives of forskolin have been synthesized, 7-O-((2-(3-(4-azido-3-({sup 125}I)iodophenyl)propionamido)ethyl)carbamyl)forskolin, {sup 125}I-6-AIPP-Fsk, and 6-O-((2-(3-(4-azido-3-({sup 125}I)iodophenyl)propionamido)ethyl)carbamyl)forskolin, {sup 125}I-6-AIPP-Fsk, which exhibit specificity for labeling the glucose transporter and aing lyl cyclase, respectively. Both photolabels identified a 140-kDa protein in membranes from SKVLB cells whose labeling was inhibited by forskolin and 1,9-dideoxyforskolin. The data are consistent with forskolin binding to the P-glycoprotein analogous to that of other chemosensitizing drugs that have been shown to partially reverse MDR. The ability of forskolin photolabels to specifically label the transporter, the adenylyl cyclase, and the P-glycoprotein suggests that these proteins may share a common biing g domain for forskolin analogues.

  18. Diatrizoate, Iopromide and Iotrolan Enhanced Cytotoxicity of Daunorubicin in Multidrug Resistant K562/adr Cells: Impaired the Mitochondrial and Inhibited the P-Glycoprotein Function

    Directory of Open Access Journals (Sweden)

    Nitaya S.N. Ayudhya

    2009-01-01

    Full Text Available Multidrug resistance was an obstacle in cancer chemotherapy because the cells decreased their intracellular drug accumulation by energy-dependent compounds efflux pumps such as P-glycoprotein (P-gp. This study observed some iodinated radiographic contrast media, diatrizoate, iopromide and iotrolan affected the cellular energetic state and the kinetics of P-gp in drug-sensitive K562 and drug resistant K562/adr cell lines using spectrophotometer and spectrofluorometer. By colorimetric MTT assay, it was found that contrast media (0-3500 M had no effect on both K562 and K562/adr cell viabilities, but in co-treatment with daunorubicin (DNR, diatrizoate decreased cell viability in K562/adr cells by decreasing ICso of DNR from 610.7 74.5 nM to 360108.9 nM. The change in cellular energetic state was studied using rhodamine B as a probe to estimate mitochondrial membrane potential (??m. The results showed that 3500 M diatrizoate decreased ??m from 162.20.3 mV to 86.99.9 mV in K562/adr cells. The kinetics of P-gp-mediated efflux of DNR could be reduced by diatrizoate from 0 (no inhibition to 0.650.11. This inhibition could be partially prevented in co-incubation with 20 nM concanamycin A or 10 M cytochalasin B. Among the three molecules, diatrizoate showed the best efficiency. It could be proposed for further studies that diatrizoate could be used as MDR identification or MDR imaging and also acted as MDR sensitizing agent in cancer treatments.

  19. The study of relationship between breast cancer 99Tcm-MIBI imaging with the expression of P-glycoprotein and multidrug resistance-associated protein

    International Nuclear Information System (INIS)

    Objective: To evaluate the relationship between the uptake, washout of 99Tcm-methoxy-isobutylisonitrile (MIBI) and P-glycoprotein (P-gp) or multidrug resistance-related protein (MRP) expression in 36 breast cancer patients. Methods: 36 patients with untreated breast cancer were studied prospectively a week before surgical operation, all were injected intravenously with 740 MBq 99Tcm-MIBI in the arm contralateral to the lesion. Anterior planar images were acquired at 10 and 180 min after injection and the tumor-to-normal breast ratios (T/N) and washout rates (WR) were calculated. Immunohistochemical analyses of P-gp and MRP expression were used to evaluate the removed tumor tissues after operation and categorized into four groups. The differences of the early T/N ratios, the late T/N ratios and the WR among them were compared. Results: The early T/N ratios in group A and B were higher than that in group D. There was statistic difference between group A and D (P=0.001 ), and also in group B and D (P=0.045). The late T/N ratios had no statistic differences among them (F=0.499, P=0.686). The WR of group A, B, C were higher than that in group D and there were significant differences between them (P99Tcm-MIBI from the lesions and expression of P-gp or MRP in untreated breast cancer patients. 99Tcm-MIBI imaging with washout analysis might be a useful method for evaluating P-gp or MRP overexpression and their function in breast cancer. (authors)

  20. Clinical study of 99mTc-MIBI SPECT imaging for detection of multidrug resistant p-glycoprotein expression in lung cancer

    International Nuclear Information System (INIS)

    Purpose: Multidrug resistance (MDR) of tumor to cytotoxic drugs is a common cause for failure of chemotherapy in the majority of cancer patients. One of the mechanisms of MDR is due to drug efflux driven by p-glycoprotein (p-GP) expressed on the membrane of tumor cells. the aim of the present study was to develop a method of functional imaging with 99mTc-MIBI to detect the drug efflux mediated by p-GP in lesion of lung cancer. Methods: Before chemotherapy 99mTc-MIBI imaging was performed on each patient with a two-phase protocol (30 and 120 minutes postinjection) in a tomographic mode. Retention indices (RIs) of 99mTc-MIBI at tumor sites were calculated from counts at the lesion sites and the negative value of RI was defined as p-GP positive. According to criteria proposed by the WHO, therapeutic tumor response was scored as no response (NR), partial regression (PR) or complete regression (CR) after 3 courses of chemotherapy. Then, the significance of this technique was assessed. Results: In total, 71 original lesions of lung cancer patients (staged as IIIb?IV) were included in this study. 35 lesions were p-GP(+) and 36 lesions were p-GP(-) by MIBI imaging. 29 (82.9%) lesions in the p-GP (+) group had a therapeutic score of NR, while 24 lesions (66.7%) in p-GP(-) were scored as CR or PR. The accuracy of this method was 74.6%(53/71). Conclusions: Several invasive methods such as immunohistochemical staining and PCR have been developed to detect p-GP in tissue. Compared with biopsy, which was subject to sampling errors and heterogeneity of p-GP expression, the present technique was a non-invasive and independent from sampling errors. Therefore, it might serve as an effective complement to the other techniques to detect p-GP mediated MDR

  1. Interaction of the P-Glycoprotein Multidrug Transporter with Sterols.

    Science.gov (United States)

    Clay, Adam T; Lu, Peihua; Sharom, Frances J

    2015-11-01

    The ABC transporter P-glycoprotein (Pgp, ABCB1) actively exports structurally diverse substrates from within the lipid bilayer, leading to multidrug resistance. Many aspects of Pgp function are altered by the phospholipid environment, but its interactions with sterols remain enigmatic. In this work, the functional interaction between purified Pgp and various sterols was investigated in detergent solution and proteoliposomes. Fluorescence studies showed that dehydroergosterol, cholestatrienol, and NBD-cholesterol interact intimately with Pgp, resulting in both quenching of protein Trp fluorescence and enhancement of sterol fluorescence. Kd values indicated binding affinities in the range of 3-9 μM. Collisional quenching experiments showed that Pgp-bound NBD-cholesterol was protected from the external milieu, resonance energy transfer was observed between Pgp Trp residues and the sterol, and the fluorescence emission of bound sterol was enhanced. These observations suggested an intimate interaction of bound sterols with the transporter at a protected nonpolar site. Cholesterol hemisuccinate altered the thermal unfolding of Pgp and greatly stabilized its basal ATPase activity in both a detergent solution and reconstituted proteoliposomes of certain phospholipids. Other sterols, including dehydroergosterol, did not stabilize the basal ATPase activity of detergent-solubilized Pgp, which suggests that this is not a generalized sterol effect. The phospholipid composition and cholesterol hemisuccinate content of Pgp proteoliposomes altered the basal ATPase and drug transport cycles differently. Sterols may interact with Pgp and modulate its structure and function by occupying part of the drug-binding pocket or by binding to putative consensus cholesterol-binding (CRAC/CARC) motifs located within the transmembrane domains. PMID:26484739

  2. Multi-drug resistance in a canine lymphoid cell line due to increased P-glycoprotein expression, a potential model for drug-resistant canine lymphoma.

    OpenAIRE

    Zandvliet, M.; TESKE, ERIK; Schrickx, J.A.

    2014-01-01

    Canine lymphoma is routinely treated with a doxorubicin-based multidrug chemotherapy protocol, and although treatment is initially successful, tumor recurrence is common and associated with therapy resistance. Active efflux of chemotherapeutic agents by transporter proteins of the ATP-Binding Cassette superfamily forms an effective cellular defense mechanism and a high expression of these transporters is frequently observed in chemotherapy-resistant tumors in both humans and dogs. In this stu...

  3. Assessment of the in vitro and in vivo properties of a {sup 99m}Tc-labeled inhibitor of the multidrug resistant gene product P-glycoprotein

    Energy Technology Data Exchange (ETDEWEB)

    Bergmann, R. E-mail: R.Bergmann@fz-rossendorf.de; Brust, P.; Scheunemann, M.; Pietzsch, H.-J.; Seifert, S.; Roux, F.; Johannsen, B

    2000-02-01

    Overexpression of P-glycoprotein (Pgp), which is present in the plasma membrane of various tumor cells and in several normal cell types, contributes to the multidrug resistance (MDR) phenotype of many human cancers. As a prerequisite for therapy, the expression of Pgp must be studied. The available clinical radiopharmaceuticals for studying the expression of Pgp include the lipophilic {sup 99m}Tc cations (sestamibi, tetrofosmin) as well as [{sup 99m}Tc]Q57, [{sup 99m}Tc]Q58, and [{sup 99m}Tc]Q63. Here we describe the in vitro and in vivo properties of the structurally different complex (3-thiapentane-1,5-dithiolato)[[N-(3-phenylpropyl)-N-2(3-quinazoline-2,4 -dionyl)-ethyl]amino-ethylthiolato] oxotechnetium(V) ({sup 99/99m}Tc1) as a potential inhibitor of Pgp. {sup 99}Tc1 enhances the net cell accumulation of Pgp substrates [{sup 3}H]vinblastine, [{sup 3}H]vincristine, [{sup 3}H]colchicine, [{sup 99m}Tc]sestamibi, and [{sup 99m}Tc]tetrofosmin in rat brain endothelial cells (RBE4), an immortalized endothelial cell line that expresses Pgp. In addition, the cell accumulation of {sup 99m}Tc1 could be increased by verapamil and reserpine, which are known Pgp inhibitors. A multitracer approach was used to study the side effects of {sup 99}Tc1 on cell metabolism. The cells were simultaneously incubated with [{sup 99m}Tc]sestamibi, 2-[{sup 18}F]fluoro-2-deoxyglucose ([{sup 18}F]FDG), and various {sup 3}H-labeled tracers. Two-dimensional scatter plots of [{sup 99m}Tc]sestamibi uptake/[{sup 18}F]FDG uptake show typical changes of known Pgp inhibitors including {sup 99}Tc1. The effects of {sup 99}Tc1 on the in vivo distribution of [{sup 99m}Tc]sestamibi and [{sup 18}F]FDG in rats also are comparable with the effects of verapamil, an established Pgp inhibitor and calcium channel blocker. We conclude that {sup 99/99m}Tc1 is a transport substrate and a potential inhibitor of Pgp. Our approach may be useful in the design of further radiotracers with specificity to Pgp.

  4. Distinct P-glycoprotein precursors are overproduced in independently isolated drug-resistant cell lines.

    Science.gov (United States)

    Greenberger, L M; Lothstein, L; Williams, S S; Horwitz, S B

    1988-06-01

    A family of P-glycoproteins are overproduced in multidrug-resistant cells derived from the murine macrophage-like line J774.2. To determine whether individual family members are overproduced in response to different drugs, the P-glycoprotein precursors in several independently isolated cell lines, which were selected for resistance to vinblastine or taxol, were compared. Individual cell lines selected with vinblastine overproduced P-glycoprotein precursors of either 120 or 125 kDa. Taxol-selected cell lines overproduced either the 125-kDa precursor or both precursors simultaneously. Two similar but distinct peptide maps for the mature P-glycoproteins were observed. These maps corresponded to each precursor regardless of the drug used for selection. One vinblastine-resistant cell line switched from the 125- to the 120-kDa precursor when grown in increasing concentrations of drug. This change coincided with the overexpression of a distinct subset of mRNA species that code for P-glycoprotein. It is concluded that precursor expression is not drug-specific. These data suggest that individual overproduced P-glycoprotein family members are translated as distinct polypeptides. The results may help to explain the diversity in the multidrug-resistant phenotype. PMID:2897689

  5. Placental passage of olomoucine II, but not purvalanol A, is affected by p-glycoprotein (ABCB1), breast cancer resistance protein (ABCG2) and multidrug resistance-associated proteins (ABCCs).

    Science.gov (United States)

    Hofman, Jakub; Kučera, Radim; Neumanova, Zuzana; Klimes, Jiri; Ceckova, Martina; Staud, Frantisek

    2016-05-01

    1. Purine cyclin-dependent kinase inhibitors have recently been recognised as promising candidates for the treatment of various cancers. While pharmacodynamic properties of these compounds are relatively well understood, their pharmacokinetics including possible interactions with placental transport systems have not been characterised to date. 2. In this study, we investigated transplacental passage of olomoucine II and purvalanol A in rat focusing on possible role of p-glycoprotein (ABCB1), breast cancer resistance protein (ABCG2) and/or multidrug resistance-associated proteins (ABCCs). Employing the in situ method of dually perfused rat term placenta, we demonstrate transplacental passage of both olomoucine II and purvalanol A against the concentration gradient in foetus-to-mother direction. Using several ATP-binding cassette (ABC) drug transporter inhibitors, we confirm the participation of ABCB1, ABCG2 and ABCCs transporters in the placental passage of olomoucine II, but not purvalanol A. 3. Transplacental passage of olomoucine II and purvalanol A from mother to foetus is significantly reduced by active transporters, restricting thereby foetal exposure and providing protection against harmful effects of these xenobiotics. Importantly, we demonstrate that in spite of their considerable structural similarity, the two molecules utilise distinct placental transport systems. These facts should be kept in mind when introducing these prospective anticancer candidates and/or their analogues into the clinical area. PMID:26364927

  6. pH-Responsive therapeutic solid lipid nanoparticles for reducing P-glycoprotein-mediated drug efflux of multidrug resistant cancer cells

    Directory of Open Access Journals (Sweden)

    Chen HH

    2015-08-01

    Full Text Available Hsin-Hung Chen,1 Wen-Chia Huang,2 Wen-Hsuan Chiang,2 Te-I Liu,2 Ming-Yin Shen,2,3 Yuan-Hung Hsu,4 Sung-Chyr Lin,1 Hsin-Cheng Chiu2 1Department of Chemical Engineering, National Chung Hsing University, Taichung, 2Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, 3Department of Surgery, National Taiwan University Hospital-Hsinchu Branch, 4Pharmaceutical Optimization Technology Division, Biomedical Technology and Device Research Laboratory, Industrial Technology Research Institute, Hsinchu, Taiwan Abstract: In this study, a novel pH-responsive cholesterol-PEG adduct-coated solid lipid nanoparticles (C-PEG-SLNs carrying doxorubicin (DOX capable of overcoming multidrug resistance (MDR breast cancer cells is presented. The DOX-loaded SLNs have a mean hydrodynamic diameter of ~100nm and a low polydispersity index (under 0.20 with a high drug-loading efficiency ranging from 80.8% to 90.6%. The in vitro drug release profiles show that the DOX-loaded SLNs exhibit a pH-controlled drug release behavior with the maximum and minimum unloading percentages of 63.4% at pH 4.7 and 25.2% at pH 7.4, respectively. The DOX-loaded C-PEG-SLNs displayed a superior ability in inhibiting the proliferation of MCF-7/MDR cells. At a DOX concentration of 80 M, the cell viabilities treated with C-PEG-SLNs were approximately one-third of the group treated with free DOX. The inhibition activity of C-PEG-SLNs could be attributed to the transport of C-PEG to cell membrane, leading to the change of the composition of the cell membrane and thus the inhibition of permeability glycoprotein activity. This hypothesis is supported by the confocal images showing the accumulation of DOX in the nuclei of cancer cells and the localization of C-PEG on the cell membranes. The results of in vivo study further demonstrated that the DOX delivered by the SLNs accumulates predominantly in tumor via enhanced permeability and retention effect, the enhanced passive tumor accumulation due to the loose intercellular junctions of endothelial cells lining inside blood vessels at tumor site, and the lack of lymphatic drainage. The growth of MCF-7/MDR xenografted tumor on Balb/c nude mice was inhibited to ~400mm3 in volume as compared with the free DOX treatment group, 1,140mm3, and the group treated with 1,2 distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol] solid lipid nanoparticles, 820mm3. Analysis of the body weight of nude mice and the histology of organs and tumor after the administration of DOX-loaded SLNs show that the SLNs have no observable side effects. These results indicate that the C-PEG-SLN is a promising platform for the delivery of therapeutic agents for MDR cancer chemotherapy. Keywords: pH-responsive, solid lipid nanoparticles, multidrug resistance, permeability glycoprotein

  7. P-glycoprotein and Its Role in Treatment Resistance

    Directory of Open Access Journals (Sweden)

    Isil Gogcegoz Gul

    2016-03-01

    Full Text Available Polypharmacy which has often used to increase efficacy of treatment and to prevent resistance in psychiatry may lead to pharmacokinetic and pharmacodynamic drug interactions. One of the inten-sively studied topic in recent years to clarify the mechanism of drug interactions, in the pharmacoki-netic area is p-glycoprotein related drug-drug and drug-food interactions. The interactions of some drugs with p-glycoprotein which is a carrier protein, can lead to a decrease in the bioavailability of these drugs and reduction in passage through the blood-brain barrier. In this review, the role of p-glycoprotein on drug pharmacokinetics and bioavailability of psychiatric drugs are discussed. [Psikiyatride Guncel Yaklasimlar - Current Approaches in Psychiatry 2016; 8(1: 19-31

  8. P-glycoprotein and Its Role in Treatment Resistance

    OpenAIRE

    Isil Gogcegoz Gul; Gul Eryilmaz; K. Oguz Karamustafalioglu

    2016-01-01

    Polypharmacy which has often used to increase efficacy of treatment and to prevent resistance in psychiatry may lead to pharmacokinetic and pharmacodynamic drug interactions. One of the inten-sively studied topic in recent years to clarify the mechanism of drug interactions, in the pharmacoki-netic area is p-glycoprotein related drug-drug and drug-food interactions. The interactions of some drugs with p-glycoprotein which is a carrier protein, can lead to a decrease in the bioavailability of ...

  9. Technetium-99m sestamibi single photon emission computed tomography findings correlated with p-glycoprotein expression, encoded by the multidrug resistance gene-1 messenger ribonucleic acid, in intracranial meningiomas

    International Nuclear Information System (INIS)

    The present study evaluated whether technetium-99m sestamibi (99mTc-MIBI) single photon emission computed tomography (SPECT) characteristics of intracranial meningioma are correlated with the histological malignancy, proliferative potential, and P-glycoprotein (Pgp) expression, encoded by the multidrug resistance gene-1 (MDR-1) messenger ribonucleic acid (mRNA). Twenty-one patients with intracranial meningiomas, including 17 benign and four nonbenign meningiomas, underwent 99mTc-MIBI SPECT imaging at 15 minutes (early) and 3 hours (delayed) after injection. The tumor-to-normal pituitary gland ratio was calculated on both early (ER) and delayed (DR) images. Retention index (RI) was calculated using the following formula: (DR-ER)/ER x 100%. Meningioma specimens were examined by immunohistochemistry using anti-Pgp and MIB-1 monoclonal antibody. MDR-1 mRNA expression was also investigated using reverse transcription-polymerase chain reaction assay. 99mTc-MIBI was highly accumulated and retained in the tumors. 99mTc-MIBI SPECT findings were not related to MIB-1 labeling index. 99mTc-MIBI SPECT RI of the Pgp-positive group (-9.1222.27%) was significantly lower than that of the Pgp-negative group (28.7922.80%) (p=0.0016). No significant difference was seen in ER and DR between the positive and negative groups. These results show that 99mTc-MIBI may not be useful for determining proliferative potential and histological malignancy, but could predict anticancer drug resistance related to the expression of MDR-1 mRNA and its gene product Pgp in patients with intracranial meningiomas. (author)

  10. HIV-1 integrase inhibitors are substrates for the multidrug transporter MDR1-P-glycoprotein

    OpenAIRE

    Cara Andrea; Andreotti Mauro; Galluzzo Clementina; Verdoliva Antonio; Costi Roberta; Molinari Agnese; Dupuis Maria; Cianfriglia Maurizio; Di Santo Roberto; Palmisano Lucia

    2007-01-01

    Abstract Background The discovery of diketoacid-containing derivatives as inhibitors of HIV-1 Integrase (IN) (IN inhibitors, IINs) has played a major role in validating this enzyme as an important target for antiretroviral therapy. Since the in vivo efficacy depends on access of these drugs to intracellular sites where HIV-1 replicates, we determined whether the IINs are recognized by the multidrug transporter MDR1-P-glycoprotein (P-gp) thereby reducing their intracellular accumulation. To ad...

  11. HIV-1 integrase inhibitors are substrates for the multidrug transporter MDR1-P-glycoprotein

    Directory of Open Access Journals (Sweden)

    Cara Andrea

    2007-03-01

    Full Text Available Abstract Background The discovery of diketoacid-containing derivatives as inhibitors of HIV-1 Integrase (IN (IN inhibitors, IINs has played a major role in validating this enzyme as an important target for antiretroviral therapy. Since the in vivo efficacy depends on access of these drugs to intracellular sites where HIV-1 replicates, we determined whether the IINs are recognized by the multidrug transporter MDR1-P-glycoprotein (P-gp thereby reducing their intracellular accumulation. To address the effect of IINs on drug transport, nine quinolonyl diketo acid (DKA derivatives active on the HIV-1 IN strand transfer (ST step and with EC50 ranging from 1.83 to >50 μm in cell-based assays were tested for their in vitro interaction with P-gp in the CEM-MDR cell system. IINs were investigated for the inhibition and induction of the P-gp function and expression as well as for multidrug resistance (MDR reversing ability. Results The HIV-1 IINs act as genuine P-gp substrates by inhibiting doxorubicin efflux and inducing P-gp functional conformation changes as evaluated by the modulation of UIC2 mAb epitope. Further, IINs chemosensitize MDR cells to vinblastine and induce P-gp expression in drug sensitive revertants of CEM-MDR cells. Conclusion To our knowledge, this is the first demonstration that HIV-1 IINs are P-gp substrates. This biological property may influence the absorption, distribution and elimination of these novels anti HIV-1 compounds.

  12. Multiple efflux pumps are involved in the transepithelial transport of colchicine: combined effect of p-glycoprotein and multidrug resistance-associated protein 2 leads to decreased intestinal absorption throughout the entire small intestine.

    Science.gov (United States)

    Dahan, Arik; Sabit, Hairat; Amidon, Gordon L

    2009-10-01

    The purpose of this study was to thoroughly characterize the efflux transporters involved in the intestinal permeability of the oral microtubule polymerization inhibitor colchicine and to evaluate the role of these transporters in limiting its oral absorption. The effects of P-glycoprotein (P-gp), multidrug resistance-associated protein 2 (MRP2), and breast cancer resistance protein (BCRP) inhibitors on colchicine bidirectional permeability were studied across Caco-2 cell monolayers, inhibiting one versus multiple transporters simultaneously. Colchicine permeability was then investigated in different regions of the rat small intestine by in situ single-pass perfusion. Correlation with the P-gp/MRP2 expression level throughout different intestinal segments was investigated by immunoblotting. P-gp inhibitors [N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918), verapamil, and quinidine], and MRP2 inhibitors [3-[[3-[2-(7-chloroquinolin-2-yl)vinyl]phenyl]-(2-dimethylcarbamoylethylsulfanyl)methylsulfanyl] propionic acid (MK571), indomethacin, and p-aminohippuric acid (p-AH)] significantly increased apical (AP)-basolateral (BL) and decreased BL-AP Caco-2 transport in a concentration-dependent manner. No effect was obtained by the BCRP inhibitors fumitremorgin C (FTC) and pantoprazole. P-gp/MRP2 inhibitors combinations greatly reduced colchicine mucosal secretion, including complete abolishment of efflux (GF120918/MK571). Colchicine displayed low (versus metoprolol) and constant permeability along the rat small-intestine. GF120918 significantly increased colchicine permeability in the ileum with no effect in the jejunum, whereas MK571 augmented jejunal permeability without changing the ileal transport. The GF120918/MK571 combination caused an effect similar to that of MK571 alone in the jejunum and to that of GF120918 alone in the ileum. P-gp expression followed a gradient increasing from proximal to distal segments, whereas MRP2 decreased from proximal to distal small intestinal regions. Overall, it was revealed that the combined effect of P-gp and MRP2, but not BCRP, dominates colchicine transepithelial transport, leading to complete coverage of the entire small intestine, and makes the efflux transport dominate the intestinal permeability process. PMID:19589874

  13. Influence of the multidrug transporter P-glycoprotein on the intracellular pharmacokinetics of vandetanib.

    Science.gov (United States)

    Jovelet, C; Deroussent, A; Broutin, S; Paci, A; Farinotti, R; Bidart, J M; Gil, S

    2013-09-01

    Efflux transporters play an important role in the resistance of tumor cells against anticancer agents. Interaction between these transporters, including P-glycoprotein (P-gp), and drugs might influence their pharmacological properties and toxicities. The aim of this study was to investigate whether vandetanib (Caprelsa(®)), a small tyrosine kinase inhibitor, could interact with the multidrug transporter P-gp. Interaction of vandetanib with the P-gp was investigated using the parental cell line (IGROV1) and the P-gp doxorubicin-resistant (IGROV1-DXR) cell line, derived from the parental drug-sensitive IGROV1 cells. Cytotoxicity tests were assessed in both cell lines to examine the impact of P-gp on the cell survival after a vandetanib treatment. The effects of P-gp on vandetanib intracellular pharmacokinetics were investigated. To this aim, we developed a quantitative liquid chromatography tandem mass spectrometry to quantify vandetanib in cell medium. Results showed that overexpression of P-gp confers resistance to vandetanib in the IGROV1-DXR cell line. Using a LC-MS/MS assay validated in cell medium, cellular pharmacokinetic studies revealed that in cells overexpressing the P-gp intracellular concentrations of vandetanib were decreased compared to parental cell line. For the first time, vandetanib is described as a substrate of P-gp. In tumor cells, P-gp could be responsible for cellular resistance to vandetanib. It may be relevant to the clinical efficacy of vandetanib. Moreover, interaction of vandetanib with P-gp could modify the pharmacodynamics of other conventional chemotherapeutics, substrates of P-gp. It could impact on the overall response to anticancer therapy. PMID:23446814

  14. Usefulness of technetium-99m tetrofosmin liver imaging to detect hepatocellular carcinoma and related to expression of P-glycoprotein or multidrug resistance associated protein-a preliminary report

    International Nuclear Information System (INIS)

    Technetium-99m Tetrofsomin (Tc-TF) has been shown to be useful in identifying several types of tumors, such as breast, lung, and thyroid cancers. There was no report in the literature for Tc-TF uptake in hepatocellular carcinoma (HCC). The aim of this study was to evaluate the usefulness of Tc-TF liver imaging to detect HCC and investigate the relationship between Tc-TF liver imaging findings and P-glycoprotein (Pgp) and multidrug resistance associated protein (MRP) expression. Before any therapy, 22 patients with HCC were enrolled in this study. Tc-TF liver images were performed l0 minutes after intravenous injection of 20mCi Tc-TF. All patients had liver biopsy or surgery within l week after Tc-TF liver imaging. Immunohistochemical study of the biopsy or resected HCC specimens was performed using anti-human Pgp and MRP antibodies. Twenty of the 22 (90.9%) patients showed negative Tc-TF liver imaging results without significant Tc-TF uptake in HCC, whereas only the remaining 2 (9.1%) patients showed positive Tc-TF liver imaging results with significant Tc-TF uptake in HCC. Positive Pgp expression was observed in 13 of 20 patients with negative Tc-TF liver imaging results, whereas positive MRP expression was observed in 6 of the remaining 7 patients with negative both Tc-TF liver imaging results and Pgp expression. However, negative Pgp expression but positive MRP expression was observed in all of the remaining 2 patients with positive Tc-TF liver imaging results. The correlation between Tc-TF liver imaging findings and Pgp expression was significant and better than between Tc-TF liver imaging findings and MRP expression. Pgp or MRP expression in HCC may induce no significant Tc-TF uptake in HCC resulting in negative Tc-TF liver imaging findings. Therefore, Tc-TF liver imaging is potential to be a non-invasive method to predict Pgp or MRP expression in HCC. However, further studies with a larger series of patients and longer follow-up time are necessary to confirm our findings

  15. Role of multidrug resistance in photodynamic therapy

    Science.gov (United States)

    Diddens, Heyke C.

    1992-06-01

    Multidrug resistance in cancer chemotherapy is a well established phenomenon. One of the most common phenotypical changes in acquired or intrinsic multidrug resistance in human tumor cells is the overexpression of the mdrl gene product P-glycoprotein, which acts as an active efflux pump. Increased levels of P-glycoprotein are associated with resistance to a variety of anticancer drugs commonly used in tumor chemotherapy like anthracyclins, vinca- alcaloids, epipodophyllotoxins or actinomycin D. We investigated the efficacy or photodynamic therapy in the treatment of tumor cells expressing the multidrug resistance phenotype. Our data show that multidrug resistant cells are highly cross resistant to the phototoxic stain rhodamine 123 but exhibit only low degrees of cross resistance (2 - 3 -folds) to the photosensitizers Photosan-3, Clorin-2, methylene blue and meso-tetra (4- sulfonatophenyl) porphine (TPPS4). Resistance is associated with a decrease in intracellular accumulation of the photosensitizer. Verapamil, a membrane active compound known to enhance drug sensitivity in multidrug resistant cells by inhibition of P-glycoprotein, also increases phototoxicity in multidrug resistant cells. Our results imply that tumors expressing the multidrug resistance phenotype might fail to respond to photochemotherapy with rhodamine 123. On the other hand, multidrug resistance may not play an important role in photodynamic therapy with Photosan-3, Chlorin-2, methylene blue or TPPS4.

  16. Identification of Possible Binding Sites for Morphine and Nicardipine on the Multidrug Transporter P-Glycoprotein Using Umbrella Sampling Techniques.

    Science.gov (United States)

    Subramanian, Nandhitha; Condic-Jurkic, Karmen; Mark, Alan E; O'Mara, Megan L

    2015-06-22

    The multidrug transporter P-glycoprotein (P-gp) is central to the development of multidrug resistance in cancer. While residues essential for transport and binding have been identified, the location, composition, and specificity of potential drug binding sites are uncertain. Here molecular dynamics simulations are used to calculate the free energy profile for the binding of morphine and nicardipine to P-gp. We show that morphine and nicardipine primarily interact with key residues implicated in binding and transport from mutational studies, binding at different but overlapping sites within the transmembrane pore. Their permeation pathways were distinct but involved overlapping sets of residues. The results indicate that the binding location and permeation pathways of morphine and nicardipine are not well separated and cannot be considered as unique. This has important implications for our understanding of substrate uptake and transport by P-gp. Our results are independent of the choice of starting structure and consistent with a range of experimental studies. PMID:25938863

  17. Multidrug resistance in tumour cells: characterisation of the multidrug resistant cell line K562-Lucena 1

    OpenAIRE

    RUMJANEK VIVIAN M.; TRINDADE GILMA S.; WAGNER-SOUZA KAREN; MELETTI-DE-OLIVEIRA MICHELE C.; MARQUES-SANTOS LUIS F.; MAIA RAQUEL C.; CAPELLA MÁRCIA A. M.

    2001-01-01

    Multidrug resistance to chemotherapy is a major obstacle in the treatment of cancer patients. The best characterised mechanism responsible for multidrug resistance involves the expression of the MDR-1 gene product, P-glycoprotein. However, the resistance process is multifactorial. Studies of multidrug resistance mechanisms have relied on the analysis of cancer cell lines that have been selected and present cross-reactivity to a broad range of anticancer agents. This work characterises a multi...

  18. Inhibition of P-glycoprotein functionality by vandetanib may reverse cancer cell resistance to doxorubicin.

    Science.gov (United States)

    Jovelet, C; Bénard, J; Forestier, F; Farinotti, R; Bidart, J M; Gil, S

    2012-08-15

    P-glycoprotein belongs to the ATP binding cassette transporters, responsible for the multidrug resistance of cancer cells. These transporters efflux hydrophobic drugs outside cells and decrease their therapeutic efficacy. The aim of this study was to investigate the effect of vandetanib, an oral tyrosine kinase inhibitor of EGFR, VEGFR 2 and RET kinases, on the functionality of P-gp after a 24h-treatment at therapeutic concentration (2μM), and its ability to increase the cytotoxicity of chemotherapeutic agents in multidrug resistance cancer cells. In this study we found that IGROV1-DXR and IGROV1-CDDP cells were resistant to doxorubicin and cisplatin respectively, compare to parental cell line IGROV1. The parental sensitive and the two resistant cell lines similarly expressed MRP1 and did not express BCRP. Moreover, in contrast to the IGROV1 and IGROV1-CDDP cells, IGROV1-DXR cell line overexpressed P-gp. Functional activity studies demonstrated that MRP1 was not functional and the MDR phenotype in IGROV1-DXR cells was linked to P-gp functionality. Results also showed that vandetanib reversed resistance to doxorubicin in IGROV1-DXR cells, but not to cisplatin in IGROV1-CDDP cells. After 24h of treatment, vandetanib increased the accumulation of rhodamine 123 and calcein AM, demonstrating a functional inhibition of the transporter. In IGROV1-DXR cell line, vandetanib reverse resistance to doxorubicin by inhibiting the functionality of P-gp. In conclusion, vandetanib should be an option for drug combination in patients already developing a P-gp mediated multidrug resistance. PMID:22484209

  19. Complex interplay between the P-glycoprotein multidrug efflux pump and the membrane: its role in modulating protein function

    Directory of Open Access Journals (Sweden)

    FrancesJaneSharom

    2014-03-01

    Full Text Available Multidrug resistance in cancer is linked to expression of the P-glycoprotein multidrug transporter (Pgp, ABCB1, which exports many structurally diverse compounds from cells. Substrates first partition into the bilayer and then interact with a large flexible binding pocket within the transporter’s transmembrane regions. Pgp has been described as a hydrophobic vacuum cleaner or an outwardly-directed drug/lipid flippase. Recent X-ray crystal structures have shed some light on the nature of the drug-binding pocket and suggested routes by which substrates can enter it from the membrane. Detergents have profound effects on Pgp function, and several appear to be substrates. Biochemical and biophysical studies in vitro, some using purified reconstituted protein, have explored the effects of the membrane environment. They have demonstrated that Pgp is involved in a complex relationship with its lipid environment, which modulates the behaviour of its substrates, as well as various functions of the protein, including ATP hydrolysis, drug binding and drug transport. Membrane lipid composition and fluidity, phospholipid headgroup and acyl chain length all influence Pgp function. Recent studies focusing on thermodynamics and kinetics have revealed some important principles governing Pgp-lipid and substrate-lipid interactions, and how these affect drug binding and transport. In some cells, Pgp is associated with cholesterol-rich microdomains which may modulate its functions. The relationship between Pgp and cholesterol remains an open question; however it clearly affects several aspects of its function in addition to substrate-membrane partitioning. The action of Pgp modulators appears to depend on their membrane permeability, and membrane fluidizers and surfactants reverse drug resistance, likely via an indirect mechanism. A detailed understanding of how the membrane affects Pgp substrates and Pgp’s catalytic cycle may lead to new strategies to combat clinical drug resistance.

  20. Enhanced gene delivery efficiency of cationic liposomes coated with PEGylated hyaluronic acid for anti P-glycoprotein siRNA: a potential candidate for overcoming multi-drug resistance.

    Science.gov (United States)

    Ran, Rui; Liu, Yayuan; Gao, Huile; Kuang, Qifang; Zhang, Qianyu; Tang, Jie; Huang, Kai; Chen, Xiaoxiao; Zhang, Zhirong; He, Qin

    2014-12-30

    RNA interference is an effective method to achieve highly specific gene regulation. However, the commonly used cationic liposomes have poor biocompatibility, which may lead to systematic siRNA delivery of no avail. PEGylation is a good strategy in shielding the positive charge of cationic liposomes, but the enhanced serum stability is often in company with compromised cellular uptake and endosome escape. In this study, PEG was covalently linked to negatively charged hyaluronic acid and it was used to coat the liposome-siRNA nanoparticles. The resulting PEG-HA-NP complex had a diameter of 188.6 10.8 nm and a dramatically declined zeta-potential from +34.9 4.0 mV to -18.2 2.2 mV. Owing to the reversed surface charge, PEG-HA-NP could remain stable in fetal bovine serum (FBS) to up to 24h. In contrast with normal PEGylation, hyaluronic acid and PEG co-modified PEG-HA-NP provided comparable cellular uptake and P-glycoprotein downregulation efficacy in MCF-7/ADR cells compared with Lipofectamine RNAiMAX and naked NP regardless of its anionic charged surface. Because of its good biocompatibility in serum, PEG-HA-NP possessed the best tumor accumulation, cellular uptake and subsequently the strongest P-glycoprotein silencing capability in tumor bearing mice compared with naked NP and HA-NP after i.v. injection, with a 34% P-glycoprotein downregulation. Therefore, PEG-HA coated liposomal complex was demonstrated to be a promising siRNA delivery system in adjusting solid tumor P-glycoprotein expression, which may become a potential carrier in reversing MDR for breast cancer therapy. PMID:25448564

  1. New structure-activity relationship studies in a series of N,N-bis(cyclohexanol)amine aryl esters as potent reversers of P-glycoprotein-mediated multidrug resistance (MDR).

    Science.gov (United States)

    Orlandi, Francesca; Coronnello, Marcella; Bellucci, Cristina; Dei, Silvia; Guandalini, Luca; Manetti, Dina; Martelli, Cecilia; Romanelli, Maria Novella; Scapecchi, Serena; Salerno, Milena; Menif, Hayette; Bello, Ivan; Mini, Enrico; Teodori, Elisabetta

    2013-01-15

    As a continuation of previous research on a new series of potent and efficacious P-gp-dependent multidrug resistant (MDR) reversers with a N,N-bis(cyclohexanol)amine scaffold, we have designed and synthesized several analogs by modulation of the two aromatic moieties linked through ester functions to the N,N-bis(cyclohexanol)amine, aiming to optimize activity and to extend structure-activity relationships (SAR) within the series. This scaffold, when esterified with two different aromatic carboxylic acids, gives origin to four geometric isomers (cis/trans, trans/trans, cis/cis and trans/cis). The new compounds were tested on doxorubicin-resistant erythroleukemia K562 cells (K562/DOX) in the pirarubicin uptake assay. Most of them resulted in being potent modulators of the extrusion pump P-gp, showing potency values ([I](0.5)) in the submicromolar and nanomolar range. Of these, compounds 2b, 2c, 3d, 5a-d and 6d, showed excellent efficacy with a ?(max) close to 1. Selected compounds (2d, 3a, 3b, 5a-d) were further studied to evaluate their doxorubicin cytotoxicity potentiation (RF) on doxorubicin-resistant erythroleukemia K562 cells and were found able to enhance significantly doxorubicin cytotoxicity on K562/DOX cells. The results of both pirarubicin uptake and the cytotoxicity assay, indicate that the new compounds of the series are potent P-gp-mediated MDR reversers. They present a structure with a mix of flexible and rigid moieties, a property that seems critical to allow the molecules to choose the most productive of the several binding modes possible in the transporter recognition site. In particular, compounds 5c and 5d, similar to the already reported analogous isomers 1c and 1d,(29) are potent and efficacious modulators of P-gp-dependent MDR and may be promising leads for the development of MDR-reversal drugs. PMID:23245571

  2. P-glycoprotein inhibition of drug resistant cell lines by nanoparticles.

    Science.gov (United States)

    Singh, Manu Smriti; Lamprecht, Alf

    2016-02-01

    Several pharmaceutical excipients are known for their ability to interact with cell membrane lipids and reverse the phenomenon of multidrug resistance (MDR) in cancer. Interestingly, many excipients act as stabilizers and are key ingredients in a variety of nano-formulations. In this study, representatives of ionic and non-ionic excipients were used as surface active agents in nanoparticle (NP) formulations to utilize their MDR reversing potential. In-vitro assays were performed to elucidate particle-cell interaction and accumulation of P-glycoprotein (P-gp) substrates-rhodamine-123 and calcein AM, in highly drug resistant glioma cell lines. Chemosensitization achieved using NPs and their equivalent dose of free excipients was assessed with the co-administered anti-cancer drug doxorubicin. Among the excipients used, non-ionic surfactant, Cremophor EL, and cationic surfactant, cetyltrimethylammonuium bromide (CTAB), demonstrated highest P-gp modulatory activity in both free solution form (up to 7-fold lower IC50) and as a formulation (up to 4.7-fold lower IC50) as compared to doxorubicin treatment alone. Solutol HS15 and Tween 80 exhibited considerable chemosensitization as free solution but not when incorporated into a formulation. Sodium dodecyl sulphate (SDS)-based nanocarriers resulted in slightly improved cytotoxicity. Overall, the results highlight and envisage the usage of excipient in nano-formulations in a bid to improve chemosensitization of drug resistant cancer cells towards anti-cancer drugs. PMID:26065532

  3. Overcoming Multidrug Resistance in Human Cancer Cells by Natural Compounds

    Directory of Open Access Journals (Sweden)

    Tomohiro Nabekura

    2010-05-01

    Full Text Available Multidrug resistance is a phenomenon whereby tumors become resistant to structurally unrelated anticancer drugs. P-glycoprotein belongs to the large ATP-binding cassette (ABC transporter superfamily of membrane transport proteins. P-glycoprotein mediates resistance to various classes of anticancer drugs including vinblastine, daunorubicin, and paclitaxel, by actively extruding the drugs from the cells. The quest for inhibitors of anticancer drug efflux transporters has uncovered natural compounds, including (--epigallocatechin gallate, curcumin, capsaicin, and guggulsterone, as promising candidates. In this review, studies on the effects of natural compounds on P-glycoprotein and anticancer drug efflux transporters are summarized.

  4. Effect of pentoxifylline on P-glycoprotein mediated vincristine resistance of L1210 mouse leukemic cell line

    International Nuclear Information System (INIS)

    Effect of pentoxifylline (PTX) on vincristine (VCR) resistance of multidrug resistant L1210/VCR mouse leukemic cell line was studied. Reversal effect of PTX (in concentration 50-150 mg dm-3) on vincristine resistance, i.e. potentiation of vincristine cytotoxicity on L1210/VCR cells by PTX was found. PTX alone in the above concentration did not exert any significant effect on sensitive or resistant cell lines in the absence of vincristine. Resistance of L1210/VCR cell line was found previously to be accompanied with overexpression of drug transporting P-glycoprotein. Indeed, lower level of 3H-vincristine accumulation by resistant L1210/VCR cell line in comparison with sensitive L1210 cell line was observed. Accumulation of 3H-vincristine by L1210/VCR cell line was significantly increased in the presence of PTX. PTX in the same condition did not exert any considerable effect on accumulation of 3H-vincristine by nonresistant L1210 cells. Observable morphological damage was observed in 1210/VCR cells cultivated in medium containing vincristine (0.2 mg dm-3) and pentoxifylline (100 mg dm-3) in comparison with the non-damaged cells in the presence of vincristine or pentoxifylline alone. The results obtained indicate that pentoxifylline may be considered as a reversal agent in multidrug resistance. (author)

  5. Functional expression of murine multidrug resistance in Xenopus laevis oocytes

    International Nuclear Information System (INIS)

    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 MDR-like phenotype. Immunological analysis indicated that oocytes injected with the mdr1b RNA synthesized a protein with the size and immunological characteristics of the mouse mdr1b P glycoprotein. These oocytes exhibited a decreased accumulation of [3H]vinblastine and showed an increased capacity to extrude the drug compared to control oocytes not expressing the P glycoprotein. In addition, competition experiments indicated that verapamil, vincristine, daunomycin, and quinidine, but not colchicine, can overcome the rapid drug efflux conferred by the expression of the mouse P glycoprotein

  6. Nanodrug Delivery in Reversing Multidrug Resistance in Cancer Cells

    OpenAIRE

    MayurYergeri; RohitSrivastava; ThirumalaGovender

    2014-01-01

    Different mechanisms in cancer cells become resistant to one or more chemotherapeutics is known as multidrug resistance (MDR) which hinders chemotherapy efficacy. Potential factors for MDR includes enhanced drug detoxification, decreased drug uptake, increased intracellular nucleophiles levels, enhanced repair of drug induced DNA damage, overexpression of drug transporter such as P-glycoprotein(P-gp), multidrug resistance-associated proteins (MRP1, MRP2), and breast cancer resistance protein ...

  7. Potential contribution of P-glycoproteins to macrocyclic lactone resistance in the cattle parasitic nematode Cooperia oncophora.

    Science.gov (United States)

    Demeler, Janina; Krücken, Jürgen; AlGusbi, Salha; Ramünke, Sabrina; De Graef, Jessie; Kerboeuf, Dominique; Geldhof, Peter; Pomroy, William E; von Samson-Himmelstjerna, Georg

    2013-03-01

    Resistance against macrocyclic lactones such as ivermectin is widespread among parasitic gastrointestinal nematodes of small ruminants and is rapidly increasing in cattle parasites. ABC transporters of the subfamily B, the so-called P-glycoproteins (Pgps) have been frequently implicated in ivermectin resistance and are a major cause of multi-drug resistance in protozoa and helminths. The Pgp inhibitor verapamil (VPL) dramatically enhanced susceptibility of the cattle parasitic nematode Cooperia oncophora to ivermectin in vitro as measured in a larval developmental assay and a larval migration inhibition assay using third stage larvae. Moreover, VPL completely restored susceptibility to ivermectin in a resistant isolate resulting in virtually identical dose-response curves of susceptible and resistant isolates in the presence of VPL. Further characterisation of the molecular mechanisms resulting in Pgp-mediated ivermectin resistance is still hampered by the lack of molecular and biochemical information for Pgps of parasitic nematodes. Using PCR with degenerate primers, fragments of four different C. oncophora Pgps could be amplified and the Conpgp-2, previously implicated in macrocyclic lactone resistance in Haemonchus contortus, and Conpgp-3 full-length cDNAs were obtained by RACE PCR. The pgp sequences presented here contribute important data required to systematically screen resistant C. oncophora isolates for up- or down-regulation of Pgps and for the detection of single nucleotide polymorphisms in Pgps to detect selection of specific Pgp alleles by anthelmintics as early as possible. PMID:23384738

  8. Resistance to paclitaxel in a cisplatin-resistant ovarian cancer cell line is mediated by P-glycoprotein

    OpenAIRE

    Stordal, Britta K.; Hamon, Marion; McEneaney, Victoria; Roche, Sandra; Gillet, Jean-Pierre; O'Leary, John J.; Gottesman, Michael; Clynes, Martin

    2012-01-01

    The IGROVCDDP cisplatin-resistant ovarian cancer cell line is also resistant to paclitaxel and models the resistance phenotype of relapsed ovarian cancer patients after first-line platinum/taxane chemotherapy. A TaqMan low-density array (TLDA) was used to characterise the expression of 380 genes associated with chemotherapy resistance in IGROVCDDP cells. Paclitaxel resistance in IGROVCDDP is mediated by gene and protein overexpression of P-glycoprotein and the protein is functionally active. ...

  9. Multidrug resistance in tumour cells: characterisation of the multidrug resistant cell line K562-Lucena 1

    Directory of Open Access Journals (Sweden)

    RUMJANEK VIVIAN M.

    2001-01-01

    Full Text Available Multidrug resistance to chemotherapy is a major obstacle in the treatment of cancer patients. The best characterised mechanism responsible for multidrug resistance involves the expression of the MDR-1 gene product, P-glycoprotein. However, the resistance process is multifactorial. Studies of multidrug resistance mechanisms have relied on the analysis of cancer cell lines that have been selected and present cross-reactivity to a broad range of anticancer agents. This work characterises a multidrug resistant cell line, originally selected for resistance to the Vinca alkaloid vincristine and derived from the human erythroleukaemia cell K562. This cell line, named Lucena 1, overexpresses P-glycoprotein and have its resistance reversed by the chemosensitisers verapamil, trifluoperazine and cyclosporins A, D and G. Furthermore, we demonstrated that methylene blue was capable of partially reversing the resistance in this cell line. On the contrary, the use of 5-fluorouracil increased the resistance of Lucena 1. In addition to chemotherapics, Lucena 1 cells were resistant to ultraviolet A radiation and hydrogen peroxide and failed to mobilise intracellular calcium when thapsigargin was used. Changes in the cytoskeleton of this cell line were also observed.

  10. Macrocyclic diterpenes resensitizing multidrug resistant phenotypes.

    Science.gov (United States)

    Reis, Mariana A; Paterna, Angela; Ferreira, Ricardo J; Lage, Hermann; Ferreira, Maria-José U

    2014-07-15

    Herein, collateral sensitivity effect was exploited as a strategy to select effective compounds to overcome multidrug resistance in cancer. Thus, eleven macrocyclic diterpenes, namely jolkinol D (1), isolated from Euphorbia piscatoria, and its derivatives (2-11) were evaluated for their activity on three different Human cancer entities: gastric (EPG85-257), pancreatic (EPP85-181) and colon (HT-29) each with a variant selected for resistance to mitoxantrone (EPG85-257RN; EPP85-181RN; HT-29RN) and one to daunorubicin (EPG85-257RD; EPP85-181RD; HT-29RD). Jolkinol D (1) and most of its derivatives (2-11) exhibited significant collateral sensitivity effect towards the cell lines EPG85-257RN (associated with P-glycoprotein overexpression) and HT-29RD (altered topoisomerase II expression). The benzoyl derivative, jolkinoate L (8) demonstrated ability to target different cellular contexts with concomitant high antiproliferative activity. These compounds were previously assessed as P-glycoprotein modulators, at non-cytotoxic doses, on MDR1-mouse lymphoma cells. A regression analysis between the antiproliferative activity presented herein and the previously assessed P-glycoprotein modulatory effect showed a strong relation between the compounds that presented both high P-glycoprotein modulation and cytotoxicity. PMID:24864039

  11. Multidrug Resistance in Bacteria

    OpenAIRE

    Nikaido, Hiroshi

    2009-01-01

    Large amounts of antibiotics used for human therapy, as well as for farm animals and even for fish in aquaculture, resulted in the selection of pathogenic bacteria resistant to multiple drugs. Multidrug resistance in bacteria may be generated by one of two mechanisms. First, these bacteria may accumulate multiple genes, each coding for resistance to a single drug, within a single cell. This accumulation occurs typically on resistance (R) plasmids. Second, multidrug resistance may also occur b...

  12. Overexpression of P-glycoprotein induces acquired resistance to imatinib in chronic myelogenous leukemia cells

    OpenAIRE

    PENG, XING-XIANG; Tiwari, Amit K.; Wu, Hsiang-Chun; CHEN, ZHE-SHENG

    2012-01-01

    Imatinib, a breakpoint cluster region (BCR)-Abelson murine leukemia (ABL) tyrosine kinase inhibitor (TKI), has revolutionized the treatment of chronic myelogenous leukemia (CML). However, development of multidrug resistance (MDR) limits the use of imatinib. In the present study, we aimed to investigate the mechanisms of cellular resistance to imatinib in CML. Therefore, we established an imatinib-resistant human CML cell line (K562-imatinib) through a stepwise selection process. While charact...

  13. Intracellular trafficking of P-glycoprotein

    OpenAIRE

    Fu, Dong; Arias, Irwin M.

    2011-01-01

    Overexpression of P-glycoprotein (P-gp) is a major cause of multidrug resistance in cancer. P-gp is mainly localized in the plasma membrane and can efflux structurally and chemically unrelated substrates, including anticancer drugs. P-gp is also localized in intracellular compartments, such as ER, Golgi, endosomes and lysosomes, and cycles between endosomal compartments and the plasma membrane in a microtubular-actin dependent manner. Intracellular trafficking pathways for P-gp and participat...

  14. Cytotoxicity of rhein, the active metabolite of sennoside laxatives, is reduced by multidrug resistance-associated protein 1

    OpenAIRE

    van Gorkom, B A P; Timmer-Bosscha, H; de Jong, S.; van der Kolk, D.M.; Kleibeuker, J. H.; de Vries, E. G. E.

    2002-01-01

    Anthranoid laxatives, belonging to the anthraquinones as do anthracyclines, possibly increase colorectal cancer risk. Anthracyclines interfere with topoisomerase II, intercalate DNA and are substrates for P-glycoprotein and multidrug resistance-associated protein 1. P-glycoprotein and multidrug resistance-associated protein 1 protect colonic epithelial cells against xenobiotics. The aim of this study was to analyse the interference of anthranoids with these natural defence mechanisms and the ...

  15. The combined use of paclitaxel-loaded nanoparticles with a low-molecular-weight copolymer inhibitor of P-glycoprotein to overcome drug resistance

    Directory of Open Access Journals (Sweden)

    Wan CP

    2013-01-01

    Full Text Available Chung Ping Leon Wan,* Kevin Letchford,* John K Jackson, Helen M Burt Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada*These authors contributed equally to this workAbstract: Two types of nanoparticles were prepared using the diblock copolymer methoxy poly(ethylene glycol-block-poly(caprolactone (MePEG-b-PCL, with either a short PCL block length, which forms micelles, or with a longer PCL block length, which forms kinetically "frozen core" structures termed nanospheres. Paclitaxel (PTX-loaded micelles and nanospheres were evaluated for their cytotoxicity, cellular polymer uptake, and drug accumulation in drug-sensitive (Madin–Darby Canine Kidney [MDCK]II and multidrug-resistant (MDR P-glycoprotein (P-gp-overexpressing (MDCKII-MDR1 cell lines. Both types of PTX-loaded nanoparticles were equally effective at inhibiting proliferation of MDCKII cells, but PTX-loaded micelles were more cytotoxic than nanospheres in MDCKII-MDR1 cells. The intracellular accumulation of both PTX and the diblock copolymers were similar for both nanoparticles, suggesting that the difference in cytotoxicity might be due to the different drug-release profiles. Furthermore, the cytotoxicity of these PTX-loaded nanoparticles was enhanced when these systems were subsequently or concurrently combined with a low-molecular-weight MePEG-b-PCL diblock copolymer, which we have previously demonstrated to be an effective P-gp inhibitor. These results suggest that the dual functionality of MePEG-b-PCL might be useful in delivering drug intracellularly and in modulating P-gp in order to optimize the cytotoxicity of PTX in multidrug-resistant cells.Keywords: multidrug resistance, paclitaxel, nanoparticles, micelles, nanospheres, P-glycoprotein

  16. P-glycoprotein-mediated resistance to chemotherapy in cancer cells: using recombinant cytosolic domains to establish structure-function relationships

    Directory of Open Access Journals (Sweden)

    Di Pietro A.

    1999-01-01

    Full Text Available Resistance to chemotherapy in cancer cells is mainly mediated by overexpression of P-glycoprotein (Pgp, a plasma membrane ATP-binding cassette (ABC transporter which extrudes cytotoxic drugs at the expense of ATP hydrolysis. Pgp consists of two homologous halves each containing a transmembrane domain and a cytosolic nucleotide-binding domain (NBD which contains two consensus Walker motifs, A and B, involved in ATP binding and hydrolysis. The protein also contains an S signature characteristic of ABC transporters. The molecular mechanism of Pgp-mediated drug transport is not known. Since the transporter has an extraordinarily broad substrate specificity, its cellular function has been described as a "hydrophobic vacuum cleaner". The limited knowledge about the mechanism of Pgp, partly due to the lack of a high-resolution structure, is well reflected in the failure to efficiently inhibit its activity in cancer cells and thus to reverse multidrug resistance (MDR. In contrast to the difficulties encountered when studying the full-length Pgp, the recombinant NBDs can be obtained in large amounts as soluble proteins. The biochemical and biophysical characterization of recombinant NBDs is shown here to provide a suitable alternative route to establish structure-function relationships. NBDs were shown to bind ATP and analogues as well as potent modulators of MDR, such as hydrophobic steroids, at a region close to the ATP site. Interestingly, flavonoids also bind to NBDs with high affinity. Their binding site partly overlaps both the ATP-binding site and the steroid-interacting region. Therefore flavonoids constitute a new promising class of bifunctional modulators of Pgp.

  17. Temozolomide reverses doxorubicin resistance by inhibiting P-glycoprotein in malignant glioma cells.

    Science.gov (United States)

    Zhang, Rong; Saito, Ryuta; Shibahara, Ichiyo; Sugiyama, Shinichiro; Kanamori, Masayuki; Sonoda, Yukihiko; Tominaga, Teiji

    2016-01-01

    Temozolomide is a standard chemotherapy agent for malignant gliomas, but the efficacy is still not satisfactory. Therefore, combination chemotherapy using temozolomide with other anti-tumor compounds is now under investigation. Here we studied the mechanism of the synergistic anti-tumor effect achieved by temozolomide and doxorubicin, and elucidated the inhibitory effect of temozolomide on P-glycoprotein (P-gp). Temozolomide significantly enhanced sensitivity to P-gp substrate in glioma cells, particularly in P-gp-overexpressed cells. Synergetic effects, as determined by isobologram analysis, were observed by combining temozolomide and doxorubicin. Subsequently, flow cytometry was utilized to assess the intracellular retention of doxorubicin in cells treated with doxorubicin with or without temozolomide. Temozolomide significantly increased the accumulation of doxorubicin in these cells. The P-gp adenosine triphosphatase (ATPase) assay showed that temozolomide inhibited the ATPase activity of P-gp. In addition, temozolomide combined with doxorubicin significantly prolonged the survival of 9L intracranial allografted glioma-bearing rats compared to single agent treatment. Collectively, our findings suggest that temozolomide can reverse doxorubicin resistance by directly affecting P-gp transport activity. Combination chemotherapy using temozolomide with other agents may be effective against gliomas in clinical applications. PMID:26530267

  18. Drug accumulation in the presence of the multidrug resistance pump

    DEFF Research Database (Denmark)

    Ayesh, S; Litman, Thomas; Stein, W D

    P388 leukemia cell line, P388/ADR. The time course of accumulation of these drugs, and the effect of energy starvation and the presence of chloroquine on the level of their steady-state accumulation were quite disparate. Vinblastine inhibited the accumulation of verapamil whereas it enhanced the......We studied the interaction between the multidrug transporter, P-glycoprotein, and two compounds that interact with it: vinblastine, a classical substrate of the pump, and verapamil, a classical reverser. Steady-state levels of accumulation of these two drugs were determined in a multidrug resistant...

  19. Kinetic Validation of the Models for P-Glycoprotein ATP Hydrolysis and Vanadate-Induced Trapping. Proposal for Additional Steps

    OpenAIRE

    Lugo, Miguel Ramn; Sharom, Frances Jane

    2014-01-01

    P-Glycoprotein, a member of the ATP-binding cassette (ABC) superfamily, is a multidrug transporter responsible for cellular efflux of hundreds of structurally unrelated compounds, including natural products, many clinically used drugs and anti-cancer agents. Expression of P-glycoprotein has been linked to multidrug resistance in human cancers. ABC transporters are driven by ATP hydrolysis at their two cytoplasmic nucleotide-binding domains, which interact to form a closed ATP-bound sandwich d...

  20. Phosphorylation of the multidrug resistance associated glycoprotein

    International Nuclear Information System (INIS)

    Drug-resistant cell lines derived from the mouse macrophage-like cell line J774.2 express the multidrug resistant phenotype which includes the overexpression of a membrane glycoprotein (130-140 kilodaltons). Phosphorylation of this resistant-specific glycoprotein (P-glycoprotein) in intact cells and in cell-free membrane fractions has been studied. The phosphorylated glycoprotein can be immunoprecipitated by a rabbit polyclonal antibody specific for the glycoprotein. Phosphorylation studies done with partially purified membrane fractions derived from colchicine-resistant cells indicated that (a) phosphorylation of the glycoprotein in 1 mM MgCl2 was enhanced a minimum of 2-fold by 10 μM cAMP and (b) the purified catalytic subunit of the cAMP-dependent protein kinase (protein kinase A) phosphorylated partially purified glycoprotein that was not phosphorylated by [γ-32P]ATP alone, suggesting that autophosphorylation was not involved. These results indicate that the glycoprotein is a phosphoprotein and that at least one of the kinases responsible for its phosphorylation is a membrane-associated protein kinase A. The state of phosphorylation of the glycoprotein, which is a major component of the multidrug resistance phenotype, may be related to the role of the glycoprotein in maintaining drug resistance

  1. Phosphorylation of the multidrug resistance associated glycoprotein.

    Science.gov (United States)

    Mellado, W; Horwitz, S B

    1987-11-01

    Drug-resistant cell lines derived from the mouse macrophage-like cell line J774.2 express the multidrug resistance phenotype which includes the overexpression of a membrane glycoprotein (130-140 kilodaltons). Phosphorylation of this resistant-specific glycoprotein (P-glycoprotein) in intact cells and in cell-free membrane fractions has been studied. The phosphorylated glycoprotein can be immunoprecipitated by a rabbit polyclonal antibody specific for the glycoprotein. Phosphorylation studies done with partially purified membrane fractions derived from colchicine-resistant cells indicated that (a) phosphorylation of the glycoprotein in 1 mM MgCl2 was enhanced a minimum of 2-fold by 10 microM cAMP and (b) the purified catalytic subunit of the cAMP-dependent protein kinase (protein kinase A) phosphorylated partially purified glycoprotein that was not phosphorylated by [gamma-32P]ATP alone, suggesting that autophosphorylation was not involved. These results indicate that the glycoprotein is a phosphoprotein and that at least one of the kinases responsible for its phosphorylation is a membrane-associated protein kinase A. The state of phosphorylation of the glycoprotein, which is a major component of the multidrug resistance phenotype, may be related to the role of the glycoprotein in maintaining drug resistance. PMID:3427052

  2. Multidrug-Resistant Tuberculosis

    Centers for Disease Control (CDC) Podcasts

    2008-10-28

    In this podcast, Dr. Oeltmann discusses multidrug-resistant tuberculosis. An outbreak occurred in Thailand, which led to 45 cases in the U.S. This serious illness can take up to 2 years to treat. MDR TB is a real threat and a serious condition.  Created: 10/28/2008 by Emerging Infectious Diseases.   Date Released: 10/28/2008.

  3. Enhanced Brain Disposition and Effects of Δ9-Tetrahydrocannabinol in P-Glycoprotein and Breast Cancer Resistance Protein Knockout Mice

    OpenAIRE

    Spiro, Adena S.; Wong, Alexander; Boucher, Aurélie A.; Arnold, Jonathon C.

    2012-01-01

    The ABC transporters P-glycoprotein (P-gp, Abcb1) and breast cancer resistance protein (Bcrp, Abcg2) regulate the CNS disposition of many drugs. The main psychoactive constituent of cannabis Δ9-tetrahydrocannabinol (THC) has affinity for P-gp and Bcrp, however it is unknown whether these transporters modulate the brain accumulation of THC and its functional effects on the CNS. Here we aim to show that mice devoid of Abcb1 and Abcg2 retain higher brain THC levels and are more sensitive to cann...

  4. Quercetin as a Potential Modulator of P-Glycoprotein Expression and Function in Cells of Human Pancreatic Carcinoma Line Resistant to Daunorubicin

    Directory of Open Access Journals (Sweden)

    Piotr Dziegiel

    2010-02-01

    Full Text Available P-glycoprotein (P-gp is one of the ABC transporters responsible for the resistance of several tumours to successful chemotherapy. Numerous agents are capable of interfering with the P-gp-mediated export of drugs but unfortunately most of them produce serious side effects. Some plant polyphenols, including the flavonol quercetin (Q, manifest anti-neoplastic activity mainly due to their influence on cell cycle control and apoptosis. Reports are also available which show that Q may intensify action of cytostatic drugs and suppress the multidrug resistance (MDR phenomenon. The study aimed at determination if Q sensitizes cells resistant to daunorubicin (DB through its effect on P-gp expression and action. The experiments were conducted on two cell lines of human pancreatic carcinoma, resistant to DB EPP85-181RDB and sensitive EPP85-181P as a comparison. Cells of both lines were exposed to selected concentrations of Q and DB, and then membranous expression of P-gp and its transport function were examined. The influence on expression of gene for P-gp (ABCB1 was also investigated. Results of the studies confirmed that Q affects expression and function of P-gp in a concentration-dependent manner. Moreover it decreased expression of ABCB1. Thus, Q may be considered as a potential modulator of P-gp.

  5. Dynamic Assessment of Mitoxantrone Resistance and Modulation of Multidrug Resistance by Valspodar (PSC833) in Multidrug Resistance Human Cancer Cells

    OpenAIRE

    Shen, Fei; Bailey, Barbara J.; Chu, Shaoyou; Bence, Aimee K.; Xue, Xinjian; Erickson, Priscilla; Safa, Ahmad R; Beck, William T.; Erickson, Leonard C.

    2009-01-01

    P-glycoprotein (Pgp), a member of the ATP-binding cassette transporter family, is one of the major causes for multidrug resistance (MDR). We report using confocal microscopy to study the roles of Pgp in mediating the efflux of the anticancer agent mitoxantrone and the reversal of MDR by the specific Pgp inhibitor valspodar (PSC833). The net uptake and efflux of mitoxantrone and the effect of PSC833 were quantified and compared in Pgp-expressing human cancer MDA-MB-435 ...

  6. THE ROLE OF P-GLYCOPROTEIN IN RATIONAL PHARMACOTHERAPY IN CARDIOLOGY

    Directory of Open Access Journals (Sweden)

    A. V. Shulkin

    2015-09-01

    Full Text Available On the basis of the analysis of published data the role of P-glycoprotein, carrier protein, in rational pharmacotherapy in cardiology was shown on the example of its substrates – digoxin, antiplatelet agents and anticoagulants. Determination of C3435T polymorphism of multidrug resistance gene (MDR1, encoding P-glycoprotein, in pharmacotherapy with digoxin, antiplatelet drugs (clopidogrel tikagrelol, prasugrel and anticoagulants (dabigatran etexilate, rivaroxaban, edoxaban is not feasible in routine practice. Drug in- teractions have clinical implications for the efficacy and safety of pharmacotherapy in coadministration of these drugs with P-glycoprotein substrates, inducers and inhibitors.

  7. Multidrug-resistant tuberculosis

    Directory of Open Access Journals (Sweden)

    Álvarez-Gaviria Manuel

    2013-06-01

    Full Text Available Introduction: tuberculosis is an increasing problem of global health and the microbialdrug resistance a generating element of worry.Clinical case: 19 year-old patient, who admitted to the emergency room for presentinghemoptysis and who had history of pulmonary tuberculosis with irregular treatment.Multidrug-resistant tuberculosis was documented and different strategies of availablemedical treatment were considered. Due to the increased epidemiological risk and thehistory of poor adherence to the treatment, an in-hospital treatment was carried outwith a satisfactory response.Conclusion: multidrug-resistant tuberculosis is a social risk, keeping the route oftransmission of the disease. Rev.cienc.biomed. 2013;4(1:159-164RESUMEN:Introducción: la tuberculosis (TB pulmonar es un problema creciente de saludmundial y la resistencia a los antibióticos un elemento de preocupación.Caso clínico: paciente de 19 años, quien ingresó al servicio de urgencias por presentarhemoptisis. Antecedente de TB con tratamiento irregular. Se documentó resistenciaa varios medicamentos. Se consideraron las diferentes estrategias de tratamientodisponible. Debido al elevado riesgo epidemiológico y la historia de pobre adherencia altratamiento, se realizó manejo intrahospitalario con respuesta satisfactoria.Conclusiones: la tuberculosis multirresistente (MDR-TB representa un riesgo parala comunidad, teniendo en cuenta la vía de transmisión de la entidad. Rev.cienc.biomed. 2013;4(1:159-164

  8. Synthesis of 5-oxyquinoline derivatives for reversal of multidrug resistance

    Directory of Open Access Journals (Sweden)

    Torsten Dittrich

    2012-10-01

    Full Text Available The inhibition of ABC (ATP binding cassette transporters is considered a powerful tool to reverse multidrug resistance. Zosuquidar featuring a difluorocyclopropyl-annulated dibenzosuberyl moiety has been found to be an inhibitor of the P-glycoprotein, one of the best-studied multidrug efflux pumps. Twelve 5-oxyisoquinoline derivatives, which are analogues of zosuquidar wherein the dibenzosuberyl-piperazine moiety is replaced by either a diarylaminopiperidine or a piperidone-derived acetal or thioacetal group, have been synthesized as pure enantiomers. Their inhibitory power has been evaluated for the bacterial multidrug-resistance ABC transporter LmrCD and fungal Pdr5. Four of the newly synthesized compounds reduced the transport activity to a higher degree than zosuquidar, being up to fourfold more efficient than the lead compound in the case of LmrCD and about two times better for Pdr5.

  9. Development and characterization of P-glycoprotein 1 (Pgp1, ABCB1)-mediated doxorubicin-resistant PLHC-1 hepatoma fish cell line

    International Nuclear Information System (INIS)

    The development of the multidrug resistance (MDR) phenotype in mammals is often mediated by the overexpression of the P-glycoprotein1 (Pgp, ABCB1) or multidrug resistance-associated protein (MRP)-like ABC transport proteins. A similar phenomenon has also been observed and considered as an important part of the multixenobiotic resistance (MXR) defence system in aquatic organisms. We have recently demonstrated the presence of ABC transporters in the widely used in vitro fish model, the PLHC-1 hepatoma cell line. In the present study we were able to select a highly resistant PLHC-1 sub-clone (PLHC-1/dox) by culturing the wild-type cells in the presence of 1 μM doxorubicin. Using quantitative PCR a 42-fold higher expression of ABCB1 gene was determined in the PLHC-1/dox cells compared to non-selected wild-type cells (PLHC-1/wt). The efflux rates of model fluorescent Pgp1 substrates rhodamine 123 and calcein-AM were 3- to 4-fold higher in the PLHC-1/dox in comparison to the PLHC-1/wt cells. PLHC-1/dox were 45-fold more resistant to doxorubicin cytotoxicity than PLHC-1/wt. Similarly to mammalian cell lines, typical cross-resistance to cytotoxicity of other chemotherapeutics such as daunorubicin, vincristine, vinblastine, etoposide and colchicine, occurred. Furthermore, cyclosporine A, verapamil and PSC833, specific inhibitors of Pgp1 transport activity, completely reversed resistance of PLHC-1/dox cells to all tested drugs, resulting in EC50 values similar to the EC50 values found for PLHC-1/wt. In contrast, MK571, a specific inhibitor of MRP type of efflux transporters, sensitized PLHC-1/dox cells, neither to doxorubicin, nor to any other of the chemotherapeutics used in the study. These data demonstrate for the first time that a specific Pgp1-mediated doxorubicin resistance mechanism is present in the PLHC-1 fish hepatoma cell line. In addition, the fact that low micromolar concentrations of specific inhibitors may completely reverse a highly expressed doxorubicin resistance points to the fragility of Pgp1-mediated MXR defence mechanism in fish

  10. Multidrug-resistant tuberculosis

    Directory of Open Access Journals (Sweden)

    McNerney Ruth

    2008-01-01

    Full Text Available Abstract Background With almost 9 million new cases each year, tuberculosis remains one of the most feared diseases on the planet. Led by the STOP-TB Partnership and WHO, recent efforts to combat the disease have made considerable progress in a number of countries. However, the emergence of mutated strains of Mycobacterium tuberculosis that are resistant to the major anti-tuberculosis drugs poses a deadly threat to control efforts. Multidrug-resistant tuberculosis (MDR-TB has been reported in all regions of the world. More recently, extensively drug resistant-tuberculosis (XDR-TB that is also resistant to second line drugs has emerged in a number of countries. To ensure that adequate resources are allocated to prevent the emergence and spread of drug resistance it is important to understand the scale of the problem. In this article we propose that current methods of describing the epidemiology of drug resistant tuberculosis are not adequate for this purpose and argue for the inclusion of population based statistics in global surveillance data. Discussion Whereas the prevalence of tuberculosis is presented as the proportion of individuals within a defined population having disease, the prevalence of drug resistant tuberculosis is usually presented as the proportion of tuberculosis cases exhibiting resistance to anti-tuberculosis drugs. Global surveillance activities have identified countries in Eastern Europe, the former Soviet Union and regions of China as having a high proportion of MDR-TB cases and international commentary has focused primarily on the urgent need to improve control in these settings. Other regions, such as sub-Saharan Africa have been observed as having a low proportion of drug resistant cases. However, if one considers the incidence of new tuberculosis cases with drug resistant disease in terms of the population then countries of sub-Saharan Africa have amongst the highest rates of transmitted MDR-TB in the world. We propose that inclusion of population based statistics in global surveillance data is necessary to better inform debate on the control of drug resistant tuberculosis. Summary Re-appraisal of global MDR-TB data to include population based statistics suggests that the problem of drug resistant tuberculosis in sub-Saharan Africa is more critical than previously perceived.

  11. P-glycoprotein Mediates Ceritinib Resistance in Anaplastic Lymphoma Kinase-rearranged Non-small Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Ryohei Katayama

    2016-01-01

    Full Text Available The anaplastic lymphoma kinase (ALK fusion oncogene is observed in 3%–5% of non-small cell lung cancer (NSCLC. Crizotinib and ceritinib, a next-generation ALK tyrosine kinase inhibitor (TKI active against crizotinib-refractory patients, are clinically available for the treatment of ALK-rearranged NSCLC patients, and multiple next-generation ALK-TKIs are currently under clinical evaluation. These ALK-TKIs exhibit robust clinical activity in ALK-rearranged NSCLC patients; however, the emergence of ALK-TKI resistance restricts the therapeutic effect. To date, various secondary mutations or bypass pathway activation-mediated resistance have been identified, but large parts of the resistance mechanism are yet to be identified. Here, we report the discovery of p-glycoprotein (P-gp/ABCB1 overexpression as a ceritinib resistance mechanism in ALK-rearranged NSCLC patients. P-gp exported ceritinib and its overexpression conferred ceritinib and crizotinib resistance, but not to PF-06463922 or alectinib, which are next-generation ALK inhibitors. Knockdown of ABCB1 or P-gp inhibitors sensitizes the patient-derived cancer cells to ceritinib, in vitro and in vivo. P-gp overexpression was identified in three out of 11 cases with in ALK-rearranged crizotinib or ceritinib resistant NSCLC patients. Our study suggests that alectinib, PF-06463922, or P-gp inhibitor with ceritinib could overcome the ceritinib or crizotinib resistance mediated by P-gp overexpression.

  12. Direct interaction between verapamil and doxorubicin causes the lack of reversal effect of verapamil on P-glycoprotein mediated resistance to doxorubicin in vitro using L1210/VCR cells

    International Nuclear Information System (INIS)

    Mouse leukemic cell sub-line L 1210/VCR exerts expressive multidrug resistance (MDR) that is mediated by P-glycoprotein. Cells originally adapted to vincristine are also extremely resistant to doxorubicin. Resistance to both vincristine and doxorubicin is connected with depression of drug uptake. While resistance of L 121 O cells to vincristine could be reversed by verapamil as chemo-sensitizer, resistance of cells to doxorubicin was insensitive to verapamil. Action of verapamil (well-known inhibitor of PGP activity) on multidrug resistance was often used as evidence that MDR is mediated by PGP. From this point it may be possible that the resistance of L1210/VCR cells to vincristine is mediated by PGP and the resistance to doxorubicin is mediated by other PGP-independent system. Another and more probable explanation of different effect of verapamil on resistance of L1210/VCR cells to vincristine and doxorubicin may be deduced from the following fact: Using UV spectroscopy we found that doxorubicin dissolved in water buffered medium interacts effectively with verapamil. This interaction may be responsible for the decrease of concentration of both drugs in free effective form and consequently for higher survival of cells. In contrast to doxorubicin vincristine does not give any interaction with verapamil that is measurable by UV spectroscopy and resistance of L1210/VCR cells to vincristine may be fully reversed by verapamil. (authors)

  13. CD44-engineered mesoporous silica nanoparticles for overcoming multidrug resistance in breast cancer

    Science.gov (United States)

    Wang, Xin; Liu, Ying; Wang, Shouju; Shi, Donghong; Zhou, Xianguang; Wang, Chunyan; Wu, Jiang; Zeng, Zhiyong; Li, Yanjun; Sun, Jing; Wang, Jiandong; Zhang, Longjiang; Teng, Zhaogang; Lu, Guangming

    2015-03-01

    Multidrug resistance is a major impediment for the successful chemotherapy in breast cancer. CD44 is over-expressed in multidrug resistant human breast cancer cells. CD44 monoclonal antibody exhibits anticancer potential by inhibiting proliferation and regulating P-glycoprotein-mediated drug efflux activity in multidrug resistant cells. Thereby, CD44 monoclonal antibody in combination with chemotherapeutic drug might be result in enhancing chemosensitivity and overcoming multidrug resistance. The purpose of this study is to investigate the effects of the CD44 monoclonal antibody functionalized mesoporous silica nanoparticles containing doxorubicin on human breast resistant cancer MCF-7 cells. The data showed that CD44-modified mesoporous silica nanoparticles increased cytotoxicity and enhanced the downregulation of P-glycoprotein in comparison to CD44 antibody. Moreover, CD44-engineered mesoporous silica nanoparticles provided active target, which promoted more cellular uptake of DOX in the resistant cells and more retention of DOX in tumor tissues than unengineered counterpart. Animal studies of the resistant breast cancer xenografts demonstrated that CD44-engineered drug delivery system remarkably induced apoptosis and inhibited the tumor growth. Our results indicated that the CD44-engineered mesoporous silica nanoparticle-based drug delivery system offers an effective approach to overcome multidrug resistance in human breast cancer.

  14. Marine Natural Products with P-Glycoprotein Inhibitor Properties

    Directory of Open Access Journals (Sweden)

    Dioxelis Lopez

    2014-01-01

    Full Text Available P-glycoprotein (P-gp is a protein belonging to the ATP-binding cassette (ABC transporters superfamily that has clinical relevance due to its role in drug metabolism and multi-drug resistance (MDR in several human pathogens and diseases. P-gp is a major cause of drug resistance in cancer, parasitic diseases, epilepsy and other disorders. This review article aims to summarize the research findings on the marine natural products with P-glycoprotein inhibitor properties. Natural compounds that modulate P-gp offer great possibilities for semi-synthetic modification to create new drugs and are valuable research tools to understand the function of complex ABC transporters.

  15. P-glycoprotein and breast cancer resistance protein in acute myeloid leukaemia cells treated with the Aurora-B Kinase Inhibitor barasertib-hQPA

    Directory of Open Access Journals (Sweden)

    Russell Nigel H

    2011-06-01

    Full Text Available Abstract Background Aurora kinases play an essential role in orchestrating chromosome alignment, segregation and cytokinesis during mitotic progression, with both aurora-A and B frequently over-expressed in a variety of human malignancies. Over-expression of the ABC drug transporter proteins P-glycoprotein (Pgp and Breast cancer resistance protein (BCRP is a major obstacle for chemotherapy in many tumour types with Pgp conferring particularly poor prognosis in acute myeloid leukaemia (AML. Barasertib-hQPA is a highly selective inhibitor of aurora-B kinase that has shown tumouricidal activity against a range tumour cell lines including those of leukaemic AML origin. Methods Effect of barasertib-hQPA on the pHH3 biomarker and cell viability was measured in a panel of leukaemic cell lines and 37 primary AML samples by flow cytometry. Pgp status was determined by flow cytometry and BCRP status by flow cytometry and real-time PCR. Results In this study we report the creation of the cell line OCI-AML3DNR, which over-expresses Pgp but not BCRP or multidrug resistance-associated protein (MRP, through prolonged treatment of OCI-AML3 cells with daunorubicin. We demonstrate that Pgp (OCI-AML3DNR and KG-1a and BCRP (OCI-AML6.2 expressing AML cell lines are less sensitive to barasertib-hQPA induced pHH3 inhibition and subsequent loss of viability compared to transporter negative cell lines. We also show that barasertib-hQPA resistance in these cell lines can be reversed using known Pgp and BCRP inhibitors. We report that barasertib-hQPA is not an inhibitor of Pgp or BCRP, but by using 14[C]-barasertib-hQPA that it is effluxed by these transporters. Using phosphoHistone H3 (pHH3 as a biomarker of barasertib-hQPA responsiveness in primary AML blasts we determined that Pgp and BCRP positive primary samples were less sensitive to barasertib-hQPA induced pHH3 inhibition (p = 50 inhibition of pHH3 by barasertib-hQPA was achieved in 94.6% of these samples after 1 hour drug treatment, in contrast to the resistance of the cell lines. Conclusion We conclude that Pgp and BCRP status and pHH3 down-regulation in patients treated with barasertib should be monitored in order to establish whether transporter-mediated efflux is sufficient to adversely impact on the efficacy of the agent.

  16. P-glycoprotein and breast cancer resistance protein in acute myeloid leukaemia cells treated with the Aurora-B Kinase Inhibitor barasertib-hQPA

    International Nuclear Information System (INIS)

    Aurora kinases play an essential role in orchestrating chromosome alignment, segregation and cytokinesis during mitotic progression, with both aurora-A and B frequently over-expressed in a variety of human malignancies. Over-expression of the ABC drug transporter proteins P-glycoprotein (Pgp) and Breast cancer resistance protein (BCRP) is a major obstacle for chemotherapy in many tumour types with Pgp conferring particularly poor prognosis in acute myeloid leukaemia (AML). Barasertib-hQPA is a highly selective inhibitor of aurora-B kinase that has shown tumouricidal activity against a range tumour cell lines including those of leukaemic AML origin. Effect of barasertib-hQPA on the pHH3 biomarker and cell viability was measured in a panel of leukaemic cell lines and 37 primary AML samples by flow cytometry. Pgp status was determined by flow cytometry and BCRP status by flow cytometry and real-time PCR. In this study we report the creation of the cell line OCI-AML3DNR, which over-expresses Pgp but not BCRP or multidrug resistance-associated protein (MRP), through prolonged treatment of OCI-AML3 cells with daunorubicin. We demonstrate that Pgp (OCI-AML3DNR and KG-1a) and BCRP (OCI-AML6.2) expressing AML cell lines are less sensitive to barasertib-hQPA induced pHH3 inhibition and subsequent loss of viability compared to transporter negative cell lines. We also show that barasertib-hQPA resistance in these cell lines can be reversed using known Pgp and BCRP inhibitors. We report that barasertib-hQPA is not an inhibitor of Pgp or BCRP, but by using 14[C]-barasertib-hQPA that it is effluxed by these transporters. Using phosphoHistone H3 (pHH3) as a biomarker of barasertib-hQPA responsiveness in primary AML blasts we determined that Pgp and BCRP positive primary samples were less sensitive to barasertib-hQPA induced pHH3 inhibition (p = <0.001) than samples without these transporters. However, we demonstrate that IC50 inhibition of pHH3 by barasertib-hQPA was achieved in 94.6% of these samples after 1 hour drug treatment, in contrast to the resistance of the cell lines. We conclude that Pgp and BCRP status and pHH3 down-regulation in patients treated with barasertib should be monitored in order to establish whether transporter-mediated efflux is sufficient to adversely impact on the efficacy of the agent

  17. Activity of the dietary flavonoid, apigenin, against multidrug-resistant tumor cells as determined by pharmacogenomics and molecular docking.

    Science.gov (United States)

    Saeed, Mohamed; Kadioglu, Onat; Khalid, Hassan; Sugimoto, Yoshikazu; Efferth, Thomas

    2015-01-01

    Apigenin is a common dietary flavonoid with considerable cytotoxic activity in vitro and in vivo. Despite many mechanistic studies, less is known about resistance factors hampering apigenin's activity. We investigated the ATP-binding cassette (ABC) transporters BCRP/ABCG2, P-glycoprotein/ABCB1 and its close relative ABCB5. Multidrug-resistant cells overexpressing these ABC transporters were not cross-resistant toward apigenin. Moreover, apigenin inhibited not only P-glycoprotein but also BCRP by increasing cellular uptake of doxorubicin and synergistic inhibition of cell viability in combination with doxorubicin or docetaxel in multidrug-resistant cells. To perform in silico molecular docking studies, we first generated homology models for human P-glycoprotein and ABCB5 based on the crystal structure of murine P-glycoprotein. Their nucleotide binding domains (NDBs) revealed the highest degrees of sequence homologies (89%-100%), indicating that ATP binding and cleavage is of crucial importance for ABC transporters. Molecular docking of apigenin bound to the NDBs of P-glycoprotein and ABCB5 in molecular docking studies. Hence, apigenin may compete with ATP for NDB-binding leading to energy depletion to fuel the transport of ABC transporter substrates. Furthermore, we performed COMPARE and hierarchical cluster analyses of transcriptome-wide mRNA expression profiles of the National Cancer Institute tumor cell line panel. Microarray-based mRNA expressions of genes of diverse biological functions (signal transduction, transcriptional regulation, ubiquitination, autophagy, metabolic activity, xenobiotic detoxification and microtubule formation) significantly predicted responsiveness of tumor cells to apigenin. In conclusion, apigenin's activity is not hampered by classical mechanisms of multidrug resistance and the inhibition of ABC transporters by apigenin indicates that apigenin may overcome multidrug resistance in otherwise refractory tumors. PMID:25459885

  18. Characterisation of multidrug-resistant Ehrlich ascites tumour cells selected in vivo for resistance to etoposide

    DEFF Research Database (Denmark)

    Nielsen, D; Maare, C; Eriksen, J; Litman, Thomas; Friche, E; Skovsgaard, T

    2000-01-01

    M. ATPase activity was slightly stimulated by daunorubicin, whereas vinblastine, verapamil, and cyclosporin A had no effect. In conclusion, development of resistance to VP16 in EHR2 is accompanied by a significant reduction in topoisomerase II (alpha and beta) and by increased expression of MRP mRNA (20......-extractable immunoreactive topoisomerase IIalpha and beta in EHR2/VP16 was reduced by 30-40% relative to that in EHR2. The multidrug resistance-associated protein (MRP) mRNA was increased 20-fold in EHR2/VP16 as compared with EHR2, whereas the expression of P-glycoprotein was unchanged. In EHR2/VP16, the steady......-fold). MRP displays several points of resemblance to P-glycoprotein in its mode of action: 1) like P-glycoprotein, MRP causes resistance to a range of hydrophobic drugs; 2) MRP decreases drug accumulation in the cells and this decrease is abolished by omission of energy; and 3) MRP increases efflux of...

  19. Current Status on Marine Products with Reversal Effect on Cancer Multidrug Resistance

    Directory of Open Access Journals (Sweden)

    Huiqin Guo

    2012-10-01

    Full Text Available The resistance of tumor cells to a broad range of anticancer agents continues to be a problem for the success of cancer chemotherapy. Multidrug resistance (MDR is due in part to three drug transporter proteins: ABCB1/P-glycoprotein (P-gp, ABCC1/multidrug resistance protein 1 (MRP1 and ABCG2/breast cancer resistance protein (BCRP. These transporters are part of the ATP-binding cassette (ABC superfamily, whose members function as ATP-dependent drug-efflux pumps. Their activity can be blocked by various drugs such as verapamil (calcium channel blocker and cyclosporin A (immunosuppressive agent, etc. These compounds are called MDR modulators or reversals. This review highlights several marine natural products with reversal effect on multidrug resistance in cancer, including agosterol A, ecteinascidin 743, sipholane triterpenoids, bryostatin 1, and welwitindolinones.

  20. Current status on marine products with reversal effect on cancer multidrug resistance.

    Science.gov (United States)

    Abraham, Ioana; El Sayed, Khalid; Chen, Zhe-Sheng; Guo, Huiqin

    2012-10-01

    The resistance of tumor cells to a broad range of anticancer agents continues to be a problem for the success of cancer chemotherapy. Multidrug resistance (MDR) is due in part to three drug transporter proteins: ABCB1/P-glycoprotein (P-gp), ABCC1/multidrug resistance protein 1 (MRP1) and ABCG2/breast cancer resistance protein (BCRP). These transporters are part of the ATP-binding cassette (ABC) superfamily, whose members function as ATP-dependent drug-efflux pumps. Their activity can be blocked by various drugs such as verapamil (calcium channel blocker) and cyclosporin A (immunosuppressive agent), etc. These compounds are called MDR modulators or reversals. This review highlights several marine natural products with reversal effect on multidrug resistance in cancer, including agosterol A, ecteinascidin 743, sipholane triterpenoids, bryostatin 1, and welwitindolinones. PMID:23170086

  1. Visualization of multidrug resistance in vivo

    International Nuclear Information System (INIS)

    Various mechanisms are involved in multidrug resistance (MDR) for chemotherapeutic drugs, such as the drug efflux pumps, P-glycoprotein (Pgp) and multidrug resistance-associated protein (MRP). In this review the mechanisms involved in MDR are described and results are reviewed with particular attention to the in vivo imaging of Pgp and MRP. Various detection assays provide information about the presence of drug efflux pumps at the mRNA and protein levels. However, these methods do not yield information about the dynamic function of Pgp and MRP in vivo. For the study of Pgp- and MRP-mediated transport, single-photon emission tomography (SPET) and positron emission tomography (PET) are available. Technetium-99m sestamibi is a substrate for Pgp and MRP, and has been used in clinical studies for tumour imaging, and to visualize blockade of Pgp-mediated transport after modulation of the Pgp pump. Other 99mTc radiopharmaceuticals, such as 99mTc-tetrofosmin and several 99Tc-Q complexes, are also substrates for Pgp, but to date only results from in vitro and animal studies are available for these compounds. Several agents, including [11C]colchicine, [11C]verapamil and [11C]daunorubicin, have been evaluated for the quantification of Pgp-mediated transport with PET in vivo. The results suggest that radiolabelled colchicine, verapamil and daunorubicin are feasible substrates with which to image Pgp function in tumours. Uptake of [11C]colchicine and [11C]verapamil is relatively high in the chest area, reducing the value of both tracers for monitoring Pgp-mediated drug transport in tumours located in this region. In addition, it has to be borne in mind that only comparison of Pgp-mediated transport of radioalabelled substrates in the absence and in the presence of Pgp blockade gives quantitative information on Pgp-mediated pharmacokinetics. Leukotrienes are specific substrates for MRP. Therefore, N-[11C]acetyl-leukotriene E4 provides an opportunity to study MRP function non-invasively. Results obtained in MRP2 mutated GY/TR rats have demonstrated visualization of MRP-mediated transport. This tracer permits the study of MRP transport function abnormalities in vivo, e.g. in Dubin-Johnson patients, who are MRP2 gene deficient. Results obtained show the feasibility of using SPET and PET to study the functionality of MDR transporters in vivo. (orig.)

  2. Visualization of multidrug resistance in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Hendrikse, N.H. [PET Center, University Hospital, Groningen (Netherlands)]|[Department of Internal Medicine, Division of Medical Oncology, University Hospital, Groningen (Netherlands); Franssen, E.J.F. [PET Center, University Hospital, Groningen (Netherlands)]|[Department of Nuclear Medicine, University Hospital, Groningen (Netherlands); Graaf, W.T.A. van der; Vries, E.G.E. de [Department of Internal Medicine, Division of Medical Oncology, University Hospital, Groningen (Netherlands); Vaalburg, W. [PET Center, University Hospital, Groningen (Netherlands)

    1999-03-01

    Various mechanisms are involved in multidrug resistance (MDR) for chemotherapeutic drugs, such as the drug efflux pumps, P-glycoprotein (Pgp) and multidrug resistance-associated protein (MRP). In this review the mechanisms involved in MDR are described and results are reviewed with particular attention to the in vivo imaging of Pgp and MRP. Various detection assays provide information about the presence of drug efflux pumps at the mRNA and protein levels. However, these methods do not yield information about the dynamic function of Pgp and MRP in vivo. For the study of Pgp- and MRP-mediated transport, single-photon emission tomography (SPET) and positron emission tomography (PET) are available. Technetium-99m sestamibi is a substrate for Pgp and MRP, and has been used in clinical studies for tumour imaging, and to visualize blockade of Pgp-mediated transport after modulation of the Pgp pump. Other {sup 99m}Tc radiopharmaceuticals, such as {sup 99m}Tc-tetrofosmin and several {sup 99}Tc-Q complexes, are also substrates for Pgp, but to date only results from in vitro and animal studies are available for these compounds. Several agents, including [{sup 11}C]colchicine, [{sup 11}C]verapamil and [{sup 11}C]daunorubicin, have been evaluated for the quantification of Pgp-mediated transport with PET in vivo. The results suggest that radiolabelled colchicine, verapamil and daunorubicin are feasible substrates with which to image Pgp function in tumours. Uptake of [{sup 11}C]colchicine and [{sup 11}C]verapamil is relatively high in the chest area, reducing the value of both tracers for monitoring Pgp-mediated drug transport in tumours located in this region. In addition, it has to be borne in mind that only comparison of Pgp-mediated transport of radioalabelled substrates in the absence and in the presence of Pgp blockade gives quantitative information on Pgp-mediated pharmacokinetics. Leukotrienes are specific substrates for MRP. Therefore, N-[{sup 11}C]acetyl-leukotriene E{sub 4} provides an opportunity to study MRP function non-invasively. Results obtained in MRP{sub 2} mutated GY/TR rats have demonstrated visualization of MRP-mediated transport. This tracer permits the study of MRP transport function abnormalities in vivo, e.g. in Dubin-Johnson patients, who are MRP{sub 2} gene deficient. Results obtained show the feasibility of using SPET and PET to study the functionality of MDR transporters in vivo. (orig.) With 3 figs., 91 refs.

  3. CD44-engineered mesoporous silica nanoparticles for overcoming multidrug resistance in breast cancer

    International Nuclear Information System (INIS)

    Graphical abstract: - Highlights: • CD44-engineered mesoporous silica nanoparticles are synthesized. • The mechanism of CD44-engineered mesoporous silica nanoparticles is revealed. • This new delivery system increased the drug accumulation in vitro and in vivo. • This new delivery system offers an effective approach to treat multidrug resistance. - Abstract: Multidrug resistance is a major impediment for the successful chemotherapy in breast cancer. CD44 is over-expressed in multidrug resistant human breast cancer cells. CD44 monoclonal antibody exhibits anticancer potential by inhibiting proliferation and regulating P-glycoprotein-mediated drug efflux activity in multidrug resistant cells. Thereby, CD44 monoclonal antibody in combination with chemotherapeutic drug might be result in enhancing chemosensitivity and overcoming multidrug resistance. The purpose of this study is to investigate the effects of the CD44 monoclonal antibody functionalized mesoporous silica nanoparticles containing doxorubicin on human breast resistant cancer MCF-7 cells. The data showed that CD44-modified mesoporous silica nanoparticles increased cytotoxicity and enhanced the downregulation of P-glycoprotein in comparison to CD44 antibody. Moreover, CD44-engineered mesoporous silica nanoparticles provided active target, which promoted more cellular uptake of DOX in the resistant cells and more retention of DOX in tumor tissues than unengineered counterpart. Animal studies of the resistant breast cancer xenografts demonstrated that CD44-engineered drug delivery system remarkably induced apoptosis and inhibited the tumor growth. Our results indicated that the CD44-engineered mesoporous silica nanoparticle-based drug delivery system offers an effective approach to overcome multidrug resistance in human breast cancer

  4. CD44-engineered mesoporous silica nanoparticles for overcoming multidrug resistance in breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Xin; Liu, Ying; Wang, Shouju; Shi, Donghong [Department of Radiology, Jinling Hospital, Clinical School of Medical College, Nanjing University, Nanjing 210002 (China); Zhou, Xianguang [National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing 210016 (China); Wang, Chunyan; Wu, Jiang; Zeng, Zhiyong; Li, Yanjun; Sun, Jing [Department of Radiology, Jinling Hospital, Clinical School of Medical College, Nanjing University, Nanjing 210002 (China); Wang, Jiandong [Department of Pathology, Jinling Hospital, Clinical School of Medical College, Nanjing University, Nanjing 210002 (China); Zhang, Longjiang [Department of Radiology, Jinling Hospital, Clinical School of Medical College, Nanjing University, Nanjing 210002 (China); Teng, Zhaogang, E-mail: tzg@fudan.edu.cn [Department of Radiology, Jinling Hospital, Clinical School of Medical College, Nanjing University, Nanjing 210002 (China); State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093 (China); Lu, Guangming, E-mail: cjr.luguangming@vip.163.com [Department of Radiology, Jinling Hospital, Clinical School of Medical College, Nanjing University, Nanjing 210002 (China); State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093 (China)

    2015-03-30

    Graphical abstract: - Highlights: • CD44-engineered mesoporous silica nanoparticles are synthesized. • The mechanism of CD44-engineered mesoporous silica nanoparticles is revealed. • This new delivery system increased the drug accumulation in vitro and in vivo. • This new delivery system offers an effective approach to treat multidrug resistance. - Abstract: Multidrug resistance is a major impediment for the successful chemotherapy in breast cancer. CD44 is over-expressed in multidrug resistant human breast cancer cells. CD44 monoclonal antibody exhibits anticancer potential by inhibiting proliferation and regulating P-glycoprotein-mediated drug efflux activity in multidrug resistant cells. Thereby, CD44 monoclonal antibody in combination with chemotherapeutic drug might be result in enhancing chemosensitivity and overcoming multidrug resistance. The purpose of this study is to investigate the effects of the CD44 monoclonal antibody functionalized mesoporous silica nanoparticles containing doxorubicin on human breast resistant cancer MCF-7 cells. The data showed that CD44-modified mesoporous silica nanoparticles increased cytotoxicity and enhanced the downregulation of P-glycoprotein in comparison to CD44 antibody. Moreover, CD44-engineered mesoporous silica nanoparticles provided active target, which promoted more cellular uptake of DOX in the resistant cells and more retention of DOX in tumor tissues than unengineered counterpart. Animal studies of the resistant breast cancer xenografts demonstrated that CD44-engineered drug delivery system remarkably induced apoptosis and inhibited the tumor growth. Our results indicated that the CD44-engineered mesoporous silica nanoparticle-based drug delivery system offers an effective approach to overcome multidrug resistance in human breast cancer.

  5. [18F]FDG is not transported by P-glycoprotein and breast cancer resistance protein at the rodent blood–brain barrier

    International Nuclear Information System (INIS)

    Introduction: Transport of 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) by the multidrug efflux transporters P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) at the blood–brain barrier (BBB) may confound the interpretation of [18F]FDG brain PET data. Aim of this study was to assess the influence of ABCB1 and ABCG2 at the BBB on brain distribution of [18F]FDG in vivo by performing [18F]FDG PET scans in wild-type and transporter knockout mice and by evaluating changes in [18F]FDG brain distribution after transporter inhibition. Methods: Dynamic small-animal PET experiments (60 min) were performed with [18F]FDG in groups of wild-type and transporter knockout mice (Abcb1a/b(−/−), Abcg2(−/−) and Abcb1a/b(−/−)Abcg2(−/−)) and in wild-type rats without and with i.v. pretreatment with the known ABCB1 inhibitor tariquidar (15 mg/kg, given at 2 h before PET). Blood was sampled from animals from the orbital sinus vein at the end of the PET scans and measured in a gamma counter. Brain uptake of [18F]FDG was expressed as the brain-to-blood radioactivity concentration ratio in the last PET time frame (Kb,brain). Results: Kb,brain values of [18F]FDG were not significantly different between different mouse types both without and with tariquidar pretreatment. The blood-to-brain transfer rate constant of [18F]FDG was significantly lower in tariquidar-treated as compared with vehicle-treated rats (0.350 ± 0.025 mL/min/g versus 0.416 ± 0.024 mL/min/g, p = 0.026, paired t-test) but Kb,brain values were not significantly different between both rat groups. Conclusion: Our results show that [18F]FDG is not transported by Abcb1 at the mouse and rat BBB in vivo. In addition we found no evidence for Abcg2 transport of [18F]FDG at the mouse BBB. Advances in knowledge and implications for patient care: Our findings imply that functional activity of ABCB1 and ABCG2 at the BBB does not need to be taken into account when interpreting brain [18F]FDG PET data

  6. Selective modulation of P-glycoprotein activity by steroidal saponines from Paris polyphylla.

    Science.gov (United States)

    Nguyen, Van Thi Bao; Darbour, Nicole; Bayet, Christine; Doreau, Agns; Raad, Imad; Phung, Binh Hoa; Dumontet, Charles; Di Pietro, Attilio; Dijoux-Franca, Marie-Genevive; Guilet, David

    2009-01-01

    Bio-guided fractionation of the roots of Paris polyphylla (Trilliaceae), based on inhibition of P-glycoprotein-mediated daunorubicin efflux in K562/R7 cell line, led to isolation and identification of the three saponins 3-O-Rha(1-->2)[Ara(1-->4)]Glc-pennogenine, gracillin and polyphyllin D, and the two ecdysteroids 20-hydroxyecdysone and pinnatasterone. These compounds were tested for multidrug reversion on P-glycoprotein (ABCB1) with both drug-selected and transfected cell lines, and also on Breast Cancer Resistance Protein (BCRP/ABCG2). By contrast to a weak efficiency on BCRP, the three saponins displayed significant effects as inhibitors of P-glycoprotein-mediated drug efflux. PMID:18940238

  7. Effects of dietary chemopreventive phytochemicals on P-glycoprotein function.

    Science.gov (United States)

    Nabekura, Tomohiro; Kamiyama, Shizu; Kitagawa, Shuji

    2005-02-18

    The effects of dietary phytochemicals on P-glycoprotein function were investigated using human multidrug-resistant carcinoma KB-C2 cells and the fluorescent P-glycoprotein substrates daunorubicin and rhodamine 123. The effects of natural chemopreventive compounds, capsaicin found in chilli peppers, curcumin in turmeric, [6]-gingerol in ginger, resveratrol in grapes, sulforaphane in broccoli, 6-methylsulfinyl hexyl isothiocyanate (6-HITC) in Japanese horseradish wasabi, indole-3-carbinol (I3C) in cabbage, and diallyl sulfide and diallyl trisulfide in garlic, were examined. The accumulation of daunorubicin in KB-C2 cells increased in the presence of capsaicin, curcumin, [6]-gingerol, and resveratrol in a concentration-dependent manner. The accumulation of rhodamine 123 in KB-C2 cells was also increased, and the efflux of rhodamine 123 from KB-C2 cells was decreased by these phytochemicals. Sulforaphane, 6-HITC, I3C, and diallyl sulfide and diallyl trisulfide had no effect. These results suggest that dietary phytochemicals, such as capsaicin, curcumin, [6]-gingerol, and resveratrol, have inhibitory effects on P-glycoprotein and potencies to cause drug-food interactions. PMID:15649425

  8. Cattle nematodes resistant to macrocyclic lactones: comparative effects of P-glycoprotein modulation on the efficacy and disposition kinetics of ivermectin and moxidectin.

    Science.gov (United States)

    Lifschitz, A; Suarez, V H; Sallovitz, J; Cristel, S L; Imperiale, F; Ahoussou, S; Schiavi, C; Lanusse, C

    2010-06-01

    The role of the drug efflux pump, known as P-glycoprotein, in the pharmacokinetic disposition (host) and resistance mechanisms (target parasites) of the macrocyclic lactone (ML) antiparasitic compounds has been demonstrated. To achieve a deeper comprehension on the relationship between their pharmacokinetic and pharmacodynamic behaviors, the aim of the current work was to assess the comparative effect of loperamide, a well-established P-glycoprotein modulator, on the ivermectin and moxidectin disposition kinetics and efficacy against resistant nematodes in cattle. Fifty (50) Aberdeen Angus male calves were divided into five (5) experimental groups. Group A remained as an untreated control. Animals in the other experimental Groups received ivermectin (Group B) and moxidectin (Group C) (200 microg/kg, subcutaneously) given alone or co-administered with loperamide (0.4 mg/kg, three times every 24 h) (Groups D and E). Blood samples were collected over 30 days post-treatment and drug plasma concentrations were measured by HPLC with fluorescence detection. Estimation of the anthelmintic efficacy for the different drug treatments was performed by the faecal egg count reduction test (FECRT). Nematode larvae were identified by pooled faecal cultures for each experimental group. Cooperia spp. and Ostertagia spp. were the largely predominant nematode larvae in pre-treatment cultures. A low nematodicidal efficacy (measured by the FECRT) was observed for both ivermectin (23%) and moxidectin (69%) in cattle, which agrees with a high degree of resistance to both molecules. Cooperia spp. was the most abundant nematode species recovered after the different drug treatments. The egg output reduction values increased from 23% to 50% (ivermectin) and from 69% to 87% (moxidectin) following their co-administration with loperamide. Enhanced systemic concentrations and an altered disposition of both ML in cattle, which correlates with a tendency to increased anthelmintic efficacy, were observed in the presence of loperamide. Overall, the in vivo modulation of P-glycoprotein activity modified the kinetic behavior and improved the efficacy of the ML against resistant nematodes in cattle. The work provides further evidence on the high degree of resistance to ML in cattle nematodes and, shows for the first time under field conditions, that modulation of P-glycoprotein may be a valid pharmacological approach to improve the activity and extend the lifespan of these antiparasitic molecules. PMID:20109455

  9. Reversal of Multidrug Resistance in Mouse Lymphoma Cells by Extracts and Flavonoids from Pistacia integerrima.

    Science.gov (United States)

    Rauf, Abdur; Uddin, Ghias; Raza, Muslim; Ahmad, Bashir; Jehan, Noor; Siddiqui, Bina S; Molnar, Joseph; Csonka, Akos; Szabo, Diana

    2016-01-01

    Phytochemical investigation of Pistacia integerrima has highlighted isolation of two known compounds naringenin (1) and dihydrokaempferol (2). A crude extract and these isolated compounds were here evaluated for their effects on reversion of multidrug resistance (MDR) mediated by P-glycoprotein (P-gp). The multidrug resistance P-glycoprotein is a target for chemotherapeutic drugs from cancer cells. In the present study rhodamine- 123 exclusion screening test on human mdr1 gene transfected mouse gene transfected L5178 and L5178Y mouse T-cell lymphoma cells showed excellent MDR reversing effects in a dose dependent manner. In-silico molecular docking investigations demonstrated a common binding site for Rhodamine123, and compounds naringenin and dihydrokaempferol. Our results showed that the relative docking energies estimated by docking softwares were in satisfactory correlation with the experimental activities. Preliminary interaction profile of P-gp docked complexes were also analysed in order to understand the nature of binding modes of these compounds. Our computational investigation suggested that the compounds interactions with the hydrophobic pocket of P-gp are mainly related to the inhibitory activity. Moreover this study s a platform for the discovery of novel natural compounds from herbal origin, as inhibitor molecules against the P-glycoprotein for the treatment of cancer. PMID:26838254

  10. Tumor endothelial expression of P-glycoprotein upon microvesicular transfer of TrpC5 derived from adriamycin-resistant breast cancer cells

    International Nuclear Information System (INIS)

    Highlights: • TrpC5 was mainly accumulated in microvesicles of drug-resistant MCF-7/ADM cells. • Microvesicles from MCF-7/ADM transferred TrpC5 to endothelial cells. • TrpC5 inhibition reduced P-glycoprotein accumulation on tumor blood vessels in vivo. - Abstract: Treatment of carcinoma commonly fails due to chemoresistance. Studies have shown that endothelial cells acquire resistance via the tumor microenvironment. Microvesicle (MV) shedding from the cell membrane to the microenvironment plays an important role in communication between cells. The aim of the present study was to determine whether MCF-7 adriamycin-resistant cells (MCF-7/ADM) shed MVs that alter the characteristics of human microvessel endothelial cells (HMECs). MVs from tumor cells transferred a Ca2+-permeable channel TrpC5 to HMECs, inducing the expression of P-glycoprotein (P-gp) by activation of the transcription factor NFATc3 (nuclear factor of activated T cells isoform c3). Expression of the mdr1 gene was blocked by the TrpC5-blocking antibody T5E3, and the production of P-gp in HMECs was reduced by blockade of TrpC5. Thus, we postulate that endothelial cells acquire the resistant protein upon exposure to TrpC5-containg MVs in the microenvironment, and express P-gp in the TrpC5–NFATc3 signal pathway

  11. P-glycoprotein targeted nanoscale drug carriers

    KAUST Repository

    Li, Wengang

    2013-02-01

    Multi-drug resistance (MDR) is a trend whereby tumor cells exposed to one cytotoxic agent develop cross-resistance to a range of structurally and functionally unrelated compounds. P -glycoprotein (P -gp) efflux pump is one of the mostly studied drug carrying processes that shuttle the drugs out of tumor cells. Thus, P -gp inhibitors have attracted a lot of attention as they can stop cancer drugs from being pumped out of target cells with the consumption of ATP. Using quantitive structure activity relationship (QSAR), we have successfully synthesized a series of novel P -gp inhibitors. The obtained dihydropyrroloquinoxalines series were fully characterized and then tested against bacterial and tumor assays with over-expressed P -gps. All compounds were bioactive especially compound 1c that had enhanced antibacterial activity. Furthermore, these compounds were utilized as targeting vectors to direct drug delivery vehicles such as silica nanoparticles (SNPs) to cancerous Hela cells with over expressed P -gps. Cell uptake studies showed a successful accumulation of these decorated SNPs in tumor cells compared to undecorated SNPs. The results obtained show that dihydropyrroloquinoxalines constitute a promising drug candidate for targeting cancers with MDR. Copyright © 2013 American Scientific Publishers All rights reserved.

  12. Functional imaging of the multidrug resistance in vivo

    International Nuclear Information System (INIS)

    Although diverse mechanisms are involved in multidrug resistance for chemotherapeutic drugs, the development of cellular P-glycoprotein(Pgp) and multidrug-resistance associated protein (MRP) are improtant factors in the chemotherapy failure to cancer. Various detection assays provide information about the presence of drug efflux pumps at the mRNA and protein levels. However these methods do not yield information about dynamic function of Pgp and MRP in vivo. Single photon emission tomograpy (SPECT) and positron emission tomograpy (PET) are available for the detection of Pgp and MRP-mediated transport. 99mTc-sestaMIBI and other 99mTc-radiopharmaceuticals are substrates for Pgp and MRP, and have been used in clinical studies of tumor imaging, and to visualize blockade of Pgp-mediated transport after modulation of Pgp pump. Colchicine, verapamil and daunorubicin labeled with 11C have been evaluated for the quantification of Pgp-mediated transport with PET in vivo and reported to be feasible substrates with which to image Pgp function in tumors. Leukotrienes are specific substrates for MRP and N-(11C]acetyl-leukotriene E4 provides an opportunity to study MRP function non-invasively in vivo. Results obtained from recent publications are reviewed to confirm the feasibility of using SPECT and PET to study the functionality of MDR transportes in vivo

  13. Functional imaging of the multidrug resistance in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Jae Tae [College of Medicine, Kyungpook National Univ., Taegu (Korea, Republic of)

    2001-07-01

    Although diverse mechanisms are involved in multidrug resistance for chemotherapeutic drugs, the development of cellular P-glycoprotein(Pgp) and multidrug-resistance associated protein (MRP) are improtant factors in the chemotherapy failure to cancer. Various detection assays provide information about the presence of drug efflux pumps at the mRNA and protein levels. However these methods do not yield information about dynamic function of Pgp and MRP in vivo. Single photon emission tomograpy (SPECT) and positron emission tomograpy (PET) are available for the detection of Pgp and MRP-mediated transport. {sup 99m}Tc-sestaMIBI and other {sup 99m}Tc-radiopharmaceuticals are substrates for Pgp and MRP, and have been used in clinical studies of tumor imaging, and to visualize blockade of Pgp-mediated transport after modulation of Pgp pump. Colchicine, verapamil and daunorubicin labeled with {sup 11}C have been evaluated for the quantification of Pgp-mediated transport with PET in vivo and reported to be feasible substrates with which to image Pgp function in tumors. Leukotrienes are specific substrates for MRP and N-{sup (11}C]acetyl-leukotriene E4 provides an opportunity to study MRP function non-invasively in vivo. Results obtained from recent publications are reviewed to confirm the feasibility of using SPECT and PET to study the functionality of MDR transportes in vivo.

  14. Multidrug-Resistant Tuberculosis (MDR TB)

    Science.gov (United States)

    ... can die if they do not get proper treatment. What is multidrug-resistant tuberculosis (MDR TB)? Multidrug-resistant TB (MDR TB) is ... most potent TB drugs, patients are left with treatment options that are much less effective. XDR TB is of special concern for persons with HIV ...

  15. Overcoming of P-glycoprotein mediated vincristine resistance of L1210/VCR mouse leukemic cells could be induced by pentoxifylline but not by theophylline and caffeine

    International Nuclear Information System (INIS)

    Effects of xanthine derivatives (pentoxifylline (PTX), caffeine, theophylline, 1-methyl-3-isobutylxanthine) on P-glycoprotein mediated vincristine resistance of L1210/VCR mouse leukemic cell sub-line were studied. From the applied xanthines only PTX was found to reverse the vincristine resistance of the above cells. Moreover, only PTX, but not other xanthine, increased the accumulation of [3H]vincristine by L1210/VCR cells. Thus it may be concluded that PTX-induced reversal of vincristine (VCR) resistance could not be explained from the point of known pharmacological effects of PTX that are common for other xanthines such as inhibition of phosphodiesterase activity, calcium mobilizing effect, inhibition of tumor necrosis factor α (TNF), etc. (author)

  16. Nanodrug Delivery in Reversing Multidrug Resistance in Cancer Cells

    Directory of Open Access Journals (Sweden)

    MayurYergeri

    2014-07-01

    Full Text Available Different mechanisms in cancer cells become resistant to one or more chemotherapeutics is known as multidrug resistance(MDR which hinders chemotherapy efficacy. Potential factors for MDR includes enhanced drug detoxification, decreased drug uptake, increased intracellular nucleophiles levels, enhanced repair of drug induced DNA damage, overexpression of drug transporter such as P-glycoprotein(P-gp, multidrug resistance-associated proteins(MRP1, MRP2 and breast cancer resistance protein(BCRP. Currently nanoassemblies such as polymeric/solid lipid/inorganic/metal nanoparticles, quantum dots, dendrimers, liposomes, micelles has emerged as an innovative, effective and promising platforms for treatment of drug resistant cancer cells. Nanocarriers have potential to improve drug therapeutic index, ability for multifunctionality, divert ABC-transporter mediated drug efflux mechanism and selective targeting to tumor cells, cancer stem cells, tumor initiating cells or cancer microenvironment. Selective nanocarrier targeting to tumor overcomes dose-limiting side effects, lack of selectivity, tissue toxicity, limited drug access to tumor tissues, high drug doses and emergence of multiple drug resistance with conventional or combination chemotherapy. Current review highlights various nanodrug delivery systems to overcome mechanism of MDR by neutralizing, evading or exploiting the drug efflux pumps and those independent of drug efflux pump mechanism by silencing Bcl-2 and HIF1? gene expressions by siRNA and miRNA, modulating ceramide levels and targeting NF-?B. Theragnostics combining a cytotoxic agent, targeting moiety, chemosensitizing agent and diagnostic imaging aid are highlighted as effective and innovative systems for tumor localization and overcoming MDR. Physical approaches such as combination of drug with thermal/ultrasound/photodynamic therapies to overcome MDR are focused. The review focuses on newer drug delivery systems developed to overcome MDR in cancer cell

  17. Kinetic validation of the models for P-glycoprotein ATP hydrolysis and vanadate-induced trapping. Proposal for additional steps.

    Science.gov (United States)

    Lugo, Miguel Ramn; Sharom, Frances Jane

    2014-01-01

    P-Glycoprotein, a member of the ATP-binding cassette (ABC) superfamily, is a multidrug transporter responsible for cellular efflux of hundreds of structurally unrelated compounds, including natural products, many clinically used drugs and anti-cancer agents. Expression of P-glycoprotein has been linked to multidrug resistance in human cancers. ABC transporters are driven by ATP hydrolysis at their two cytoplasmic nucleotide-binding domains, which interact to form a closed ATP-bound sandwich dimer. Intimate knowledge of the catalytic cycle of these proteins is clearly essential for understanding their mechanism of action. P-Glycoprotein has been proposed to hydrolyse ATP by an alternating mechanism, for which there is substantial experimental evidence, including inhibition of catalytic activity by trapping of ortho-vanadate at one nucleotide-binding domain, and the observation of an asymmetric occluded state. Despite many studies of P-glycoprotein ATPase activity over the past 20 years, no comprehensive kinetic analysis has yet been carried out, and some puzzling features of its behaviour remain unexplained. In this work, we have built several progressively more complex kinetic models, and then carried out simulations and detailed analysis, to test the validity of the proposed reaction pathway employed by P-glycoprotein for ATP hydrolysis. To establish kinetic parameters for the catalytic cycle, we made use of the large amount of published data on ATP hydrolysis by hamster P-glycoprotein, both purified and in membrane vesicles. The proposed kinetic scheme(s) include a high affinity priming reaction for binding of the first ATP molecule, and an independent pathway for ADP binding outside the main catalytic cycle. They can reproduce to varying degrees the observed behavior of the protein's ATPase activity and its inhibition by ortho-vanadate. The results provide new insights into the mode of action of P-glycoprotein, and some hypotheses about the nature of the occluded nucleotide-bound state. PMID:24897122

  18. P-glycoprotein is expressed and causes resistance to chemotherapy in EBV-positive T-cell lymphoproliferative diseases

    International Nuclear Information System (INIS)

    Epstein–Barr virus-positive T-cell lymphoproliferative diseases (EBV-T-LPDs) are rare lymphomas with poor prognosis. Although chemotherapeutic strategies such as CHOP have been often selected, they have exhibited only limited efficacy. To clarify the mechanism of chemoresistance, we examined P-glycoprotein (P-gp) expression. P-gp acts as an energy-dependent efflux pump that excretes drugs from the cytoplasm, resulting in low-intracellular drug concentrations and poor sensitivity to chemotherapy. We examined P-gp expression in EBV-positive cells by immunohistochemistry staining in three patients of EBV-T-LPDs and the expression was detected in all patients. We also examined mdr1 mRNA expression by reverse-transcriptase polymerase-chain reaction (RT-PCR) in EBV-positive tumor cells from these patients and additional three patients. The expression was detected in all examined patients. In five EBV-T-LPDs patients, P-gp function was detected by Rhodamine-123 efflux assay in these cells. The efflux was inhibited by treatment with a P-gp inhibitor, cyclosporine A (CsA). We also examined and detected P-gp expression in EBV-positive T-cell lines SNT8 and SNT16 established from EBV-T-LPDs patients, by RT-PCR and western blotting. The function was also detected by Rhodamine-123 efflux in these cell lines. Inhibition and knock down of P-gp by CsA and siRNA, respectively, enhanced etoposide- and doxorubicin-induced cell death in the EBV-positive T-cell lines. Finally, we infected the T-cell line MOLT4 with EBV, and found that mdr1 mRNA expression and Rhodamine 123 efflux were upregulated after infection. These results indicated that enhanced P-gp expression contributed to the chemoresistance of EBV-T-LPDs

  19. Effects of PEMF on a murine osteosarcoma cell line: drug-resistant (P-glycoprotein-positive) and non-resistant cells.

    Science.gov (United States)

    Miyagi, N; Sato, K; Rong, Y; Yamamura, S; Katagiri, H; Kobayashi, K; Iwata, H

    2000-02-01

    After pulsed exposure of Dunn osteosarcoma cells (nonresistant cells) to Adriamycin (ADR) at increasing concentrations and single-cell cloning of surviving cells, ADR-resistant cells were obtained. These resistant cells expressed P-glycoprotein and had resistance more than 10 times that of their nonresistant parent cells. Compared to the nonresistant cells not exposed to pulsing electromagnetic fields (PEMF) in ADR-free medium, their growth rates at ADR concentrations of 0.01 and 0.02 micrograms/ml, which were below IC50, were 83.0% and 61.8%, respectively. On the other hand, in the nonresistant cells exposed to PEMF (repetition frequency, 10 Hz; rise time, 25 microsec, peak magnetic field intensity, 0.4-0.8 mT), the growth rate was 111.9% in ADR-free medium, 95.5% at an ADR concentration of 0.01 micrograms/ml, and 92.2% at an ADR concentration of 0.02 micrograms/ml. This promotion of growth by PEMF is considered to be a result of mobilization of cells in the non-proliferative period of the cell cycle due to exposure to PEMF. However, at ADR concentrations above the IC50, the growth rate tended to decrease in the cells not exposed to PEMF. This may be caused by an increase in cells sensitive to ADR resulting from mobilization of cells in the non-proliferative period to the cell cycle. The growth rate in the resistant cells exposed to PEMF was significantly lower than that in the non-exposed resistant cells at all ADR concentrations, including ADR-free culture (P

  20. Different types of non-P-glycoprotein mediated multiple drug resistance in children with relapsed acute lymphoblastic leukaemia.

    OpenAIRE

    Pieters, R; Hongo, T.; Loonen, A. H.; Huismans, D. R.; Broxterman, H.J.; Hählen, K; Veerman, A. J.

    1992-01-01

    Although cellular drug resistance is considered to be an important cause of the poor prognosis of children with relapsed acute lymphoblastic leukaemia (ALL), the knowledge of drug resistance in these patients is very limited. Different aspects of drug resistance were studied in 17 children with relapsed ALL. The in vitro sensitivity profile was determined using the MTT assay. Cells from relapsed children were significantly more resistant to 6-thioguanine, prednisolone, cytosine arabinoside, d...

  1. Modulation of human multidrug-resistance MDR-1 gene by natural curcuminoids

    International Nuclear Information System (INIS)

    Multidrug resistance (MDR) is a phenomenon that is often associated with decreased intracellular drug accumulation in patient's tumor cells resulting from enhanced drug efflux. It is related to the overexpression of a membrane protein, P-glycoprotein (Pgp-170), thereby reducing drug cytotoxicity. A variety of studies have tried to find MDR modulators which increase drug accumulation in cancer cells. In this study, natural curcuminoids, pure curcumin, demethoxycurcumin and bisdemethoxycurcumin, isolated from turmeric (Curcuma longa Linn), were compared for their potential ability to modulate the human MDR-1 gene expression in multidrug resistant human cervical carcinoma cell line, KB-V1 by Western blot analysis and RT-PCR. Western blot analysis and RT-PCR showed that all the three curcuminoids inhibited MDR-1 gene expression, and bisdemethoxycurcumin produced maximum effect. In additional studies we found that commercial grade curcuminoid (approximately 77% curcumin, 17% demethoxycurcumin and 3% bisdemthoxycurcumin) decreased MDR-1 gene expression in a dose dependent manner and had about the same potent inhibitory effect on MDR-1 gene expression as our natural curcuminoid mixtures. These results indicate that bisdemethoxycurcumin is the most active of the curcuminoids present in turmeric for modulation of MDR-1 gene. Treatment of drug resistant KB-V1 cells with curcumin increased their sensitivity to vinblastine, which was consistent with a decreased MDR-1 gene product, a P-glycoprotein, on the cell plasma membrane. Although many drugs that prevent the P-glycoprotein function have been reported, this report describes the inhibition of MDR-1 expression by a phytochemical. The modulation of MDR-1 expression may be an attractive target for new chemosensitizing agents

  2. Detection of multidrug resistance using molecular nuclear technique

    International Nuclear Information System (INIS)

    Although the outcome of cancer patients after cytotoxic chemotherapy is related diverse mechanisms, multidrug resistance (MDR) for chemotherapeutic drugs due to cellular P-glycoprotein (Pgp) or multidrug-resistance associated protein (MRP) is most important factor in the chemotherapy failure to cancer. A large number of pharmacologic compounds, including verapamil, quinidine, tamoxifen, cyclosporin A and quinolone derivatives have been reported to overcome MDR. Single photon emission computed tomography (SPECT) and positron emission tomography (PET) are available for the detection of Pgp and MRP-mediated transporter. 99m-Tc-MIBI and other 99m-Tc-radiopharmaceuticals are substrates for Pgp and MRP, and have been used in clinical studies for tumor imaging, and to visualize blockade of Pgp-mediated transport after modulation of Pgp pump. Colchicine, verapamil and daunorubicin labeled with 11C have been evaluated for the quantification of Pgp-mediated transport with PET in vivo and reported to be feasible substrates with which to image Pgp function in tumors. Leukotrienes are specific substrates for MRP and N-(11C)acetyl-leukotriene E4 provides an opportunity to study MRP function non-invasively in vivo. SPECT and PET pharmaceuticals have successfully used to evaluate pharmacologic effects of MDR modulators. Imaging of MDR and reversal of MDR with bioluminescence in a living animal is also evaluated for future clinical trial. We have described recent advances in molecular imaging of MDR and reviewed recent publications regarding feasibility of SPECT and PET imaging to study the functionality of MDR transporters in vivo

  3. Detection of multidrug resistance using molecular nuclear technique

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Jae Tae; Ahn, Byeong Cheol [School of Medicine, Kyungpook National Univ., Daegu (Korea, Republic of)

    2004-04-01

    Although the outcome of cancer patients after cytotoxic chemotherapy is related diverse mechanisms, multidrug resistance (MDR) for chemotherapeutic drugs due to cellular P-glycoprotein (Pgp) or multidrug-resistance associated protein (MRP) is most important factor in the chemotherapy failure to cancer. A large number of pharmacologic compounds, including verapamil, quinidine, tamoxifen, cyclosporin A and quinolone derivatives have been reported to overcome MDR. Single photon emission computed tomography (SPECT) and positron emission tomography (PET) are available for the detection of Pgp and MRP-mediated transporter. {sup 99}m-Tc-MIBI and other {sup 99}m-Tc-radiopharmaceuticals are substrates for Pgp and MRP, and have been used in clinical studies for tumor imaging, and to visualize blockade of Pgp-mediated transport after modulation of Pgp pump. Colchicine, verapamil and daunorubicin labeled with {sup 11}C have been evaluated for the quantification of Pgp-mediated transport with PET in vivo and reported to be feasible substrates with which to image Pgp function in tumors. Leukotrienes are specific substrates for MRP and N-({sup 11}C)acetyl-leukotriene E4 provides an opportunity to study MRP function non-invasively in vivo. SPECT and PET pharmaceuticals have successfully used to evaluate pharmacologic effects of MDR modulators. Imaging of MDR and reversal of MDR with bioluminescence in a living animal is also evaluated for future clinical trial. We have described recent advances in molecular imaging of MDR and reviewed recent publications regarding feasibility of SPECT and PET imaging to study the functionality of MDR transporters in vivo.

  4. ABC transporters as multidrug resistance mechanisms and the development of chemosensitizers for their reversal

    Directory of Open Access Journals (Sweden)

    Choi Cheol-Hee

    2005-10-01

    Full Text Available Abstract One of the major problems related with anticancer chemotherapy is resistance against anticancer drugs. The ATP-binding cassette (ABC transporters are a family of transporter proteins that are responsible for drug resistance and a low bioavailability of drugs by pumping a variety of drugs out cells at the expense of ATP hydrolysis. One strategy for reversal of the resistance of tumor cells expressing ABC transporters is combined use of anticancer drugs with chemosensitizers. In this review, the physiological functions and structures of ABC transporters, and the development of chemosensitizers are described focusing on well-known proteins including P-glycoprotein, multidrug resistance associated protein, and breast cancer resistance protein.

  5. Noninvasive functional imaging of P-glycoprotein-mediated doxorubicin resistance in a mouse model of hereditary breast cancer to predict response, and assign P-gp inhibitor sensitivity

    Energy Technology Data Exchange (ETDEWEB)

    Leeuwen, Fijs W.B. van; Buckle, Tessa; Gilhuijs, Kenneth G.A. [The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Departments of Radiology and Nuclear Medicine, Amsterdam (Netherlands); Kersbergen, Ariena; Rottenberg, Sven [The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Department of Molecular Biology, Amsterdam (Netherlands)

    2009-03-15

    Using a ''spontaneous'' mammary mouse tumor model we set out to develop diagnostic approaches for non-invasive P-glycoprotein (P-gp) staging and response prediction. {sup 99m}Tc-MIBI efflux rates were measured using a gamma camera in three Brca1 {sup -/-}; p53 {sup -/-} mouse mammary tumors that have different Mdr1a/b expression levels. The efflux rates were quantified in the 10-30-min period after injection. In addition to the P-gp-mediated efflux measurements in untreated tumors, efflux measurements were performed in the presence of the P-gp inhibitor tariquidar. Volumetric doxorubicin response patterns for the different tumors were determined and correlated with the efflux rates. Combined pre- and post-inhibitor treatment imaging of P-gp-mediated efflux correlated with Mdr1a/b expression: basal (0.0026, p = 0.16), 3-fold Mdr1a/b (0.0074, p = 0.02), and 17-fold Mdr1a and 46-fold Mdr1b (0.012, p = 0.002). Based on the doxorubicin response of these tumors, we generated a computer-aided diagnosis model that predicts the likelihood of drug resistance. Quantified {sup 99m}Tc-MIBI efflux has potential to: (1) noninvasively assign Mdr1 expression levels, (2) predict the therapeutic impact of a P-gp inhibitor, and (3) noninvasively assess the probability of drug resistance. (orig.)

  6. Effects of natural nuclear factor-kappa B inhibitors on anticancer drug efflux transporter human P-glycoprotein.

    Science.gov (United States)

    Nabekura, Tomohiro; Hiroi, Takashi; Kawasaki, Tatsuya; Uwai, Yuichi

    2015-03-01

    Drug efflux transporter P-glycoprotein plays an important role in cancer chemotherapy. The nuclear factor-?B (NF-?B) transcription factors play critical roles in development and progression of cancer. In this study, the effects of natural compounds that can inhibit NF-?B activation on the function of P-glycoprotein were investigated using human MDR1 gene-transfected KB/MDR1 cells. The accumulation of daunorubicin or rhodamine 123, fluorescent substrates of P-glycoprotein, in KB/MDR1 cells increased in the presence of caffeic acid phenetyl ester (CAPE), licochalcone A, anacardic acid, celastrol, xanthohumol, magnolol, and honokiol in a concentration-dependent manner. In contrast, lupeol, zerumbone, thymoquinone, emodin, and anethol had no effects. The ATPase activities of P-glycoprotein were stimulated by CAPE, licochalcone A, anacardic acid, celastrol, xanthohumol, magnolol, and honokiol. Tumor necrosis factor (TNF)-? stimulated NF-?B activation was inhibited by CAPE, licochalcone A, anacardic acid, and xanthohumol. KB/MDR1 cells were sensitized to vinblastine cytotoxicity by CAPE, licochalcone A, anacardic acid, xanthohumol, magnolol, and honokiol, showing that these natural NF-?B inhibitors reverse multidrug resistance. These results suggest that natural compounds, such as CAPE, licochalcone A, and anacardic acid, have dual inhibitory effects on the anticancer drug efflux transporter P-glycoprotein and NF-?B activation, and may become useful to enhance the efficacy of cancer chemotherapy. PMID:25776492

  7. Functional study of the novel multidrug resistance gene HA117 and its comparison to multidrug resistance gene 1

    Directory of Open Access Journals (Sweden)

    Chen Tingfu

    2010-07-01

    Full Text Available Abstract Background The novel gene HA117 is a multidrug resistance (MDR gene expressed by all-trans retinoic acid-resistant HL-60 cells. In the present study, we compared the multidrug resistance of the HA117 with that of the classical multidrug resistance gene 1 (MDR1 in breast cancer cell line 4T1. Methods Transduction of the breast cancer cell line 4T1 with adenoviral vectors encoding the HA117 gene and the green fluorescence protein gene (GFP (Ad-GFP-HA117, the MDR1 and GFP (Ad-GFP-MDR1 or GFP (Ad-GFP was respectively carried out. The transduction efficiency and the multiplicity of infection (MOI were detected by fluorescence microscope and flow cytometry. The transcription of HA117 gene and MDR1 gene were detected by reverse transcription polymerase chain reaction (RT-PCR. Western blotting analysis was used to detect the expression of P-glycoprotein (P-gp but the expression of HA117 could not be analyzed as it is a novel gene and its antibody has not yet been synthesized. The drug-excretion activity of HA117 and MDR1 were determined by daunorubicin (DNR efflux assay. The drug sensitivities of 4T1/HA117 and 4T1/MDR1 to chemotherapeutic agents were detected by Methyl-Thiazolyl-Tetrazolium (MTT assay. Results The transducted efficiency of Ad-GFP-HA117 and Ad-GFP-MDR1 were 75%-80% when MOI was equal to 50. The transduction of Ad-GFP-HA117 and Ad-GFP-MDR1 could increase the expression of HA117 and MDR1. The drug resistance index to Adriamycin (ADM, vincristine (VCR, paclitaxel (Taxol and bleomycin (BLM increased to19.8050, 9.0663, 9.7245, 3.5650 respectively for 4T1/HA117 and 24.2236, 11.0480, 11.3741, 0.9630 respectively for 4T1/MDR1 as compared to the control cells. There were no significant differences in drug sensitivity between 4T1/HA117 and 4T1/MDR1 for the P-gp substrates (ADM, VCR and Taxol (P Conclusions These results confirm that HA117 is a strong MDR gene in both HL-60 and 4T1 cells. Furthermore, our results indicate that the MDR mechanism of the HA117 gene may not be similar to that of MDR1.

  8. Chromosomal Instability Confers Intrinsic Multidrug Resistance

    DEFF Research Database (Denmark)

    Lee, Alvin J. X.; Endesfelder, David; Rowan, Andrew J.; Walther, Axel; Birkbak, Nicolai Juul; Futreal, P. Andrew; Downward, Julian; Szallasi, Zoltan Imre; Tomlinson, Ian P. M.; Howell, Michael; Kschischo, Maik; Swanton, Charles

    2011-01-01

    Aneuploidy is associated with poor prognosis in solid tumors. Spontaneous chromosome missegregation events in aneuploid cells promote chromosomal instability (CIN) that may contribute to the acquisition of multidrug resistance in vitro and heighten risk for tumor relapse in animal models...... chromosomally unstable (CIN+) or diploid/near-diploid (CIN-), and treated them individually with a library of kinase inhibitors targeting components of signal transduction, cell cycle, and transmembrane receptor signaling pathways. CIN+ cell lines displayed significant intrinsic multidrug resistance compared...... than their diploid parental cells only with increasing chromosomal heterogeneity and isogenic cell line models of CIN+ displayed multidrug resistance relative to their CIN- parental cancer cell line derivatives. In a meta-analysis of CRC outcome following cytotoxic treatment, CIN+ predicted worse...

  9. Intracellular targeted co-delivery of shMDR1 and gefitinib with chitosan nanoparticles for overcoming multidrug resistance

    Directory of Open Access Journals (Sweden)

    Yu XW

    2015-11-01

    Full Text Available Xiwei Yu,1,* Guang Yang,2,* Yijie Shi,1 Chang Su,3 Ming Liu,1 Bo Feng,1 Liang Zhao1 1School of Pharmacy, Liaoning Medical University, Jinzhou, People’s Republic of China; 2Department of Oncology, BenQ Medical Center, Nanjing Medical University, Nanjing, People’s Republic of China; 3School of Veterinary Medicine, Liaoning Medical University, Jinzhou, People’s Republic of China *These authors contributed equally to this work Abstract: Nowadays, multidrug resistance and side effects of drugs limit the effectiveness of chemotherapies in clinics. P-glycoprotein (P-gp (MDR1, as a member of the ATP-binding cassette family, acts on transporting drugs into cell plasma across the membrane of cancer cells and leads to the occurrence of multidrug resistance, thus resulting in the failure of chemotherapy in cancer. The main aims of this research were to design a nanodelivery system for accomplishing the effective co-delivery of gene and antitumor drug and overcoming multidrug resistance effect. In this study, shMDR1 and gefitinib-encapsulating chitosan nanoparticles with sustained release, small particle size, and high encapsulation efficiency were prepared. The serum stability, protection from nuclease, and transfection efficiency of gene in vitro were investigated. The effects of co-delivery of shMDR1 and gefitinib in nanoparticles on reversing multidrug resistance were also evaluated by investigating the cytotoxicity, cellular uptake mechanism, and cell apoptosis on established gefitinib-resistant cells. The results demonstrated that chitosan nanoparticles entrapping gefitinib and shMDR1 had the potential to overcome the multidrug resistance and improve cancer treatment efficacy, especially toward resistant cells. Keywords: P-glycoprotein, nanodelivery system, chemotherapy, gene

  10. Effects of cyclosporin at various concentrations on dexamethasone intracellular uptake in multidrug resistant cells

    Science.gov (United States)

    Maillefert, J; Duchamp, O; Solary, E; Genne, P; Tavernier, C

    2000-01-01

    BACKGROUND—The multidrug resistance phenomenon results from the expression of P-glycoprotein (P-gp), a drug-efflux pump. Corticosteroids are substrates for P-gp, whose function can be inhibited by cyclosporin. This study evaluates the ability of cyclosporin to modulate dexamethasone uptake in multidrug resistant cells.
METHODS—The K 562 cell line, which does not express P-gp and a P-gp expressing clone, K562/ADM, were used. Cells were incubated with H3-dexamethasone in the absence or presence of cyclosporin at various concentrations. Then, cells were washed, lysed, and radioactivity was measured.
RESULTS—The uptake of dexamethasone alone was higher in sensitive than in resistant cells. Addition of cyclosporin induced a dose dependent increase of dexamethasone uptake in resistant cells, whereas the drug did not influence dexamethasone uptake in parental cells.
CONCLUSION—Cyclosporin, at therapeutic concentrations induces a moderate, but significant increase in dexamethasone accumulation in multidrug resistant cells. Thus, cyclosporin might increase the intestinal absorption of corticosteroids or their accumulation in mononuclear cells, or both, thereby increasing their therapeutic efficacy.

 PMID:10666173

  11. Human multidrug-resistant (MRP,p190) myeloid leukemia HL-60/ADR cells in vitro: resistance to the mevalonate pathway inhibitor lovastatin.

    Science.gov (United States)

    Hunkov, L; Sedlk, J; Sulikov, M; Chovancov, J; Duraj, J; Chorvth, B

    1997-01-01

    Mevalonate pathway inhibitor lovastatin inhibited proliferation of human multidrug-resistant promyelocytic leukemia HL-60/ADR cells in vitro, with MRP-gene coded p190 mediated drug resistance, to a markedly lesser extent than that of the parental drug sensitive HL-60 cells and also that of the other human multidrug resistant (MDR-1, P-glycoprotein) myeloid leukemia cell line HL-60/VCR. The sensitivity of the examined human leukemia cell lines to the cytostatic activity of lovastatin correlated approximately with the potential of lovastatin to induce the characteristic cell cycle alteration (i.e. the accumulation of lovastatin-treated cells in the G0/G1 phase of the cell cycle). The P-glycoprotein positive HL-60/VCR cells and the parental drug sensitive HL-60 cells were more sensitive to this cell cycle alteration than the HL-60/ADR multidrug resistant leukemia cells with MRP drug resistance. Lovastatin (72 hours, 20 micromol) induced apoptosis and cell necrosis in HL-60 cells, apoptosis but not cell necrosis in HL-60/VCR cells and neither apoptosis nor necrosis in HL-60/ADR cells. PMID:9605009

  12. Polymorphisms in the multiple drug resistance protein 1 and in P-glycoprotein 1 are associated with time to event outcomes in patients with advanced multiple myeloma treated with bortezomib and pegylated liposomal doxorubicin

    OpenAIRE

    2010-01-01

    Single nucleotide polymorphisms (SNPs) in the multiple drug resistance protein 1 (MRP1) and P-glycoprotein 1 (MDR1) genes modulate their ability to mediate drug resistance. We therefore sought to retrospectively evaluate their influence on outcomes in relapsed and/or refractory myeloma patients treated with bortezomib or bortezomib with pegylated liposomal doxorubicin (PLD). The MRP1/R723Q polymorphism was found in five subjects among the 279 patient study population, all of whom received PLD...

  13. Do drugs have access to the P-glycoprotein drug-binding pocket through gates?

    Science.gov (United States)

    Ferreira, Ricardo J; Ferreira, Maria-José U; Dos Santos, Daniel J V A

    2015-10-13

    The P-glycoprotein efflux mechanism is being studied since its identification as a leading protagonist in multidrug resistance. Recently, it was suggested that drugs enter the drug-binding pocket (DBP) through gates located between the transmembrane domains. For both a substrate and a modulator, the potential of mean force curves along the reaction coordinate obtained with the WHAM approach were similar, with no activation energy required for crossing the gate. Moreover, drug transit from bulk water into the DBP was characterized as an overall free-energy downhill process. PMID:26574244

  14. Influence of multidrug resistance on {sup 18}F-FCH cellular uptake in a glioblastoma model

    Energy Technology Data Exchange (ETDEWEB)

    Vanpouille, Claire; Jeune, Nathalie le; Clotagatide, Anthony; Dubois, Francis [Universite de Lyon, Universite Jean Monnet-Cancer Research Group IFRESIS 143, Saint-Etienne (France); Kryza, David; Janier, Marc [Hospice Civils de Lyon, Quai Des Celestins, CREATIS, UMR CNRS, Lyon (France); Perek, Nathalie [Universite de Lyon, Universite Jean Monnet-Cancer Research Group IFRESIS 143, Saint-Etienne (France); Laboratoire de Biophysique, Faculte de Medecine, Saint-Etienne (France)

    2009-08-15

    Multidrug resistance, aggressiveness and accelerated choline metabolism are hallmarks of malignancy and have motivated the development of new PET tracers like {sup 18}F-FCH, an analogue of choline. Our aim was to study the relationship of multidrug resistance of cultured glioma cell lines and {sup 18}F-FCH tracer uptake. We used an in vitro multidrug-resistant (MDR) glioma model composed of sensitive parental U87MG and derived resistant cells U87MG-CIS and U87MG-DOX. Aggressiveness, choline metabolism and transport were studied, particularly the expression of choline kinase (CK) and high-affinity choline transporter (CHT1). FCH transport studies were assessed in our glioblastoma model. As expected, the resistant cell lines express P-glycoprotein (Pgp), multidrug resistance-associated protein isoform 1 (MRP1) and elevated glutathione (GSH) content and are also more mobile and more invasive than the sensitive U87MG cells. Our results show an overexpression of CK and CHT1 in the resistant cell lines compared to the sensitive cell lines. We found an increased uptake of FCH (in % of uptake per 200,000 cells) in the resistant cells compared to the sensitive ones (U87MG: 0.89{+-}0.14; U87MG-CIS: 1.27{+-}0.18; U87MG-DOX: 1.33{+-}0.13) in line with accelerated choline metabolism and aggressive phenotype. FCH uptake is not influenced by the two ATP-dependant efflux pumps: Pgp and MRP1. FCH would be an interesting probe for glioma imaging which would not be effluxed from the resistant cells by the classic MDR ABC transporters. Our results clearly show that FCH uptake reflects accelerated choline metabolism and is related to tumour aggressiveness and drug resistance. (orig.)

  15. Influence of multidrug resistance on 18F-FCH cellular uptake in a glioblastoma model

    International Nuclear Information System (INIS)

    Multidrug resistance, aggressiveness and accelerated choline metabolism are hallmarks of malignancy and have motivated the development of new PET tracers like 18F-FCH, an analogue of choline. Our aim was to study the relationship of multidrug resistance of cultured glioma cell lines and 18F-FCH tracer uptake. We used an in vitro multidrug-resistant (MDR) glioma model composed of sensitive parental U87MG and derived resistant cells U87MG-CIS and U87MG-DOX. Aggressiveness, choline metabolism and transport were studied, particularly the expression of choline kinase (CK) and high-affinity choline transporter (CHT1). FCH transport studies were assessed in our glioblastoma model. As expected, the resistant cell lines express P-glycoprotein (Pgp), multidrug resistance-associated protein isoform 1 (MRP1) and elevated glutathione (GSH) content and are also more mobile and more invasive than the sensitive U87MG cells. Our results show an overexpression of CK and CHT1 in the resistant cell lines compared to the sensitive cell lines. We found an increased uptake of FCH (in % of uptake per 200,000 cells) in the resistant cells compared to the sensitive ones (U87MG: 0.89±0.14; U87MG-CIS: 1.27±0.18; U87MG-DOX: 1.33±0.13) in line with accelerated choline metabolism and aggressive phenotype. FCH uptake is not influenced by the two ATP-dependant efflux pumps: Pgp and MRP1. FCH would be an interesting probe for glioma imaging which would not be effluxed from the resistant cells by the classic MDR ABC transporters. Our results clearly show that FCH uptake reflects accelerated choline metabolism and is related to tumour aggressiveness and drug resistance. (orig.)

  16. Multidrug-resistant Mycobacterium tuberculosis, Southwestern Colombia.

    Science.gov (United States)

    Ferro, Beatriz E; Nieto, Luisa Maria; Rozo, Juan C; Forero, Liliana; van Soolingen, Dick

    2011-07-01

    Using spoligotyping, we identified 13 genotypes and 17 orphan types among 160 Mycobacterium tuberculosis isolates from patients in Valle del Cauca, Colombia. The Beijing genotype represented 15.6% of the isolates and was correlated with multidrug-resistant tuberculosis, female sex of the patients, and residence in Buenaventura and may represent a new public health threat. PMID:21762581

  17. Multidrug-Resistant Mycobacterium tuberculosis, Southwestern Colombia

    OpenAIRE

    Ferro, Beatriz E.; Nieto, Luisa Maria; Rozo, Juan C.; Forero, Liliana; Van Soolingen, Dick

    2011-01-01

    Using spoligotyping, we identified 13 genotypes and 17 orphan types among 160 Mycobacterium tuberculosis isolates from patients in Valle del Cauca, Colombia. The Beijing genotype represented 15.6% of the isolates and was correlated with multidrug-resistant tuberculosis, female sex of the patients, and residence in Buenaventura and may represent a new public health threat.

  18. Integrated assessment of ivermectin pharmacokinetics, efficacy against resistant Haemonchus contortus and P-glycoprotein expression in lambs treated at three different dosage levels.

    Science.gov (United States)

    Alvarez, Luis; Suarez, Gonzalo; Ceballos, Laura; Moreno, Laura; Canton, Candela; Lifschitz, Adrián; Maté, Laura; Ballent, Mariana; Virkel, Guillermo; Lanusse, Carlos

    2015-05-30

    The main goals of the current work were: (a) to assess the ivermectin (IVM) systemic exposure and plasma disposition kinetics after its administration at the recommended dose, x5 and x10 doses to lambs, (b) to compare the clinical efficacy of the same IVM dosages in lambs infected with an IVM-resistant isolate of Haemonchus contortus, and (c) to assess the expression of the transporter protein P-glycoprotein (P-gp) in H. contortus recovered at 14 days after administration of the IVM dose regimens. There were two separated trials where IVM was administered either subcutaneously (SC, Experiment I) or intraruminally (IR, Experiment II). Each experiment involved twenty-four (24) lambs artificially infected with a highly resistant H. contortus isolate. Animals were allocated into 4 groups (n=6) and treated with IVM at either 0.2 (IVM x1), 1 (IVM x5) or 2mg/kg (IVM x10). Plasma samples were collected up to 12 days post-treatment and analysed by HPLC. An untreated-control Group was included to assess the comparative anthelmintic efficacy of the different treatments. The level of expression of Pgp in H. contortus specimens obtained from lambs both untreated and IR treated with the different IVM doses was quantified by real time PCR. Parametric and non-parametric tests were used to compare the statistical significance of the results (Pabomasum may explain the improved efficacy against this recalcitrant H. contortus isolate observed only after the IR administration at 5- and 10-fold the IVM therapeutic dosage. PMID:25841863

  19. Comparison of an immunoperoxidase "sandwich" staining method and western blot detection of P-glycoprotein in human cell lines and sarcomas.

    OpenAIRE

    K. Tóth; Vaughan, M M; Slocum, H. K.; Fredericks, W J; Chen, Y. F.; Arredondo, M. A.; Harstrick, A.; Karakousis, C.; Baker, R M; Rustum, Y M

    1992-01-01

    The applicability of a multilayer immunoperoxidase "sandwich" method (IpS) developed by Chan14 for the amplified detection of P-glycoprotein (Pgp) was investigated. The authors examined 15 formalin-fixed cell lines, as well as formalin-fixed, paraffin-embedded sections from single biopsies of 46 sarcomas. The cell lines included sensitive and multidrug resistant sublines (KB, A2780, MCF-7, HeLa) with various relative degrees of resistance to doxorubicin (Dox). The sarcoma biopsy specimens wer...

  20. Persistent expression and function of P-glycoprotein on peripheral blood lymphocytes identifies corticosteroid resistance in patients with systemic lupus erythematosus.

    Science.gov (United States)

    Kansal, Amit; Tripathi, Deepak; Rai, Mohit K; Agarwal, Vikas

    2016-02-01

    Corticosteroids (CS) are the mainstay of treatment in systemic lupus erythematosus (SLE) patients. However, some patients have poor response to CS treatment. Among the multiple mechanisms of CS resistance, overexpression of P-glycoprotein (P-gp) on peripheral blood lymphocytes (PBL) may be one of them as this result in efflux of CS from lymphocytes. Thus, we evaluated the role of P-gp protein on PBLs in patients with SLE in its response to CS therapy. SLE patients (n = 42) (fulfilling ACR revised criteria) who were naïve to CS and immunosuppressive drugs were enrolled. Disease activity was assessed using SLE disease activity index (SLEDAI) and expression, and function of P-gp was evaluated by flow cytometry at baseline and after 3 months of therapy with CS. At 3 months, patients with SLEDAI >4 and SLEDAI ≤4 were grouped as nonresponders and responders, respectively. P-gp expression was significantly increased on PBLs of SLE patients as compared to healthy controls (p < 0.001). P-gp expression and function correlated with SLEDAI (r = 0.49, p = 0.005; and r = 0.49, p = 0.001, respectively). P-gp expression and function were not different in responders and nonresponders at baseline. However, at 3 months of CS therapy, P-gp expression and function decreased in responders (p < 0.001 and p < 0.005, respectively), whereas in nonresponders, it remained unchanged. Persistent overexpression and activity of P-gp are associated with poor response to CS in CS naïve patients of SLE. PMID:26415739

  1. Study of tea polyphenol as a reversal agent for carcinoma cell lines' multidrug resistance (study of TP as a MDR reversal agent)

    International Nuclear Information System (INIS)

    The aim of this study was to examine MDR1 expression product P-glycoprotein (Pgp) and study the effect and mechanism of tea polyphenol (TP) in reversion of multidrug resistance (MDR) in carcinoma cell lines. Immunocytochemical method was used for qualitative detection of Pgp. A comparative study of cytotoxicity and multidrug resistance reversion effect was made by MTT assay for tea polyphenol and quinidine in MCF-7 and MCF-7/Adr cell lines. The multidrug resistance reversion effect and mechanism were studied by measuring the uptake of 99mTc-tetrofosmin in the carcinoma cell lines. (1) The Pgp overexpression in MCF-7/Adr cells was found to be strong positive, while the Pgp expression of MCF-7 was negative. (2) Although both tea polyphenol and quinidine could not remarkably change the toxicity of adriamycin to MCF-7, they could improve the sensitivity of MCF-7/Adr to adriamycin. The reversion index of tea polyphenol and quinidine was 3 and 10 respectively. (3) The cellular uptake of 99mTc-tetrofosmin was remarkably lower in MCF-7/Adr than in MCF-7. The uptake of 99mTc-tetrofosmin in MCF-7/Adr exhibited a 4, 13, 16 fold increase in the presence of 200, 400 and 500 μg/ml of tea polyphenol respectively. The uptake of 99mTc-tetrofosmin in MCF-7/Adr exhibited only a 4-fold increase in the presence of 200 μM of quinidine. Immunocytochemistry can detect P-glycoprotein expression level qualitatively. Tea polyphenol is not only an anti-tumor agent, but also a multidrug resistant modulator similar to quinidine. The multidrug resistance reversion mechanism of tea polyphenol seems to be its inhibition of the activity of P-glycoprotein. Tea polyphenol has the advantage of very low toxicity in tumor treatment

  2. Phospholipid-modified PEI-based nanocarriers for in vivo siRNA therapeutics against multi-drug resistant tumors

    OpenAIRE

    Essex, Sean; Navarro, Gemma; Sabhachandani, Pooja; Chordia, Aabha; Trivedi, Malav; Movassaghian, Sara; Torchilin, Vladimir P.

    2014-01-01

    Multidrug resistance (MDR) mediated by P-glycoprotein overexpression in solid tumors is a major factor in the failure of many forms of chemotherapy. Here, we evaluated phospholipid-modified, low molecular weight polyethylenimine (DOPE-PEI) nanocarriers for intravenous delivery of anti-P-pg siRNA to tumors with the final goal of modulating MDR in breast cancer. First, we studied the biodistribution of DOPE-PEI nanocarriers and the effect of PEG coating in a s.c. breast tumor model. Four hours ...

  3. Primary disseminated extrapulmonary multidrug resistant tuberculosis

    Directory of Open Access Journals (Sweden)

    S K Das

    2012-01-01

    Full Text Available Disseminated tuberculosis is a common mode of presentation of tuberculosis in patients both with and without HIV/AIDS in India. However, primary multidrug resistance in disseminated tuberculosis involving only the extrapulmonary sites in an immunocompetent adult is rare. Here, we report a case of a 19-year-old man who had disseminated tuberculosis involving left pleura, pericardium, peritoneum and intraabdominal lymph nodes. He was initially taking WHO category I antituberculous drugs, but was not responding in spite of 5 months of chemotherapy. Culture of the pleural biopsy specimen grew Mycobacterium tuberculosis which was resistant to isoniazid and rifampicin. He was put on therapy for multidrug resistant tuberculosis,following 24 months of chemotherapyhe had an uneventful recovery.

  4. P53 protein expression in human multidrug-resistant CEM lymphoblasts.

    Science.gov (United States)

    Rafki, N; Liautaud-Roger, F; Devy, L; Trentesaux, C; Dufer, J

    1997-02-01

    A role for p53 in the regulation of multidrug-resistance (MDR) has been postulated as wild-type p53 suppresses and mutant p53 specifically activates the mdr1 promoter. Moreover, changes in p53 expression and/or functions could be implicated in drug resistance. As the parental lymphoblastic CCRF-CEM cell line has been described as expressing a mutated form of p53, we have examined p53 and mdm2 protein levels in the human multidrug-resistant CEM-VLB cell line variant. These drug-resistant CEM-VLB cells, which have increased expressions of mdr1 and P-glycoprotein, displayed p53 and mdm2 protein expressions similar to those observed in their sensitive CCRF-CEM counterparts. Treatment of these drug-resistant cells with non-toxic doses of the resistance-inducing drug vinblastin induced a strong increase in p53 protein and mRNA but was ineffective on mdm2 protein expression, or mdr1 mRNA expression. These data indicate that mutant p53 protein was not overexpressed in these MDR cells. This overexpression could be induced by microtubule-active drug treatment, but, as previously observed in other sensitive cell lines, mutant p53 from these MDR cells was unable to positively regulate mdm2 gene product expression. PMID:9112432

  5. Imaging and Targeted Therapy of Multidrug Resistance. Final Report

    International Nuclear Information System (INIS)

    One focus area of DOE Office of Science was the Imaging of Gene Expression in Health and Disease in real time in tissue culture, whole animals and ultimately patients. Investigators of the Molecular Imaging Group, Washington University Medical School, ascribed to this objective and a major focus of this group directly tied into the DOE program through their efforts targeting the multidrug resistance gene (MDR1). Our plans for continuation of the program were to extend and build on this line of investigation, incorporating new molecular tools into our methodology to selectively inhibit MDR1 gene expression with novel modulation strategies. Two approaches were to be pursued: (1) high throughput screening of compounds that disrupted mutant p53 transactivation of the MDR1 promoter, and (2) knockdown of MDR1 messenger RNA with retroviral-mediated delivery of small interfering RNA constructs. These would be combined with our continuing effort to synthesize ligands and examine structure-activity relationships of bis-salicylaldehydes labeled with gallium-68 to generate PET agents for imaging MDR1 P-glycoprotein function. We would be uniquely positioned to correlate therapeutic modulation of MDR1 gene expression and protein function in the same systems in vivo using PET and bioluminescence reporters. Use of animal models such as the mdr1a/1b(-/-) gene deleted mice would also have enabled refined analysis of modulation and tracer pharmacokinetics in vivo. Overall, this DOE program and resultant tools would enable direct monitoring of novel therapeutic strategies and the MDR phenotype in relation to gene expression and protein function in vivo.

  6. Multi-drug resistant Ewingella Americana

    International Nuclear Information System (INIS)

    We report a case of pneumonia due to multi-drug resistant Ewingella Americana in a young patient admitted in the Intensive Care Unit of Hera General Hospital, Makkah, Saudi Arabia with severe head injury in a road traffic accident. He was an Indonesian pilgrim who had traveled to the Kingdom of Saudi Arabia to perform Hajj in December 2007. Ewingella Americana was identified to be the pathogen of pneumonia with clinical signs and symptoms along with positive radiological findings. (author)

  7. Study of multidrug resistance and radioresistance

    Energy Technology Data Exchange (ETDEWEB)

    Kang, Yoon Koo; Yoo, Young Do

    1999-04-01

    We investigated the mechanism of 5-FU, adriamycin, radiation resistance in Korean gastric cancer cells. First we investigated the relation between Rb and multidrug resistance. Rb stable transfectants exhibited 5- to 10- fold more resistance to adriamycin than the control cells. These Rb transfectants showed increased MDR1 expression. We also investigated up-regulation in radiation-resistant tumor tissues. HSP27, MRP-8, GST, and NKEF-B were up-regulated in radiation resistant tumor. Expression of NKEF-B was also increased by radiation exposure in Head and Neck cells. These results demonstrated that NKEF-B is a stress response protein and it may have an important role in radiation resistance.

  8. Study of multidrug resistance and radioresistance

    International Nuclear Information System (INIS)

    We investigated the mechanism of 5-FU, adriamycin, radiation resistance in Korean gastric cancer cells. First we investigated the relation between Rb and multidrug resistance. Rb stable transfectants exhibited 5- to 10- fold more resistance to adriamycin than the control cells. These Rb transfectants showed increased MDR1 expression. We also investigated up-regulation in radiation-resistant tumor tissues. HSP27, MRP-8, GST, and NKEF-B were up-regulated in radiation resistant tumor. Expression of NKEF-B was also increased by radiation exposure in Head and Neck cells. These results demonstrated that NKEF-B is a stress response protein and it may have an important role in radiation resistance

  9. Circumvention of multi-drug resistance of cancer cells by Chinese herbal medicines

    Directory of Open Access Journals (Sweden)

    Lin Ge

    2010-07-01

    Full Text Available Abstract Multi-drug resistance (MDR of cancer cells severely limits therapeutic outcomes. A proposed mechanism for MDR involves the efflux of anti-cancer drugs from cancer cells, primarily mediated by ATP-binding cassette (ABC membrane transporters including P-glycoprotein. This article reviews the recent progress of using active ingredients, extracts and formulae from Chinese medicine (CM in circumventing ABC transporters-mediated MDR. Among the ABC transporters, Pgp is the most extensively studied for its role in MDR reversal effects. While other MDR reversal mechanisms remain unclear, Pgp inhibition is a criterion for further mechanistic study. More mechanistic studies are needed to fully establish the pharmacological effects of potential MDR reversing agents.

  10. Congenital Transmission of Multidrug-Resistant Tuberculosis

    Science.gov (United States)

    Espiritu, Nora; Aguirre, Lino; Jave, Oswaldo; Sanchez, Luis; Kirwan, Daniela E.; Gilman, Robert H.

    2014-01-01

    This article presents a case of multidrug-resistant tuberculosis (TB) in a Peruvian infant. His mother was diagnosed with disseminated TB, and treatment commenced 11 days postpartum. The infant was diagnosed with TB after 40 days and died at 2 months and 2 days of age. Congenital transmission of TB to the infant was suspected, because direct postpartum transmission was considered unlikely; also, thorough screening of contacts for TB was negative. Spoligotyping confirmed that both mother and baby were infected with identical strains of the Beijing family (SIT1). PMID:24821847

  11. Regulation of pregnane-X-receptor, CYP3A and P-glycoprotein genes in the PCB-resistant killifish (Fundulus heteroclitus) population from New Bedford Harbor

    Energy Technology Data Exchange (ETDEWEB)

    Gräns, Johanna; Wassmur, Britt; Fernández-Santoscoy, María [Department of Biological and Environmental Sciences, University of Gothenburg, Box 463, SE 405 30 Gothenburg (Sweden); Zanette, Juliano; Woodin, Bruce R.; Karchner, Sibel I. [Biology Department, MS #32, Woods Hole Oceanographic Institution, Woods Hole, MA 02543 (United States); Nacci, Diane E.; Champlin, Denise; Jayaraman, Saro [Office of Research and Development, National Health and Environmental Effects Research Laboratory, Atlantic Ecology Division, United States Environmental Protection Agency, 27 Tarzwell Drive, Narragansett, RI 02882 (United States); Hahn, Mark E.; Stegeman, John J. [Biology Department, MS #32, Woods Hole Oceanographic Institution, Woods Hole, MA 02543 (United States); Celander, Malin C., E-mail: malin.celander@gu.se [Department of Biological and Environmental Sciences, University of Gothenburg, Box 463, SE 405 30 Gothenburg (Sweden)

    2015-02-15

    Highlights: • Basal levels of PXR and Pgp mRNA are lower in liver of fish from NBH than from SC. • Hepatic PXR, CYP3A and Pgp mRNA levels are induced by PCB in fish from NBH. • Both non-dioxin-like and dioxin-like PCBs induce PXR, CYP3A and Pgp in NBH fish. • Branchial PXR and CYP3A mRNA levels are induced by PCB 126 in fish from SC. • There is possible cross-talk between AhR and PXR signaling in killifish. - Abstract: Killifish survive and reproduce in the New Bedford Harbor (NBH) in Massachusetts (MA), USA, a site severely contaminated with polychlorinated biphenyls (PCBs) for decades. Levels of 22 different PCB congeners were analyzed in liver from killifish collected in 2008. Concentrations of dioxin-like PCBs in liver of NBH killifish were ∼400 times higher, and the levels of non-dioxin-like PCBs ∼3000 times higher than in killifish from a reference site, Scorton Creek (SC), MA. The NBH killifish are known to be resistant to the toxicity of dioxin-like compounds and to have a reduced aryl hydrocarbon receptor (AhR) signaling response. Little is known about the responses of these fish to non-dioxin-like PCBs, which are at extraordinarily high levels in NBH fish. In mammals, some non-dioxin-like PCB congeners act through nuclear receptor 1I2, the pregnane-X-receptor (PXR). To explore this pathway in killifish, a PXR cDNA was sequenced and its molecular phylogenetic relationship to other vertebrate PXRs was determined. Killifish were also collected in 2009 from NBH and SC, and after four months in the laboratory they were injected with a single dose of either the dioxin-like PCB 126 (an AhR agonist) or the non-dioxin-like PCB 153 (a mammalian PXR agonist). Gills and liver were sampled three days after injection and transcript levels of genes encoding PXR, cytochrome P450 3A (CYP3A), P-glycoprotein (Pgp), AhR2 and cytochrome P450 1A (CYP1A) were measured by quantitative PCR. As expected, there was little effect of PCB exposure on mRNA expression of AhR2 or CYP1A in liver and gills of NBH fish. In NBH fish, but not in SC fish, there was increased mRNA expression of hepatic PXR, CYP3A and Pgp upon exposure to either of the two PCB congeners. However, basal PXR and Pgp mRNA levels in liver of NBH fish were significantly lower than in SC fish. A different pattern was seen in gills, where there were no differences in basal mRNA expression of these genes between the two populations. In SC fish, but not in NBH fish, there was increased mRNA expression of branchial PXR and CYP3A upon exposure to PCB126 and of CYP3A upon exposure to PCB153. The results suggest a difference between the two populations in non-AhR transcription factor signaling in liver and gills, and that this could involve killifish PXR. It also implies possible cross-regulatory interactions between that factor (presumably PXR) and AhR2 in liver of these fish.

  12. Regulation of pregnane-X-receptor, CYP3A and P-glycoprotein genes in the PCB-resistant killifish (Fundulus heteroclitus) population from New Bedford Harbor

    International Nuclear Information System (INIS)

    Highlights: • Basal levels of PXR and Pgp mRNA are lower in liver of fish from NBH than from SC. • Hepatic PXR, CYP3A and Pgp mRNA levels are induced by PCB in fish from NBH. • Both non-dioxin-like and dioxin-like PCBs induce PXR, CYP3A and Pgp in NBH fish. • Branchial PXR and CYP3A mRNA levels are induced by PCB 126 in fish from SC. • There is possible cross-talk between AhR and PXR signaling in killifish. - Abstract: Killifish survive and reproduce in the New Bedford Harbor (NBH) in Massachusetts (MA), USA, a site severely contaminated with polychlorinated biphenyls (PCBs) for decades. Levels of 22 different PCB congeners were analyzed in liver from killifish collected in 2008. Concentrations of dioxin-like PCBs in liver of NBH killifish were ∼400 times higher, and the levels of non-dioxin-like PCBs ∼3000 times higher than in killifish from a reference site, Scorton Creek (SC), MA. The NBH killifish are known to be resistant to the toxicity of dioxin-like compounds and to have a reduced aryl hydrocarbon receptor (AhR) signaling response. Little is known about the responses of these fish to non-dioxin-like PCBs, which are at extraordinarily high levels in NBH fish. In mammals, some non-dioxin-like PCB congeners act through nuclear receptor 1I2, the pregnane-X-receptor (PXR). To explore this pathway in killifish, a PXR cDNA was sequenced and its molecular phylogenetic relationship to other vertebrate PXRs was determined. Killifish were also collected in 2009 from NBH and SC, and after four months in the laboratory they were injected with a single dose of either the dioxin-like PCB 126 (an AhR agonist) or the non-dioxin-like PCB 153 (a mammalian PXR agonist). Gills and liver were sampled three days after injection and transcript levels of genes encoding PXR, cytochrome P450 3A (CYP3A), P-glycoprotein (Pgp), AhR2 and cytochrome P450 1A (CYP1A) were measured by quantitative PCR. As expected, there was little effect of PCB exposure on mRNA expression of AhR2 or CYP1A in liver and gills of NBH fish. In NBH fish, but not in SC fish, there was increased mRNA expression of hepatic PXR, CYP3A and Pgp upon exposure to either of the two PCB congeners. However, basal PXR and Pgp mRNA levels in liver of NBH fish were significantly lower than in SC fish. A different pattern was seen in gills, where there were no differences in basal mRNA expression of these genes between the two populations. In SC fish, but not in NBH fish, there was increased mRNA expression of branchial PXR and CYP3A upon exposure to PCB126 and of CYP3A upon exposure to PCB153. The results suggest a difference between the two populations in non-AhR transcription factor signaling in liver and gills, and that this could involve killifish PXR. It also implies possible cross-regulatory interactions between that factor (presumably PXR) and AhR2 in liver of these fish

  13. Breaking the Spell: Combating Multidrug Resistant Superbugs

    Science.gov (United States)

    Khan, Shahper N.; Khan, Asad U.

    2016-01-01

    Multidrug-resistant (MDR) bacteria have become a severe threat to community wellbeing. Conventional antibiotics are getting progressively more ineffective as a consequence of resistance, making it imperative to realize improved antimicrobial options. In this review we emphasized the microorganisms primarily reported of being resistance, referred as ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa, and Enterobacteriaceae) accentuating their capacity to escape from routine antimicrobial regimes. The upcoming antimicrobial agents showing great potential and can serve as alternative therapeutic options are discussed. We also provided succinct overview of two evolving technologies; specifically network pharmacology and functional genomics profiling. Furthermore, In vivo imaging techniques can provide novel targets and a real time tool for potential lead molecule assessment. The employment of such approaches at prelude of a drug development process, will enables more informed decisions on candidate drug selection and will maximize or predict therapeutic potential before clinical testing. PMID:26925046

  14. Mechanism of Anti-Cancer Activity of Benomyl Loaded Nanoparticles in Multidrug Resistant Cancer Cells.

    Science.gov (United States)

    Kini, Sudarshan; Bahadur, Dhirendra; Panda, Dulal

    2015-05-01

    Polymeric chitosan-poly(D,L-lactide-co-glycolide) nanoparticles loaded with benomyl as anticancer drug formulation against multidrug-resistant EMT6/AR1 cells were synthesized by amine-carboxylate reaction. Using transmission electron microscopy, the average size of chitosan-poly(D,L-lactide-co-glycolide) nanoparticles and benomyl-encapsulated polymeric chitosan-poly(D,L-lactide-co-glycolide) nanoparticles was estimated to be 155 20 nm and 160 25 nm, respectively. Fourier transform infrared spectroscopy revealed that poly(D,L-lactide-co-glycolide) and chitosan are linked by covalent bonds. Zeta potentials of benomyl-encapsulated polymeric chitosan-poly(D,L-lactide-co-glycolide) nanoparticles at pH 4, 7.2, and 10 were 30 1.8, 19 0.65, and -22 0.15 mV, respectively, indicating the formation of stable, hydrophilic nanoparticles. The release of benomyl from benomyl-encapsulated polymeric chitosan-poly(D,L-lactide-co-glycolide) nanoparticles followed pH-dependent kinetics. The uptake of fluorescein isothiocyanate-labeled chitosan-poly(D,L-lactide-co-glycolide) nanoparticles was concentration-dependent in both MCF-7 and multidrug-resistant EMT6/AR1 cells. EMT6/AR1 cells showed 10-fold higher resistance to benomyl compared to MCF-7 cells; in contrast, benomyl-encapsulated polymeric chitosan-poly(D,L-lactide-co-glycolide) nanoparticles effectively inhibited proliferation of MCF-7 and EMT6/AR1 cells with a half-maximal inhibitory concentration of 4 0.5 and 9 0.5 pM, respectively. In the presence of a P-glycoprotein inhibitor, the activity of benomyl was increased, suggesting that benomyl is a substrate for P-glycoprotein. Further, benomyl-encapsulated polymeric chitosan-poly(D,L-lactide-co-glycolide) nanoparticles depoly-merized microtubules both in interphase and mitosis. It blocked cell cycle progression at G2/M and induced apoptosis in EMT6/AR1 cells, suggesting that benomyl-encapsulated polymeric chitosan-poly(D,L-lactide-co-glycolide) nanoparticles have chemotherapeutic activity against multidrug-resistant cancer cells. PMID:26349399

  15. Effect of multidrug resistance gene-1(MDR1) expression on in-vitro uptake of Tc-99m sestaMIBI(MIBI) in murine L1210 leukemia cells

    International Nuclear Information System (INIS)

    Resistance of malignant tumors to multiple chemotherapeutic agents is a major cause of treatment failure and one of the most important mechanisms of multidrug resistance is an increased expression of plasma membrane P-glycoprotein. P-glycoprotein can recognize and transport a large group of cytotoxic compounds sharing little or no structural or functional similarities, other than being relatively small, hydrophobic and cationic. Recent studies have proved that Tc-99m MIBI is transported by the P-glycoprotein in insect cells with overexpression of recombinant multidrug resistance P-glycoprotein. To demonstrate that Tc-99m MIBI is recognized by the multidrug resistant P-glycoprotein, we have quantitatively measured Tc-99m MIBI uptake in cancer cells with or without expression of MDR1 gene which is responsible for P-glycoprotein. The relationship between Tc-99m MIBI uptake and expression of MDR1 gene was evaluated. Multidrug resistance cell lines were induced from murine leukemia cell line(L1210, mouse lymphocytic leukemia cell, ATCC) with continuous challenging low dose adriamycin (Adr cell) or vincristine (Vcr cell) in culture media. Expression of MDR1 RNA was measured with reverse transcriptase polymerase chain reaction (RT-PCR) using 243 base pair primer (Kizaki et al. Blood 87:725, 1996). Cellular uptake of Tc-99m MIBI was measured at 4 .deg. C and 37 .deg. C condition, and after incubating for 60-min in 37 .deg. C RPMI media with or without 50uM or 200uM verapamil. RT-PCR of Adr cells revealed an intense band corresponding expression of MDR1 RNA, whereas Vcr cells weaker linear band. In contrast, RT-PCR specimen of L1210 did not show MDR1 band. Incubation of cells with Tc-99m MIBI resulted in higher uptake with L1210 than Adr or Vcr cells in either 4 .deg. C (37% L1210 vs 17% Adr or 9% Vcr, p<0.05 respectively) or 37 .deg. C (48% vs 25% or 23%, p<0.01 respectively). In the presence of verapamil, known reverser of PgP functions, incubation with verapamil resulted in increased Tc-99m MIBI uptake in Adr cell line (from 25% to 29% with 50uM or 45% with 200uM) and Vcr cell line(from 23% to 27% with 50uM or 35% with 200uM). Tc-99m MIBI uptake was not changed with verapamil in L1210 cells. These results demonstrate that MDR1 gene expressing cell lines were effectively induced in in-vitro and Tc-99m MIBI is a transporter substrate recognized by the MDR1 P-glycoprotein. Tc-99m MIBI may be useful for characterizing P-glycoprotein expression in leukemic cells in vitro

  16. SmeDEF Multidrug Efflux Pump Contributes to Intrinsic Multidrug Resistance in Stenotrophomonas maltophilia

    OpenAIRE

    Zhang, Li; Li, Xian-Zhi; Poole, Keith

    2001-01-01

    Stenotrophomonas maltophilia is an emerging nosocomial pathogen that displays high-level intrinsic resistance to a variety of structurally unrelated antimicrobial agents. Efflux mechanisms are known to contribute to acquired multidrug resistance in this organism, and indeed, one such multidrug efflux system, SmeDEF, was recently identified. Still, the importance of SmeDEF to intrinsic antibiotic resistance in S. maltophilia had not yet been determined. Reverse transcription-PCR confirmed expr...

  17. Correlation between uptake of 99TcM-MIBI and multidrug resistant proteins of breast cancer

    International Nuclear Information System (INIS)

    Objectives: To assess the correlation between 99Tcm-MIBI uptake and the expression level of multidrug resistant proteins of breast cancer. Methods: Thirty patients with infiltrating ductal carcinoma were enrolled in this study. 99Tcm-MIBI scintigraphy were performed at 15 min and 90 min after injecting the tracer. The uptake of 99Tcm-MIBI were evaluated as tumor over background ratio with region of interest technique. Such indexes as early uptake ratio (EUR), delay uptake ratio (DUR) and retention index (RI) were calculated respectively. P-gp (P-glycoprotein) and MRP (multidrug resistant-associated protein) expression in surgically resected tumors were investigated by immunohistochemistry. Immunohistochemistry HPIAS-1000 image analysis system was used to determined the level of P-gp and MRP expression. The difference of P-gp and MRP level in the group with RI ≥ 0 and the group with RI99Tcm-MIBI on delayed scans in breast cancer. The uptake of 99Tcm-MIBI may be not related to the levels of MRP expression. Thus 99Tcm-MIBI scintigraphy may predict the MDR development which associated with P-gp expression in breast carcinoma. (authors)

  18. KEGG DISEASE / Multidrug-resistant Pseudomonas aeruginosa infection [KEGG DISEASE

    Lifescience Database Archive (English)

    Full Text Available DISEASE: H00313 Entry H00313Disease Name Multidrug-resistant Pseudomonas aeruginosa infection De ... , Watkins K, Mahamoud Y, Paulsen IT Title Complete genome ... sequence of the multiresistant taxonomic outlier P ... ahara T, Tada T, Kitao T, Kirikae T Title Complete genome ... sequence of highly multidrug-resistant Pseudomonas ...

  19. The influence of a caveolin-1 mutant on the function of P-glycoprotein.

    Science.gov (United States)

    Lee, Chih-Yuan; Lai, Ting-Yu; Tsai, Meng-Kun; Ou-Yang, Pu; Tsai, Ching-Yi; Wu, Shu-Wei; Hsu, Li-Chung; Chen, Jin-Shing

    2016-01-01

    The genetic heterogeneity in cancer cells has an increased chance in the acquisition of new mutant such as drug-resistant phenotype in cancer cells. The phenotype of drug resistance in cancer cells could be evaluated by the number or function of drug transporters on cell membranes, which would lead to decreased intracellular anti-cancer drugs concentration. Caveolae are flask-shaped invaginations on cell membrane that function in membrane trafficking, endocytosis, and as a compartment where receptors and signaling proteins are concentrated. Caveolin-1 (CAV1) is the principal structural protein of caveolae and closely correlates with multidrug resistance in cancer cells. In a systematic study of the ubiquitin-modified proteome, lysine 176 of CAV1 was identified as a potential post-translational modification site for ubiquitination. In this article, we identified a mutation at lysine 176 to arginine (K176R) on CAV1 would interfere with the biogenesis of caveolae and broke the interaction of CAV1 with P-glycoprotein. Functional assays further revealed that K176R mutant of CAV1 in cancer cells increased the transport activity of P-glycoprotein and decreased the killing ability of anti-cancer drugs in non-small-cell lung cancer cell lines. PMID:26843476

  20. Molecular/cytogenetic alterations accompanying the development of multidrug resistance in the J774.2 murine cell line.

    Science.gov (United States)

    Slovak, M L; Lothstein, L; Horwitz, S B; Trent, J M

    1988-07-01

    Mouse macrophage-like J774.2 cells were selected for resistance to colchicine and examined by molecular/cytogenetic analysis to determine whether the acquisition of the multidrug resistant (mdr) phenotype was associated with specific chromosomal rearrangements. Cytogenetic studies of the J774.2 parental and two colchicine-resistant (CLCR) sublines--J7.Cl-30 (770-fold CLCR) and J7.Cl-100 (2500-fold CLCR)--demonstrated specific numeric and structural karyotypic alterations accompanying the emergence of mdr. The parental cells demonstrated a modal chromosome number of 63, while the modal number of the J7.Cl-30 subline was 53. The most striking difference between the parental and J7.Cl-30 subline was the presence of an average of 60 double minutes (DMs) per cell in the CLCR cells. The 2500-fold resistant J7.Cl-100 subline displayed a modal number of 50, which included structural rearrangements involving chromosomes 2 and 7 and concomitant replacement of DMs by a homogeneously staining region (HSR). Southern blotting analysis demonstrated a approximately 35-fold amplification of P-glycoprotein homologous sequences in the J7.Cl-30 subline and approximately 70-fold amplification in the J7.Cl-100 subline. Chromosomal in situ hybridization localized the amplified P-glycoprotein sequences to DMs (J7.Cl-30) and the HSR (J7.Cl-100) in these CLCR sublines. Our results suggest that CLCR in J774.2 cells results from overexpression of P-glycoprotein via gene amplification which was accompanied by chromosomal evolution from DMs to an HSR. PMID:2899184

  1. Probenecid-resistant J774 cell expression of enhanced organic anion transport by a mechanism distinct from multidrug resistance.

    Science.gov (United States)

    Cao, C; Steinberg, T H; Neu, H C; Cohen, D; Horwitz, S B; Hickman, S; Silverstein, S C

    1993-08-01

    Macrophages possess organic anion transporters that carry membrane-impermeant fluorescent dyes, such as lucifer yellow (LY) and carboxy-fluorescein, from the cytoplasm into endosomes and out of the cells. Probenecid, an organic anion transport inhibitor, blocks these processes. Prolonged incubation of J774 cells in medium containing 2.5 mM probenecid eventually kills most of these cells. To identify J774 variants that express increased organic anion transport activity, we selected probenecid-resistant (PBR) J774 cells by growing them in medium containing increasing concentrations of probenecid. When PBR and unselected J774 cells were loaded with LY by ATP4- permeabilization, the amount of LY accumulated by the PBR cells was about half that in the unselected cells. This difference was abolished by adding 10 mM probenecid to the medium in which the cells were loaded, suggesting that the diminished LY accumulation in PBR cells was due to enhanced LY secretion and that the PBR cells expressed increased organic anion transport activity. Direct comparison of LY efflux from J774 and PBR J774 cells showed a faster initial rate of secretion of LY from PBR J774 cells than from unselected J774 cells. To determine whether LY efflux is mediated by P-glycoprotein, we compared LY efflux in unselected J774 cells, PBR J774 cells, and multidrug-resistant J774 cells (J7.C1). LY efflux from J7.C1 cells was not sensitive to verapamil, which inhibits multidrug-resistance transporters, and reverses the multidrug-resistant phenotype of J7.C1 cells. The rates of LY efflux from unselected J774 and J7.C1 cells were virtually identical.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7909709

  2. Design real-time reversal of tumormultidrug resistance cleverly with shortened carbon nanotubes

    Directory of Open Access Journals (Sweden)

    Wu P

    2014-12-01

    Full Text Available Pingping Wu,1 Shang Li,2 Haijun Zhang2 1Jiangsu Cancer Hospital, Nanjing, Peoples Republic of China; 2Department of Oncology, Zhongda Hospital, Medical School, Southeast University, Nanjing, PeoplesRepublicof ChinaAbstract: Multidrug resistance (MDR in tumors renders many currently available chemotherapeutic drugs ineffective. Research in nanobiotechnology-based therapeutic alternatives has provided innovative and promising strategies to overcome MDR. The aim of this study was to investigate whether the new strategy of a co-loaded reversal agent and chemotherapeutic drug with shortened carbon nanotubes (CNTs would show useful effects on the real-time reversal of tumor MDR. CNTs were cut and purified via ultrasonication and oxidative acid treatment to optimize their length for drug-delivery vehicles, then verapamil (Ver and doxorubicin (Dox were co-loaded on shortened CNTs (denoted as Ver/Dox/shortened CNTs, which acted as a drug delivery system. The multidrug resistant leukemia K562/A02 cells were treated with the denoted Ver/Dox/shortened CNTs. The real-time reversal of tumor MDR were evaluated by flow cytometer, 3-(4,5-Dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide assays, acridine orange/ethidium bromide staining, and Western blot analysis. In the same MDR tumor cells the new strategy of a co-loaded reversal agent and chemotherapeutic drug with CNTs could inhibit the function of P-glycoprotein in real-time by Ver as reversal agent, significantly increase the uptake of Dox, enhance the sensitivity of the MDR cancer cells to the chemotherapeutic agent, and induce apoptosis. It was therefore concluded that a co-loaded reversal agent and chemotherapeutic drug with shortened CNTs could have real-time reversal ability of MDR in tumors, which could represent a promising approach in cancer therapy.Keywords: multidrug resistance, carbon nanotubes, drug delivery system, tumor

  3. Nosocomial transmission of multidrug-resistant tuberculosis.

    Science.gov (United States)

    Crudu, V; Merker, M; Lange, C; Noroc, E; Romancenco, E; Chesov, D; Gnther, G; Niemann, S

    2015-12-01

    Nosocomial transmission of multidrug-resistant tuberculosis (MDR-TB) was ascertained by 24-locus mycobacterial interspersed repetitive units-variable number of tandem repeats (MIRU-VNTR) and spoligotyping at four hospitals in the Republic of Moldova, a high MDR-TB burden country. Overall, 5.1% of patients with pan-susceptible TB at baseline were identified with MDR-TB during in-patient treatment. In 75% of cases, the MDR-TB strain was genetically distinct from the non-MDR-TB strain at baseline, suggesting a high rate of nosocomial transmission of MDR-TB. The highest proportion (40.3%) of follow-up MDR-TB isolates was associated with the M. tuberculosis URAL 163-15 strain. PMID:26614195

  4. Multidrug-resistant tuberculosis in pregnancy

    International Nuclear Information System (INIS)

    This is a case report of 26 years old pregnant woman with multidrug-resistant tuberculosis (MDR TB), treated at outpatient department of New Delhi Tuberculosis (NDTB) Centre, India with second line agents. Before presentation at NDTB Centre, she had been treated with first line drugs for approximately one and-a-half-year, including category II re-treatment DOTS regimen under RNTCP. Patient conceived twice during her anti-TB treatment. The first one was during her category II treatment, when put on second line drugs. We describe congenital abnormalities documented in her second child exposed in-utero to second line anti-tubercular drugs with a brief review of treatment of MDR TB in pregnancy. (author)

  5. [Multidrug resistance in Klebsiella pneumoniae: multicenter study].

    Science.gov (United States)

    Boutiba-Ben Boubaker, Ilhem; Ben Salah, Dorra; Besbes, Makram; Mahjoubi, Faouzia; Ghozzi, Rafiaa; Ben Redjeb, Saida; Ben Hassen, Assia; Hammami, Adnène

    2002-01-01

    The extensive use of broad spectrum antibiotics, especially the third generation cephalosporins (C3G), was followed by the emergence of newer plasmid mediated betalactamases called extended spectrum betalactamases (ESBLs). To assess the impact of K. pneumoniae resistant to 3GC in Tunisia, this study was conducted in 3 teaching hospitals. A total of 1110 strains of K pneumoniae was collected. The antibiotics susceptibilities were tested by diffusion method using Mueller-Hinton agar. The quality control was regularly performed. I ESBLs producing solates were detected using the double-disc synergy test. Data analysis was done using the Whonet 4 software. 23.6% K. pneumoniae isolates showed phenotype pattern of ESBLs producers. The double-disc synergy test was positive in 75% of the cases. These isolates were recovered from hospitalized patients in different wards but mainly from pediatrics (23.6%), medicine (23.2%), surgery (22.9%), intensive care units (11%) and neonatology (11%). 54% were isolated from urines, 22% from blood cultures. These isolates remained susceptible to imipenem (100%) and most of them to cefoxitin (96.4%) but all had associated resistance to aminoglycosides, quinolones and trimethoprim-sulfamethoxazole. The prevalence of multidrug resistant K. pneumoniae is high. This resistance can be minimized by the implementation of infection control measures including handwashing and isolation procedures. PMID:12071040

  6. Salinomycin overcomes ABC transporter-mediated multidrug and apoptosis resistance in human leukemia stem cell-like KG-1a cells

    Energy Technology Data Exchange (ETDEWEB)

    Fuchs, Dominik [Research Group Molecular Neuro-Oncology, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg (Germany); Institute of Immunology, University of Heidelberg, Im Neuenheimer Feld 305, D-69120 Heidelberg (Germany); Daniel, Volker; Sadeghi, Mahmoud; Opelz, Gerhard [Institute of Immunology, University of Heidelberg, Im Neuenheimer Feld 305, D-69120 Heidelberg (Germany); Naujokat, Cord, E-mail: cord.naujokat@med.uni-heidelberg.de [Institute of Immunology, University of Heidelberg, Im Neuenheimer Feld 305, D-69120 Heidelberg (Germany)

    2010-04-16

    Leukemia stem cells are known to exhibit multidrug resistance by expression of ATP-binding cassette (ABC) transporters which constitute transmembrane proteins capable of exporting a wide variety of chemotherapeutic drugs from the cytosol. We show here that human promyeloblastic leukemia KG-1a cells exposed to the histone deacetylase inhibitor phenylbutyrate resemble many characteristics of leukemia stem cells, including expression of functional ABC transporters such as P-glycoprotein, BCRP and MRP8. Consequently, KG-1a cells display resistance to the induction of apoptosis by various chemotherapeutic drugs. Resistance to apoptosis induction by chemotherapeutic drugs can be reversed by cyclosporine A, which effectively inhibits the activity of P-glycoprotein and BCRP, thus demonstrating ABC transporter-mediated drug resistance in KG-1a cells. However, KG-1a are highly sensitive to apoptosis induction by salinomycin, a polyether ionophore antibiotic that has recently been shown to kill human breast cancer stem cell-like cells and to induce apoptosis in human cancer cells displaying multiple mechanisms of drug and apoptosis resistance. Whereas KG-1a cells can be adapted to proliferate in the presence of apoptosis-inducing concentrations of bortezomib and doxorubicin, salinomycin does not permit long-term adaptation of the cells to apoptosis-inducing concentrations. Thus, salinomycin should be regarded as a novel and effective agent for the elimination of leukemia stem cells and other tumor cells exhibiting ABC transporter-mediated multidrug resistance.

  7. Salinomycin overcomes ABC transporter-mediated multidrug and apoptosis resistance in human leukemia stem cell-like KG-1a cells

    International Nuclear Information System (INIS)

    Leukemia stem cells are known to exhibit multidrug resistance by expression of ATP-binding cassette (ABC) transporters which constitute transmembrane proteins capable of exporting a wide variety of chemotherapeutic drugs from the cytosol. We show here that human promyeloblastic leukemia KG-1a cells exposed to the histone deacetylase inhibitor phenylbutyrate resemble many characteristics of leukemia stem cells, including expression of functional ABC transporters such as P-glycoprotein, BCRP and MRP8. Consequently, KG-1a cells display resistance to the induction of apoptosis by various chemotherapeutic drugs. Resistance to apoptosis induction by chemotherapeutic drugs can be reversed by cyclosporine A, which effectively inhibits the activity of P-glycoprotein and BCRP, thus demonstrating ABC transporter-mediated drug resistance in KG-1a cells. However, KG-1a are highly sensitive to apoptosis induction by salinomycin, a polyether ionophore antibiotic that has recently been shown to kill human breast cancer stem cell-like cells and to induce apoptosis in human cancer cells displaying multiple mechanisms of drug and apoptosis resistance. Whereas KG-1a cells can be adapted to proliferate in the presence of apoptosis-inducing concentrations of bortezomib and doxorubicin, salinomycin does not permit long-term adaptation of the cells to apoptosis-inducing concentrations. Thus, salinomycin should be regarded as a novel and effective agent for the elimination of leukemia stem cells and other tumor cells exhibiting ABC transporter-mediated multidrug resistance.

  8. Changes in subcellular doxorubicin distribution and cellular accumulation alone can largely account for doxorubicin resistance in SW-1573 lung cancer and MCF-7 breast cancer multidrug resistant tumour cells.

    Science.gov (United States)

    Schuurhuis, G. J.; van Heijningen, T. H.; Cervantes, A.; Pinedo, H. M.; de Lange, J. H.; Keizer, H. G.; Broxterman, H. J.; Baak, J. P.; Lankelma, J.

    1993-01-01

    Doxorubicin accumulation defects in multidrug resistant tumour cells are generally small in comparison to the resistance factors. Therefore additional mechanisms must be operative. In this paper we show by a quantitative approach that doxorubicin resistance in several P-glycoprotein-positive non-small cell lung cancer and breast cancer multidrug resistant cell lines can be explained by a summation of accumulation defect and alterations in the efficacy of the drug once present in the cell. This alteration of efficacy was partly due to changes in intracellular drug localisation, characterised by decreased nuclear/cytoplasmic doxorubicin fluorescence ratios (N/C-ratios). N/C-ratios were 2.8-3.6 in sensitive cells, 0.1-0.4 in cells with high (> 70-fold) levels of doxorubicin resistance and 1.2 and 1.9 in cells with low or intermediate (7.5 and 24-fold, respectively) levels of doxorubicin resistance. The change of drug efficacy was reflected by an increase in the total amount of doxorubicin present in the cell at equitoxic (IC50) concentrations. N/C ratios in highly resistant P-glycoprotein-containing cells could be increased with the resistance modifier verapamil to values of 1.3-2.7, a process that was paralleled by a decrease of the cellular doxorubicin amounts present at IC50. At the low to moderate residual levels of resistance, obtained with different concentrations of verapamil, a linear relationship between IC50 and cellular doxorubicin amounts determined at IC50 was found. This shows that at this stage of residual resistance, extra reversal by verapamil should be explained by further increase of drug efficacy rather than by increase of cellular drug accumulation. A similar relationship was found for P-glycoprotein-negative MDR cells with low levels of resistance. Since in these cells N/C ratios could not be altered, verapamil-induced decrease of IC50 must be due to increased drug efficacy by action on as yet unidentified targets. Although the IC50 of sensitive human cells cannot be reached with resistance modifiers, when using these relationships it can be shown by extrapolation that cellular and nuclear doxorubicin amounts at IC50 at complete reversal of resistance were the same as in sensitive cells. It is concluded that doxorubicin resistance factors for multidrug resistant cells can for a large part, and in the case of P-glycoprotein-containing cells probably fully, be accounted for by decreased amounts of drug at nuclear targets, which in turn is characterised by two processes only: decreased cellular accumulation and a shift in the ratio nuclear drug/cytoplasmic drug. Images Figure 7 Figure 9 PMID:8105865

  9. Successful treatment of multidrug resistant Acinetobacter baumannii meningitis

    OpenAIRE

    Acinetobacter baumannii, Post-surgical meningitis, High dose meropenem

    2007-01-01

    Background: Acinetobacter baumannii is a major cause of nosocomial infections in many hospitals and appears to have a propensity for developing multiple antimicrobial resistance rapidly.Cases: We report two cases with post-surgical meningitis due to multidrug resistant A. baumannii which were successfully treated with high-dose intravenous meropenem therapy.Conclusions: Multidrug resistant Acinetobacter spp. in intensive care units are a growing concern. High-dose meropenem is used in the tre...

  10. Risk factors for acquired multidrug-resistant tuberculosis

    OpenAIRE

    Barroso Elizabeth Clara; Mota Rosa Maria Salani; Santos Raimunda Oliveira; Sousa Ana Lúcia Oliveira; Barroso Joana Brasileiro; Rodrigues Jorge Luís Nobre

    2003-01-01

    Multidrug-resistant tuberculosis (MDR-TB) is a severe and feared problem, that is difficult to control and has shown a tendency to increase worldwide. OBJECTIVE: To analyze the risk factors for acquired MDR-TB. CASUISTIC AND METHODS: A retrospective population-based case-control study was conducted. A bacillus was considered multidrug-resistant whenever it was resistant at least to rifampin (RFP) + isoniazid (INH), and a case was considered as sensitive tuberculosis (TB) if it had undergone t...

  11. Biochemical and genetic characterization of the multidrug resistance phenotype in murine macrophage-like J774.2 cells.

    Science.gov (United States)

    Kirschner, L S; Greenberger, L M; Hsu, S I; Yang, C P; Cohen, D; Piekarz, R L; Castillo, G; Han, E K; Yu, L J; Horwitz, S B

    1992-01-01

    The development of multidrug resistance (MDR) in malignant tumors is a major obstacle to the treatment of many cancers. MDR sublines have been derived from the J774.2 mouse macrophage-like cell line and utilized to characterize the phenotype at the biochemical and genetic level. Two isoforms of the drug resistance-associated P-glycoprotein are present and distinguishable both electrophoretically and pharmacologically. Genetic analysis has revealed the presence of a three-member gene family; expression of two of these genes, mdr1a and mdr1b, is associated with MDR whereas the expression of the third, mdr2, is not. Studies of these three genes have revealed similarities and differences in the manner in which they are regulated at the transcriptional level, and have suggested that post-transcriptional effects may also be important. PMID:1346495

  12. Drug resistance pattern in multidrug resistance pulmonary tuberculosis patients

    International Nuclear Information System (INIS)

    To evaluate the frequency of drug resistance profiles of multidrug resistant tuberculosis (MDR-TB) isolates of pulmonary tuberculosis patients, against both the first and the second line drugs. Study Design: An observational study. Place and Duration of Study: The multidrug resistant tuberculosis (MDR-TB) ward of Ojha Institute of Chest Diseases (OICD), Karachi, from 1996 to 2006. Methodology: Culture proven MDR-TB cases (resistant to both isoniazid and Rifampicin) were retrospectively reviewed. Susceptibility testing was performed at the clinical laboratory of the Aga Khan University. Sensitivity against both first and second line anti-tuberculosis drugs was done. Susceptibility testing was performed using Agar proportion method on enriched middle brook 7H10 medium (BBL) for Rifampicin, Isoniazid, Streptomycin, Ethambutol, Ethionamide, Capreomycin and Ciprofloxacin. Pyrazinamide sensitivity was carried out using the BACTEC 7H12 medium. During the study period MTB H37Rv was used as control. Results: Out of total 577 patients, all were resistant to both Rifampicin and Isoniazid (INH). 56.5% isolates were resistant to all five first line drugs. Resistances against other first line drugs was 76.60% for Pyrazinamide, 73% for Ethambutol and 68.11% for Streptomycin. Five hundred and ten (88%) cases were MDR plus resistant to one more first line drug. Forty (07%) isolates were MDR plus Quinolone-resistant. They were sensitive to Capreomycin but sensitivity against Amikacin and Kanamycin were not tested. Conclusion: There were high resistance rates in MDR-TB to remaining first line and second line drugs. Continuous monitoring of drug resistance pattern especially of MDR isolates and treatment in specialized centers is a crucial need for future TB control in Pakistan. (author)

  13. Phorbol esters induce multidrug resistance in human breast cancer cells

    International Nuclear Information System (INIS)

    Mechanisms responsible for broad-based resistance to antitumor drugs derived from natural products (multidrug resistance) are incompletely understood. Agents known to reverse the multidrug-resistant phenotype (verapamil and trifluoperazine) can also inhibit the activity of protein kinase C. When the authors assayed human breast cancer cell lines for protein kinase C activity, they found that enzyme activity was 7-fold higher in the multidrug-resistance cancer cells compared with the control, sensitive parent cells. Exposure of drug-sensitive cells to the phorbol ester phorbol 12,13-dibutyate [P(BtO)2] led to an increase in protein kinase C activity and induced a drug-resistance phenotype, whereas exposure of drug-resistant cells to P(BtO)2 further increased drug resistance. In sensitive cells, this increased resistance was accomplished by a 3.5-fold increased phosphorylation of a 20-kDa particulate protein and a 35-40% decreased intracellular accumulation of doxorubicin and vincristine. P(BtO)2 induced resistance to agents involved in the multidrug-resistant phenotype (doxorubicin and vincristine) but did not affect sensitivity to an unrelated alkylating agent (melphalan). The increased resistance was partially or fully reversible by the calcium channel blocker verapamil and by the calmodulin-antagonist trifluoperazine. These data suggest that stimulation of protein kinase C playus a role in the drug-transport changes in multidrug-resistant cells. This may occur through modulation of an efflux pump by protein phosphorylation

  14. Relation of the Allelic Variants of Multidrug Resistance Gene to Agranulocytosis Associated With Clozapine.

    Science.gov (United States)

    Anil Yağcioğlu, A Elif; Yoca, Gökhan; Ayhan, Yavuz; Karaca, R Özgür; Çevik, Lokman; Müderrisoğlu, Ahmet; Göktaş, Mustafa T; Eni, Nurhayat; Yazici, M Kâzim; Bozkurt, Atilla; Babaoğlu, Melih O

    2016-06-01

    Clozapine use is associated with leukopenia and more rarely agranulocytosis, which may be lethal. The drug and its metabolites are proposed to interact with the multidrug resistance transporter (ABCB1/MDR1) gene product, P-glycoprotein (P-gp). Among various P-glycoprotein genetic polymorphisms, nucleotide changes in exons 26 (C3435T), 21 (G2677T), and 12 (C1236T) have been implicated for changes in pharmacokinetics and pharmacodynamics of many substrate drugs. In this study, we aimed to investigate the association between these specific ABCB1 polymorphisms and clozapine-associated agranulocytosis (CAA). Ten patients with a history of CAA and 91 control patients without a history of CAA, despite 10 years of continuous clozapine use, were included. Patient recruitment and blood sample collection were conducted at the Hacettepe University Faculty of Medicine, Department of Psychiatry, in collaboration with the members of the Schizophrenia and Other Psychotic Disorders Section of the Psychiatric Association of Turkey, working in various psychiatry clinics. After DNA extraction from peripheral blood lymphocytes, genotyping was performed using polymerase chain reaction and endonuclease digestion. Patients with CAA had shorter duration of clozapine use but did not show any significant difference in other clinical, sociodemographic characteristics and in genotypic or allelic distributions of ABCB1 variants and haplotypes compared with control patients. Among the 10 patients with CAA, none carried the ABCB1 all-variant haplotype (TT-TT-TT), whereas the frequency of this haplotype was approximately 12% among the controls. Larger sample size studies and thorough genetic analyses may reveal both genetic risk and protective factors for this serious adverse event. PMID:27043126

  15. Multidrug resistant yeasts in synanthropic wild birds

    Directory of Open Access Journals (Sweden)

    Somanath Sushela

    2010-03-01

    Full Text Available Abstract Background The aim of this study was to investigate the presence of multidrug resistant yeasts in the faeces of synanthropic wild birds from the Bangsar suburb of Kuala Lumpur. Methods Species characterisations of yeast isolates and determinations of antimycotic susceptibility profiles were undertaken using the commercial characterization kit, Integral System Yeasts Plus (Liofilchem, Italy. Results Fourteen species of yeasts were detected in the bird faecal samples.Candida albicans was present in 28.89% of bird faecal samples, Candida krusei (13.33%, Candida tropicalis (4.44%, Candida glabrata (4.44%, Candida parapsilosis (2.22%, Candida lambica (2.22%, Candida stellatoidea (2.22%, Candida rugosa (2.22% and Candida lusitaniae (2.22%. Amongst the non-candidal yeast isolates, Cryptococcus laurentii was present in 6.67% of bird faecal samples, Cryptococcus uniguttulatus (4.44%, Saccharomyces cerevisiae (4.44%, Trichosporon pullulans (2.22%, Trichosporon pullulans/Cryptococcus albidus (8.89% and Rhodotorula rubra/Rhodotorula glutinis (4.44%. Of the isolated yeasts, 18.1% (or 26/144 were found to be resistant to all 11 antimycotic agents they were tested against i.e. Nystatin, Amphotericin B, Flucytosine, Econazole, Ketoconazole, Clotrimazole, Miconazole, Itraconazole, Voriconazole, Fluconazole 16 and Fluconazole 64. 45.8% (or 66/144 of the bird faecal yeast isolates were resistant to four or more of the 11 antimycotic agents they were tested against. Conclusions This finding is of public health significance as these synanthropic wild birds may be reservoirs for transmission of drug resistant yeast infections to humans.

  16. Inhibition of ABC transporters associated with multidrug resistance

    OpenAIRE

    Egger, Michael

    2010-01-01

    The first part of this dissertation (chapters 1 and 2) deals with the inhibition of the ABC transporters ABCB1 (p-glycoprotein) and ABCG2 (breast cancer resistance protein). Less lipophilic and better water soluble analogues of the known ABCB1 inhibitor tariquidar were synthesized from one central building block via Cu(I)-catalyzed N/O-arylation reactions. These compounds were tested for their inhibitory activity against the ABCB1 transporter in a flow cytometric calcein-AM efflux assay and a...

  17. The imaging feature of multidrug-resistant tuberculosis

    International Nuclear Information System (INIS)

    Objective: To evaluate the imaging features of multidrug-resistant tuberculosis by collecting multidrug-resistant tuberculosis verified by test of drug-sensitivity, which defined as resistance to three anti-tuberculosis drugs. Methods:Fifty-one cases of multidrug-resistant tuberculosis were categorized as group of observed, and 46 cases of drug sensitive tuberculosis were categorized as control. Cultures were positive for Mycobacterium tuberculosis in all cases with no other illness such as diabetes mellitus. All patients had chest radiographs available for review, while 64 cases had tomography and 30 cases had CT during the same time. All images were analyzed by three of the radiologists, disagreement among them was discussed and a consensus was reached. Results: There was no difference in the distribution of lesions between the multidrug-resistant tuberculosis group and control group. However, the radiological findings in the multidrug-resistant tuberculosis group were significantly more common than in control group, such as multiple nodules (10 cases), disseminated foci (23 cases), cavity (9 cases), and complications (10 cases). Comparing the dynamic cases, deteriorating cases were more commonly seen in observed group than in control group, while improved cases were less in observed group than in control group. Conclusion: Multidrug-resistant tuberculosis is the most serious tuberculosis, which is characterized with significant activity, more disseminated foci, cavity, and complications. The lesion deteriorated while correct anti-tuberculosis treatment is applied. (authors)

  18. HIF-1 activation induces doxorubicin resistance in MCF7 3-D spheroids via P-glycoprotein expression: a potential model of the chemo-resistance of invasive micropapillary carcinoma of the breast

    International Nuclear Information System (INIS)

    Invasive micropapillary carcinoma (IMPC) of the breast is a distinct and aggressive variant of luminal type B breast cancer that does not respond to neoadjuvant chemotherapy. It is characterized by small pseudopapillary clusters of cancer cells with inverted cell polarity. To investigate whether hypoxia-inducible factor-1 (HIF-1) activation may be related to the drug resistance described in this tumor, we used MCF7 cancer cells cultured as 3-D spheroids, which morphologically simulate IMPC cell clusters. HIF-1 activation was measured by EMSA and ELISA in MCF7 3-D spheroids and MCF7 monolayers. Binding of HIF-1α to MDR-1 gene promoter and modulation of P-glycoprotein (Pgp) expression was evaluated by ChIP assay and FACS analysis, respectively. Intracellular doxorubicin retention was measured by spectrofluorimetric assay and drug cytotoxicity by annexin V-FITC measurement and caspase activity assay. In MCF7 3-D spheroids HIF-1 was activated and recruited to participate to the transcriptional activity of MDR-1 gene, coding for Pgp. In addition, Pgp expression on the surface of cells obtained from 3-D spheroids was increased. MCF7 3-D spheroids accumulate less doxorubicin and are less sensitive to its cytotoxic effects than MCF7 cells cultured as monolayer. Finally, HIF-1α inhibition either by incubating cells with 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (a widely used HIF-1α inhibitor) or by transfecting cells with specific siRNA for HIF-1α significantly decreased the expression of Pgp on the surface of cells and increased the intracellular doxorubicin accumulation in MCF7 3-D spheroids. MCF7 breast cancer cells cultured as 3-D spheroids are resistant to doxorubicin and this resistance is associated with an increased Pgp expression in the plasma membrane via activation of HIF-1. The same mechanism may be suggested for IMPC drug resistance

  19. Bypassing multidrug resistance in human breast cancer cells with lipid/polymer particle assemblies

    Directory of Open Access Journals (Sweden)

    Li B

    2012-01-01

    Full Text Available Bo Li1, Hui Xu2, Zhen Li1, Mingfei Yao1, Meng Xie1, Haijun Shen1, Song Shen1, Xinshi Wang1, Yi Jin11College of Pharmaceutical sciences, Zhejiang University, Hangzhou, 2No. 202 Hospital of People's Liberation Army, Shenyang, ChinaBackground: Multidrug resistance (MDR mediated by the overexpression of adenosine triphosphate (ATP-binding cassette (ABC transporters, such as P-glycoprotein (P-gp, remains one of the major obstacles to effective cancer chemotherapy. In this study, lipid/particle assemblies named LipoParticles (LNPs, consisting of a dimethyldidodecylammonium bromide (DMAB-modified poly(lactic-co-glycolic acid (PLGA nanoparticle core surrounded by a 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC shell, were specially designed for anticancer drugs to bypass MDR in human breast cancer cells that overexpress P-gp.Methods: Doxorubicin (DOX, a chemotherapy drug that is a P-gp substrate, was conjugated to PLGA and encapsulated in the self-assembled LNP structure. Physiochemical properties of the DOX-loaded LNPs were characterized in vitro. Cellular uptake, intracellular accumulation, and cytotoxicity were compared in parental Michigan Cancer Foundation (MCF-7 cells and P-gp-overexpressing, resistant MCF-7/adriamycin (MCF-7/ADR cells.Results: This study found that the DOX formulated in LNPs showed a significantly increased accumulation in the nuclei of drug-resistant cells relative to the free drug, indicating that LNPs could alter intracellular traffic and bypass drug efflux. The cytotoxicity of DOX loaded-LNPs had a 30-fold lower half maximal inhibitory concentration (IC50 value than free DOX in MCF-7/ADR, measured by the colorimetric cell viability (MTT assay, correlated with the strong nuclear retention of the drug.Conclusion: The results show that this core-shell lipid/particle structure could be a promising strategy to bypass MDR.Keywords: chemotherapy, drug delivery, polymeric nanoparticles, multidrug resistance

  20. Co-delivery of Se nanoparticles and pooled SiRNAs for overcoming drug resistance mediated by P-glycoprotein and class III ?-tubulin in drug-resistant breast cancers.

    Science.gov (United States)

    Zheng, Wenjing; Yin, Tiantian; Chen, Qingchang; Qin, Xiuying; Huang, Xiaoquan; Zhao, Shuang; Xu, Taoyuan; Chen, Lanmei; Liu, Jie

    2016-02-01

    Drug resistance mediated by P-glycoprotein (P-gp) and class III ?-tubulin (?-tubulin III) is a major barrier in microtubule-targeting cancer chemotherapy. In this study, layered double hydroxide nanoparticles (LDHs) were employed to simultaneously deliver selenium (Se) and pooled small interfering RNAs (siRNAs) to achieve therapeutic efficacy. LDH-supported Se nanoparticles (Se@LDH) were compacted with siRNAs (anti-P-gp and anti-?-tubulin III) via electrostatic interactions, which could protect siRNA from degradation. Se@LDH showed excellent abilities to deliver siRNA into cells, including enhancing siRNA internalization, and promoting siRNA escape from endosomes. siRNA transfection experiments further confirmed a higher gene silencing efficiency of Se@LDH than LDH. Interestingly, we found Se@LDH may be a microtubule (MT) stabilizing agent which could inhibit cell proliferation by blocking cell cycle at G2/M phase, disrupting normal mitotic spindle formation and inducing cell apoptosis. When complexed with different specific siRNAs, Se@LDH/siRNA nanoparticles, especially the Se@LDH-pooled siRNAs, exhibit an efficient gene-silencing effect that significantly downregulate the expression of P-gp and ?-tubulin III. Moreover, Se@LDH-pooled siRNAs could induce cell apoptosis, change cell morphology and increase cellular ROS levels through change the expression of Bcl-2/Bax, activation of caspase-3, PI3K/AKT/mTOR and MAPK/ERK pathways. These results suggested that co-delivery of Se and pooled siRNAs may be a promising strategy for overcoming the drug resistance mediated by P-gp and ?-tubulin III in drug-resistant breast cancers. PMID:26612416

  1. Novel understanding of ABC transporters ABCB1/MDR/P-glycoprotein, ABCC2/MRP2, and ABCG2/BCRP in colorectal pathophysiology

    DEFF Research Database (Denmark)

    Andersen, Vibeke; Svenningsen, Katrine; Almind Knudsen, Lina; Hansen, Axel Kornerup; Holmskov, Uffe; Stensballe, Allan; Vogel, Ulla

    2015-01-01

    transporter proteins, inflammatory bowel disease, ulcerative, colitis, Crohns disease, colorectal cancer, colitis, intestinal inflammation, intestinal carcinogenesis, ABCB1/P-glycoprotein (P-gp/CD243/MDR1), ABCC2/multidrug resistance protein 2 (MRP2) and ABCG2/breast cancer resistance protein (BCRP), Abcb1....../Mdr1a, abcc2/Mrp2, abcg2/Bcrp, knock-out mice, tight junction, membrane lipid function. RESULTS: Recently, human studies reported that changes in the levels of ABC transporters were early events in the adenoma-carcinoma sequence leading to CRC. A link between ABCB1, high fat diet and gut microbes in...

  2. Biosynthesis of heterogeneous forms of multidrug resistance-associated glycoproteins.

    Science.gov (United States)

    Greenberger, L M; Williams, S S; Horwitz, S B

    1987-10-01

    Multidrug-resistant J774.2 mouse macrophage-like cells, selected for resistance to colchicine, vinblastine, or taxol, overexpress antigenically related glycoproteins with distinct electrophoretic mobilities. These plasma membrane glycoproteins are likely to play a pivotal role in the expression of the multidrug resistance phenotype. To determine how these multidrug resistance-associated glycoproteins differ, the biosynthesis and N-linked carbohydrate composition of these proteins were examined and compared. Vinblastineor colchicine-selected cells made a 125-kDa precursor that was rapidly processed (t1/2 approximately equal to 20 min) to mature forms of 135 and 140 kDa, respectively. Heterogeneity between the 135- and 140-kDa forms of the molecule can be attributed to N-linked carbohydrate. In contrast, taxol-selected cells made two precursors, 125 and 120 kDa, which appeared within 5 and 15 min after the onset of pulse labeling, respectively. They were processed to mature forms of 140 and 130 kDa. Since a single deglycosylated precursor or mature form was not observed after enzymatic removal of N-linked oligosaccharides, other differences, besides N-linked glycosylation, which occur in early processing compartments, are likely to account for the two multidrug resistance-associated glycoproteins in taxol-selected cells. These results demonstrate that a family of multidrug resistance-associated glycoproteins can be differentially expressed. PMID:2888763

  3. p-Glycoprotein ABCB5 and YB-1 expression plays a role in increased heterogeneity of breast cancer cells: correlations with cell fusion and doxorubicin resistance

    International Nuclear Information System (INIS)

    Cancer cells recurrently develop into acquired resistance to the administered drugs. The iatrogenic mechanisms of induced chemotherapy-resistance remain elusive and the degree of drug resistance did not exclusively correlate with reductions of drug accumulation, suggesting that drug resistance may involve additional mechanisms. Our aim is to define the potential targets, that makes drug-sensitive MCF-7 breast cancer cells turn to drug-resistant, for the anti-cancer drug development against drug resistant breast cancer cells. Doxorubicin resistant human breast MCF-7 clones were generated. The doxorubicin-induced cell fusion events were examined. Heterokaryons were identified and sorted by FACS. In the development of doxorubicin resistance, cell-fusion associated genes, from the previous results of microarray, were verified using dot blot array and quantitative RT-PCR. The doxorubicin-induced expression patterns of pro-survival and pro-apoptotic genes were validated. YB-1 and ABCB5 were up regulated in the doxorubicin treated MCF-7 cells that resulted in certain degree of genomic instability that accompanied by the drug resistance phenotype. Cell fusion increased diversity within the cell population and doxorubicin resistant MCF-7 cells emerged probably through clonal selection. Most of the drug resistant hybrid cells were anchorage independent. But some of the anchorage dependent MCF-7 cells exhibited several unique morphological appearances suggesting minor population of the fused cells maybe de-differentiated and have progenitor cell like characteristics. Our work provides valuable insight into the drug induced cell fusion event and outcome, and suggests YB-1, GST, ABCB5 and ERK3 could be potential targets for the anti-cancer drug development against drug resistant breast cancer cells. Especially, the ERK-3 serine/threonine kinase is specifically up-regulated in the resistant cells and known to be susceptible to synthetic antagonists

  4. p-Glycoprotein ABCB5 and YB-1 expression plays a role in increased heterogeneity of breast cancer cells: correlations with cell fusion and doxorubicin resistance

    Directory of Open Access Journals (Sweden)

    Yang Yun-Sik

    2010-07-01

    Full Text Available Abstract Background Cancer cells recurrently develop into acquired resistance to the administered drugs. The iatrogenic mechanisms of induced chemotherapy-resistance remain elusive and the degree of drug resistance did not exclusively correlate with reductions of drug accumulation, suggesting that drug resistance may involve additional mechanisms. Our aim is to define the potential targets, that makes drug-sensitive MCF-7 breast cancer cells turn to drug-resistant, for the anti-cancer drug development against drug resistant breast cancer cells. Methods Doxorubicin resistant human breast MCF-7 clones were generated. The doxorubicin-induced cell fusion events were examined. Heterokaryons were identified and sorted by FACS. In the development of doxorubicin resistance, cell-fusion associated genes, from the previous results of microarray, were verified using dot blot array and quantitative RT-PCR. The doxorubicin-induced expression patterns of pro-survival and pro-apoptotic genes were validated. Results YB-1 and ABCB5 were up regulated in the doxorubicin treated MCF-7 cells that resulted in certain degree of genomic instability that accompanied by the drug resistance phenotype. Cell fusion increased diversity within the cell population and doxorubicin resistant MCF-7 cells emerged probably through clonal selection. Most of the drug resistant hybrid cells were anchorage independent. But some of the anchorage dependent MCF-7 cells exhibited several unique morphological appearances suggesting minor population of the fused cells maybe de-differentiated and have progenitor cell like characteristics. Conclusion Our work provides valuable insight into the drug induced cell fusion event and outcome, and suggests YB-1, GST, ABCB5 and ERK3 could be potential targets for the anti-cancer drug development against drug resistant breast cancer cells. Especially, the ERK-3 serine/threonine kinase is specifically up-regulated in the resistant cells and known to be susceptible to synthetic antagonists.

  5. Multi-drug resistance 1 genetic polymorphism and prediction of chemotherapy response in Hodgkin's Lymphoma

    Directory of Open Access Journals (Sweden)

    Haddadin William J

    2011-07-01

    Full Text Available Abstract Background The human multi-drug resistance gene (MDR1, which encodes the major trans-membrane transporter P-glycoprotein (P-gp, was found to be associated with susceptibility to cancer and response to chemotherapy. The C3435T Polymorphism of MDR1 gene was correlated with expression levels and functions of P-gp. Here, we studied the association between MDR1 C3435T polymorphism and susceptibility to Hodgkin lymphoma (HL and patient's response to ABVD chemotherapy regimen. Methods a total of 130 paraffin embedded tissue samples collected from HL patients were analyzed to identify the C3435T polymorphism. As a control group, 120 healthy subjects were enrolled in the study. The C3435T Polymorphism was genotyped by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP method. Data analysis was carried out using the statistical package SPSS version 17 to compute all descriptive statistics. Chi-square and Fisher exact tests were used to evaluate the genotype distribution and allele frequencies of the studied polymorphism. Results these studies revealed that the frequency of T allele was significantly higher in HL patients compared to the controls (P 0.05. Conclusions these results suggest that MDR1 C3435T polymorphism might play a role in HL occurrence; however this polymorphism is not correlated with the clinical response to ABVD.

  6. Modulation of multidrug resistance 1 expression and function in retinoblastoma cells by curcumin

    Directory of Open Access Journals (Sweden)

    Seethalakshmi Sreenivasan

    2013-01-01

    Full Text Available Objective: To determine the possible interaction of curcumin with P-glycoprotein (P-gp expression and function by in vitro and in silico studies. Materials and Methods: In this study, curcumin was compared for its potential to modulate the expression and function of P-gp in Y79 RB cells by western blot, RT-PCR (reverse transcription polymerase chain reaction and functional assay. Further, in silico molecular modeling and docking simulations were performed to deduce the inhibitory binding mode of curcumin. Results: Western blot and RT-PCR analysis decreased the expression of P-gp in a dose-dependent manner. The effect of curcumin on P-gp function was demonstrated by Rhodamine 123 (Rh123 accumulation and efflux study. Curcumin increased the accumulation of Rh123 and decreased its efflux in retinoblastoma (RB cells. In addition, curcumin inhibited verapamil stimulated ATPase activity and photoaffinity labeling study showed no effect on the binding of 8-azido-ATP-biotin, indicating its interaction at the substrate binding site. Moreover, molecular docking studies concurrently infer the binding of curcumin into the substrate binding site of P-gp with a binding energy of -7.66 kcal/mol. Conclusion: These findings indicate that curcumin suppresses the MDR1 expression and function, and therefore may be useful as modulators of multidrug resistance in RB tumor.

  7. Multidrug resistance 1 gene polymorphism in amlodipine-induced gingival enlargement

    Science.gov (United States)

    Naik, Kumaraswamy Naik Lambani Rama; Jhajharia, Kapil; Chaudhary, Roopam; Tatikonda, Aravind; Dhaliwal, Aprinderpal Singh; Kaur, Rose Kanwaljeet

    2015-01-01

    Gingival enlargement comprises any clinical condition in which an increase in the size of the gingiva is observed. It is a side effect associated with some distinct classes of drugs, such as anticonvulsants, immunosuppressant, and calcium channel blockers. Among calcium channel blockers, nifedipine causes gingival enlargement in about 10% of patients, whereas the incidence of amlodipine, a third-generation calcium channel blocker, induced gingival enlargement is very limited. Because the calcium antagonists, albeit to a variable degree, act as inhibitors of P-glycoprotein (P-gp), the gene product of multidrug resistance 1 (MDR1), and inflammation may modify P-gp expression. We hereby, report a case of amlodipine-induced gingival enlargement with MDR1 3435C/T polymorphism, associated with inflammatory changes due to plaque accumulation, in a 50-year-old hypertensive male patient. The genotype obtained for the polymorphism was a heteromutant genotype, thus supporting the contention that the MDR1 polymorphism may alter the inflammatory response to the drug. PMID:26015682

  8. Multidrug-resistant tuberculosis that required 2 years for diagnosis

    OpenAIRE

    Yano, Shuichi; Kobayashi, Kanako; Ikeda, Toshikazu

    2012-01-01

    Isoniazid (H) or rifampicin (R) mono-resistant disease can be treated easily and effectively with first-line drugs, while combined H and R resistance (ie, multidrug-resistant tuberculosis (MDRTB)) requires treatment with at least four agents, including a quinolone and an injectable agent. Drug-resistant Mycobacterium tuberculosis strains are reported to be extremely difficult to cultivate invitro. The authors report a case of MDRTB that required 2 years for diagnosis, and was detected only in...

  9. Multidrug resistant to extensively drug resistant tuberculosis: What is next?

    Indian Academy of Sciences (India)

    Amita Jain; Pratima Dixit

    2008-11-01

    Drug resistant tuberculosis is a man made problem. While tuberculosis is hundred percent curable, multidrug resistant tuberculosis (MDR-TB) is difficult to treat. Inadequate and incomplete treatment and poor treatment adherence has led to a newer form of drug resistance known as extensively drug resistant tuberculosis (XDR-TB). XDR-TB is defined as tuberculosis caused by Mycobacterium tuberculosis strain, which is resistant to at least rifampicin and isoniazid among the first line anti tubercular drugs (MDR-TB) in addition to resistance to any fluroquinolones and at least one of three injectable second line anti tubercular drugs i.e. amikacin, kanamycin and/or capreomycin. Mismanagement of tuberculosis paves the way to drug resistant tuberculosis. Emergence of XDR-TB is reported world wide. Reported prevalence rates of XDR-TB of total MDR cases are; 6.6% overall worldwide, 6.5% in industrialized countries, 13.6% in Russia and Eastern Europe, 1.5% in Asia, 0.6% in Africa and Middle East and 15.4% in Republic of Korea. Better management and control of tuberculosis specially drug resistant TB by experienced and qualified doctors, access to standard microbiology laboratory, co-morbitidy of HIV and tuberculosis, new anti-TB drug regimens, better diagnostic tests, international standards for second line drugs (SLD)-susceptibility testing, invention of newer anti-tubercular molecules and vaccines and knowing the real magnitude of XDR-TB are some of the important issues to be addressed for effective prevention and management of XDR-TB.

  10. Design, synthesis and biological evaluation of (S)-valine thiazole-derived cyclic and non-cyclic peptidomimetic oligomers as modulators of human P-glycoprotein (ABCB1)

    OpenAIRE

    Singh, Satyakam; Prasad, Nagarajan Rajendra; Kapoor, Khyati; Chufan, Eduardo E.; Patel, Bhargav A.; Ambudkar, Suresh V.; Talele, Tanaji T.

    2013-01-01

    Multidrug resistance (MDR) caused by ATP-binding cassette (ABC) transporter P-glycoprotein (P-gp) through extrusion of anticancer drugs from the cells is a major cause of failure to cancer chemotherapy. Previously, selenazole containing cyclic peptides were reported as P-gp inhibitors and these were also used for co-crystallization with mouse P-gp, which has 87% homology to human P-gp. It has been reported that human P-gp, can simultaneously accommodate 2-3 moderate size molecules at the drug...

  11. Determination of P-Glycoprotein Expression by Flow Cytometry in Hematological Malignancies

    Directory of Open Access Journals (Sweden)

    Berkay Saraymen

    2016-03-01

    Full Text Available Objective: Determination the expression of P-glycoprotein is especially problematic for normal tissues because immuno­logical methods are limited in terms of sensitivity. We aimed to determine the expression of P-glycoprotein and CD34 by flow cytometry, and to evaluate the level of expression of P-glycoprotein and CD34 with unresponsive to treatment in pa­tients diagnosed with hematologic malignancy. Methods: Our study included fifty patients diagnosed with acute myeloblastic leukemia and acute lymphoblastic leuke­mia, and twenty healthy controls who were admitted to Erci­yes University Hematology-Oncology Hospital. The suspend­ed cells from bone marrow samples of patients and the pe­ripheral blood samples of healthy people were marked with P-glycoprotein phycoerythrin and CD34 FITC or PerCP Cy 5.5; and then surface expression was measured by means of flow cytometry. Results: In 6 of 30 acute myeloblastic leukemia patients P-glycoprotein and CD34 expression, in 6 of 20 acute lympho­blastic leukemia patients P-glycoprotein, in 5 of them CD34 expression were determined. A significant relation between P-glycoprotein and CD34 expressions in acute myeloblas­tic leukemia and acute lymphoblastic leukemia bone marrow samples was reported. Conclusion: Our data indicate that flow cytometry is more reliable, precise and faster than molecular methods for mea­suring P-glycoprotein expression and suggests the pos­sibility of a significant relationship between P-glycoprotein and CD34 expressions in acute myeloblastic leukemia and acute lymphoblastic leukemia bone marrow samples. The blast cells expressing CD34 on their surface along with P-glycoprotein simultaneously show that multi drug resistance 1 gene is mostly active in immature cells.

  12. pH regulation in sensitive and multidrug resistant Ehrlich ascites tumor cells

    DEFF Research Database (Denmark)

    Litman, Thomas; Pedersen, S F; Kramhøft, B; Skovsgaard, T; Hoffmann, E K

    1998-01-01

    Maintenance and regulation of intracellular pH (pHi) was studied in wild-type Ehrlich ascites tumor cells (EHR2) and five progressively daunorubicin-resistant, P-glycoprotein (P-gp)-expressing strains, the maximally resistant of which is EHR2/1.3. Steady-state pHi was similar in cells expressing...

  13. Multidrug resistance proteins in tuberous sclerosis and refractory epilepsy.

    Science.gov (United States)

    Lazarowski, Alberto; Lubieniecki, Fabiana; Camarero, Sandra; Pomata, Hugo; Bartuluchi, Marcelo; Sevlever, Gustavo; Taratuto, Ana Lía

    2004-02-01

    Tuberous sclerosis is an autosomal dominant syndrome characterized by seizures that are refractory to medication in severely affected individuals. The mechanism involved in drug resistance in tuberous sclerosis is unknown. The proteins MDR-1 (multidrug resistance) and MRP-1 (multidrug resistance-associated protein-1) are linked to chemotherapy resistance in tumor cells. However, the relationship between refractoriness to antiepileptic drugs and MDR-1 or MRP-1 brain expression has been poorly studied. We have previously described a case of tuberous sclerosis with refractory epilepsy that expressed multidrug resistance gene (MDR-1) in tuber cells from epileptogenic brain lesion. In this retrospective study, we describe the expression of MDR-1 and MRP-1 in the epileptogenic cortical tubers of three pediatric patients with tuberous sclerosis and refractory epilepsy surgically treated. Monoclonal antibodies for MDR-1 and MRP-1 proteins were used for immunohistochemistry. In epileptogenic cortical tuber brain specimens, MDR-1 and MRP-1 proteins were strongly immunoreactive in abnormal balloon cells, dysplastic neurons, astrocytes, microglial cells, and some blood-brain vessels. A more extensive MDR-1 immunoreactivity was observed. These data suggest that refractory epilepsy phenotype in tuberous sclerosis can be associated with the expression of both multidrug resistance MDR-1 and MRP-1 transporters in epileptogenic cortical tubers. PMID:14984901

  14. Cytotoxicity of the Sesquiterpene Lactones Neoambrosin and Damsin from Ambrosia maritima Against Multidrug-Resistant Cancer Cells

    Science.gov (United States)

    Saeed, Mohamed; Jacob, Stefan; Sandjo, Louis P.; Sugimoto, Yoshikazu; Khalid, Hassan E.; Opatz, Till; Thines, Eckhard; Efferth, Thomas

    2015-01-01

    Multidrug resistance is a prevailing phenomenon leading to chemotherapy treatment failure in cancer patients. In the current study two known cytotoxic pseudoguaianolide sesquiterpene lactones; neoambrosin (1) and damsin (2) that circumvent MDR were identified. The two cytotoxic compounds were isolated using column chromatography, characterized using 1D and 2D NMR, MS, and compared with literature values. The isolated compounds were investigated for their cytotoxic potential using resazurin assays and thereafter confirmed with immunoblotting and in silico studies. MDR cells overexpressing ABC transporters (P-glycoprotein, BCRP, ABCB5) did not confer cross-resistance toward (1) and (2), indicating that these compounds are not appropriate substrates for any of the three ABC transporters analyzed. Resistance mechanisms investigated also included; the loss of the functions of the TP53 and the mutated EGFR. The HCT116 p53-/- cells were sensitive to 1 but resistant to 2. It was interesting to note that resistant cells transfected with oncogenic ?EGFR exhibited hypersensitivity CS toward (1) and (2) (degrees of resistances were 0.18 and 0.15 for (1) and (2), respectively). Immunoblotting and in silico analyses revealed that 1 and 2 silenced c-Src kinase activity. It was hypothesized that inhibition of c-Src kinase activity may explain CS in EGFR-transfected cells. In conclusion, the significant cytotoxicity of 1 and 2 against different drug-resistant tumor cell lines indicate that they may be promising candidates to treat refractory tumors. PMID:26617519

  15. Functional imaging of multidrug resistance gene expression in patients with recurrent tumor following definitive irradiation

    International Nuclear Information System (INIS)

    Purpose/Objective: Definitive irradiation remains the cornerstone of management for high-grade glial tumors. If failure occurs, then salvage chemotherapy regimens (eg. PCV) are often considered. Tl-201 brain SPECT is a well-established diagnostic method to assess the recurrent or residual viable tumor. Tc-99m-MIBI is a lipophilic, cationic agent and a transport substrate recognized by the multidrug resistance (MDR) P-glycoprotein. This study investigates the feasibility of imaging P-glycoprotein expression by dual isotope Tl-201 and Tc-MIBI scintigraphy and attempts to predict expression of the multidrug resistance gene (MDR) expression in patients with malignant glioma prior to chemotherapy. Material and Methods: Twenty-seven patients with malignant glioma were evaluated with sequential Tl-201 and Tc-MIBI brain SPECT for recurrent brain tumor. Seventeen patients (group 1) were treated with surgery, radiation therapy and chemotherapy. Ten (group 2) were treated with surgery and radiation therapy. There were 6 patients with anaplastic and 21 patients with glioblastoma, ages ranging from 29 to 74 years old (median age:41). Tumor uptake was visually graded by two interpreters and scored with respect to the degree of uptake to determine the concordance and discordance between two tracers. Brain SPECT findings were correlated with clinical follow-up, or a biopsy defined as recurrent or stable at the time of the brain SPECT. Results: Twenty-five of 27 patients showed recurrent brain tumor. Among these, five patients showed discordant findings: two patients had markedly positive thallium tumor uptake without Tc-MIBI uptake. Northern blotting of the resected tumor specimen depicted the expression of multidrug resistance gene. Both patients were proven to have glioblastoma. One patient was in group 1 and another patient was in group 2. Three patients showed partial discordance, namely thallium tumor uptake greater than Tc-MIBI uptake. Two patients were in group 1 and one was in group 2. Conclusion: Our study suggests that the absence of Tc-MIBI tumor uptake in the presence of Tl-201 tumor uptake indicates MDR gene expression in the recurrent brain tumor. The frequency of MDR occurred in 2 out of 9 patients with recurrent brain tumor without chemotherapy and in 3 of 17 patients treated with chemotherapy. The partial discordance finding in 3 out of 5 cases implies that MDR can express heterogenously (partially) within the tumor. Utilizing the dual isotope technique, Tl-201 and Tc-99m-MIBI brain SPECT, it may be feasible to monitor the MDR expression in-vivo and predict MDR gene expression in a patient with recurrent brain tumor before and during chemotherapy. Patients with MDR gene expression should be considered for alternative salvage strategies. (e.g. radiosurgery)

  16. Human ABCB1 (P-glycoprotein) and ABCG2 Mediate Resistance to BI 2536, a Potent and Selective Inhibitor of Polo-like Kinase 1

    OpenAIRE

    Wu, Chung-pu; Hsiao, Sung-Han; Sim, Hong-May; Luo, Shi-Yu; Tuo, Wei-Cherng; Cheng, Hsing-Wen; Li, Yan-Qing; Huang, Yang-Hui; Ambudkar, Suresh V.

    2013-01-01

    The overexpression of the serine/threonine specific polo-like kinase 1 (Plk1) has been detected in various types of cancer, and thus has fast become an attractive therapeutic target for cancer therapy. BI 2536 is the first selective inhibitor of Plk1 that inhibits cancer cell proliferation by promoting G2/M cell cycle arrest at nanomolar concentrations. Unfortunately, alike most chemotherapeutic agents, the development of acquired resistance to BI 2536 is prone to present a significant therap...

  17. Cost-Effectiveness of Treating Multidrug-Resistant Tuberculosis

    OpenAIRE

    Resch, Stephen C; Salomon, Joshua A.; Murray, Megan; Weinstein, Milton C

    2006-01-01

    Editors' Summary   Background. Tuberculosis (TB) remains one of the most entrenched diseases on the planet—an estimated one in three people worldwide are infected with Mycobacterium tuberculosis, which causes the disease. Although effective drugs exist, a major reason for the failure to stem the spread of TB lies in the rise of drug-resistant strains of the bacterium. Some strains are resistant to several drugs; patients with this sort of infection are said to have multidrug-resistant (MDR) T...

  18. Multidrug Resistant Shigella flexneri Infection Simulating Intestinal Intussusception

    Science.gov (United States)

    Sreenivasan, Srirangaraj; Kali, Arunava; Pradeep, Jothimani

    2016-01-01

    Shigella enteritis remains an important cause of mortality and morbidity in all age groups, in developing as well as developed countries. Owing to the emerging resistance to multiple antibiotics among Shigella spp., it has been recognized as a major global public health concern and warrants constant monitoring of its resistance pattern. We report a case of segmental ileitis caused by non.-ESBL producing multidrug resistant Shigella flexneri in an infant clinically mimicking intussusception, which was effectively treated by ceftriaxone. PMID:27013815

  19. Multidrug Resistant Shigella flexneri Infection Simulating Intestinal Intussusception.

    Science.gov (United States)

    Sreenivasan, Srirangaraj; Kali, Arunava; Pradeep, Jothimani

    2016-01-01

    Shigella enteritis remains an important cause of mortality and morbidity in all age groups, in developing as well as developed countries. Owing to the emerging resistance to multiple antibiotics among Shigella spp., it has been recognized as a major global public health concern and warrants constant monitoring of its resistance pattern. We report a case of segmental ileitis caused by non.-ESBL producing multidrug resistant Shigella flexneri in an infant clinically mimicking intussusception, which was effectively treated by ceftriaxone. PMID:27013815

  20. Polymorphisms in Plasmodium falciparum chloroquine resistance transporter and multidrug resistance 1 genes

    DEFF Research Database (Denmark)

    Venkatesan, Meera; Gadalla, Nahla B; Stepniewska, Kasia; Dahal, Prabin; Nsanzabana, Christian; Moriera, Clarissa; Price, Ric N; Mårtensson, Andreas; Rosenthal, Philip J; Dorsey, Grant; Sutherland, Colin J; Guérin, Philippe; Davis, Timothy M E; Ménard, Didier; Adam, Ishag; Ademowo, George; Arze, Cesar; Baliraine, Frederick N; Berens-Riha, Nicole; Björkman, Anders; Borrmann, Steffen; Checchi, Francesco; Desai, Meghna; Dhorda, Mehul; Djimdé, Abdoulaye A; El-Sayed, Badria B; Eshetu, Teferi; Eyase, Frederick; Falade, Catherine; Faucher, Jean-François; Fröberg, Gabrielle; Grivoyannis, Anastasia; Hamour, Sally; Houzé, Sandrine; Johnson, Jacob; Kamugisha, Erasmus; Kariuki, Simon; Kiechel, Jean-René; Kironde, Fred; Kofoed, Poul-Erik; LeBras, Jacques; Malmberg, Maja; Mwai, Leah; Ngasala, Billy; Nosten, Francois; Nsobya, Samuel L; Nzila, Alexis; Oguike, Mary; Otienoburu, Sabina Dahlström; Ogutu, Bernhards; Ouédraogo, Jean-Bosco; Piola, Patrice; Rombo, Lars; Schramm, Birgit; Somé, A Fabrice; Thwing, Julie; Ursing, Johan; Wong, Rina P M; Zeynudin, Ahmed; Zongo, Issaka; Plowe, Christopher V; Sibley, Carol Hopkins

    2014-01-01

    Adequate clinical and parasitologic cure by artemisinin combination therapies relies on the artemisinin component and the partner drug. Polymorphisms in the Plasmodium falciparum chloroquine resistance transporter (pfcrt) and P. falciparum multidrug resistance 1 (pfmdr1) genes are associated with...

  1. Intractable epilepsy and the P-glycoprotein hypothesis.

    Science.gov (United States)

    Wang, Guang-Xin; Wang, Da-Wei; Liu, Yong; Ma, Yan-Hui

    2016-05-01

    Epilepsy is a serious neurological disorder that affects more than 60 million people worldwide. Intractable epilepsy (IE) refers to approximately 20%-30% of epileptic patients who fail to achieve seizure control with antiepileptic drug (AED) treatment. Although the mechanisms underlying IE are not well understood, it has been hypothesized that multidrug transporters such as P-glycoprotein (P-gp) play a major role in drug efflux at the blood-brain barrier, and may be the underlying factor in the variable responses of patients to AEDs. The main goal of the present review is to show evidence from different areas that support the idea that the overexpression of P-gp is associated with IE. We discuss here evidence from animal studies, pharmacology, clinical cases and genetic studies. PMID:26000919

  2. Antimicrobial activity of peptidomimetics against multidrug-resistant Escherichia coli

    DEFF Research Database (Denmark)

    Jahnsen, Rasmus D; Frimodt-Møller, Niels; Franzyk, Henrik

    2012-01-01

    -lactamase-producing Escherichia coli was assessed by testing an array comprising different types of cationic peptidomimetics obtained by a general monomer-based solid-phase synthesis protocol. Most of the peptidomimetics possessed high to moderate activity toward multidrug-resistant E. coli as opposed to the corresponding...

  3. Infection by multidrug-resistant Elizabethkingia meningoseptica: case reports

    Directory of Open Access Journals (Sweden)

    Jailton Lobo da Costa Lima

    2014-12-01

    Full Text Available We report two cases of sepsis in critically ill patients in two tertiary care hospitals in Recife-PE, Brazil. The first case is an 87-year-old patient with chronic myeloid leukemia and sepsis; and the second case is a 93-year-old patient with prostate cancer and septic shock caused by multidrug-resistant (MDR Elizabethkingia meningoseptica.

  4. Multidrug-Resistant Acinetobacter baumannii in Veterinary Clinics, Germany

    OpenAIRE

    Zordan, Sabrina; Prenger-Berninghoff, Ellen; Weiss, Reinhard; van der Reijden, Tanny; van den Broek, Peterhans; Baljer, Georg; Dijkshoorn, Lenie

    2011-01-01

    An increase in prevalence of multidrug-resistant Acinetobacter spp. in hospitalized animals was observed at the Justus-Liebig-University (Germany). Genotypic analysis of 56 isolates during 2000–2008 showed 3 clusters that corresponded to European clones I–III. Results indicate spread of genotypically related strains within and among veterinary clinics in Germany.

  5. Molecular Surveillance for Multidrug-Resistant Plasmodium falciparum, Cambodia

    OpenAIRE

    Shah, Naman K; Alker, Alisa P.; Sem, Rithy; Susanti, Agustina Ika; Muth, Sinuon; Maguire, Jason D; Duong, Socheat; Ariey, Frederic; Meshnick, Steven R; Wongsrichanalai, Chansuda

    2008-01-01

    We conducted surveillance for multidrug-resistant Plasmodium falciparum in Cambodia during 20042006 by assessing molecular changes in pfmdr1. The high prevalence of isolates with multiple pfmdr1 copies found in western Cambodia near the Thai border, where artesunatemefloquine therapy failures occur, contrasts with isolates from eastern Cambodia, where this combination therapy remains highly effective.

  6. Multidrug-Resistant Escherichia fergusonii: a Case of Acute Cystitis▿

    OpenAIRE

    Savini, Vincenzo; Catavitello, Chiara; Talia, Marzia; Manna, Assunta; Pompetti, Franca; Favaro, Marco; Fontana, Carla; Febbo, Fabio; Balbinot, Andrea; Di Berardino, Fabio; Di Bonaventura, Giovanni; Di Zacomo, Silvia; Esattore, Francesca; D'Antonio, Domenico

    2008-01-01

    We report a case in which Escherichia fergusonii, an emerging pathogen in various types of infections, was associated with cystitis in a 52-year-old woman. The offending strain was found to be multidrug resistant. Despite in vitro activity, beta-lactam treatment failed because of a lack of patient compliance with therapy. The work confirms the pathogenic potential of E. fergusonii.

  7. Cell biological mechanisms of multidrug resistance in tumors.

    OpenAIRE

    Simon, S. M.; Schindler, M.

    1994-01-01

    Multidrug resistance (MDR) is a generic term for the variety of strategies tumor cells use to evade the cytotoxic effects of anticancer drugs. MDR is characterized by a decreased sensitivity of tumor cells not only to the drug employed for chemotherapy but also to a broad spectrum of drugs with neither obvious structural homology nor common targets. This pleiotropic resistance is one of the major obstacles to the successful treatment of tumors. MDR may result from structural or functional cha...

  8. Heteroresistance to Colistin in Multidrug-Resistant Acinetobacter baumannii

    OpenAIRE

    Li, Jian; Rayner, Craig R.; Roger L. Nation; Owen, Roxanne J.; Spelman, Denis; Tan, Kar Eng; Liolios, Lisa

    2006-01-01

    Multidrug-resistant Acinetobacter baumannii has emerged as a significant clinical problem worldwide and colistin is being used increasingly as “salvage” therapy. MICs of colistin against A. baumannii indicate its significant activity. However, resistance to colistin in A. baumannii has been reported recently. Clonotypes of 16 clinical A. baumannii isolates and ATCC 19606 were determined by pulsed-field gel electrophoresis (PFGE), and colistin MICs were measured. The time-kill kinetics of coli...

  9. Multidrug-Resistant Enterococci Lack CRISPR-cas

    OpenAIRE

    Palmer, Kelli L.; Gilmore, Michael S.

    2010-01-01

    Clustered, regularly interspaced short palindromic repeats (CRISPR) provide bacteria and archaea with sequence-specific, acquired defense against plasmids and phage. Because mobile elements constitute up to 25% of the genome of multidrug-resistant (MDR) enterococci, it was of interest to examine the codistribution of CRISPR and acquired antibiotic resistance in enterococcal lineages. A database was built from 16 Enterococcus faecalis draft genome sequences to identify commonalities and polymo...

  10. Carriage and transmission dynamics of multidrug-resistant Enterobacteriaceae

    OpenAIRE

    Haverkate, M.R.

    2015-01-01

    Antimicrobial-resistant bacteria cause big problems in health care. Infections with these bacteria are hard to treat and lead to high morbidity, mortality, and costs. In this PhD thesis, carriage and transmission dynamics of multidrug-resistant Enterobacteriaceae have been investigated in various settings. Mathematical models were used to derive estimates for these epidemiological traits. Mathematical modeling can support in the decision making and provide guidance to policymakers on how to m...

  11. Evaluation of the P-glycoprotein- and breast cancer resistance protein-mediated brain penetration of {sup 11}C-labeled topotecan using small-animal positron emission tomography

    Energy Technology Data Exchange (ETDEWEB)

    Yamasaki, Tomoteru; Fujinaga, Masayuki; Kawamura, Kazunori; Hatori, Akiko; Yui, Joji [Department of Molecular Probes, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555 (Japan); Nengaki, Nobuki; Ogawa, Masanao; Yoshida, Yuichiro [Department of Molecular Probes, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555 (Japan); SHI Accelerator Service, Ltd., Tokyo 141-8686 (Japan); Wakizaka, Hidekatsu [Department of Biophysics, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555 (Japan); Yanamoto, Kazuhiko [Division of Health Sciences, Graduate School of Medicine, Osaka University, Osaka 565-0871 (Japan); Fukumura, Toshimitsu [Department of Molecular Probes, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555 (Japan); Zhang Mingrong, E-mail: zhang@nirs.go.jp [Department of Molecular Probes, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555 (Japan)

    2011-07-15

    Introduction: Topotecan (TPT) is a camptothecin derivative and is an anticancer drug working as a topoisomerase-I-specific inhibitor. But TPT cannot penetrate through the blood-brain barrier. In this study, we synthesized a new positron emission tomography (PET) probe, [{sup 11}C]TPT, to evaluate the P-glycoprotein (Pgp)- and breast cancer resistance protein (BCRP)-mediated brain penetration of [{sup 11}C]TPT using small-animal PET. Methods: [{sup 11}C]TPT was synthesized by the reaction of a desmethyl precursor with [{sup 11}C]CH{sub 3}I. In vitro study using [{sup 11}C]TPT was carried out in MES-SA and doxorubicin-resistant MES-SA/Dx5 cells in the presence or absence of elacridar, a specific inhibitor for Pgp and BCRP. The biodistribution of [{sup 11}C]TPT was determined using small-animal PET and the dissection method in mice. Results: The transport of [{sup 11}C]TPT to the extracellular side was determined in MES-SA/Dx5 cells exhibiting the expressions of Pgp and BCRP at high levels. This transport was inhibited by coincubation with elacridar. In Mdr1a/b{sup -/-}Bcrp1{sup -/-} mice, PET results indicated that the brain uptake of [{sup 11}C]TPT was about two times higher than that in wild-type mice. Similarly, the brain penetration of [{sup 11}C]TPT in wild-type mice was increased by treatment with elacridar. The radioactivity in the brain of elacridar-treated mice was maintained at a certain level after the injection of [{sup 11}C]TPT, although the radioactivity in the blood decreased with time. Conclusions: We demonstrated the increase of brain penetration of [{sup 11}C]TPT by deficiency and inhibition of Pgp and BCRP functions using small-animal PET in mice.

  12. Differential effects of the organochlorine pesticide DDT and its metabolite p,p'-DDE on p-glycoprotein activity and expression

    International Nuclear Information System (INIS)

    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 p,p'-DDE to act as efflux modulators. Using a competitive intact cell assay based on the efflux of the fluorescent dye rhodamine 123, we found that DDT, but not p,p'-DDE, stimulated dye retention. Subsequent studies using verapamil as competitor suggested that DDT is a weak p-glycoprotein inhibitor. Further studies addressed the ability of DDT and p,p'-DDE to induce MDR1, the gene encoding p-glycoprotein. In HepG2 cells, we found that both compounds induced MDR1 by twofold to threefold. Similar results were observed in mouse liver after a single dose of p,p'-DDE, although some gender-specific induction differences were noted. By contrast, p,p'-DDE failed to induce MDR1 in HeLa cells, indicating some cell-specific effects for induction. Further expression studies demonstrated increased levels of the endoplasmic reticulum molecular chaperone, Bip, in response to DDT, but not p,p'-DDE. These results suggest that DDT, but not p,p'-DDE, induces an endoplasmic reticulum stress response

  13. [Investigation of extensive drug resistance in multidrug resistance tuberculosis isolates].

    Science.gov (United States)

    Bektre, Bayhan; Haznedaro?lu, Tuner; Baylan, Orhan; Ozyurt, Mustafa; Ozktk, Nuri; Satana, Dilek; Cavu?o?lu, Cengiz; Seber, Engin

    2013-01-01

    Increasing number of drug resistant tuberculosis (TB) cases, observed in recent years, is an important public health problem. Extensively drug resistant TB (XDR-TB) is the development of resistance against any fluoroquinolones and at least one of the injectable second line anti-TB drugs in addition to resistance against isoniazide and rifampicin which are the first line anti-TB drugs [definition of multidrug resistant TB (MDR-TB)]. Anti-TB therapy failed with first-line anti-TB drugs due to MDR-TB cases is being planned according to second-line anti-TB drug susceptibility test results if available and if not, standart treatment protocols are used. Although it is recommended that individual anti-TB therapy should be designed according to the isolate's susceptibility test results, standart therapeutic protocols are always needed since second-line anti-TB drug susceptibility testing generally could not be performed in developing countries like Turkey. For this reason, nationwide and regional surveillance studies to determine the resistance patterns are always needed to make decisions about the standard therapy algorithms. In this study, it was aimed to investigate the presence of extensive drug resistance among 81 MDR-TB isolates obtained from various health care facilities from Istanbul, Izmir and Manisa and to determine the XDR-TB incidence in Marmara and Aegean regions. Furthermore, we aimed to provide epidemiological data to clinicians to support their choice of second-line anti-TB drugs for MDR-TB infections. Susceptibility testing of isolates for the first and the second-line anti-TB drugs were performed by using modified Middlebrook 7H9 broth in fluorometric BACTEC MGIT 960 system (Becton Dickinson, USA). Eighty-one MDR-TB isolates included in this study were isolated from 43 (53.1%) patients residing in Istanbul, 26 (32.1%) in Izmir and 12 (14.8%) in Manisa provinces. We could not find any isolate consistent with XDR-TB definition in this study. Second-line drug resistance rates of MDR-TB isolates to amikacin and kanamycin were 1.2%, ofloxacin and levofloxacin were 2.5%, capreomycin was 14.8%, ethionamide was 37% whereas linezolid resistance was not detected. Statistically significant correlation was detected between resistance rates of these antibiotic pairs; levofloxacin-ofloxacin (p< 0.01), amikacin-kanamycin (p= 0.01) and streptomycin-ethionamide (p= 0.04). In our study, extensive drug resistance was not encountered in any MDR-TB isolates while high resistance rates was observed against ethionamide and capreomycin. It can be concluded that parenteral aminoglycosides amikasin and kanamycin, fluoroquinolones and linezolid seemed to be reliable anti-TB agents in MDR-TB treatment, however, further larger scale studies are needed. PMID:23390903

  14. P-Glycoprotein/MDR1 Regulates Pokemon Gene Transcription Through p53 Expression in Human Breast Cancer Cells

    Directory of Open Access Journals (Sweden)

    Wei Xu

    2010-08-01

    Full Text Available 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 that Pgp can bind the pokemon prompter to repress pokemon transcription activity. Furthermore, Pgp regulated pokemon transcription activity through expression of p53 as seen by use of p53 siRNA transfected MCF-7 cells or p53 mutated MDA-MB-231 cells. Moreover, p53 was detected to bind with Pgp in vivo using immunoprecipitation assay. Taken together, we conclude that Pgp can regulate the expression of pokemon through the presence of p53, suggesting that Pgp is a potent regulator and may offer an effective novel target for cancer therapy.

  15. P-Glycoprotein/MDR1 regulates pokemon gene transcription through p53 expression in human breast cancer cells.

    Science.gov (United States)

    He, Shengnan; Liu, Feng; Xie, Zhenhua; Zu, Xuyu; Xu, Wei; Jiang, Yuyang

    2010-01-01

    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 that Pgp can bind the pokemon prompter to repress pokemon transcription activity. Furthermore, Pgp regulated pokemon transcription activity through expression of p53 as seen by use of p53 siRNA transfected MCF-7 cells or p53 mutated MDA-MB-231 cells. Moreover, p53 was detected to bind with Pgp in vivo using immunoprecipitation assay. Taken together, we conclude that Pgp can regulate the expression of pokemon through the presence of p53, suggesting that Pgp is a potent regulator and may offer an effective novel target for cancer therapy. PMID:20957096

  16. The B-cell lymphoma 2 (BCL2)-inhibitors, ABT-737 and ABT-263, are substrates for P-glycoprotein

    International Nuclear Information System (INIS)

    Highlights: → The BCL2-inhibitor ABT-263 is a substrate for P-glycoprotein. → Apoptosis is inhibited by P-glycoprotein expression. → Overexpression of P-glycoprotein may contribute to resistance to ABT-263 or ABT-737. -- Abstract: Inhibition of BCL2 proteins is one of the most promising new approaches to targeted cancer therapy resulting in the induction of apoptosis. Amongst the most specific BCL2-inhibitors identified are ABT-737 and ABT-263. However, targeted therapy is often only effective for a limited amount of time because of the occurrence of drug resistance. In this study, the interaction of BCL2-inhibitors with the drug efflux transporter P-glycoprotein was investigated. Using 3H labelled ABT-263, we found that cells with high P-glycoprotein activity accumulated less drug. In addition, cells with increased P-glycoprotein expression were more resistant to apoptosis induced by either ABT-737 or ABT-263. Addition of tariquidar or verapamil sensitized the cells to BCL2-inhibitor treatment, resulting in higher apoptosis. Our data suggest that the BCL2-inhibitors ABT-737 and ABT-263 are substrates for P-glycoprotein. Over-expression of P-glycoprotein may be, at least partly, responsible for resistance to these BCL2-inhibitors.

  17. Effect of multidrug resistance modulators on the activity of ivermectin and moxidectin against selected strains of Haemonchus contortus infective larvae

    Directory of Open Access Journals (Sweden)

    Molento Marcelo B.

    2001-01-01

    Full Text Available Nematode parasites have shown resistance to the anthelmintics, ivermectin and moxidectin, and there is evidence that the over-expression of parasite P-glycoprotein (P-gp may account, at least in part, for resistance to ivermectin. The objective of this study was to evaluate whether the multidrug resistance (MDR modulators, verapamil, CL 347.099 (an analog of verapamil and cyclosporin A, would enhance the efficacy of ivermectin and moxidectin against selected strains of Haemonchus contortus using an in vitro larval migration assay. The modulators had no effects on the number of migrating larvae when used alone. Ivermectin and moxidectin showed a significant (P<0.05 increase in its efficacy by 52.8 and 58.5% respectively, when used in association with verapamil against a moxidectin-selected strain. CL 347,099 also increased significantly (P<0.05 the ivermectin and moxidectin efficacy by 24.2 and 40.0% respectively, against an ivermectin-selected strain and by 40.0 and 75.6% respectively, against an moxidectin-selected strain. At the concentrations tested cyclosporin A showed a variable effect on increasing the efficacy of the anthelmintics against the susceptible and resistant strains.

  18. P-glycoprotein inhibitors of natural origin as potential tumor chemo-sensitizers: A review

    Science.gov (United States)

    Abdallah, Hossam M.; Al-Abd, Ahmed M.; El-Dine, Riham Salah; El-Halawany, Ali M.

    2014-01-01

    Resistance of solid tumors to treatment is significantly attributed to pharmacokinetic reasons at both cellular and multi-cellular levels. Anticancer agent must be bio-available at the site of action in a cytotoxic concentration to exert its proposed activity. P-glycoprotein (P-gp) is a member of the ATP-dependent membrane transport proteins; it is known to pump substrates out of cells in ATP-dependent mechanism. The over-expression of P-gp in tumor cells reduces the intracellular drug concentrations, which decreases the cytotoxicity of a broad spectrum of antitumor drugs. Accordingly, P-gp inhibitors/blockers are potential enhancer for the cellular bioavailability of several clinically important anticancer drugs such as, anthracyclines, taxanes, vinca alkaloids, and podophyllotoxins. Besides several chemically synthesized P-gp inhibitors/blockers, some naturally occurring compounds and plant extracts were reported for their modulation of multidrug resistance; however, this review will focus only on major classes of naturally occurring inhibitors viz., flavonoids, coumarins, terpenoids, alkaloids and saponins. PMID:25685543

  19. Multidrug-Resistant Pseudomonas aeruginosa: Risk Factors and Clinical Impact†

    OpenAIRE

    Aloush, Valerie; Navon-Venezia, Shiri; Seigman-Igra, Yardena; Cabili, Shaltiel; Carmeli, Yehuda

    2006-01-01

    Pseudomonas aeruginosa, a leading nosocomial pathogen, may become multidrug resistant (MDR). Its rate of occurrence, the individual risk factors among affected patients, and the clinical impact of infection are undetermined. We conducted an epidemiologic evaluation and molecular typing using pulsed-field gel electrophoresis (PFGE) of 36 isolates for 82 patients with MDR P. aeruginosa and 82 controls matched by ward, length of hospital stay, and calendar time. A matched case-control study iden...

  20. Clonality of multidrug-resistant nontypeable strains of Haemophilus influenzae.

    OpenAIRE

    Fust, M C; Pineda, M. A.; Palomar, J.; M. Vias; Lorn, J G

    1996-01-01

    The genetic structure of a population of multidrug-resistant nontypeable (unencapsulated) Haemophilus influenzae strains isolated at a hospital in Barcelona, Spain, was investigated by using multilocus enzyme electrophoresis to determine the allelic variation in 15 structural loci. In our study we have also included some antimicrobial agent-susceptible strains isolated at the same hospital. All enzymes were polymorphic for two to eight electromorphs, and the analysis revealed 43 distinct elec...

  1. Combination therapy for multidrug-resistant cytomegalovirus disease.

    Science.gov (United States)

    Stuehler, C; Stssi, G; Halter, J; Nowakowska, J; Schibli, A; Battegay, M; Dirks, J; Passweg, J; Heim, D; Rovo, A; Kalberer, C; Bucher, C; Weisser, M; Dumoulin, A; Hirsch, H H; Khanna, N

    2015-10-01

    Multidrug-resistant (MDR) cytomegalovirus (CMV) emerged after transient responses to ganciclovir, foscarnet, and cidofovir in a CMV-seropositive recipient who underwent allogeneic hematopoietic stem cell transplantation from a CMV-seronegative donor. Experimental treatments using leflunomide and artesunate failed. Re-transplantation from a CMV-seropositive donor supported by adoptive transfer of pp65-specific T cells and maribavir was followed by lasting suppression. This case illustrates that successful MDR CMV therapy may require individualized multidisciplinary approaches. PMID:26432076

  2. Global dissemination of a multidrug resistant Escherichia coli clone

    OpenAIRE

    Petty, Nicola K; Ben Zakour, Nouri L; Stanton-Cook, Mitchell; Skippington, Elizabeth; Totsika, Makrina; Forde, Brian M.; Phan, Minh-Duy; Gomes Moriel, Danilo; Peters, Kate M; Davies, Mark; Rogers, Benjamin A.; Dougan, Gordon; Rodriguez-Baño, Jesús; Pascual, Alvaro; Pitout, Johann D.D.

    2014-01-01

    Escherichia coli sequence type 131 (ST131) is a globally disseminated multidrug-resistant clone associated with human urinary tract and bloodstream infections. Here, we have used genome sequencing to map the temporal and spatial relationship of a large collection of E. coli ST131 strains isolated from six distinct geographical regions across the world. We show that E. coli ST131 strains are distinct from other extraintestinal pathogenic E. coli and arose from a single progenitor strain prior ...

  3. Cost-Effectiveness of Treating Multidrug-Resistant Tuberculosis

    OpenAIRE

    Resch, Stephen C; Salomon, Joshua A.; Murray, Megan Blanche; Weinstein, Milton C

    2006-01-01

    Background: Despite the existence of effective drug treatments, tuberculosis (TB) causes 2 million deaths annually worldwide. Effective treatment is complicated by multidrug-resistant TB (MDR TB) strains that respond only to second-line drugs. We projected the health benefits and cost-effectiveness of using drug susceptibility testing and second-line drugs in a lower-middle-income setting with high levels of MDR TB. Methods and Findings: We developed a dynamic state-transition model of TB. In...

  4. Linezolid in multidrug-resistant tuberculosis

    OpenAIRE

    Bolhuis, Mathieu

    2015-01-01

    Tuberculose is een potentieel dodelijke infectieziekte die wordt veroorzaakt door de bacterie Mycobacterium tuberculosis. Een deel van de tuberculosepatiënten is besmet met multiresistente tuberculose. In het geval van multiresistente tuberculose is de bacterie resistent tegen de twee belangrijkste anti-tuberculosegeneesmiddelen rifampicine en isoniazide; sommige MDR-TB stammen zijn daarnaast ook nog resistent tegen andere antibiotica. Om multiresistente tuberculose te behandelen raadt de Wer...

  5. Antiviral Drug- and Multidrug Resistance in Cytomegalovirus Infected SCT Patients

    Directory of Open Access Journals (Sweden)

    Katharina Ghring

    2015-01-01

    Full Text Available In pediatric and adult patients after stem cell transplantation (SCT disseminated infections caused by human cytomegalovirus (HCMV can cause life threatening diseases. For treatment, the three antivirals ganciclovir (GCV, foscarnet (PFA and cidofovir (CDV are approved and most frequently used. Resistance to all of these antiviral drugs may induce a severe problem in this patient cohort. Responsible for resistance phenomena are mutations in the HCMV phosphotransferase-gene (UL97 and the polymerase-gene (UL54. Most frequently mutations in the UL97-gene are associated with resistance to GCV. Resistance against all three drugs is associated to mutations in the UL54-gene. Monitoring of drug resistance by genotyping is mostly done by PCR-based Sanger sequencing. For phenotyping with cell culture the isolation of HCMV is a prerequisite. The development of multidrug resistance with mutation in both genes is rare, but it is often associated with a fatal outcome. The manifestation of multidrug resistance is mostly associated with combined UL97/UL54-mutations. Normally, mutations in the UL97 gene occur initially followed by UL54 mutation after therapy switch. The appearance of UL54-mutation alone without any detection of UL97-mutation is rare. Interestingly, in a number of patients the UL97 mutation could be detected in specific compartments exclusively and not in blood.

  6. Antiviral Drug- and Multidrug Resistance in Cytomegalovirus Infected SCT Patients.

    Science.gov (United States)

    Ghring, Katharina; Hamprecht, Klaus; Jahn, Gerhard

    2015-01-01

    In pediatric and adult patients after stem cell transplantation (SCT) disseminated infections caused by human cytomegalovirus (HCMV) can cause life threatening diseases. For treatment, the three antivirals ganciclovir (GCV), foscarnet (PFA) and cidofovir (CDV) are approved and most frequently used. Resistance to all of these antiviral drugs may induce a severe problem in this patient cohort. Responsible for resistance phenomena are mutations in the HCMV phosphotransferase-gene (UL97) and the polymerase-gene (UL54). Most frequently mutations in the UL97-gene are associated with resistance to GCV. Resistance against all three drugs is associated to mutations in the UL54-gene. Monitoring of drug resistance by genotyping is mostly done by PCR-based Sanger sequencing. For phenotyping with cell culture the isolation of HCMV is a prerequisite. The development of multidrug resistance with mutation in both genes is rare, but it is often associated with a fatal outcome. The manifestation of multidrug resistance is mostly associated with combined UL97/UL54-mutations. Normally, mutations in the UL97 gene occur initially followed by UL54 mutation after therapy switch. The appearance of UL54-mutation alone without any detection of UL97-mutation is rare. Interestingly, in a number of patients the UL97 mutation could be detected in specific compartments exclusively and not in blood. PMID:25750703

  7. Biodegradable cationic polymeric nanocapsules for overcoming multidrug resistance and enabling drug-gene co-delivery to cancer cells

    Science.gov (United States)

    Chen, Chih-Kuang; Law, Wing-Cheung; Aalinkeel, Ravikumar; Yu, Yun; Nair, Bindukumar; Wu, Jincheng; Mahajan, Supriya; Reynolds, Jessica L.; Li, Yukun; Lai, Cheng Kee; Tzanakakis, Emmanuel S.; Schwartz, Stanley A.; Prasad, Paras N.; Cheng, Chong

    2014-01-01

    Having unique architectural features, cationic polymeric nanocapsules (NCs) with well-defined covalently stabilized biodegradable structures were generated as potentially universal and safe therapeutic nanocarriers. These NCs were synthesized from allyl-functionalized cationic polylactide (CPLA) by highly efficient UV-induced thiol-ene interfacial cross-linking in transparent miniemulsions. With tunable nanoscopic sizes, negligible cytotoxicity and remarkable degradability, they are able to encapsulate doxorubicin (Dox) with inner cavities and bind interleukin-8 (IL-8) small interfering RNA (siRNA) with cationic shells. The Dox-encapsulated NCs can effectively bypass the P-glycoprotein (Pgp)-mediated multidrug resistance of MCF7/ADR cancer cells, thereby resulting in increased intracellular drug concentration and reduced cell viability. In vitro studies also showed that the NCs loaded with Dox, IL-8 siRNA and both agents can be readily taken up by PC3 prostate cancer cells, resulting in a significant chemotherapeutic effect and/or IL-8 gene silencing.Having unique architectural features, cationic polymeric nanocapsules (NCs) with well-defined covalently stabilized biodegradable structures were generated as potentially universal and safe therapeutic nanocarriers. These NCs were synthesized from allyl-functionalized cationic polylactide (CPLA) by highly efficient UV-induced thiol-ene interfacial cross-linking in transparent miniemulsions. With tunable nanoscopic sizes, negligible cytotoxicity and remarkable degradability, they are able to encapsulate doxorubicin (Dox) with inner cavities and bind interleukin-8 (IL-8) small interfering RNA (siRNA) with cationic shells. The Dox-encapsulated NCs can effectively bypass the P-glycoprotein (Pgp)-mediated multidrug resistance of MCF7/ADR cancer cells, thereby resulting in increased intracellular drug concentration and reduced cell viability. In vitro studies also showed that the NCs loaded with Dox, IL-8 siRNA and both agents can be readily taken up by PC3 prostate cancer cells, resulting in a significant chemotherapeutic effect and/or IL-8 gene silencing. Electronic supplementary information (ESI) available: Experimental section and Fig. S1-S6. See DOI: 10.1039/c3nr04804g

  8. Importance of multidrug efflux pumps in the antimicrobial resistance property of clinical multidrug-resistant isolates of Neisseria gonorrhoeae.

    Science.gov (United States)

    Golparian, Daniel; Shafer, William M; Ohnishi, Makoto; Unemo, Magnus

    2014-06-01

    The contribution of drug efflux pumps in clinical isolates of Neisseria gonorrhoeae that express extensively drug-resistant or multidrug-resistant phenotypes has heretofore not been examined. Accordingly, we assessed the effect on antimicrobial resistance of loss of the three gonococcal efflux pumps associated with a known capacity to export antimicrobials (MtrC-MtrD-MtrE, MacA-MacB, and NorM) in such clinical isolates. We report that the MIC of several antimicrobials, including seven previously and currently recommended for treatment was significantly impacted. PMID:24733458

  9. Beyond multidrug-resistant tuberculosis in Europe: a TBNET study.

    Science.gov (United States)

    Gnther, G; van Leth, F; Altet, N; Dedicoat, M; Duarte, R; Gualano, G; Kunst, H; Muylle, I; Spinu, V; Tiberi, S; Viiklepp, P; Lange, C

    2015-12-01

    The emergence of drug-resistant tuberculosis (TB) is a challenge to TB control in Europe. We evaluated second-line drug susceptibility testing in Mycobacterium tuberculosis isolates from patients with multidrug-resistant, pre-extensively drug-resistant (pre-XDR-TB) and XDR-TB at 23 TBNET sites in 16 European countries. Over 30% of bacilli from patients with pre-XDR-TB showed resistance to any fluoroquinolone and almost 70% to any second-line injectable drug. Respectively >90% and >80% of the XDR-TB strains tested showed phenotypic resistance to pyrazinamide and ethambutol. Resistance to prothionamide/ethionamide was high in bacilli from pre-XDR-TB patients (43%) and XDR-TB patients (49%). PMID:26614196

  10. Clinical evaluation of multidrug resistance associated protein expression by FDG PET and MIBI SPECT in lung cancer

    International Nuclear Information System (INIS)

    Multidrug resistance is one of the major obstacles in the successful anticancer therapy. The aim of this study is to evaluate whether FDG PET and MIBI SPECT can be markers for p-glycoprotein (Pgp), multidrug resistance-associated protein (MRP), lung resistance protein (LRP) expression in lung cancer tissues. Eighty-eight patients with 92 lung cancer lesions were enrolled in this study. Before surgery, FDG PET imaging was performed 40 min after injection of FDG 185 MBq, and standardized uptake values (SUVs) were obtained. MIBI SPECT imaging was performed 15 min and 3 hour after injection of MIBI 370 MBq. Early ratio (ER), delayed ratio (DR), and washout rate (WR) were obtained. Pgp, MRP, and LRP expression in lung cancer tissues were determined by immunohistochemical staining. No significant correlations were observed between MIBI uptake and expression of Pgp, MRP and LRP. FDG uptake significantly correlated with expression of Pgp and LRP. The lung cancer with high degree of Pgp and LRP expression had significantly low FDG uptake. However, there is no correlation between FDG uptake and MRP expression. Pgp and LRP expression of adenocarcinomas were significantly higher than that of squamous cell carcinomas. FDG uptake of adenocarcinomas were significantly lower than that of squamous cell carcinomas. In lung adenocarcinomas, Pgp and LRP expression of bronchioloalveolar carcinomas were significantly higher than that of poorly differentiated adenocarcinomas. In contrast, FDG uptake of bronchioloalveolar carcinomas were significantly low when compared with that of poorly differentiated adenocarcinomas. In addition, it was also suggested that biological behavior of LRP expression was similar to that of Pgp expression. FDG uptake may be a marker for Pgp and LRP expression but not for MRP expression in patients with lung cancer. Both Pgp, LRP expression and FDG uptake correlate with cellular differentiation and histological type. (author)

  11. Anticancer Effects of the Nitric Oxide-Modified Saquinavir Derivative Saquinavir-NO against Multidrug-Resistant Cancer Cells

    Directory of Open Access Journals (Sweden)

    Florian Rothweiler

    2010-12-01

    Full Text Available The human immunodeficiency virus (HIV protease inhibitor saquinavir shows anticancer activity. Although its nitric oxide-modified derivative saquinavir-NO (saq-NO was less toxic to normal cells, it exerted stronger inhibition of B16 melanoma growth in syngeneic C57BL/6 mice than saquinavir did. Saq-NO has been shown to block proliferation, upregulate p53 expression, and promote differentiation of C6 glioma and B16 cells. The anticancer activity of substances is frequently hampered by cancer cell chemoresistance mechanisms. Therefore, we here investigated the roles of p53 and the ATP-binding cassette (ABC transporters P-glycoprotein (P-gp, multidrug resistance-associated protein 1 (MRP1, and breast cancer resistance protein 1 (BCRP1 in cancer cell sensitivity to saq-NO to get more information about the potential of saq-NO as anticancer drug. Saq-NO exerted anticancer effects in lower concentrations than saquinavir in a panel of human cancer cell lines. Neither p53 mutation or depletion nor expression of P-gp, MRP1, or BCRP1 affected anticancer activity of saq-NO or saquinavir. Moreover, saq-NO sensitized P-gp-, MRP1-, or BCRP1-expressing cancer cells to chemotherapy. Saq-NO induced enhanced sensitization of P-gp- or MRP1-expressing cancer cells to chemotherapy compared with saquinavir, whereas both substances similarly sensitized BCRP1-expressing cells. Washout kinetics and ABC transporter ATPase activities demonstrated that saq-NO is a substrate of P-gp as well as of MRP1. These data support the further investigation of saq-NO as an anticancer drug, especially in multidrug-resistant tumors.

  12. Tuberculosis Multidrogoresistente / Multidrug-resistant tuberculosis

    Scientific Electronic Library Online (English)

    German A, Acevedo; Agustn, Vega; Wellman, Ribn.

    2013-12-01

    Full Text Available La tuberculosis es una enfermedad infecciosa causada por el Mycobacterium tuberculosis. En el ao 2010 se registraron 8.8 millones de casos incidentes en el mundo y en los ltimos aos han aparecido poblaciones bacterianas de micobacterias con resistencia a los frmacos de primera lnea. Se ha defin [...] ido la presencia de resistencia a rifampicina e isoniacida como multidrogoresistencia, estimndose una incidencia mundial aproximada de 3.6%. Esta revisin de tema se centrar en la situacin de la tuberculosis multidrogoresistente en el mundo, incluyendo un anlisis regional de la casustica Colombiana. Se comentarn los principales mecanismos de resistencia del microorganismo, los genes implicados en la misma y los factores de riesgo asociados a la generacin de resistencia en algunas comunidades. Abstract in english Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis. In 2010, there were 8.8 million incident cases in the world, and, in recent years, populations of mycobacteria with resistance to first-line drugs have emerged. The resistance to rifampin and isoniazid has been defined as mu [...] ltidrugresistant tuberculosis (TB MDR). TB MDR has an incidence of approximately 3.6% in the world. This review will focus on the current stage TB MDR in the world, including a regional analysis of Colombian cases. It will discuss the mechanism of resistance of the microorganism, genes involved, and the risk factors associated with the generation of resistance in some communities

  13. Medical Treatment of Pulmonary Multidrug-Resistant Tuberculosis

    OpenAIRE

    Shim, Tae Sun; Jo, Kyung-Wook

    2013-01-01

    Treatment of multidrug-resistant tuberculosis (MDR-TB) is challenging because of the high toxicity of second-line drugs and the longer treatment duration required compared with drug-susceptible TB. The efficacy of treatment for MDR-TB is poorer than that for drug-susceptible TB. The selection of drugs in MDR-TB is based on previous treatment history, drug susceptibility results, and TB drug resistance patterns in the each region. Recent World Health Organization guidelines recommend the use o...

  14. New insight into p-glycoprotein as a drug target.

    Science.gov (United States)

    Breier, Albert; Gibalova, Lenka; Seres, Mario; Barancik, Miroslav; Sulova, Zdenka

    2013-01-01

    Multidrug resistance (MDR) of cancer tissue is a phenomenon in which cancer cells exhibit reduced sensitivity to a large group of unrelated drugs with different mechanisms of pharmacological activity. Mechanisms that reduce cell sensitivity to damage induced by a variety of chemicals were found to be caused by diverse, albeit well-defined, phenotypic alterations. The molecular basis of MDR commonly involves overexpression of the plasma membrane drug efflux pump - P-glycoprotein (P-gp). This glycoprotein is an ABCB1 member of the ABC transporter family. Cells that develop MDR of this type express massive amounts of P-gp that can induce a drug resistance of more than 100 times higher than normal cells to several drugs, which are substrates of P-gp. Expression of P-gp could be inherent to cancer cells with regard to the specialized tissues from which the cells originated. This is often designated as intrinsic Pgp- mediated MDR. However, overexpression of P-gp may be induced by selection and/or adaptation of cells during exposure to anticancer drugs; this particular example is known as acquired P-gp-mediated MDR. Drugs that are potential inducers of P-gp are often substrates of this transporter. However, several substances that have been proven to not be transportable by P-gp (such as cisplatin or alltrans retinoic acid) could induce minor improvements in P-gp overexpression. It is generally accepted that the drug efflux activity of Pgp is a major cause of reduced cell sensitivity to several compounds. However, P-gp may have side effects that are independent of its drug efflux activity. Several authors have described a direct influence of P-gp on the function of proteins involved in regulatory pathways, including apoptotic progression (such as p53, caspase-3 and Pokemon). Moreover, alterations of cell regulatory pathways, including protein expression, glycosylation and phosphorylation, have been demonstrated in cells overexpressing P-gp, which may consequently induce changes in cell sensitivity to substances that are not P-gp substrates or modulators. We recently reported that P-gppositive L1210 cells exhibit reduced sensitivity to cisplatin, concanavalin A, thapsigargin and tunicamycin. Thus, P-gp-mediated MDR represents a more complex process than was expected, and the unintended effects of P-gp overexpression should be considered when describing this phenotype. The present review aims to provide the most current informations about P-gp-mediated MDR while paying particular attention to the possible dual function of this protein as a drug efflux pump and a regulatory protein that influences diverse cell processes. From a clinical standpoint, overexpression of P-gp in cancer cells represents a real obstacle to effective chemotherapy for malignant diseases. Therefore, this protein should be considered as a viable target for pharmaceutical design. PMID:22931413

  15. New Antibiotics in Development Against Multidrug-Resistant Bacteria

    Directory of Open Access Journals (Sweden)

    Soner Yýlmaz

    2013-05-01

    Full Text Available The rapid development of resistance to antimicrobial agents caused to investigate new antimicrobial agents for the treatment of various infections and new antibiotic effect mechanisms. Methicillin-resistant Staphylococcus aureus (MRSA, vancomycin-resistant enterococci (VRE, extended-spectrum beta-lactamase (ESBL Escherichia coli and Klebsiella spp., multidrug-resistant strains of Acinetobacter baumannii and Pseudomonas aeruginosa are the most important targets for new antibacterial. Development speed of new antibacterial agents decreased dramatically in the last ten years. Correct use of antibiotics should be the basic principle to avoid the development of resistance. In addition, although the development of new antibiotics is so important, the main purpose should be determining the new targets in order to minimize undesired effects and drug interactions, detecting new antibiotics effect mechanisms and developing new antibiotics for these purposes.

  16. P-glycoprotein expression as a predictor of response to neoadjuvant chemotherapy in breast cancer

    Directory of Open Access Journals (Sweden)

    S Vishnukumar

    2013-01-01

    Full Text Available Background: Chemoresistance is an important factor determining the response of tumor to neoadjuvant chemotherapy (NACT. P-glycoprotein (P-gp expression-mediated drug efflux is one of the mechanisms responsible for multi-drug resistance. Our study was aimed to determine the role of P-gp expression as a predictor of response to NACT in locally advanced breast cancer (LABC patients. Materials and Methods: P-gp expression was performed by real-time quantitative polymerase chain reaction [qRT-PCR] in 76 patients with LABC. Response to adriamycin-based regimen was assessed both clinically and with contrast enhanced computed tomography (CECT scan before and after NACT. The significance of correlation between tumor and P-gp levels was determined with Chi-square test. Results: Twenty-one had high and 55 had low P-gp expression. On analyzing P-gp expression with response by World Health Organization (WHO criteria, statistical significance was obtained (P = 0.038. Similarly, assessment of P-gp expression with response by Response Evaluation in Solid Tumors (RECIST criteria in 48 patients showed statistical significance (P = 0.0005. Conclusion: This study proves that P-gp expression is a determinant factor in predicting response to NACT. Finally, detection of P-gp expression status before initiation of chemotherapy can be used as a predictive marker for NACT response and will also aid in avoiding the toxic side effects of NACT in non-responders.

  17. Risk factors for acquired multidrug-resistant tuberculosis

    Directory of Open Access Journals (Sweden)

    Barroso Elizabeth Clara

    2003-01-01

    Full Text Available Multidrug-resistant tuberculosis (MDR-TB is a severe and feared problem, that is difficult to control and has shown a tendency to increase worldwide. OBJECTIVE: To analyze the risk factors for acquired MDR-TB. CASUISTIC AND METHODS: A retrospective population-based case-control study was conducted. A bacillus was considered multidrug-resistant whenever it was resistant at least to rifampin (RFP + isoniazid (INH, and a case was considered as sensitive tuberculosis (TB if it had undergone the first treatment during a similar period as the first treatment of an MDR-TB case, but was cured at the time of the interview. Case selection was made based on the list of Sensitivity Tests (ST performed at the Central Public Health Laboratory of the State of Ceará, from 1990 through 1999. The Proportion Method was used to investigate resistance to the six antituberculosis drugs (isoniazid, rifampin, pyrazinamide, ethambutol, ethionamide, streptomycin used as the standard treatment in Brazil. Controls were selected from the registry of the TB Control Program. Univariate and multivariate analysis were performed, with p < 0.05 considered significant. RESULTS: Out of the 1,500 STs performed during the studied period, 266 strains were multidrug-resistant; 153 patients were identified, 19 of which were excluded. The Group of Cases comprised 134 patients, and the Group of Controls comprised 185. Multivariate analysis helped to detect the following risk factors: lack of home sewer system, alcoholism + smoking, number of previous treatments, irregular treatment, and lung cavities. CONCLUSION: These five factors are important for the development of acquired MDR-TB, and an attempt to neutralize them might contribute to control TB.

  18. Haemonchus contortus P-glycoprotein-2: in situ localisation and characterisation of macrocyclic lactone transport.

    Science.gov (United States)

    Godoy, Pablo; Lian, Jing; Beech, Robin N; Prichard, Roger K

    2015-01-01

    Haemonchus contortus is a veterinary nematode that infects small ruminants, causing serious decreases in animal production worldwide. Effective control through anthelmintic treatment has been compromised by the development of resistance to these drugs, including the macrocyclic lactones. The mechanisms of resistance in H. contortus have yet to be established but may involve efflux of the macrocyclic lactones by nematode ATP-binding-cassette transporters such as P-glycoproteins. Here we report the expression and functional activity of H. contortus P-glycoprotein 2 expressed in mammalian cells and characterise its interaction with the macrocyclic lactones, ivermectin, abamectin and moxidectin. The ability of H. contortus P-glycoprotein 2 to transport different fluorophore substrates was markedly inhibited by ivermectin and abamectin in a dose-dependent and saturable way. The profile of transport inhibition by moxidectin was markedly different. H. contortus P-glycoprotein 2 was expressed in the pharynx, the first portion of the worm's intestine and perhaps in adjacent nervous tissue, suggesting a role for this gene in regulating the uptake of avermectins and in protecting nematode tissues from the effects of macrocyclic lactone anthelmintic drugs. H. contortus P-glycoprotein 2 may thus contribute to resistance to these drugs in H. contortus. PMID:25486495

  19. Where is it and how does it get there – intracellular localization and traffic of P-glycoprotein

    Directory of Open Access Journals (Sweden)

    DongFu

    2013-12-01

    Full Text Available P-glycoprotein (P-gp, an ATP-binding cassette (ABC, is able to transport structurally and chemically unrelated substrates. Overexpression of P-gp in cancer cells significantly decreases the intercellular amount of anticancer drugs, and results in multidrug resistance in cancer cells, a major obstacle in cancer chemotherapy. P-gp is mainly localized on the plasma membrane and functions as a drug efflux pump; however, P-gp is also localized in many intracellular compartments, such as endoplasmic reticulum, Golgi, endosomes and lysosomes. P-gp moves between the intracellular compartments and the plasma membrane in a microtubule-actin dependent manner. This review highlights our current understanding of 1 the intracellular localization of P-gp; 2 the trafficking and cycling pathways among the cellular compartments as well as between these compartments and the plasma membrane; and 3 the cellular factors regulating P-gp traffic and cycling. This review also presents a potential implication in overcoming P-gp-mediated multidrug resistance by targeting P-gp traffic and cycling pathways and impairing P-gp localization on the plasma membrane.

  20. Targeted multidrug-resistance reversal in tumor based on PEG-PLL-PLGA polymer nano drug delivery system

    Directory of Open Access Journals (Sweden)

    Guo L

    2015-07-01

    Full Text Available Liting Guo,1 Haijun Zhang,1 Fei Wang,1 Ping Liu,1 Yonglu Wang,1,2 Guohua Xia,1 Ran Liu,1 Xueming Li,2 Haixiang Yin,2 Hulin Jiang,3 Baoan Chen11Department of Hematology and Oncology (Key Department of Jiangsu Medicine, The Affiliated Zhongda Hospital, Medical School of Southeast University, 2School of Pharmacy, Nanjing University of Technology, 3Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing, People’s Republic of ChinaAbstract: The study investigated the reversal of multidrug resistance (MDR and the biodistribution of nanoparticles (NPs that target leukemia cells in a nude mice model via a surface-bound transferrin (Tf. The cytotoxic cargo of daunorubicin (DNR and tetrandrine (Tet was protected in the NPs by an outer coat composed of polyethylene glycol (PEG-poly-l-lysine (PLL-poly(lactic-co-glycolic acid (PLGA NPs. Injection of DNR-Tet-Tf-PEG-PLL-PLGA NPs into nude mice bearing MDR leukemia cell K562/A02 xenografts was shown to inhibit tumor growth, and contemporaneous immunohistochemical analysis of tumor tissue showed the targeted NPs induced apoptosis in tumor cells. Targeted tumor cells exhibited a marked increase in Tf receptor expression, with noticeable decreases in P-glycoprotein, MDR protein, and nuclear factor κB, as assessed by quantitative real-time polymerase chain reaction and Western blot analysis. Moreover, the concentration of DNR was shown to increase in plasma, tumor tissue, and major organs. Flow cytometry analysis with a near-infrared fluorescent (NIRF dye, NIR797, was used to study the effectiveness of Tf as a targeting group for leukemia cells, a finding that was supported by NIRF imaging in tumor-bearing nude mice. In summary, our studies show that DNR-Tet-Tf-PEG-PLL-PLGA NPs provide a specific and effective means to target cytotoxic drugs to MDR tumor cells.Keywords: PEG-PLL-PLGA nanoparticles, transferrin, tetrandrine, multidrug resistance

  1. Diversity and evolution of the small multidrug resistance protein family

    Directory of Open Access Journals (Sweden)

    Turner Raymond J

    2009-06-01

    Full Text Available Abstract Background Members of the small multidrug resistance (SMR protein family are integral membrane proteins characterized by four α-helical transmembrane strands that confer resistance to a broad range of antiseptics and lipophilic quaternary ammonium compounds (QAC in bacteria. Due to their short length and broad substrate profile, SMR proteins are suggested to be the progenitors for larger α-helical transporters such as the major facilitator superfamily (MFS and drug/metabolite transporter (DMT superfamily. To explore their evolutionary association with larger multidrug transporters, an extensive bioinformatics analysis of SMR sequences (> 300 Bacteria taxa was performed to expand upon previous evolutionary studies of the SMR protein family and its origins. Results A thorough annotation of unidentified/putative SMR sequences was performed placing sequences into each of the three SMR protein subclass designations, namely small multidrug proteins (SMP, suppressor of groEL mutations (SUG, and paired small multidrug resistance (PSMR using protein alignments and phylogenetic analysis. Examination of SMR subclass distribution within Bacteria and Archaea taxa identified specific Bacterial classes that uniquely encode for particular SMR subclass members. The extent of selective pressure acting upon each SMR subclass was determined by calculating the rate of synonymous to non-synonymous nucleotide substitutions using Syn-SCAN analysis. SUG and SMP subclasses are maintained under moderate selection pressure in comparison to integron and plasmid encoded SMR homologues. Conversely, PSMR sequences are maintained under lower levels of selection pressure, where one of the two PSMR pairs diverges in sequence more rapidly than the other. SMR genomic loci surveys identified potential SMR efflux substrates based on its gene association to putative operons that encode for genes regulating amino acid biogenesis and QAC-like metabolites. SMR subclass protein transmembrane domain alignments to Bacterial/Archaeal transporters (BAT, DMT, and MFS sequences supports SMR participation in multidrug transport evolution by identifying common TM domains. Conclusion Based on this study, PSMR sequences originated recently within both SUG and SMP clades through gene duplication events and it appears that SMR members may be evolving towards specific metabolite transport.

  2. Photoexcited quantum dots for killing multidrug-resistant bacteria

    Science.gov (United States)

    Courtney, Colleen M.; Goodman, Samuel M.; McDaniel, Jessica A.; Madinger, Nancy E.; Chatterjee, Anushree; Nagpal, Prashant

    2016-05-01

    Multidrug-resistant bacterial infections are an ever-growing threat because of the shrinking arsenal of efficacious antibiotics. Metal nanoparticles can induce cell death, yet the toxicity effect is typically nonspecific. Here, we show that photoexcited quantum dots (QDs) can kill a wide range of multidrug-resistant bacterial clinical isolates, including methicillin-resistant Staphylococcus aureus, carbapenem-resistant Escherichia coli, and extended-spectrum β-lactamase-producing Klebsiella pneumoniae and Salmonella typhimurium. The killing effect is independent of material and controlled by the redox potentials of the photogenerated charge carriers, which selectively alter the cellular redox state. We also show that the QDs can be tailored to kill 92% of bacterial cells in a monoculture, and in a co-culture of E. coli and HEK 293T cells, while leaving the mammalian cells intact, or to increase bacterial proliferation. Photoexcited QDs could be used in the study of the effect of redox states on living systems, and lead to clinical phototherapy for the treatment of infections.

  3. Multidrug-Resistant Tuberculosis in Europe, 20102011

    Science.gov (United States)

    Gnther, Gunar; van Leth, Frank; Alexandru, Sofia; Altet, Neus; Avsar, Korkut; Bang, Didi; Barbuta, Raisa; Bothamley, Graham; Ciobanu, Ana; Crudu, Valeriu; Davilovits, Manfred; Dedicoat, Martin; Duarte, Raquel; Gualano, Gina; Kunst, Heinke; de Lange, Wiel; Leimane, Vaira; Magis-Escurra, Cecile; McLaughlin, Anne-Marie; Muylle, Inge; Polcov, Veronika; Pontali, Emanuele; Popa, Christina; Rumetshofer, Rudolf; Skrahina, Alena; Solodovnikova, Varvara; Spinu, Victor; Tiberi, Simon; Viiklepp, Piret

    2015-01-01

    Drug-resistant Mycobacterium tuberculosis is challenging elimination of tuberculosis (TB). We evaluated risk factors for TB and levels of second-line drug resistance in M. tuberculosis in patients in Europe with multidrug-resistant (MDR) TB. A total of 380 patients with MDR TB and 376 patients with nonMDR TB were enrolled at 23 centers in 16 countries in Europe during 20102011. A total of 52.4% of MDR TB patients had never been treated for TB, which suggests primary transmission of MDR M. tuberculosis. At initiation of treatment for MDR TB, 59.7% of M. tuberculosis strains tested were resistant to pyrazinamide, 51.1% were resistant to ?1 second-line drug, 26.6% were resistant to second-line injectable drugs, 17.6% were resistant to fluoroquinolones, and 6.8% were extensively drug resistant. Previous treatment for TB was the strongest risk factor for MDR TB. High levels of primary transmission and advanced resistance to second-line drugs characterize MDR TB cases in Europe. PMID:25693485

  4. Multidrug-resistant tuberculosis in Europe, 2010-2011.

    Science.gov (United States)

    Gnther, Gunar; van Leth, Frank; Alexandru, Sofia; Altet, Neus; Avsar, Korkut; Bang, Didi; Barbuta, Raisa; Bothamley, Graham; Ciobanu, Ana; Crudu, Valeriu; Davilovits, Manfred; Dedicoat, Martin; Duarte, Raquel; Gualano, Gina; Kunst, Heinke; de Lange, Wiel; Leimane, Vaira; Magis-Escurra, Cecile; McLaughlin, Anne-Marie; Muylle, Inge; Polcov, Veronika; Pontali, Emanuele; Popa, Christina; Rumetshofer, Rudolf; Skrahina, Alena; Solodovnikova, Varvara; Spinu, Victor; Tiberi, Simon; Viiklepp, Piret; Lange, Christoph

    2015-03-01

    Drug-resistant Mycobacterium tuberculosis is challenging elimination of tuberculosis (TB). We evaluated risk factors for TB and levels of second-line drug resistance in M. tuberculosis in patients in Europe with multidrug-resistant (MDR) TB. A total of 380 patients with MDR TB and 376 patients with non-MDR TB were enrolled at 23 centers in 16 countries in Europe during 2010-2011. A total of 52.4% of MDR TB patients had never been treated for TB, which suggests primary transmission of MDR M. tuberculosis. At initiation of treatment for MDR TB, 59.7% of M. tuberculosis strains tested were resistant to pyrazinamide, 51.1% were resistant to ?1 second-line drug, 26.6% were resistant to second-line injectable drugs, 17.6% were resistant to fluoroquinolones, and 6.8% were extensively drug resistant. Previous treatment for TB was the strongest risk factor for MDR TB. High levels of primary transmission and advanced resistance to second-line drugs characterize MDR TB cases in Europe. PMID:25693485

  5. Effect of methylglyoxal on multidrug-resistant Pseudomonas aeruginosa

    Directory of Open Access Journals (Sweden)

    KunihikoNishino

    2014-04-01

    Full Text Available Honey has a complex chemistry, and its broad-spectrum antimicrobial activity varies with floral source, climate, and harvesting conditions. Methylglyoxal was identified as the dominant antibacterial component of manuka honey. Although it has been known that methylglyoxal has antibacterial activity against gram-positive bacteria, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus, there is not much information describing its activity against gram-negative bacteria. In this study, we report the effect of methylglyoxal against multidrug-resistant Pseudomonas aeruginosa (MDRP using 53 clinically isolated strains. We also assessed the effect of deleting the five multidrug efflux systems in P. aeruginosa, as well as the efflux systems in Escherichia coli and Salmonella enterica serovar Typhimurium, on MICs of methylglyoxal. Our results indicate that methylglyoxal inhibits the growth of MDRP at concentrations of 128–512 µg/ml (1.7–7.1 mM and is not recognized by drug efflux systems.

  6. Predicting P-glycoprotein-mediated drug transport based on support vector machine and three-dimensional crystal structure of P-glycoprotein.

    Science.gov (United States)

    Bikadi, Zsolt; Hazai, Istvan; Malik, David; Jemnitz, Katalin; Veres, Zsuzsa; Hari, Peter; Ni, Zhanglin; Loo, Tip W; Clarke, David M; Hazai, Eszter; Mao, Qingcheng

    2011-01-01

    Human P-glycoprotein (P-gp) is an ATP-binding cassette multidrug transporter that confers resistance to a wide range of chemotherapeutic agents in cancer cells by active efflux of the drugs from cells. P-gp also plays a key role in limiting oral absorption and brain penetration and in facilitating biliary and renal elimination of structurally diverse drugs. Thus, identification of drugs or new molecular entities to be P-gp substrates is of vital importance for predicting the pharmacokinetics, efficacy, safety, or tissue levels of drugs or drug candidates. At present, publicly available, reliable in silico models predicting P-gp substrates are scarce. In this study, a support vector machine (SVM) method was developed to predict P-gp substrates and P-gp-substrate interactions, based on a training data set of 197 known P-gp substrates and non-substrates collected from the literature. We showed that the SVM method had a prediction accuracy of approximately 80% on an independent external validation data set of 32 compounds. A homology model of human P-gp based on the X-ray structure of mouse P-gp as a template has been constructed. We showed that molecular docking to the P-gp structures successfully predicted the geometry of P-gp-ligand complexes. Our SVM prediction and the molecular docking methods have been integrated into a free web server (http://pgp.althotas.com), which allows the users to predict whether a given compound is a P-gp substrate and how it binds to and interacts with P-gp. Utilization of such a web server may prove valuable for both rational drug design and screening. PMID:21991360

  7. Resistance to fluoroquinolones and second-Line injectable drugs: impact on multidrug-resistant TB outcomes

    OpenAIRE

    Falzon, D.; Gandhi, N.; Migliori, G.B.; Sotgiu, G; Cox, H. S.; Holtz, T. H.; Hollm-Delgado, M.-G.; Keshavjee, S.; DeRiemer, K; Centis, R.; D'Ambrosio, L.; Lange, C. G.; Bauer, M.; Menzies, D.

    2013-01-01

    A meta-analysis for response to treatment was undertaken using individual data of multidrug-resistant tuberculosis (MDR-TB; resistance to isoniazid and rifampicin) patients from 26 centres. The analysis assessed the impact of additional resistance to fluoroquinolones and/or second-line injectable drugs on treatment outcome. Compared to treatment failure, relapse and death, treatment success was higher in MDR-TB patients infected with strains without additional resistance (N=4763, 64% [95% con...

  8. Anticancer effects of the organosilicon multidrug resistance modulator SILA 421.

    Science.gov (United States)

    Olszewski, Ulrike; Zeillinger, Robert; Kars, Meltem Demirel; Zalatnai, Attila; Molnar, Jozsef; Hamilton, Gerhard

    2012-07-01

    1,3-dimethyl-1,3-bis(4-fluorophenyl)-1,3-bis{3-[1(4-butylpiperazinyl)]-propyl}-disiloxan-tetrahydrochlorid (SILA 421) is a compound that was developed as modulator of the ABC cassette transporter P-glycoprotein. Furthermore, it exerted antimicrobial toxicity, vascular effects, downregulation of chaperone induction and plasmid curing in bacterial cells. Here, this drug was found to possess cytotoxic activity against a panel of human cancer cell lines that do not overexpress P-gp, with 50% inhibitory concentrations ranging between 1.75±0.38 μM for GLC14 small cell lung cancer and 34.00±4.75 μM for PC-3 prostate cancer cells. HL-60 leukemia and MDA-MB-435 breast cancer cells exhibited cell cycle arrest and apoptotic cell death in response to SILA 421. Assessment of global gene expression of SILA 421-treated HL-60 cells was employed to identify cellular pathways affected by the compound and revealed disturbance of DNA replication, transcription and production of apparently misfolded proteins. Endoplasmatic reticulum stress and downregulation of cell cycle, cellular repair mechanisms and growth factor-related signaling cascades eventually resulted in induction of apoptosis in this cell line. In addition to the well established P-gp inhibitory effect of SILA compounds, reversal of resistance to taxanes, which had been reported for SILA 421 and the related molecule SILA 409, may be linked to downregulation of gene expression of kinesins. Interference with DNA replication and transcription seems to be the common denominator of antimicrobial activity and plasmid curing, as well as anticancer toxicity in human cell lines. Thus, in consideration of the full range of putative cellular targets found in the present work, the application of these SILA compounds for treatment of tumors should be further evaluated. PMID:22263791

  9. Multidrug-resistant pathogens in the food supply.

    Science.gov (United States)

    Doyle, Marjorie E

    2015-04-01

    Antimicrobial resistance, including multidrug resistance (MDR), is an increasing problem globally. MDR bacteria are frequently detected in humans and animals from both more- and less-developed countries and pose a serious concern for human health. Infections caused by MDR microbes may increase morbidity and mortality and require use of expensive drugs and prolonged hospitalization. Humans may be exposed to MDR pathogens through exposure to environments at health-care facilities and farms, livestock and companion animals, human food, and exposure to other individuals carrying MDR microbes. The Centers for Disease Control and Prevention classifies drug-resistant foodborne bacteria, including Campylobacter, Salmonella Typhi, nontyphoidal salmonellae, and Shigella, as serious threats. MDR bacteria have been detected in both meat and fresh produce. Salmonellae carrying genes coding for resistance to multiple antibiotics have caused numerous foodborne MDR outbreaks. While there is some level of resistance to antimicrobials in environmental bacteria, the widespread use of antibiotics in medicine and agriculture has driven the selection of a great variety of microbes with resistance to multiple antimicrobials. MDR bacteria on meat may have originated in veterinary health-care settings or on farms where animals are given antibiotics in feed or to treat infections. Fresh produce may be contaminated by irrigation or wash water containing MDR bacteria. Livestock, fruits, and vegetables may also be contaminated by food handlers, farmers, and animal caretakers who carry MDR bacteria. All potential sources of MDR bacteria should be considered and strategies devised to reduce their presence in foods. Surveillance studies have documented increasing trends in MDR in many pathogens, although there are a few reports of the decline of certain multidrug pathogens. Better coordination of surveillance programs and strategies for controlling use of antimicrobials need to be implemented in both human and animal medicine and agriculture and in countries around the world. PMID:25621383

  10. Functional imaging of multidrug resistance in an orthotopic model of osteosarcoma using {sup 99m}Tc-sestamibi

    Energy Technology Data Exchange (ETDEWEB)

    Gomes, Celia M.F. [Leiden University Medical Center, Department of Radiology, Section of Nuclear Medicine, Leiden (Netherlands); Institute of Biophysics/Biomathematics, IBILI - Faculty of Medicine, Coimbra (Portugal); Welling, Mick; Pauwels, Ernest K.J. [Leiden University Medical Center, Department of Radiology, Section of Nuclear Medicine, Leiden (Netherlands); Que, Ivo; Henriquez, Niek V.; Pluijm, Gabri van der [Leiden University Medical Center, Department of Endocrinology, Leiden (Netherlands); Romeo, Salvatore; Hogendoorn, Pancras C.W.; Cleton-Jansen, Anne M. [Leiden University Medical Center, Department of Pathology, Leiden (Netherlands); Abrunhosa, Antero J.; Botelho, M.F. [Institute of Biophysics/Biomathematics, IBILI - Faculty of Medicine, Coimbra (Portugal)

    2007-11-15

    The purpose of this work was the development of an orthotopic model of osteosarcoma based on luciferase-expressing tumour cells for the in vivo imaging of multidrug resistance (MDR) with {sup 99m}Tc-sestamibi. Doxorubicin-sensitive (143B-luc{sup +}) and resistant (MNNG/HOS-luc{sup +}) osteosarcoma cell lines expressing different levels of P-glycoprotein and carrying a luciferase reporter gene were inoculated into the tibia of nude mice. Local tumour growth was monitored weekly by bioluminescence imaging and X-ray. After tumour growth, a {sup 99m}Tc-sestamibi dynamic study was performed. A subset of animals was pre-treated with an MDR inhibitor (PSC833). Images were analysed for calculation of {sup 99m}Tc-sestamibi washout half-life (t{sub 1/2}), percentage washout rate (%WR) and tumour/non-tumour (T/NT) ratio. A progressively increasing bioluminescent signal was detected in the proximal tibia after 2 weeks. The t{sub 1/2} of {sup 99m}Tc-sestamibi was significantly shorter (p < 0.05) in drug-resistant MNNG/HOS-luc{sup +} tumours (t{sub 1/2} = 87.3 {+-} 15.7 min) than in drug-sensitive 143B-luc{sup +} tumours (t{sub 1/2} = 161.0 {+-} 47.4 min) and decreased significantly with PSC833 (t{sub 1/2} = 173.0 {+-} 24.5 min, p < 0.05). No significant effects of PSC833 were observed in 143B-luc{sup +} tumours. The T/NT ratio was significantly lower (p < 0.05) in MNNG/HOS-luc{sup +} tumours than in 143B-luc{sup +} tumours at early (1.55 {+-} 0.22 vs 2.14 {+-} 0.36) and delayed times (1.12 {+-} 0.11 vs 1.62 {+-} 0.33). PSC833 had no significant effects on the T/NT ratios of either tumour. The orthotopic injection of tumour cells provides an animal model suitable for functional imaging of MDR. In vivo bioluminescence imaging allows the non-invasive monitoring of tumour growth. The kinetic analysis of {sup 99m}Tc-sestamibi washout provides information on the functional activity of MDR related to P-glycoprotein expression and its pharmacological inhibition in osteosarcoma. (orig.)

  11. Novel understanding of ABC transporters ABCB1/MDR/P-glycoprotein, ABCC2/MRP2, and ABCG2/BCRP in colorectal pathophysiology

    DEFF Research Database (Denmark)

    Andersen, Vibeke; Svenningsen, Katrine; Knudsen, Lina Almind; Hansen, Axel Kornerup; Holmskov, Uffe; Stensballe, Allan; Vogel, Ulla

    2015-01-01

    translocation from one side to the other of the cell membrane lipid bilayer by ABC transporters affecting inflammatory response and/or function of tight junctions, phagocytosis and vesicle trafficking. Also, diet and microbes give rise to molecules which are potential substrates for the ABC transporters and......AIM: To evaluate ATP-binding cassette (ABC) transporters in colonic pathophysiology as they had recently been related to colorectal cancer (CRC) development. METHODS: Literature search was conducted on PubMed using combinations of the following terms: ABC transporters, ATP binding cassette...... transporter proteins, inflammatory bowel disease, ulcerative, colitis, Crohns disease, colorectal cancer, colitis, intestinal inflammation, intestinal carcinogenesis, ABCB1/P-glycoprotein (P-gp/CD243/MDR1), ABCC2/multidrug resistance protein 2 (MRP2) and ABCG2/breast cancer resistance protein (BCRP), Abcb1...

  12. The role of structural factors in the kinetics of cellular uptake of pyrazoloacridines and pyrazolopyrimidoacridines: implications for overcoming multidrug resistance towards leukaemia K562/DOX cells.

    Science.gov (United States)

    Tarasiuk, Jolanta; Majewska, Ewelina; Seksek, Olivier; Rogacka, Dorota; Antonini, Ippolito; Garnier-Suillerot, Arlette; Borowski, Edward

    2004-11-01

    The appearance of multidrug resistance (MDR) of tumour cells to a wide array of antitumour drugs, structurally diverse and having different mechanisms of action, constitutes the major obstacle to the successful treatment of cancer. Our approach to search for non-cross resistant antitumour agents is based on the rational design of derivatives, which have a high kinetics of passive cellular uptake rendering their active efflux by MDR exporting pumps inefficient. Recently, two families of acridine cytotoxic agents were obtained, pyrazoloacridines (PACs) and pyrazolopyrimidoacridines (PPACs). The aim of this study was to examine molecular basis of the reported differences in retaining cytotoxic activity of these derivatives at cellular level against resistant erythroleukaemia K562/DOX (overexpressing P-glycoprotein) cell line. The study was performed using a spectrofluorometric method, which allows continuous monitoring of the uptake and efflux of fluorescent molecules by living cells. It was demonstrated that the presence of two additional rings, pyrazole and pyrimidine, fused to the acridine chromophore structure (PPAC) favoured more rapid cellular diffusion than the presence of only one additional pyrazole ring (PAC). The presence of hydrophobic substituent OCH3 markedly favoured the cellular uptake of pyrazoloacridines and pyrazolopyrimidoacridines while compounds having hydrophilic substituent OH exhibited very low kinetics of cellular uptake. In contrast, it was found that neither structure of the ring system nor the hydrophobic/hydrophilic character of examined substituents determined the rate of active efflux of these compounds by P-glycoprotein. Our data showed that a nearly linear relation exists between the resistance factor (RF) and lnV+ reflecting the impact of the cellular uptake rate (V+) on the ability of these compounds to overcome MDR. PMID:15450947

  13. Measurement of P-Glycoprotein expression in human neuroblastoma xenografts using in vitro quantitative autoradiography

    International Nuclear Information System (INIS)

    P-glycoprotein (P-gp) has a role in multidrug resistance (MDR) encountered in human cancers. In this study, we used the colchicine-resistant cell line BE(2)-C/CHCb(0.2), a strain of neuroblastoma cell line BE(2)-C, as a model to measure variations of P-gp expression in cells grown in vitro and in vivo. Cells were cultured in the medium supplemented with colchicine. At the beginning of the study the drug was withdrawn and, after 22 days, added back to the culture medium. Cells were harvested at various time points and xenografted in nude mice. P-gp content in cells was measured by self-competitive binding assay and in tumors, by quantitative autoradiography (QAR). Both assays were carried out using 125I-labeled monoclonal antibody MRK16, reactive with P-gp. Concentration of P-gp in cells varied from a maximum of 1,361 pmol/g in the presence of colchicine to a minimum of 374 pmol/g in the absence of colchicine in the culture medium. P-gp concentration in the tumors ranged from 929 to 188 pmol/g, which correlated with P-gp content in the cells at the time of their injection in the mice. QAR is an accurate and reliable method to quantify P-gp expression in tumors. Changes in colchicine concentration in the ambient medium of BE(2)-C/CHCb(0.2) cells growing in vitro resulted in a change in phenotype of P-gp expression, which was stable under conditions of in vivo growth over approximately 9 cell divisions in nude mice xenografts. Therefore, P-gp content in xenografts depends only on the level of resistance of the cells at the time of their injection in the mice

  14. The multidrug-resistant phenotype associated with overexpression of the new ABC half-transporter, MXR (ABCG2)

    DEFF Research Database (Denmark)

    Litman, Thomas; Brangi, M; Hudson, E; Fetsch, P; Abati, A; Ross, D D; Miyake, K; Resau, J H; Bates, S E

    by PCR, immunoblot assay and immunohistochemistry. These MXR overexpressing sublines were compared to cell lines with P-glycoprotein- and MRP-mediated resistance. High levels of cross-resistance were observed for mitoxantrone, the anthracyclines, bisantrene and topotecan. Reduced levels of...... mitoxantrone, daunorubicin, bisantrene, topotecan, rhodamine 123 and prazosin were observed in the two sublines with high MXR expression. Neither the P-glycoprotein substrates vinblastine, paclitaxel, verapamil and calcein-AM, nor the MRP substrate calcein, were extruded from MCF-7 AdVp3000 and S1-M1-80 cells...

  15. ▼Bedaquiline for multidrug-resistant tuberculosis.

    Science.gov (United States)

    2014-11-01

    Resistance to drugs used to treat tuberculosis (TB) is a major public health problem that threatens progress made in TB management and control worldwide. It may result from improper use of antibiotics, including prescription of non-standard treatment regimens and poor adherence to drug therapy. Multidrug-resistant TB (MDR-TB) is defined as resistance to isoniazid and rifampicin, with or without resistance to other first-line drugs. Extensively drug-resistant TB (XDR-TB) refers to resistance to at least isoniazid and rifampicin, and to any fluoroquinolone, and to any of the three second-line injectables  (amikacin, capreomycin and kanamycin). In 2012, DTB discussed the investigation, management and treatment of patients with MDR- and XDR-TB. Earlier this year, ▼bedaquiline (Sirturo) and ▼delamanid (Deltyba) were authorised by the European Medicines Agency (EMA) under its 'conditional market authorisation' scheme for use as part of an appropriate combination regimen for pulmonary MDR-TB in adult patients "when an effective treatment regimen cannot otherwise be composed for reasons of resistance or tolerability." In this article, we review the evidence for bedaquiline in the management of MDR-TB. PMID:25395481

  16. Inhibition of P-glycoprotein activity by limonin and other secondary metabolites from Citrus species in human colon and leukaemia cell lines.

    Science.gov (United States)

    El-Readi, Mahmoud Zaki; Hamdan, Dalia; Farrag, Nawal; El-Shazly, Assem; Wink, Michael

    2010-01-25

    P-glycoprotein (P-gp), a membrane transporter encoded by the MDR1 gene in human cells, mediates drug efflux from cells and plays a major role in causing multidrug resistance; which is one of the most accepted mechanisms for failure of chemotherapy in cancer treatment. In this study, we investigated the effects of nine naturally occurring compounds isolated from Citrus jambhiri Lush and Citrus pyriformis Hassk (Rutaceae) for their potential to modulate the activity of P-gp in the multidrug-resistant human leukaemia cell line CEM/ADR5000. Limonin, deacetylnomilin, hesperidin, neohesperidin, stigmasterol and ss-sitosterol-O-glucoside inhibited the efflux of the P-gp substrate rhodamine 123 in a concentration-dependent manner. Some of these compounds were more active than verapamil, which was used as a positive control. Treatment of drug-resistant Caco-2 cells with the most active C. jambhiri and C. pyriformis compounds increased their sensitivity to doxorubicin and completely reversed doxorubicin resistance, which agrees with a decreased P-gp activity. Limonin was the most potent P-glycoprotein inhibitor - when it was applied at a non-toxic concentration of 20 microM, it significantly enhanced doxorubicin cytotoxicity 2.98-fold (P<0.001) and 2.2-fold (P<0.001) in Caco2 and CEM/ADR5000 cells, respectively. These isolated Citrus compounds could be considered as good candidates for the development of novel P-gp/MDR1 reversal agents which may enhance the accumulation and efficacy of chemotherapy agents. PMID:19782062

  17. Diverse and abundant multi-drug resistant E. coli in Matang mangrove estuaries, Malaysia

    OpenAIRE

    Ghaderpour, Aziz; Ho, Wing Sze; Chew, Li-Lee; Bong, Chui Wei; Chong, Ving Ching; Thong, Kwai-Lin; Chai, Lay Ching

    2015-01-01

    E.coli, an important vector distributing antimicrobial resistance in the environment, was found to be multi-drug resistant, abundant, and genetically diverse in the Matang mangrove estuaries, Malaysia. One-third (34%) of the estuarine E. coli was multi-drug resistant. The highest antibiotic resistance prevalence was observed for aminoglycosides (83%) and beta-lactams (37%). Phylogenetic groups A and B1, being the most predominant E. coli, demonstrated the highest antibiotic resistant level an...

  18. Role of glycine-534 and glycine-1179 of human multidrug resistance protein (MDR1) in drug-mediated control of ATP hydrolysis.

    Science.gov (United States)

    Szakács, G; Ozvegy, C; Bakos, E; Sarkadi, B; Váradi, A

    2001-05-15

    The human multidrug resistance protein (MDR1) (P-glycoprotein), a member of the ATP-binding cassette (ABC) family, causes multidrug resistance by an active transport mechanism, which keeps the intracellular level of hydrophobic compounds below a cell-killing threshold. Human MDR1 variants with mutations affecting a conserved glycine residue within the ABC signature of either or both ABC units (G534D, G534V, G1179D and G534D/G1179D) were expressed and characterized in Spodoptera frugiperda (Sf9) cell membranes. These mutations caused a loss of measurable ATPase activity but still allowed ATP binding and the formation of a transition-state intermediate (nucleotide trapping). In contrast with the wild-type protein, in which substrate drugs accelerate nucleotide trapping, in the ABC signature mutants nucleotide trapping was inhibited by MDR1-substrate drugs, suggesting a miscommunication between the drug-binding site(s) and the catalytic domains. Equivalent mutations of the two catalytic sites resulted in a similar effect, indicating the functional equivalence of the two sites. On the basis of these results and recent structural information on an ABC-ABC dimer [Hopfner, Karcher, Shin, Craig, Arthur, Carney and Tainer (2000) Cell 101, 789-800], we propose a key role of these glycine residues in the interdomain communication regulating drug-induced ATP hydrolysis. PMID:11336637

  19. Tailoring Cytotoxicity of Antimicrobial Peptidomimetics with High Activity against Multidrug-Resistant Escherichia coli

    DEFF Research Database (Denmark)

    Jahnsen, Rasmus D; Sandberg-Schaal, Anne; Vissing, Karina Juul; Nielsen, Hanne Mørck; Frimodt-Møller, Niels; Franzyk, Henrik

    2014-01-01

    Infections with multidrug-resistant pathogens are an increasing concern for public health. Recently, subtypes of peptide-peptoid hybrids were demonstrated to display potent activity against multidrug-resistant Gram-negative bacteria. Here, structural variation of these antibacterial peptidomimeti...

  20. MICROARRAY ANALYSIS OF A LACTIC ACID STRESSED, MULTI-DRUG RESISTANT MUTANT OF SALMONELLA TYPHIMURIUM

    Science.gov (United States)

    Salmonella Typhimurium is one of the most common Salmonella serovars associated with human foodborne infections and has been associated with multi-drug resistance properties. It is important to establish the ability of multi-drug resistant Salmonella to survive food processing interventions. Lactic ...

  1. The human multidrug resistance-associated protein functionally complements the yeast cadmium resistance factor 1.

    OpenAIRE

    Tommasini, R.; Evers, R.; Vogt, E.; Mornet, C; Zaman, G.J.; Schinkel, A.H.; Borst, P; E. Martinoia

    1996-01-01

    A Saccharomyces cerevisiae strain with a disrupted yeast cadmium resistance factor (YCF1) gene (DTY168) is hypersensitive to cadmium. YCF1 resembles the human multidrug resistance-associated protein MRP (63% amino acid similarity), which confers resistance to various cytotoxic drugs by lowering the intracellular drug concentration. Whereas the mechanism of action of YCF1 is not known, MRP was recently found to transport glutathione S-conjugates across membranes. Here we show that expression o...

  2. Comparative Genomics of Multidrug Resistance in Acinetobacter baumannii.

    Directory of Open Access Journals (Sweden)

    2006-01-01

    Full Text Available Acinetobacter baumannii is a species of nonfermentative gram-negative bacteria commonly found in water and soil. This organism was susceptible to most antibiotics in the 1970s. It has now become a major cause of hospital-acquired infections worldwide due to its remarkable propensity to rapidly acquire resistance determinants to a wide range of antibacterial agents. Here we use a comparative genomic approach to identify the complete repertoire of resistance genes exhibited by the multidrug-resistant A. baumannii strain AYE, which is epidemic in France, as well as to investigate the mechanisms of their acquisition by comparison with the fully susceptible A. baumannii strain SDF, which is associated with human body lice. The assembly of the whole shotgun genome sequences of the strains AYE and SDF gave an estimated size of 3.9 and 3.2 Mb, respectively. A. baumannii strain AYE exhibits an 86-kb genomic region termed a resistance island-the largest identified to date-in which 45 resistance genes are clustered. At the homologous location, the SDF strain exhibits a 20 kb-genomic island flanked by transposases but devoid of resistance markers. Such a switching genomic structure might be a hotspot that could explain the rapid acquisition of resistance markers under antimicrobial pressure. Sequence similarity and phylogenetic analyses confirm that most of the resistance genes found in the A. baumannii strain AYE have been recently acquired from bacteria of the genera Pseudomonas, Salmonella, or Escherichia. This study also resulted in the discovery of 19 new putative resistance genes. Whole-genome sequencing appears to be a fast and efficient approach to the exhaustive identification of resistance genes in epidemic infectious agents of clinical significance.

  3. Effects of Efflux Pump Inhibitors on Colistin Resistance in Multidrug-Resistant Gram-Negative Bacteria.

    Science.gov (United States)

    Ni, Wentao; Li, Yanjun; Guan, Jie; Zhao, Jin; Cui, Junchang; Wang, Rui; Liu, Youning

    2016-05-01

    We tested the effects of various putative efflux pump inhibitors on colistin resistance in multidrug-resistant Gram-negative bacteria. Addition of 10 mg/liter cyanide 3-chlorophenylhydrazone (CCCP) to the test medium could significantly decrease the MICs of colistin-resistant strains. Time-kill assays showed CCCP could reverse colistin resistance and inhibit the regrowth of the resistant subpopulation, especially in Acinetobacter baumannii and Stenotrophomonas maltophilia These results suggest colistin resistance in Gram-negative bacteria can be suppressed and reversed by CCCP. PMID:26953203

  4. Effects of P-Glycoprotein and Its Inhibitors on Apoptosis in K562 Cells

    Directory of Open Access Journals (Sweden)

    Yaqiong Zu

    2014-08-01

    Full Text Available P-glycoprotein (P-gp is a major factor in multidrug resistance (MDR which is a serious obstacle in chemotherapy. P-gp has also been implicated in causing apoptosis of tumor cells, which was shown to be another important mechanism of MDR recently. To study the influence of P-gp in tumor cell apoptosis, K562/A cells (P-gp+ and K562/S cells (P-gp− were subjected to doxorubicin (Dox, serum withdrawal, or independent co-incubation with multiple P-gp inhibitors, including valspodar (PSC833, verapamil (Ver and H108 to induce apoptosis. Apoptosis was simultaneously detected by apoptotic rate, cell cycle by flow cytometry and cysteine aspartic acid-specific protease 3 (caspase 3 activity by immunoassay. Cytotoxicity and apoptosis induced by PSC833 were evaluated through an MTT method and apoptosis rate, and cell cycle combined with caspase 3 activity, respectively. The results show that K562/A cells are more resistant to apoptosis and cell cycle arrest than K562/S cells after treatment with Dox or serum deprivation. The apoptosis of K562/A cells increased after co-incubation with each of the inhibitors of P-gp. P-gp inhibitors also enhanced cell cycle arrest in K562/A cell. PSC833 most strikingly decreased viability and led to apoptosis and S phase arrest of cell cycle in K562/A cells. Our study demonstrates that P-gp inhibits the apoptosis of tumor cells in addition to participating in the efflux of intracellular chemotherapy drugs. The results of the caspase 3 activity assay also suggest that the role of P-gp in apoptosis avoidance is caspase-related.

  5. A multifaceted analysis of HIV-1 protease multidrug resistance phenotypes

    Directory of Open Access Journals (Sweden)

    Doherty Kathleen M

    2011-12-01

    Full Text Available Abstract Background Great strides have been made in the effective treatment of HIV-1 with the development of second-generation protease inhibitors (PIs that are effective against historically multi-PI-resistant HIV-1 variants. Nevertheless, mutation patterns that confer decreasing susceptibility to available PIs continue to arise within the population. Understanding the phenotypic and genotypic patterns responsible for multi-PI resistance is necessary for developing PIs that are active against clinically-relevant PI-resistant HIV-1 variants. Results In this work, we use globally optimal integer programming-based clustering techniques to elucidate multi-PI phenotypic resistance patterns using a data set of 398 HIV-1 protease sequences that have each been phenotyped for susceptibility toward the nine clinically-approved HIV-1 PIs. We validate the information content of the clusters by evaluating their ability to predict the level of decreased susceptibility to each of the available PIs using a cross validation procedure. We demonstrate the finding that as a result of phenotypic cross resistance, the considered clinical HIV-1 protease isolates are confined to ~6% or less of the clinically-relevant phenotypic space. Clustering and feature selection methods are used to find representative sequences and mutations for major resistance phenotypes to elucidate their genotypic signatures. We show that phenotypic similarity does not imply genotypic similarity, that different PI-resistance mutation patterns can give rise to HIV-1 isolates with similar phenotypic profiles. Conclusion Rather than characterizing HIV-1 susceptibility toward each PI individually, our study offers a unique perspective on the phenomenon of PI class resistance by uncovering major multidrug-resistant phenotypic patterns and their often diverse genotypic determinants, providing a methodology that can be applied to understand clinically-relevant phenotypic patterns to aid in the design of novel inhibitors that target other rapidly evolving molecular targets as well.

  6. Characterization and Identification of Multidrug Resistant Bacteria from Some Egyptian Patients

    Directory of Open Access Journals (Sweden)

    Seham Abdel-Shafi

    2013-01-01

    Full Text Available The isolation of multidrug resistant bacteria from Egyptian patients showed a great interest to study such phenomenon. Hence, simple methods were followed herein to isolate and characterize the antibiotic resistant variants by the common phenotypic, morphological and biochemical characters. Out of 500 clinical bacterial cultures, 50 only were multidrug resistant bacteria with a value of drug resistance ability of about 10%. About 46% of multidrug resistant bacterial cultures tested were isolated from urine samples. The percentage values of both resistance and susceptibility of the 50 multidrug resistant bacterial isolates to 14 types of antibiotics were calculated. Based on their cultural, morphological and biochemical characteristics, the 50 multidrug resistant bacterial isolates were identified and categorized into eight groups. The identified bacterial species were arranged in a descending order according to their frequency percentage viz. Escherichia coli>Staphylococcus aureus> Pseudomonas aeruginosa> Klebsiella pneumoniae>Streptococcus pyogenes> Proteus vulgaris>Streptococcus pneumoniae> Staphylococcus saprophyticus. The relationship between pathogenic cases, symptoms and the identified multidrug bacterial pathogens was studied. A simple key was designed for easy differentiation and classification of the 50 multidrug resistant bacterial organisms. It was based on easily determinable characteristics which were used for rapid assignment of bacteria into genera and species.

  7. Resistance Patterns among Multidrug-Resistant Tuberculosis Patients in Greater Metropolitan Mumbai: Trends over Time

    OpenAIRE

    Dalal, Alpa; Pawaskar, Akshay; Das, Mrinalini; Desai, Ranjan; Prabhudesai, Pralhad; Chhajed, Prashant; Rajan, Sujeet; Reddy, Deepesh; Babu, Sajit; Jayalakshmi, T. K.; Saranchuk, Peter; Rodrigues, Camilla; Isaakidis, Petros

    2015-01-01

    Background While the high burden of multidrug-resistant tuberculosis (MDR-TB) itself is a matter of great concern, the emergence and rise of advanced forms of drug-resistance such as extensively drug-resistant TB (XDR-TB) and extremely drug-resistant TB (XXDR-TB) is more troubling. The aim of this study was to investigate the trends over time of patterns of drug resistance in a sample of MDR-TB patients in greater metropolitan Mumbai, India. Methods This was a retrospective, observational stu...

  8. Preparation of silver nanoparticles fabrics against multidrug-resistant bacteria

    Science.gov (United States)

    Hanh, Truong Thi; Thu, Nguyen Thi; Hien, Nguyen Quoc; An, Pham Ngoc; Loan, Truong Thi Kieu; Hoa, Phan Thi

    2016-04-01

    The silver nanoparticles (AgNPs)/peco fabrics were prepared by immobilization of AgNPs on fabrics in which AgNPs were synthesized by γ-irradiation of the 10 mM AgNO3 chitosan solution at the dose of 17.6 kGy. The AgNPs size has been estimated to be about 11 nm from TEM image. The AgNPs content onto peco fabrics was of 143±6 mg/kg at the initial AgNPs concentration of 100 ppm. The AgNPs colloidal solution was characterized by UV-vis spectroscopy and TEM image. The antibacterial activity of AgNPs/peco fabrics after 60 washings against Staphylococcus aureus and Klebsiella pneumoniae was found to be over 99%. Effects of AgNPs fabics on multidrug-resistant pathogens from the clinical specimens were also tested.

  9. Mammalian multidrug resistance lipopentasaccharide inhibitors from Ipomoea alba seeds.

    Science.gov (United States)

    Cruz-Morales, Sara; Castaeda-Gmez, Jhon; Figueroa-Gonzlez, Gabriela; Mendoza-Garca, Alma Delia; Lorence, Argelia; Pereda-Miranda, Rogelio

    2012-09-28

    As part of an ongoing project to identify inhibitors of multidrug efflux pumps, three new resin glycosides, albinosides I-III (1-3), were isolated from a CHCl(3)-soluble extract from the seeds of moon vine (Ipomoea alba). Their structures were established through NMR spectroscopy and mass spectrometry as partially acylated branched pentasaccharides derived from three new glycosidic acids, named albinosinic acids A-C (4-6). The same oligosaccharide core formed by two D-quinovose, one D-glucose, and two L-rhamnose units was linked to either convolvulinolic or jalapinolic acid for 1 and 3, respectively. They were partially esterified with (2R,3R)-3-hydroxy-2-methylbutanoic, acetic, or 2-methyl-2-butenoic acid. Compound 2 has two D-quinovose and three L-rhamnose units, linked to convolvulinolic acid, and its esterifying residues were characterized as two units of 2-methyl-2-butenoic acid. The aglycone lactonization site was located at C-2 of the terminal rhamnose unit (Rha) for 1, at C-3 of the terminal rhamnose unit (Rha') for 2, and at C-3 of the second saccharide unit (Glc) for 3. Reversal of multidrug resistance by this class of plant metabolites was also evaluated in vinblastine-resistant human breast carcinoma cells (MCF-7/Vin). The noncytotoxic compound 3 exerted the strongest potentiation effect of vinblastine susceptibility to over 2140-fold, while a moderate activity was observed for 1 (3.1-fold) and 2 (2.6-fold) at a concentration of 25 ?g/mL. PMID:22924480

  10. Knockdown of HOXA10 reverses the multidrug resistance of human chronic mylogenous leukemia K562/ADM cells by downregulating P-gp and MRP-1.

    Science.gov (United States)

    Yi, Ying-Jie; Jia, Xiu-Hong; Wang, Jian-Yong; Li, You-Jie; Wang, Hong; Xie, Shu-Yang

    2016-05-01

    Multidrug resistance (MDR) of leukemia cells is a major obstacle in chemotherapeutic treatment. The high expression and constitutive activation of P-glycoprotein (P-gp) and multidrug resistance protein-1 (MRP-1) have been reported to play a vital role in enhancing cell resistance to anticancer drugs in many tumors. The present study aimed to investigate the reversal of MDR by silencing homeobox A10 (HOXA10) in adriamycin (ADR)-resistant human chronic myelogenous leukemia (CML) K562/ADM cells by modulating the expression of P-gp and MRP-1. K562/ADM cells were stably transfected with HOXA10-targeted short hairpin RNA (shRNA). The results of reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis showed that the mRNA and protein expression of HOXA10 was markedly suppressed following transfection with a shRNA-containing vector. The sensitivity of the K562/ADM cells to ADR was enhanced by the silencing of HOXA10, due to the increased intracellular accumulation of ADR. The accumulation of ADR induced by the silencing of HOXA10 may be due to the downregulation of P-gp and MRP-1. Western blot analysis revealed that downregulating HOXA10 inhibited the protein expression of P-gp and MRP-1. Taken together, these results suggest that knockdown of HOXA10 combats resistance and that HOXA10 is a potential target for resistant human CML. PMID:27035504

  11. Molecular model of the outward facing state of the human P-glycoprotein (ABCB1, and comparison to a model of the human MRP5 (ABCC5

    Directory of Open Access Journals (Sweden)

    Sager Georg

    2007-09-01

    Full Text Available Abstract Background Multidrug resistance is a particular limitation to cancer chemotherapy, antibiotic treatment and HIV medication. The ABC (ATP binding cassette transporters human P-glycoprotein (ABCB1 and the human MRP5 (ABCC5 are involved in multidrug resistance. Results In order to elucidate structural and molecular concepts of multidrug resistance, we have constructed a molecular model of the ATP-bound outward facing conformation of the human multidrug resistance protein ABCB1 using the Sav1866 crystal structure as a template, and compared the ABCB1 model with a previous ABCC5 model. The electrostatic potential surface (EPS of the ABCB1 substrate translocation chamber, which transports cationic amphiphilic and lipophilic substrates, was neutral with negative and weakly positive areas. In contrast, EPS of the ABCC5 substrate translocation chamber, which transports organic anions, was generally positive. Positive-negative ratios of amino acids in the TMDs of ABCB1 and ABCC5 were also analyzed, and the positive-negative ratio of charged amino acids was higher in the ABCC5 TMDs than in the ABCB1 TMDs. In the ABCB1 model residues Leu65 (transmembrane helix 1 (TMH1, Ile306 (TMH5, Ile340 (TMH6 and Phe343 (TMH6 may form a binding site, and this is in accordance with previous site directed mutagenesis studies. Conclusion The Sav1866 X-ray structure may serve as a suitable template for the ABCB1 model, as it did with ABCC5. The EPS in the substrate translocation chambers and the positive-negative ratio of charged amino acids were in accordance with the transport of cationic amphiphilic and lipophilic substrates by ABCB1, and the transport of organic anions by ABCC5.

  12. The radiological spectrum of pulmonary multidrug-resistant tuberculosis: in HIV-Negative patients

    International Nuclear Information System (INIS)

    Background: Multidrug-resistant tuberculosis is a major worldwide health problem. In countries where tuberculosis is of moderate to high prevalence, the issue of Multidrug-resistant tuberculosis carries significant importance. Multidrug-resistant tuberculosis, similar to drug-sensitive tuberculosis, is contagious. Meanwhile its treatment is not only more difficult but also more expensive with lower success rates. Regarding clinical findings, there is no significant difference between Multidrug-resistant tuberculosis and drug-sensitive tuberculosis. Therefore determination of characteristic radiological findings in cases of Multidrug-resistant tuberculosis might be of help in early detection, and hence appropriate management of this disease condition. Objective: To explain the radiological spectrum of pulmonary Multidrug-resistant tuberculosis. Patients and methods: We retrospectively evaluated the radiographic images of 35 patients with clinically-and microbiologically- proven Multidrug-resistant tuberculosis admitted to our tertiary-care tuberculosis unit over a period of 13 months. The latest chest x-ray of all patients and the conventional chest CT scan without contrast of 15 patients were reviewed by three expert radiologists who rendered consensus opinion. Results: Of the 35 patients with imaging studies, 23 (66%) were male and 12 (34%) were female. The mean±SD age of participants was 38.2±17.3 (range: 16-20) years. 33 patients were known as secondary and only 2 had primary Multidrug-resistant tuberculosis. Chest radiography revealed cavitary lesion in 80% pulmonary infiltration in 89% and nodules in 80% of the cases. Pleurisy was the rarest finding observed in only 5 (14%) patients. All of 15 chest CT scans revealed cavitation, 93% of which were bilateral and multiple. Pleural involvement was seen in 93% of patients. Conclusion: Presence of multiple cavities, especially in both lungs, nodular and infiltrative lesions, and pleural effusion are main features of multidrug-resistant tuberculosis as compared to drug-sensitive tuberculosis

  13. Effect of NlpE Overproduction on Multidrug Resistance in Escherichia coli▿

    OpenAIRE

    Nishino, Kunihiko; Yamasaki, Seiji; Hayashi-Nishino, Mitsuko; Yamaguchi, Akihito

    2010-01-01

    NlpE, an outer membrane lipoprotein, functions during envelope stress responses in Gram-negative bacteria. In this study, we report that overproduction of NlpE increases multidrug and copper resistance through activation of the genes encoding the AcrD and MdtABC multidrug efflux pumps in Escherichia coli.

  14. Epidemic Spread of Multidrug-Resistant Tuberculosis in Johannesburg, South Africa

    OpenAIRE

    Marais, Ben J.; Mlambo, Charmaine K.; Rastogi, Nalin; Zozio, Thierry; Duse, Adriano G.; Victor, Thomas C; Marais, Else; Warren, Robin M

    2013-01-01

    Numerous reports have documented isolated transmission events or clonal outbreaks of multidrug-resistant Mycobacterium tuberculosis strains, but knowledge of their epidemic spread remains limited. In this study, we evaluated drug resistance, strain diversity, and clustering rates in patients diagnosed with multidrug-resistant (MDR) tuberculosis (TB) at the National Health Laboratory Service (NHLS) Central TB Laboratory in Johannesburg, South Africa, between March 2004 and December 2007. Pheno...

  15. Risk factors for acquired multidrug-resistant tuberculosis Fatores de risco para tuberculose multirresistente adquirida

    OpenAIRE

    Elizabeth Clara Barroso; Rosa Maria Salani Mota; Raimunda Oliveira Santos; Ana Lúcia Oliveira Sousa; Joana Brasileiro Barroso; Jorge Luís Nobre Rodrigues

    2003-01-01

    Multidrug-resistant tuberculosis (MDR-TB) is a severe and feared problem, that is difficult to control and has shown a tendency to increase worldwide. OBJECTIVE: To analyze the risk factors for acquired MDR-TB. CASUISTIC AND METHODS: A retrospective population-based case-control study was conducted. A bacillus was considered multidrug-resistant whenever it was resistant at least to rifampin (RFP) + isoniazid (INH), and a case was considered as sensitive tuberculosis (TB) if it had undergone t...

  16. Acquired Multidrug Antifungal Resistance in Candida lusitaniae during Therapy.

    Science.gov (United States)

    Asner, Sandra A; Giulieri, Stefano; Diezi, Manuel; Marchetti, Oscar; Sanglard, Dominique

    2015-12-01

    Candida lusitaniae is usually susceptible to echinocandins. Beta-1,3-glucan synthase encoded by FKS genes is the target of echinocandins. A few missense mutations in the C. lusitaniae FKS1 hot spot 1 (HS1) have been reported. We report here the rapid emergence of antifungal resistance in C. lusitaniae isolated during therapy with amphotericin B (AMB), caspofungin (CAS), and azoles for treatment of persistent candidemia in an immunocompromised child with severe enterocolitis and visceral adenoviral disease. As documented from restriction fragment length polymorphism (RFLP) and random amplified polymorphic DNA (RAPD) analysis, the five C. lusitaniae isolates examined were related to each other. From antifungal susceptibility and molecular analyses, 5 different profiles (P) were obtained. These profiles included the following: profile 1 (P1) (CAS MIC [?g/ml], 0.5; fluconazole [FLC] MIC, 0.25), determined while the patient was being treated with liposomal AMB for 3 months; P2 (FLC MIC [?g/ml], 0.25; CAS MIC, 4), while the patient was being treated with CAS for 2 weeks; P3 (CAS MIC [?g/ml], 0.5; FLC MIC, 32), while the patient was being treated with azoles and CAS initially followed by azoles alone for a week; P4 (CAS MIC [?g/ml], 8; FLC MIC, 8), while the patient was being treated with both drugs for 3 weeks; and P5 (AMB MIC [?g/ml], 0.125; CAS MIC, 8), while the patient was being treated with AMB and FLC for 2 weeks. CAS resistance was associated with resistance not only to micafungin and anidulafungin but also to AMB. Analysis of CAS resistance revealed 3 novel FKS1 mutations in CAS-resistant isolates (S638Y in P2; S631Y in P4; S638P in P5). While S638Y and -P are within HS1, S631Y is in close proximity to this domain but was confirmed to confer candin resistance using a site-directed mutagenesis approach. FLC resistance could be linked with overexpression of major facilitator gene 7 (MFS7) in C. lusitaniae P2 and P4 and was associated with resistance to 5-flurocytosine. This clinical report describes resistance of C. lusitaniae to all common antifungals. While candins or azole resistance followed monotherapy, multidrug antifungal resistance emerged during combined therapy. PMID:26438490

  17. Multidrug Resistance-Associated Protein 1 (MRP1) mediated vincristine resistance: effects of N-acetylcysteine and Buthionine Sulfoximine

    OpenAIRE

    Savas Burhan; Akca Hakan; Akan Selma; Akan Ilhan; Ozben Tomris

    2005-01-01

    Abstract Background Multidrug resistance mediated by the multidrug resistance-associated protein 1 (MRP1) decreases cellular drug accumulation. The exact mechanism of MRP1 involved multidrug resistance has not been clarified yet, though glutathione (GSH) is likely to have a role for the resistance to occur. N-acetylcysteine (NAC) is a pro-glutathione drug. DL-Buthionine (S,R)-sulfoximine (BSO) is an inhibitor of GSH synthesis. The aim of our study was to investigate the effect of NAC and BSO ...

  18. Sensitive, resistant and multi-drug resistant Acinetobacter baumanii at Saudi Arabia hospital eastern region.

    Science.gov (United States)

    Ahmed, Mughis Uddin; Farooq, Reshma; Al-Hawashim, Nadia; Ahmed, Motasim; Yiannakou, Nearchos; Sayeed, Fatima; Sayed, Ali Rifat; Lutfullah, Sualiha

    2015-05-01

    Since the Physicians start use of antibiotics long ago with un-notice drug resistance. However actual problem was recognized about 85 years ago. Antibiotic resistant and Multi-drug resistant bacterial strains are at rise throughout the world. It is physicians and researchers to take scientific research based appropriate action to overcome this ever-spreading problem. This study is designed to find out sensitive (S), resistant (R) and multi-drug resistant (MDR) Acinetobacter baumanii strain along with other isolates in the resident patients of Eastern Region of Saudi Arabia. Pseudomonas aeruginosa is excluded from other gram-negative organisms isolated from different sites as it will be dealt separately. This study is based in was retrospective observations designed to collect data of different stains of Acinetobacter baumanii with reference to their Sensitivity (S), Resistance (R), Multi-Drug Resistance (MDR) along with other Gram negative isolated from different sites (from 1st January 2004 to 31st December 2011) at King Abdulaziz Hospital located Eastern Region of Kingdom of Saudi Arabia (KSA). All necessary techniques were used to culture and perform sensitivity of these isolates. There were 4532 isolates out of which 3018 (67%) were from patients. Out of Acinetobacter baumanii infected were 906 (20%) while other 3626 (80%) isolates were miscellaneous. Numbers of patients or cases were 480 (53%) out of 906 isolates and numbers of patients or cases in other organisms were 2538 (70%) out of 3626 isolates. Acinetobacter baumanii infected patients 221 (46%) were male and 259 (54%) were female and the male and female ratio of 1:1.2. In other organisms this male female ratio was almost same. There was steady rise in number of patients and the hence the isolates from 2004 to 2011. Majority of the bacterial strains were isolated as single organism but some were isolated as double or triple or quadruple or more organisms from different sites. Sensitive, Resistant and Multi-Drug Resistant Acinetobacter baumanii have been isolated from different sites. The other Gram negative isolates included Escherichia coli, Klebsiella pneumoniae, Proteus vulgaris, Klebsiella oxytoca, Serratia marcescens and Stenotrophomonas maltophilia. A significant rise in R and MDR but there is rise in R and MDR Acinetobacter baumanii Strains has been interceded other isolates. It is important to adopt proper and sustainable policies and guideline regarding antibiotics prescription and used. We should also check our infection control practices in our hospital or healthcare settings. We should start antibiotics stewardship in our hospital in order to reducing or overcoming antibiotics Resistant (R) and Multi-Drug Resistant (MDR) strains prevalence. PMID:26004714

  19. Effects of Astragalus polysaccharides on P-glycoprotein efflux pump function and protein expression in H22 hepatoma cells in vitro

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    Tian Qing E

    2012-07-01

    Full Text Available Abstract Background Astragalus polysaccharides (APS are active constituents of Astragalus membranaceus. They have been widely studied, especially with respect to their immunopotentiating properties, their ability to counteract the side effects of chemotherapeutic drugs, and their anticancer properties. However, the mechanism by which APS inhibit cancer and the issue of whether that mechanism involves the reversal of multidrug resistance (MDR is not completely clear. The present paper describes an investigation of the effects of APS on P-glycoprotein function and expression in H22 hepatoma cell lines resistant to Adriamycin (H22/ADM. Methods H22/ADM cell lines were treated with different concentrations of APS and/or the most common chemotherapy drugs, such as Cyclophosphamid, Adriamycin, 5-Fluorouracil, Cisplatin, Etoposide, and Vincristine. Chemotherapeutic drug sensitivity, P-glycoprotein function and expression, and MDR1 mRNA expression were detected using MTT assay, flow cytometry, Western blotting, and quantitative RT-PCR. Results When used alone, APS had no anti-tumor activity in H22/ADM cells in vitro. However, it can increase the cytotoxicity of certain chemotherapy drugs, such as Cyclophosphamid, Adriamycin, 5-Fluorouracil, Cisplatin, Etoposide, and Vincristine, in H22/ADM cells. It acts in a dose-dependent manner. Compared to a blank control group, APS increased intracellular Rhodamine-123 retention and decreased P-glycoprotein efflux function in a dose-dependent manner. These factors were assessed 24 h, 48 h, and 72 h after administration. APS down regulated P-glycoprotein and MDR1 mRNA expression in a concentration-dependent manner within a final range of 0.8–500 mg/L and in a time-dependent manner from 24–72 h. Conclusion APS can enhance the chemosensitivity of H22/ADM cells. This may involve the downregulation of MDR1 mRNA expression, inhibition of P-GP efflux pump function, or both, which would decrease the expression of the MDR1 protein.

  20. Higher Desolvation Energy Reduces Molecular Recognition in Multi-Drug Resistant HIV-1 Protease

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    Ladislau C. Kovari

    2012-05-01

    Full Text Available Designing HIV-1 protease inhibitors that overcome drug-resistance is still a challenging task. In this study, four clinical isolates of multi-drug resistant HIV-1 proteases that exhibit resistance to all the US FDA-approved HIV-1 protease inhibitors and also reduce the substrate recognition ability were examined. A multi-drug resistant HIV-1 protease isolate, MDR 769, was co-crystallized with the p2/NC substrate and the mutated CA/p2 substrate, CA/p2 P1’F. Both substrates display different levels of molecular recognition by the wild-type and multi-drug resistant HIV-1 protease. From the crystal structures, only limited differences can be identified between the wild-type and multi-drug resistant protease. Therefore, a wild-type HIV-1 protease and four multi-drug resistant HIV-1 proteases in complex with the two peptides were modeled based on the crystal structures and examined during a 10 ns-molecular dynamics simulation. The simulation results reveal that the multi-drug resistant HIV-1 proteases require higher desolvation energy to form complexes with the peptides. This result suggests that the desolvation of the HIV-1 protease active site is an important step of protease-ligand complex formation as well as drug resistance. Therefore, desolvation energy could be considered as a parameter in the evaluation of future HIV-1 protease inhibitor candidates.

  1. Human multidrug-resistant Mycobacterium bovis infection in Mexico.

    Science.gov (United States)

    Vazquez-Chacon, Carlos A; Martínez-Guarneros, Armando; Couvin, David; González-Y-Merchand, Jorge A; Rivera-Gutierrez, Sandra; Escobar-Gutierrez, Alejandro; De-la-Cruz López, Juan J; Gomez-Bustamante, Adriana; Gonzalez-Macal, Gabriela A; Gonçalves Rossi, Livia Maria; Muñiz-Salazar, Raquel; Rastogi, Nalin; Vaughan, Gilberto

    2015-12-01

    Here, we describe the molecular characterization of six human Mycobacterium bovis clinical isolates, including three multidrug resistant (MDR) strains, collected in Mexico through the National Survey on Tuberculosis Drug Resistance (ENTB-2008), a nationally representative survey conducted during 2008-2009 in nine states with a stratified cluster sampling design. The genetic background of bovine M. bovis strains identified in three different states of Mexico was studied in parallel to assess molecular relatedness of bovine and human strains. Additionally, resistance to first and second line anti-tuberculosis (TB) drugs and molecular identification of mutations conferring drug resistance was also performed. All strains were characterized by spoligotyping and 24-loci MIRU-VNTRs, and analyzed using the SITVIT2 (n = 112,000 strains) and SITVITBovis (n = 25,000 strains) proprietary databases of Institut Pasteur de la Guadeloupe. Furthermore, data from this study (n = 55 isolates), were also compared with genotypes recorded for M. bovis from USA (n = 203), Argentina (n = 726), as well as other isolates from Mexico (independent from the present study; n = 147), to determine any evidence for genetic relatedness between circulating M. bovis strains. The results showed that all human M. bovis cases were not genetically related between them or to any bovine strain. Interestingly, a high degree of genetic variability was observed among bovine strains. Several autochthonous and presumably imported strains were identified. The emergence of drug-resistant M. bovis is an important public health problem that jeopardizes the success of TB control programs in the region. PMID:26299906

  2. Technetium-99m-hexakis-2-methoxyisobutylisonitrile scintigraphy and multidrug resistance-related protein expression in human primary lung cancer

    International Nuclear Information System (INIS)

    The occurrence of multidrug resistance (MDR) is a major cause of resistance to chemotherapeutic agents in patients with lung cancer, in part owing to the overexpression of MDR-related proteins. Technetium-99m-hexakis-2-methoxyisobutylisonitrile (99mTc-MIBI) has been shown to be a substrate for some MDR-related proteins. The aim of this study is to evaluate the role of 99mTc-MIBI scintigraphy for functional imaging of MDR-related protein phenotypes. To determine the correlation between 99mTc-MIBI scintigraphy and the expression level of P-glycoprotein (Pgp), multidrug-resistance protein (MRP), and glutathione-S-transferase Pi (GSTπ), 26 patients (17 men and 9 women, median age 57.5 years) with primary lung cancer were investigated. Following intravenous administration of 925 MBq 99mTc-MIBI, single-photon emission computed tomography (SPECT) and computed tomography (CT) were performed at 15 min and 2 h. On the basis of the fused images, tumor to background (T/B) ratio of both early and delayed images, and washout rate (WR%) of 99mTc-MIBI were calculated. The immunohistochemical staining of Pgp, MRP, and GSTπ was performed, and the expression level was semiquantitated using a pathoimage analysis system. The imaging results were compared with the status of Pgp, MRP, and GSTπ expression. The WR% of 99mTc-MIBI showed a significant positive correlation with Pgp expression (r=0.560, P=0.003), as no correlation was observed between WR% and MRP or GSTπ (r=0.354, P=0.076; r=0.324, P=0.106). Neither early T/B nor delayed T/B correlated with the expression level of Pgp, MRP, and GSTπ. WR%, Pgp, and GSTπ expression showed significant differences between squamous cell carcinoma (group A) and adenocarcinoma (group B). There was no significant difference among Pgp, MRP, and GSTπ expression levels in any cases (P>0.05). Our data confirmed that 99mTc-MIBI scintigraphy is useful for determining the MDR caused by Pgp in patients with primary lung cancer. (author)

  3. Molecular characterization of multidrug-resistant Klebsiella pneumoniae isolates

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    Xiang-hua Hou

    2015-09-01

    Full Text Available Klebsiella pneumoniae is an important cause of healthcare-associated infections worldwide. Selective pressure, the extensive use of antibiotics, and the conjugational transmission of antibiotic resistance genes across bacterial species and genera facilitate the emergence of multidrug-resistant (MDR K. pneumoniae. Here, we examined the occurrence, phenotypes and genetic features of MDR K. pneumoniae isolated from patients in intensive care units (ICUs at the First Affiliated Hospital of Xiamen University in Xiamen, China, from January to December 2011. Thirty-eight MDR K. pneumoniae strains were collected. These MDR K. pneumoniae isolates possessed at least seven antibiotic resistance determinants, which contribute to the high-level resistance of these bacteria to aminoglycosides, macrolides, quinolones and β-lactams. Among these isolates, 24 strains were extended-spectrum β-lactamase (ESBL producers, 2 strains were AmpC producers, and 12 strains were both ESBL and AmpC producers. The 38 MDR isolates also contained class I (28/38 and class II integrons (10/38. All 28 class I-positive isolates contained aacC1, aacC4, orfX, orfX’ and aadA1 genes. β-lactam resistance was conferred through blaSHV (22/38, blaTEM (10/38, and blaCTX-M (7/38. The highly conserved blaKPC-2 (37/38 and blaOXA-23(1/38 alleles were responsible for carbapenem resistance, and a gyrAsite mutation (27/38 and the plasmid-mediated qnrB gene (13/38 were responsible for quinolone resistance. Repetitive-sequence-based PCR (REP-PCR fingerprinting of these MDR strains revealed the presence of five groups and sixteen patterns. The MDR strains from unrelated groups showed different drug resistance patterns; however, some homologous strains also showed different drug resistance profiles. Therefore, REP-PCR-based analyses can provide information to evaluate the epidemic status of nosocomial infection caused by MDR K. pneumoniae; however, this test lacks the power to discriminate some isolates. Thus, we propose that both genotyping and REP-PCR typing should be used to distinguish genetic groups beyond the species level.

  4. Prognostic significance of multidrug-resistance protein (MDR-1) in renal clear cell carcinomas: A five year follow-up analysis

    International Nuclear Information System (INIS)

    A large number of renal cancer patients shows poor or partial response to chemotherapy and the mechanisms have not been still understood. Multi-drug resistance is the principal mechanism by which many cancers develop resistance to chemotherapic drugs. The role of the multi-drug resistant transporter (MDR-1/P-glycoprotein), the gene product of MDR-1, and that one of the so-called multi-drug resistance associated protein (MRP), two energy-dependent efflux pumps, are commonly known to confer drug resistance. We studied MDR-1 expression in selected cases of renal cell carcinoma (RCC), clear cell type, with long-term follow-up, in order to establish its prognostic role and its possible contribution in the choice of post-surgical therapy. MDR-1 has been studied by standard LSAB-HRP immunohistochemical technique, in paraffin embedded RCC samples. Protein expression has been compared to clinical and histopathological data and to disease specific survival of RCC patients, by Kaplan-Meier curve and Cox multivariate regression analyses. Two groups of RCCs were obtained by esteeming MDR-1 expression and disease specific survival (obtained with Kaplan-Meier curve and Cox multivariate regression analyses): the first one presents low or absent MDR-1 expression and good survival; the second one is characterized by high MDR-1 expression and significant poor outcome (p < 0.05). Afterwards, we have found disease specific survival, adjusted for stages and independent of therapy: this difference of survival rates was statistically significant (p < 0.05). Stage adjusted disease specific survival rate, according to MDR-1 expression and therapy in patients affected by RCC in early stage (stage I), has revealed that the group of patients with high MDR-1 expression and without adjuvant therapy showed poor survival (p < 0.05). Cox multivariate regression analysis has confirmed that, in our cohort of RCC (clear cell type) patients, the strong association between MDR-1 and worse outcome is independent not only of the adjuvant therapy, but also of the other prognostic parameters (p < 0.05). In our opinion, the results of this study well prove the relationship between MDR-1 expression and worse clinical prognosis in RCC, because MDR-1 over-expressing RCCs can be considered a group of tumours with a more aggressive behavior. This finding outlines a possible role of MDR-1 as prognostic factor, dependent and independent of multidrug resistance. These results could be useful to predict cancer evolution and to choose the appropriate treatment: this is another step that can stimulate further promising and interesting investigations on broader study population

  5. ANTIBIOTIC SYNERGY TEST: CHECKERBOARD METHOD ON MULTIDRUG RESISTANT PSEUDOMONAS AERUGINOSA

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    Spoorthi N. Jain

    2011-12-01

    Full Text Available Pseudomonas aeruginosa is a global emergence of multidrug resistant strains leading to a wide variety of nosocomial infections in humans. The clinical use of combination of antibiotic therapy for gram negative infections is probably more effective than monotherapy. Certain combinations of antibiotic exhibit synergistic antibacterial effects. Ampicillin and Kanamycin are the commonly used potent bactericidal antibiotics, active against gram negative bacteria and also act synergistically. Antibiotic susceptibility of Pseudomonas aeruginosa showed a high level of resistance with Optochin and Rifamycin. An intermediate effect was seen to Erythromycin and Chloramphenicol, Kanamycin and Ampicillin showed different minimum inhibitory concentration (MIC. Thus, the susceptible antibiotics were used in the checker board technique, which appears useful for determining antibiotic synergism against Pseudomonas aeruginosa.. The ?FIC results showed synergy for concentrations of 80g/ml and 40g/ml of antibiotic combinations with fractional inhibitory concentration (FIC of 0.48 at 37?C over night incubation per ml. Thus, the combinations tested were bactericidal indicating the minimum inhibitory concentration and no growth illustrated the extensive activity of kanamycin which was enforced by the ampicillin resulting in an antibacterial effect.

  6. Multidrug Resistance in Fungi: Regulation of Transporter-encoding Gene Expression

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    ScottMoye-Rowley

    2014-04-01

    Full Text Available A critical risk to the continued success of antifungal chemotherapy is the acquisition of resistance; a risk exacerbated by the few classes of effective antifungal drugs. Predictably, as the use of these drugs increases in the clinic, more resistant organisms can be isolated from patients. A particularly problematic form of drug resistance that routinely emerges in the major fungal pathogens is known as multidrug resistance. Multidrug resistance refers to the simultaneous acquisition of tolerance to a range of drugs via a limited or even single genetic change. This review will focus on recent progress in understanding pathways of multidrug resistance in fungi including those of most medical relevance. Analyses of multidrug resistance in Saccharomyces cerevisiae have provided the most detailed outline of multidrug resistance in a eukaryotic microorganism. Multidrug resistant isolates of S. cerevisiae typically result from changes in the activity of a pair of related transcription factors that in turn elicit overproduction of several target genes. Chief among these is the ATP-binding cassette-encoding gene PDR5. Interestingly, in the medically important Candida species, very similar pathways are involved in acquisition of multidrug resistance. In both C. albicans and C. glabrata, changes in the activity of transcriptional activator proteins elicits overproduction of a protein closely related to S. cerevisiae Pdr5 called Cdr1. The major filamentous fungal pathogen, Aspergillus fumigatus, was previously thought to acquire resistance to azole compounds (the principal antifungal drug class via alterations in the azole drug target-encoding gene cyp51A. More recent data indicate that pathways in addition to changes in the cyp51A gene are important determinants in A. fumigatus azole resistance. We will discuss findings that suggest azole resistance in A. fumigatus and Candida species may share more mechanistic similarities than previously thought.

  7. Reversal of the multidrug resistance by drug combination using multifunctional liposomes

    Science.gov (United States)

    Patel, Niravkumar R.

    One of the major obstacles to the success of cancer chemotherapy is the multi-drug resistance (MDR) that results due mainly to the over-expression of drug efflux transporter pumps such as P-glycoprotein (P-gp). Highly efficacious third generation P-gp inhibitors, like tariquidar, have shown promising results against MDR. However, P-gp is also expressed in normal tissues like the blood-brain barrier, gastrointestinal tract, liver and kidney. It is therefore important to limit the exposure of P-gp inhibitors to normal tissues and increase their co-localization with anticancer agents in tumor tissues to maximize the efficacy of a P-gp inhibitor. To minimize non-specific binding and increase its delivery to tumor tissues, liposomes, self-assembling phospholipid vesicles, were chosen as a drug delivery vehicle. The liposome has been identified as a system capable of carrying molecules with diverse physicochemical properties. It can also alter the pharmacokinetic profile of loaded molecules which is a concern with both tariquidar and paclitaxel. Liposomes can easily be surface-modified rendering them cell-specific as well as organelle-specific. The main objective of present study was to develop an efficient liposomal delivery system which would deliver therapeutic molecules of interest to tumor tissues and avoid interaction with normal tissues. In this study, the co-delivery of tariquidar and paclitaxel into tumor cells to reverse the MDR using long-circulating cationic liposomes was investigated. SKOV-3TR, the resistant variant of SKOV-3 and MCF-7/ADR, the resistant variant of MCF-7 were used as model cell lines. Uniform liposomal formulations were generated with high incorporation efficiency and no apparent decrease in tariquidar potency towards P-gp. Tariquidar- and paclitaxel- co-loaded long-circulating liposomes showed significant re-sensitization of SKOV-3TR and MCF-7/ADR for paclitaxel in vitro. Further modification of these liposomes with antitumor 2C5 resulted in increased cell association with these cancer cells. The 2C5-modified immunoliposomes, along with unmodified liposomes co-loaded with tariquidar and paclitaxel were tested for their antitumor effects in vivo. Significant tumor growth inhibition occurred with combination therapy in resistant as well as sensitive cell lines. However, immunoliposomes failed to increase antitumor effect in vivo as spontaneous accumulation of liposomes at added dose may have saturated tumor accumulation. We were also interested in evaluating physiological factors responsible for the MDR. Spheroids grown in vitro provided platform to demonstrate many characteristics of tumor tissues such as cell-cell interaction, a hypoxic core, low pH environment at core and a relevant genetic profile. In this study, spheroids were utilized to evaluate paclitaxel cytotoxity and to evaluate effects of 2C5 modification on cellular uptake. Lack of cytotoxicity was observed in spheroids treated with paclitaxel alone as well as in combination with tariquidar. Likely explanations could be the presence of cells in diverse cell cycle stages and limited penetration. Also, increased uptake was observed in spheroids when treated with 2C5-modified Rh-labeled liposomes compared to UPC10-modified Rh-labeled liposomes. Such results have clearly demonstrated the importance of using this novel research model in cancer research.

  8. Multiple Antibiotic Resistance in Stenotrophomonas maltophilia: Involvement of a Multidrug Efflux System

    OpenAIRE

    Zhang, Li; Li, Xian-Zhi; Poole, Keith

    2000-01-01

    Clinical strains of Stenotrophomonas maltophilia are often highly resistant to multiple antibiotics, although the mechanisms of resistance are generally poorly understood. Multidrug resistant (MDR) strains were readily selected by plating a sensitive reference strain of the organism individually onto a variety of antibiotics, including tetracycline, chloramphenicol, ciprofloxacin, and norfloxacin. Tetracycline-selected MDR strains typically showed cross-resistance to erythromycin and fluoroqu...

  9. Development of PET and SPECT radiopharmaceuticals to study multi-drug resistance (MDR)

    International Nuclear Information System (INIS)

    Full text: Cellular resistance or Multidrug Resistance (MDR) to cytotoxic agents is the major cause of treatment failure in many human cancers. P-glycoprotein (Pgp), a Mr 17,0000 transmembrane protein and Multi Resistance Protein (MRP) are two proteins that are over expressed and confer resistance to a large number of chemotherapeutic agents by enhancing their extracellular transport. P-glycoprotein is expressed at a relative high level in treated and untreated human malignant tumours, including renal, colonic, adrenal, hepatocellular carcinoma and a considerable percentage of breast carcinomas. 99mTc-Sestamibi, a lipophilic cationic complex is a transport substrate for Pgp. In clinical studies of human neoplasms it was found that tumour uptake and clearance of this tracer correlate with Pgp expression and may be used for the phenotypic assessment of MDR. However, new tracers with better substrate specificity for Pgp and other drug transporters would greatly assist in optimising chemotherapeutic treatment and improving patient management by predicting tumour response to therapy and to assist in the development of antagonists, which may reverse or halt MDR. The aim of this project is therefore to develop PET and SPECT radiopharmaceuticals with improved affinity and selectivity for Pgp and MRP for the clinical evaluation of MDR in cancer patients. To optimise cellular transport characteristics, a number of chemical families that have been found to be substrates of Pgp and other drug efflux pumps, will be investigated. In the first instance, a series of drugs based on the flavonol natural product, Quercetin will be developed, screened for MDR and radiolabelled with PET and SPECT isotopes. Quercetin and related flavonol derivatives have been selected for this project because of their moderate to good affinity for Pgp. With the assistance of molecular modeling and in vitro studies, structural modification will be undertaken to improve the specificity and affinity for PgP. This generic structure also offers the flexibility to prepare a wide range of molecules that are readily suitable for halogenation with either Iodine-123 or F-18 for radiopharmaceutical development. Finally these phenolic type of molecules based on Quercetin are relatively less toxic than equivalent drugs. In this proposal an extensive research program is required to develop specific drugs for the different efflux pumps present in the body, which represent multi drug resistance. A successful outcome is critically dependent on the initial synthesis of a large number of compounds for screening. The combined effort of the three institutions will boost resources significantly to a critical level required to competitively produce successful outcomes in the project. Optimisation studies on derivatives of these flavonols will be made in parallel with the assistance of in vitro studies by measuring the binding of compounds to the ATP sites of Pgp. An extensive in vitro screening program has been established in Paris, prior to radiolabelling and in vivo evaluation. Structural optimisation and attachment of radionuclides to promising molecular targets will be explored using molecular modelling. Initially computational chemistry using Sybyl will be undertaken to develop a pharmacophore and to assist with the incorporation of the radionuclide in the appropriate position. In vivo evaluation will be undertaken in specific animal models both at the University of Tours in France as well as at the Sydney Cancer Centre in Australia. PET functional imaging studies may be undertaken on successful candidates at the SHFJ in Orsay, France whilst SPECT imaging will be undertaken in both Tours and in Sydney. In addition to intellectual property and potential commercial product(s), specific PET or SPECT radiopharmaceuticals can provide valuable information on the assessment of MDR in cancer patients through functional, non-invasive, imaging and therefore make significant contributions to the understanding of MDR. Scientific and clinical researchers from both countries identified the use of PET and SPECT functional imaging of MDR as a priority area of research. Finally the clear benefits to cancer patients include choice of treatment, with minimisation of ineffective drug treatments at an earlier stage, hence reduced drug side effects and discomfort to patients and improvements in their quality of life. There are also reduced health costs by avoiding expensive and ineffective drug treatments

  10. Transgenic mice that express the human multidrug-resistance gene in bone marrow enable a rapid identification of agents that reverse drug resistance.

    OpenAIRE

    Mickisch, G H; Merlino, G T; Galski, H.; Gottesman, M M; Pastan, I.

    1991-01-01

    The development of preclinical models for the rapid testing of agents that circumvent multidrug resistance in cancer is a high priority of research on drug resistance. A common form of multidrug resistance in human cancer results from expression of the MDR1 gene, which encodes a Mr 170,000 glycoprotein that functions as a plasma membrane energy-dependent multidrug efflux pump. We have engineered transgenic mice that express this multidrug transporter in their bone marrow and demonstrated that...

  11. Additional Drug Resistance of Multidrug-Resistant Tuberculosis in Patients in 9 Countries

    OpenAIRE

    Kurbatova, Ekaterina V.; Dalton, Tracy; Ershova, Julia; Tupasi, Thelma; Caoili, Janice Campos; van der Walt, Martie; Kvasnovsky, Charlotte; Yagui, Martin; Bayona, Jaime; Carmen CONTRERAS; Leimane, Vaira; Via, Laura E.; Kim, HeeJin; Akksilp, Somsak; Kazennyy, Boris Y.

    2015-01-01

    Data from a large multicenter observational study of patients with multidrug-resistant tuberculosis (MDR TB) were analyzed to simulate the possible use of 2 new approaches to treatment of MDR TB: a short (9-month) regimen and a bedaquiline-containing regimen. Of 1,254 patients, 952 (75.9%) had no resistance to fluoroquinolones and second-line injectable drugs and thus would qualify as candidates for the 9-month regimen; 302 (24.1%) patients with resistance to a fluoroquinolone or second-line ...

  12. Prevalence of Multidrug Resistant Mycobacterium tuberculosis by Mycobacteria growth

    Directory of Open Access Journals (Sweden)

    Livani S

    2012-01-01

    Full Text Available Background and objectives: Identification and monitoring ofmultidrugresistant Mycobacterium tuberculosis strains (MDR ishighlighted by the high risk of their spreading in different areas.Prevalence of these strains was evaluated in Golestan province innortheast of Iran.Material and Methods: Drug susceptibility testing to Isoniazid andrifampin was carried out for 148 clinical samples that had grown inMycobacteria growth indicator tube (MGIT system, according to themanufacturer's instructions (Becton-Dickinson, USA. The associationof drug resistance frequency with demographic characteristics andgrowth time were investigated. The appropriate statistical tests, X2 andstudent Ttest were performed for comparison of these variants. A pvalue>0.05 was considered significant in all cases.Results: The turnaround time required for growth of Mycobacteriumtuberculosis in MGIT system was between 2 to 55 days (mean16.3±10.4 days. Of all samples studied, 17.6% and 3.4% wereresistant to Isoniazid and rifampin, respectively, and 3.4% (5 sampleswere MDR (CI 95%; 1- 6%. The turnaround time required fordetermining MDR cases was 9.6 days. No statistically significantassociation was found between the resistance to the drugs and none ofthe factors including sex, age, type of clinical sample, and positivity ofthe smear.Conclusion: The prevalence of MDR in the studied region wasdetermined to be 3.4% which is similar to the country-wideevaluations. The turnaround time for Mycobacterium growth and antidrug susceptibility result can be shortened by MGIT method.Key words: Mycobacterium tuberculosis, Mycobacterium GrowthIndicator Tube, Multidrug Resistant

  13. Detergents as intrinsic P-glycoprotein substrates and inhibitors.

    Science.gov (United States)

    Li-Blatter, Xiaochun; Nervi, Pierluigi; Seelig, Anna

    2009-10-01

    We assessed the interaction of three electrically neutral detergents (Triton X-100, C(12)EO(8), and Tween 80) with P-glycoprotein (ABCB1, MDR1) and identified the molecular elements responsible for this interaction. To this purpose we titrated P-glycoprotein in inside-out plasma membrane vesicles of MDR1-transfected mouse embryo fibroblasts (NIH-MDR1-G185) with the detergents below their critical micelle concentration, CMC. The P-glycoprotein ATPase measured as a function of the detergent concentration yielded bell-shaped activity curves which were evaluated with a two-site binding model. The lipid-water partition coefficient and the transporter-water binding constant of the detergents were measured independently. Knowledge of these two parameters allowed assessment of the free energy of detergent binding to P-glycoprotein in the lipid membrane, DeltaG(tl)(0), that reflects the direct detergent-transporter affinity. It increased as the number of ethoxyl groups increased, suggesting that these hydrogen bond acceptor groups are the key elements for the detergent-transporter interaction in the lipid membrane. The free energy of binding to P-glycoprotein per ethoxyl group (EO) was determined as approximately DeltaG(EO)(0)=-1.6 kJ/mol. The present findings moreover document that, depending on the concentration applied, detergents are intrinsic substrates for, or inhibitors of P-glycoprotein. PMID:19631191

  14. Bloodstream infections caused by multi-drug resistant Proteus mirabilis: Epidemiology, risk factors and impact of multi-drug resistance.

    Science.gov (United States)

    Korytny, Alexander; Riesenberg, Klaris; Saidel-Odes, Lisa; Schlaeffer, Fransisc; Borer, Abraham

    2016-06-01

    Background The prevalence of antimicrobial co-resistance among ESBL-producing Enterobactereaceae is extremely high in Israel. Multidrug-resistant Proteus mirabilis strains (MDR-PM), resistant to almost all antibiotic classes have been described. The aim was to determine the risk factors for bloodstream infections caused by MDR-PM and clinical outcomes. Methods A retrospective case-control study. Adult patients with PM bacteremia during 7 years were identified retrospectively and their files reviewed for demographics, underlying diseases, Charlson Comorbidity Index, treatment and outcome. Results One hundred and eighty patients with PM-bloodstream infection (BSI) were included; 90 cases with MDR-PM and 90 controls with sensitive PM (S-PM). Compared to controls, cases more frequently were from nursing homes, had recurrent hospital admissions in the past year and received antibiotic therapy in the previous 3 months, were bedridden and suffered from peripheral vascular disease and peptic ulcer disease (p < 0.001). Two-thirds of the MDR-PM isolates were ESBL-producers vs 4.4% of S-PM isolates (p < 0.001, OR = 47.6, 95% CI = 15.9-142.6). In-hospital crude mortality rate of patients with MDR-PM BSI was 37.7% vs 23.3% in those with S-PM BSI (p = 0.0359, OR = 2, 95% CI = 1.4-3.81). Conclusions PM bacteremia in elderly and functionally-dependent patients is likely to be caused by nearly pan-resistant PM strains in the institution; 51.8% of the patients received inappropriate empiric antibiotic treatment. The crude mortality rate of patients with MDR-PM BSI was significantly higher than that of patients with S-PM BSI. PMID:26763474

  15. Investigation of multidrug-resistant fatal colisepticaemia in weanling pigs

    Directory of Open Access Journals (Sweden)

    Folorunso O. Fasina

    2015-02-01

    Full Text Available Escherichia coli is usually a benign commensal of the gut microflora. However, when E. coli acquires virulence genes it can multiply rapidly and cause disease through colonisation of the intestinal mucosa. Escherichia coli can become a significant pathogen in young pigs. We report an investigation of fatal colisepticaemia in weanling pigs from emerging farms where piglets and weaners were diarrhoeic and the mortality rate ranged between 15% and 70% in each litter. Faecal and tissue samples were processed for histopathology, bacteriology and molecular biology (multiplex and monoplex polymerase chain reaction and we recovered enteroaggregative multidrug-resistant E. coli producing EAST-1 enterotoxin. An association between poor housing conditions and the observed cases was established and future management programmes were recommended to reduce the impact of such pathogens. Enteroaggregative E. coli is becoming a major problem in the pig industry. It therefore becomes necessary to establish the full impact of E. coli on the South African pig industry and to determine the geographic extent of the problem.

  16. The Role of CD44 and ERM Proteins in Expression and Functionality of P-glycoprotein in Breast Cancer Cells.

    Science.gov (United States)

    Pokharel, Deep; Padula, Matthew P; Lu, Jamie F; Jaiswal, Ritu; Djordjevic, Steven P; Bebawy, Mary

    2016-01-01

    Multidrug resistance (MDR) is often attributed to the over-expression of P-glycoprotein (P-gp), which prevents the accumulation of anticancer drugs within cells by virtue of its active drug efflux capacity. We have previously described the intercellular transfer of P-gp via extracellular vesicles (EVs) and proposed the involvement of a unique protein complex in regulating this process. In this paper, we investigate the role of these mediators in the regulation of P-gp functionality and hence the acquisition of MDR following cell to cell transfer. By sequentially silencing the FERM domain-binding proteins, Ezrin, Radixin and Moesin (ERM), as well as CD44, which we also report a selective packaging in breast cancer derived EVs, we have established a role for these proteins, in particular Radixin and CD44, in influencing the P-gp-mediated MDR in whole cells. We also report for the first time the role of ERM proteins in the vesicular transfer of functional P-gp. Specifically, we demonstrate that intercellular membrane insertion is dependent on Ezrin and Moesin, whilst P-gp functionality is governed by the integrity of all ERM proteins in the recipient cell. This study identifies these candidate proteins as potential new therapeutic targets in circumventing MDR clinically. PMID:26938523

  17. The Role of CD44 and ERM Proteins in Expression and Functionality of P-glycoprotein in Breast Cancer Cells

    Directory of Open Access Journals (Sweden)

    Deep Pokharel

    2016-03-01

    Full Text Available Multidrug resistance (MDR is often attributed to the over-expression of P-glycoprotein (P-gp, which prevents the accumulation of anticancer drugs within cells by virtue of its active drug efflux capacity. We have previously described the intercellular transfer of P-gp via extracellular vesicles (EVs and proposed the involvement of a unique protein complex in regulating this process. In this paper, we investigate the role of these mediators in the regulation of P-gp functionality and hence the acquisition of MDR following cell to cell transfer. By sequentially silencing the FERM domain-binding proteins, Ezrin, Radixin and Moesin (ERM, as well as CD44, which we also report a selective packaging in breast cancer derived EVs, we have established a role for these proteins, in particular Radixin and CD44, in influencing the P-gp-mediated MDR in whole cells. We also report for the first time the role of ERM proteins in the vesicular transfer of functional P-gp. Specifically, we demonstrate that intercellular membrane insertion is dependent on Ezrin and Moesin, whilst P-gp functionality is governed by the integrity of all ERM proteins in the recipient cell. This study identifies these candidate proteins as potential new therapeutic targets in circumventing MDR clinically.

  18. Quinine improves the results of intensive chemotherapy in myelodysplastic syndromes expressing P glycoprotein: results of a randomized study.

    Science.gov (United States)

    Wattel, E; Solary, E; Hecquet, B; Caillot, D; Ifrah, N; Brion, A; Mahé, B; Milpied, N; Janvier, M; Guerci, A; Rochant, H; Cordonnier, C; Dreyfus, F; Buzyn, A; Hoang-Ngoc, L; Stoppa, A M; Gratecos, N; Sadoun, A; Stamatoulas, A; Tilly, H; Brice, P; Maloisel, F; Lioure, B; Desablens, B; Fenaux, P

    1998-09-01

    Intensive chemotherapy produces a lower complete remission (CR) rate in the myelodysplastic syndromes (MDS) than in de novo acute myeloid leukaemia (AML), possibly due in part to a higher incidence of P glycoprotein (PGP) expression in MDS blast cells. We designed a randomized trial of intensive chemotherapy with or without quinine, an agent capable of reverting the multidrug resistance (mdr) phenotype, in patients aged < or = 65 years with high-risk MDS. Patients were randomized to receive mitoxantrone 12 mg/m2/d days 2-5 + AraC 1 g/m2/12 h days 1-5, with (Q+) or without (Q-) quinine (30 mg/kg/d). 131 patients were included. PGP expression analysis was successful in 91 patients. In the 42 PGP-positive cases, 13/25 (52%) patients in the Q+ group achieved CR, compared to 3/17 (18%) patients in the Q- group (P = 0.02) and median Kaplan-Meier survival was 13 months in the Q+ group, and 8 months in the Q- group (P = 0.01). No life-threatening toxicity was observed with quinine. In conclusion, the results of this randomized study show that quinine increases the CR rate and survival in PGP-positive MDS cases treated with intensive chemotherapy. PMID:9734653

  19. Identification of antimicrobial resistance genes in multidrug-resistant clinical Bacteroides fragilis isolates by whole genome shotgun sequencing

    DEFF Research Database (Denmark)

    Sydenham, Thomas Vognbjerg; Sóki, József; Hasman, Henrik; Wang, Mikala; Stenz Justesen, Ulrik

    2015-01-01

    genome shotgun sequencing as a method for predicting antimicrobial resistance properties, one meropenem resistant and five multidrug-resistant blood culture isolates were sequenced and antimicrobial resistance genes and IS elements identified using ResFinder 2.1 (http://cge.cbs.dtu.dk/services...

  20. Principles for designing future regimens for multidrug-resistant tuberculosis

    Directory of Open Access Journals (Sweden)

    Grania Brigden

    2014-01-01

    Full Text Available Fewer than 20% of patients with multidrug-resistant (MDR tuberculosis are receiving treatment and there is an urgent need to scale up treatment programmes. One of the biggest barriers to scale-up is the treatment regimen, which is lengthy, complex, ineffective, poorly tolerated and expensive. For the first time in over 50 years, new drugs have been developed specifically to treat tuberculosis, with bedaquiline and potentially delamanid expected to be available soon for treatment of MDR cases. However, if the new drugs are merely added to the current treatment regimen, the new regimen will be at least as lengthy, cumbersome and toxic as the existing one. There is an urgent need for strategy and evidence on how to maximize the potential of the new drugs to improve outcomes and shorten treatment. We devised eight key principles for designing future treatment regimens to ensure that, once they are proven safe in clinical trials, they will be clinically effective and programmatically practicable. Regimens should contain at least one new class of drug; be broadly applicable for use against MDR and extensively drug-resistant Mycobacterium tuberculosis complex strains; contain three to five effective drugs, each from a different drug class; be delivered orally; have a simple dosing schedule; have a good side-effect profile that allows limited monitoring; last a maximum of 6 months; and have minimal interaction with antiretrovirals. Following these principles will maximize the potential of new compounds and help to overcome the clinical and programmatic disadvantages and scale-up constraints that plague the current regimen.

  1. Interleukin-6: A Critical Cytokine in Cancer Multidrug Resistance.

    Science.gov (United States)

    Ghandadi, Morteza; Sahebkar, Amirhossein

    2016-01-01

    Multidrug resistance (MDR) is a phenomenon through which tumor cells develop resistance against the cytotoxic effects of various structurally and mechanistically unrelated chemotherapeutic agents. The most consistent feature in MDR is overexpression and/or overactivity of ATP-dependent drug efflux transporters. Other mechanisms such as overexpression of drug-detoxifying enzymes and alterations in pro-survival or pro-death signaling pathways are also responsible for MDR. Inflammatory mediators including interleukin-6 (IL-6) play important roles in various events during inflammation and are also involved in development and progression of several types of cancers. Mounting evidence has suggested a crosstalk between IL-6 and MDR in cancer, highlighting the role of IL-6 in chemotherapy response, and the potential opportunity to control MDR through modulation of IL-6 expression. Upregulation of IL-6 has been shown to promote MDR through activation of Janus kinases (JAK)/signal transducer and activator of transcription 3 (STAT3), phosphatidylinositol-3 kinase (PI3K)/protein kinase B (Akt), and Ras-MAPK (mitogen-activated protein kinase) pathways. Activation of the aforementioned pathways changes the expression pattern of several genes involved in proliferation, survival and cell cycle regulation, thus facilitating MDR. Conversely, IL-6 inhibition using different strategies (antibodies, siRNA, and antisense transfection) has been shown to improve tumor responsiveness and mitigate MDR in different cancer cell lines. This review focuses on the in vitro, experimental and clinical findings on the role of IL-6 in MDR, and potential therapeutic opportunities arising from this role of IL-6. PMID:26601970

  2. Dominance of multidrug resistant CC271 clones in macrolide-resistant streptococcus pneumoniae in Arizona

    Directory of Open Access Journals (Sweden)

    Bowers Jolene R

    2012-01-01

    Full Text Available Abstract Background Rates of resistance to macrolide antibiotics in Streptococcus pneumoniae are rising around the world due to the spread of mobile genetic elements harboring mef(E and erm(B genes and post-vaccine clonal expansion of strains that carry them. Results Characterization of 592 clinical isolates collected in Arizona over a 10 year period shows 23.6% are macrolide resistant. The largest portion of the macrolide-resistant population, 52%, is dual mef(E/erm(B-positive. All dual-positive isolates are multidrug-resistant clonal lineages of Taiwan19F-14, mostly multilocus sequence type 320, carrying the recently described transposon Tn2010. The remainder of the macrolide resistant S. pneumoniae collection includes 31% mef(E-positive, and 9% erm(B-positive strains. Conclusions The dual-positive, multidrug-resistant S. pneumoniae clones have likely expanded by switching to non-vaccine serotypes after the heptavalent pneumococcal conjugate vaccine release, and their success limits therapy options. This upsurge could have a considerable clinical impact in Arizona.

  3. Multidrug and extensively drug-resistant tuberculosis from a general practice perspective

    Directory of Open Access Journals (Sweden)

    BM Yashodhara

    2010-10-01

    Full Text Available BM Yashodhara1, Choo Beng Huat1, Lakshmi Nagappa Naik1, Shashikiran Umakanth2, Manjunatha Hande2, Joseph M Pappachan31Department of Medicine, Melaka Manipal Medical College, Melaka, India; 2Department of Medicine, Kasturaba Medical College, Manipal; 3Department of Medicine, Kottayam Medical College, Kerala, IndiaAbstract: Despite intensive efforts to eradicate the disease, tuberculosis continues to be a major threat to Indian society, with an estimated prevalence of 3.45 million cases in 2006. Emergence of multidrug-resistant tuberculosis has complicated eradication attempts in recent years. Incomplete and/inadequate treatment are the main causes for development of drug resistance. Directly observed therapy, short-course (DOTS is the World Health Organization (WHO strategy for worldwide eradication of tuberculosis, and our country achieved 100% coverage for DOTS through the Revised National Tuberculosis Control Program in 2006. For patients with multidrug-resistant tuberculosis, the WHO recommends a DOTS-Plus treatment strategy. Early detection and prompt treatment of multidrug-resistant tuberculosis is crucial to avoid spread of the disease and also because of the chances of development of potentially incurable extensively drug-resistant tuberculosis in these cases. This review discusses the epidemiologic, diagnostic, and therapeutic aspects of multidrug-resistant tuberculosis, and also outlines the role of primary care doctors in the management of this dangerous disease.Keywords: multidrug-resistant, extensively drug-resistant, tuberculosis, general practice

  4. Emergence of fluoroquinolones-resistant strains of Salmonella typhi: Watch on multidrug-resistant isolates

    Directory of Open Access Journals (Sweden)

    Subhash C Arya

    2010-05-01

    Full Text Available Subhash C Arya, Nirmala Agarwal, Shekhar Agarwal, Dolly WadhwaSant Parmanand Hospital, Delhi, IndiaEmergence of multidrug-resistant Salmonella typhi has been responsible for clinical challenges for clinicians. Recently, frequent isolation and dissemination of fluoroquinolones-resistant strains of S. enterica in Surabaya, Indonesia was in the news. Subsequently, Yangai and colleagues1 recommended regular communications between laboratory professionals and clinicians. Collaboration between laboratory personnel and clinicians would be essential to offer a rational empiric antibiotic recipe while awaiting antibiotic susceptibility test results (AST for any patient.

  5. Draft genome sequence of a multidrug-resistant Chryseobacterium indologenes isolate from Malaysia

    Directory of Open Access Journals (Sweden)

    Choo Yee Yu

    2016-03-01

    Full Text Available Chryseobacterium indologenes is an emerging pathogen which poses a threat in clinical healthcare setting due to its multidrug-resistant phenotype and its common association with nosocomial infections. Here, we report the draft genome of a multidrug-resistant C. indologenes CI_885 isolated in 2014 from Malaysia. The 908,704-kb genome harbors a repertoire of putative antibiotic resistance determinants which may elucidate the molecular basis and underlying mechanisms of its resistant to various classes of antibiotics. The genome sequence has been deposited in DDBJ/EMBL/GenBank under the accession number LJOD00000000.

  6. ACTION OF NEWER DISINFECTANTS ON MULTIDRUG RESISTANT BACTERIA

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    Bipasa

    2014-03-01

    Full Text Available BACKGROUND: Current procedures for infection control in hospital environments have not been successful in curbing the rise in infections by multi-drug-resistant (MDR pathogens. Emergence of resistance to chemical disinfectants is increasing steadily and has been reported worldwide. So prevention of multidrug-resistant health care associated infections (HAI has become a priority issue and great challenge to clinicians. This requires appropriate sterilization and disinfection procedures and strict adherence to protocol in infection control policy. There is a need to evaluate the efficacy of newer disinfectants which have come into the market for better control of HAI. AIMS AND OBJECTIVES: The aim of this study was to evaluate and compare disinfection efficacy of three newer disinfectants– Novacide (didecyldimethylammonium chloride and polyhexamethylene biguanide, Silvicide a strong oxidizing agent (hydrogen peroxide and silver nitrate and Virkon, a powerful oxidizing agent (a stabilized blend of peroxygen compounds and potassium salts, pitting them against two time-honored conventional disinfectants phenol and lysol and testing them against common MDR clinical isolates, reference strains and spores. MATERIALS AND METHODS: All the disinfectants at different dilutions were tested for bactericidal efficacy by liquid suspension time-kill tests. A heavy initial microbial load was simulated by preparing bacterial inoculum. Numbers of viable cells were counted and reduction in microbial colony counts before and after disinfectant exposure was expressed as log reduction. RESULTS: Among the disinfectants, Novacide was most effective. All clinical MDR bacterial isolates and reference strains were killed within 30 seconds of exposure at 0.156% solution, whereas spores got killed after 30 minutes of exposure at 2.5% solution which is the recommended concentration. For Silvicide all vegetative bacteria were killed at 5% solution after 20 minutes contact time and at 20% solution after 10 minutes contact time where recommended concentration is 20%. Spores also were killed at 20% solution after 1 hour contact time. Virkon was very effective for vegetative bacteria at 1% solution (which is the recommended concentration, killing within 30 seconds, but for exerting sporicidal action took 2 hours contact time. The conventional disinfectant phenol has currently restricted use because of its corrosive nature and high toxicity but still is considered as standard disinfectant for microbicidal efficacy testing methods. Lysol, the most widely used hospital disinfectant was found to be least effective among the five disinfectants. Both phenol and Lysol exerted poor sporicidal effect. CONCLUSION: Novacide is the most effective disinfectant in our study. Also Silvicide and Virkon being sporicidal agent can be considered as high level disinfectant, but Virkon required much greater time exposure inappropriate for routine hospital uses including instrument disinfection, floor cleaning and waste disposal

  7. Multidrug resistant Gram-negative bacilli in lower respiratory tract infections.

    Directory of Open Access Journals (Sweden)

    Shashidhar Vishwanath

    2013-12-01

    Full Text Available Lower respiratory tract infections are among important causes of morbidity and mortality for all age groups. The emergence of multidrug resistant Gram-negative bacilli is an issue of increasing concern.A retrospective study including respiratory specimens (sputum and BAL was conducted in our tertiary care centre. Samples were processed for microscopy, culture and susceptibility testing following standard methods. Multidrug resistant Gram-negative bacilli causing lower respiratory tract infections were studied for their causation of disease. The effect of appropriate treatment on clinical outcome was observed.A total of 472 Gram-negative pathogens were isolated from sputum and broncho-alveolar lavage fluid specimens during the study period. Among these Gram-negative pathogens 175 (37% were found to be multidrug resistant. Klebsiella pneumoniae 85 (48.6% and Acinetobacter spp. 59 (33.7% were the predominant multidrug resistant Gram-negative bacilli isolated. Based on clinico-microbiological correlation, 138 (78.9% multidrug resistant isolates were found to be pathogenic and the rest 37 (21.1% were considered as colonizers. After initiating appropriate antibiotic therapy, clinical improvement was seen in 110 (79.7% patients. In the patients who showed improvement, amikacin (34.3% and cefoperazone-sulbactum (21.8% were found to be the most effective drugs.A large majority of the isolated multidrug resistant Gram-negative bacilli were found to be pathogenic. Regular surveillance which directs appropriate empirical therapy; and good clinic-microbiological workup of each case of lower respiratory tract infection can reduce the morbidity and mortality associated with multidrug resistant organisms.

  8. Effect of multidrug resistance gene-1(mdr1) overexpression on in-vitro uptake of {sup 99m}Tc-sestaMIBI in murine L1210 leukemia cells

    Energy Technology Data Exchange (ETDEWEB)

    Chun, Kyung Ah; Lee, Jae Tae; Lee, Sang Woo; Kang, Do Young; Sohn, Snag Kyun; Lee, Jong Kee; Jun, Soo Han; Lee, Kyu Bo [College of Medicine, Kyungpook National Univ., Taegu (Korea, Republic of); Chung, June Key [College of Medicine, Seoul National Univ., Seoul (Korea, Republic of)

    1999-02-01

    To determine whether {sup 99m}Tc-MIBI is recognized by the multidrug resistant P-glycoprotein (Pgp), we have measured quantitatively {sup 99m}Tc-MIBI uptake in cancer cells. The effects of various Pgp reversing agents on cellular {sup 99m}Tc-MIBI uptake were also investigated in the presence of multidrug resistance gene-1 (mdr 1 gene) overexpression. We measured percentage uptake of {sup 99m}Tc-MIBI at different incubation temperatures both in mdr1 positive and negative cells. The effects of verapamil, cyclosporin, and dipyridamole on cellular uptake of {sup 99m}Tc-MIBI were also evaluated with or without overexpression of mdr1 gene in cultured murine leukemia L1210 cells. The mdr1 gene expressing cell lines were effectively induced in in vitro with continuous application of low-dose adriamycin or vincristine. Cellular uptake of {sup 99m}Tc-MIBI was higher in mdr1 negative L1210 cells than those of mdr1 positive cells, and higher when incubated in 37 .deg. C than 4 .deg. C. In the presence of verapamil, cyclosporin or dipyridamole, {sup 99m}Tc-MIBI uptake was increased upto 604% in mdr1 positive cells. Cellular uptake of {sup 99m}Tc-MIBI is lower in leukemia cells over-expressing mdr1 gene, and MDR-reversing agents increase cellular uptake. These results suggest the {sup 99m}Tc-MIBI can be used for characterizing Pgp expression and developing MDR-reversing agents in vitro.

  9. The involvement of a LINE-1 element in a DNA rearrangement upstream of the mdr1a gene in a taxol multidrug-resistant murine cell line.

    Science.gov (United States)

    Cohen, D; Higman, S M; Hsu, S I; Horwitz, S B

    1992-10-01

    Two closely related but functionally distinct P-glycoprotein isoforms are encoded by the murine multidrug-resistance genes mdr1a and mdr1b. In a series of independently selected multidrug-resistant (MDR) J774.2 cell lines, mdr gene amplification and/or overexpression and overproduction of either the mdr1a or mdr1b products, or both gene products, correlates with the MDR phenotype. To investigate the possibility that mutations in the promoter regions of the mdr1a or mdr1b genes could influence their differential expression, mdr promoter-specific probes were used to detect and map potential structural alterations. An unusual structural rearrangement was found in the 5'-region of the amplified mdr1a allele in J7.T1, a cell line selected with taxol. To characterize this rearrangement, the regulatory regions of the mdr1a and mdr1b genes were analyzed. Whereas no gross structural alterations were detected by Southern blot hybridization using the mdr1b promoter probe, a novel amplified EcoRI fragment was detected by the mdr1a promoter probe. To determine the precise nature of this mutation, an mdr1a 5'-genomic clone was isolated from J7.T1 cells. Sequence analysis revealed an unusual DNA rearrangement consisting of the mdr1b gene, from its fourth intron toward its 3'-end, upstream of an intact mdr1a promoter on the amplified allele. We propose that this event occurred by an unequal sister chromatid exchange that was mediated by LINE-1 repetitive elements. PMID:1356977

  10. In vivo detection of multidrug-resistant (MDR1) phenotype by technetium-99m sestamibi scan in untreated breast cancer patients

    International Nuclear Information System (INIS)

    Technetium-99m sestamibi is a transport substrate recognised by the multidrug-resistant P-glycoprotein (Pgp). To test whether 99mTc-sestamibi efflux is enhanced in breast carcinomas overexpressing Pgp, we determined the efflux rates of 99mTc-sestamibi and Pgp levels in tumours from 30 patients with untreated breast carcinoma. Patients were intravenously injected with 740 MBq of 99mTc-sestamibi and underwent a 15-min dynamic study followed by the acquisition of static planar images at 0.5, 1, 2 and 4 h. Tumour specimens were obtained from each patient 24 h after 99mTc-sestamibi scan and Pgp levels were determined using 125I-MRK16 monoclonal antibody and in vitro quantitative autoradiography. All breast carcinomas showed high uptake of 99mTc-sestamibi and data from region of interest analysis on sequential images were fitted with a monoexponential function. The efflux rates of 99mTc-sestamibi, calculated from decay-corrected time-activity curves, ranged between 0.00121 and 0.01690 min-1and were directly correlated with Pgp levels measured in the same tumours (r=0.62; P 99mTc-sestamibi efflux from tumours of group A was 2.7 times higher than that observed in tumours of group B (0.00686 0.00390 min -1vs 0.00250 0.00090 min -1, P 99mTc-sestamibi showed a sensitivity and a specificity of 80% and 95%, respectively. In conclusion, the efflux rate of 99mTc-sestamibi may be used for the in vivo identification of the multidrug resistant (MDR1) phenotype in untreated breast cancer patients. (orig.). With 7 figs., 3 tabs

  11. Prevalence of multidrug resistant pathogens in children with urinary tract infection: a retrospective analysis

    OpenAIRE

    Srinivasan S, Madhusudhan NS

    2014-01-01

    Urinary tract infection (UTI) is one of the commonest medical problems in children. It can distress the child and may cause kidney damage. Prompt diagnosis and effective treatment can prevent complications in the child. But treatment of UTI in children has now become a challenge due to the emergence of multidrug resistant bacteria. Aims & Objectives: To know the bacteriological profile and susceptibility pattern of urinary tract infections in children and to know the prevalence of multidrug r...

  12. Anthracyclines, proteasome activity and multi-drug-resistance

    Directory of Open Access Journals (Sweden)

    Pajonk Frank

    2005-09-01

    Full Text Available Abstract Background P-glycoprotein is responsible for the ATP-dependent export of certain structurally unrelated compounds including many chemotherapeutic drugs. Amplification of P-glycoprotein activity can result in multi-drug resistance and is a common cause of chemotherapy treatment failure. Therefore, there is an ongoing search for inhibitors of P-glycoprotein. Observations that cyclosporin A, and certain other substances, inhibit both the proteasome and P-glycoprotein led us to investigate whether anthracyclines, well known substrates of P-gp, also inhibit the function of the proteasome. Methods Proteasome function was measured in cell lysates from ECV304 cells incubated with different doses of verapamil, doxorubicin, daunorubicin, idarubicin, epirubicin, topotecan, mitomycin C, and gemcitabine using a fluorogenic peptide assay. Proteasome function in living cells was monitored using ECV304 cells stably transfected with the gene for an ubiquitin/green fluorescent protein fusion protein. The ability of the proteasome inhibitor MG-132 to affect P-glycoprotein function was monitored by fluorescence due to accumulation of daunorubicin in P-glycoprotein overexpressing KB 8-5 cells. Results Verapamil, daunorubicin, doxorubicin, idarubicin, and epirubicin inhibited 26S chymotrypsin-like function in ECV304 extracts in a dose-dependent fashion. With the exception of daunorubicin, 20S proteasome function was also suppressed. The proteasome inhibitor MG-132 caused a dose-dependent accumulation of daunorubicin in KB 8-5 cells that overexpress P-glycoprotein, suggesting that it blocked P-glycoprotein function. Conclusion Our data indicate that anthracyclines inhibit the 26S proteasome as well as P-glycoprotein. Use of inhibitors of either pathway in cancer therapy should take this into consideration and perhaps use it to advantage, for example during chemosensitization by proteasome inhibitors.

  13. Anthracyclines, proteasome activity and multi-drug-resistance

    International Nuclear Information System (INIS)

    P-glycoprotein is responsible for the ATP-dependent export of certain structurally unrelated compounds including many chemotherapeutic drugs. Amplification of P-glycoprotein activity can result in multi-drug resistance and is a common cause of chemotherapy treatment failure. Therefore, there is an ongoing search for inhibitors of P-glycoprotein. Observations that cyclosporin A, and certain other substances, inhibit both the proteasome and P-glycoprotein led us to investigate whether anthracyclines, well known substrates of P-gp, also inhibit the function of the proteasome. Proteasome function was measured in cell lysates from ECV304 cells incubated with different doses of verapamil, doxorubicin, daunorubicin, idarubicin, epirubicin, topotecan, mitomycin C, and gemcitabine using a fluorogenic peptide assay. Proteasome function in living cells was monitored using ECV304 cells stably transfected with the gene for an ubiquitin/green fluorescent protein fusion protein. The ability of the proteasome inhibitor MG-132 to affect P-glycoprotein function was monitored by fluorescence due to accumulation of daunorubicin in P-glycoprotein overexpressing KB 8-5 cells. Verapamil, daunorubicin, doxorubicin, idarubicin, and epirubicin inhibited 26S chymotrypsin-like function in ECV304 extracts in a dose-dependent fashion. With the exception of daunorubicin, 20S proteasome function was also suppressed. The proteasome inhibitor MG-132 caused a dose-dependent accumulation of daunorubicin in KB 8-5 cells that overexpress P-glycoprotein, suggesting that it blocked P-glycoprotein function. Our data indicate that anthracyclines inhibit the 26S proteasome as well as P-glycoprotein. Use of inhibitors of either pathway in cancer therapy should take this into consideration and perhaps use it to advantage, for example during chemosensitization by proteasome inhibitors

  14. Multidrug Resistant CTX-M-Producing Escherichia coli: A Growing Threat among HIV Patients in India

    Science.gov (United States)

    Padmavathy, Kesavaram; Padma, Krishnan; Rajasekaran, Sikhamani

    2016-01-01

    Extended Spectrum β-Lactamases (ESBLs) confer resistance to third-generation cephalosporins and CTX-M types have emerged as the most prominent ESBLs worldwide. This study was designed to determine the prevalence of CTX-M positive ESBL-producing urinary E. coli isolates from HIV patients and to establish the association of multidrug resistance, phylogeny, and virulence profile with CTX-M production. A total of 57 ESBL producers identified among 76 E. coli strains isolated from HIV patients from South India were screened for blaCTX-M, AmpC production, multidrug resistance, and nine virulence associated genes (VAGs), fimH, pap, afa/dra, sfa/foc, iutA, fyuA, iroN, usp, and kpsMII. The majority (70.2%) of the ESBL producers harbored blaCTX-M and were AmpC coproducers. Among the CTX-M producers, 47.5% were found to be UPEC, 10% harbored as many as 7 VAGs, and 45% possessed kpsMII. Multidrug resistance (CIPRSXTRGENR) was significantly more common among the CTX-M producers compared to the nonproducers (70% versus 41.2%). However, 71.4% of the multidrug resistant CTX-M producers exhibited susceptibility to nitrofurantoin thereby making it an effective alternative to cephalosporins/fluoroquinolones. The emergence of CTX-M-producing highly virulent, multidrug resistant uropathogenic E. coli is of significant public health concern in countries like India with a high burden of HIV/AIDS.

  15. Multidrug resistance 1 gene polymorphisms may determine Crohn's disease behavior in patients from Rio de Janeiro

    Directory of Open Access Journals (Sweden)

    Ana Teresa P. Carvalho

    2014-01-01

    Full Text Available OBJECTIVES: Conflicting data from studies on the potential role of multidrug resistance 1 gene polymorphisms in inflammatory bowel disease may result from the analysis of genetically and geographically distinct populations. Here, we investigated whether multidrug resistance 1 gene polymorphisms are associated with inflammatory bowel diseases in patients from Rio de Janeiro. METHODS: We analyzed 123 Crohn's disease patients and 83 ulcerative colitis patients to determine the presence of the multidrug resistance 1 gene polymorphisms C1236T, G2677T and C3435T. In particular, the genotype frequencies of Crohn's disease and ulcerative colitis patients were analyzed. Genotype-phenotype associations with major clinical characteristics were established, and estimated risks were calculated for the mutations. RESULTS: No significant difference was observed in the genotype frequencies of the multidrug resistance 1 G2677T/A and C3435T polymorphisms between Crohn's disease and ulcerative colitis patients. In contrast, the C1236T polymorphism was significantly more common in Crohn's disease than in ulcerative colitis (p = 0.047. A significant association was also found between the multidrug resistance 1 C3435T polymorphism and the stricturing form of Crohn's disease (OR: 4.13; p = 0.009, whereas no association was found with penetrating behavior (OR: 0.33; p = 0.094. In Crohn's disease, a positive association was also found between the C3435T polymorphism and corticosteroid resistance/refractoriness (OR: 4.14; p = 0.010. However, no significant association was found between multidrug resistance 1 gene polymorphisms and UC subphenotypic categories. CONCLUSION: The multidrug resistance 1 gene polymorphism C3435T is associated with the stricturing phenotype and an inappropriate response to therapy in Crohn's disease. This association with Crohn's disease may support additional pathogenic roles for the multidrug resistance 1 gene in regulating gut-microbiota interactions and in mediating fibrosis. Understanding the effects of several drugs associated with multidrug resistance 1 gene variants may aid in the selection of customized therapeutic regimens.

  16. Reversal in multidrug resistance by magnetic nanoparticle of Fe3O4 loaded with adriamycin and tetrandrine in K562/A02 leukemic cells

    Directory of Open Access Journals (Sweden)

    Baoan Chen

    2008-06-01

    Full Text Available Baoan Chen1,5, Qian Sun1,5, Xuemei Wang2, Feng Gao1, Yongyuan Dai1, Yan Yin1, Jiahua Ding1, Chong Gao1, Jian Cheng1, Jingyuan Li2, Xinchen Sun1, Ningna Chen1, Wenlin Xu3, Huiling Shen3, Delong Liu41Department of Hematology, Zhongda Hospital, Southeast University, Nanjing, China; 2State Key Lab of Bioelectronics(Chien-Shiung Wu Laboratory, Southeast University, Nanjing 210096, China; 3Department of Hematology, The First Peoples Hospital of Zhenjiang, Zhenjiang, China; 4Westchester Medical Center, New York Medical College, NY, USA; 5These authors have contributed equally to this work.Abstract: Drug resistance is a primary hindrance for efficiency of chemotherapy. To investigate whether Fe3O4-magnetic nanoparticles (Fe3O4-MNPs loaded with adriamycin (ADM and tetrandrine (Tet would play a synergetic reverse role in multidrug resistant cell, we prepared the drug-loaded nanoparticles by mechanical absorption polymerization to act with K562 and one of its resistant cell line K562/A02. The survival of cells which were cultured with these conjugates for 48 h was observed by MTT assay. Using cells under the same condition described before, we took use of fluorescence microscope to measure fluorescence intensity of intracellular ADM at an excitation wavelength of 488 nm. P-glycoprotein (P-gp was analyzed with flow cytometer. The expression of mdr1 mRNA was measured by RT-PCR. The results showed that the growth inhibition efficacy of both the two cells increased with augmenting concentrations of Fe3O4-MNPs which were loaded with drugs. No linear correlation was found between fluorescence intensity of intracellular adriamycin and augmenting concentration of Fe3O4-MNPs. Tet could downregulate the level of mdr-1 gene and decrease the expression of P-gp. Furthermore, Tet polymerized with Fe3O4-MNPs reinforced this downregulation, causing a 100-fold more decrease in mdr1 mRNA level, but did not reduce total P-gp content. Our results suggest that Fe3O4-MNPs loaded with ADM or Tet can enhance the effective accumulation of the drugs in K562/A02. We propose that Fe3O4-MNPs loaded with ADM and Tet probably have synergetic effect on reversal in multidrug resistance.Keywords: magnetic nanoparticles, tetrandrine, adriamycin, multidrug resistance reversal, leukemia K562/A02

  17. Prediction and characterization of P-glycoprotein substrates potentially bound to different sites by emerging chemical pattern and hierarchical cluster analysis.

    Science.gov (United States)

    Pan, Xianchao; Mei, Hu; Qu, Sujun; Huang, Shuheng; Sun, Jiaying; Yang, Li; Chen, Hua

    2016-04-11

    P-glycoprotein (P-gp), an ATP-binding cassette (ABC) multidrug transporter, can actively transport a broad spectrum of chemically diverse substrates out of cells and is heavily involved in multidrug resistance (MDR) in tumors. So far, the multiple specific binding sites remain a major obstacle in developing an efficient prediction method for P-gp substrates. Herein, emerging chemical pattern (ECP) combined by hierarchical cluster analysis was utilized to predict P-gp substrates as well as their potential binding sites. An optimal ECP model using only 3 descriptors was established with prediction accuracies of 0.80, 0.81 and 0.74 for 803 training samples, 120 test samples, and 179 independent validation samples, respectively. Hierarchical cluster analysis (HCA) of the ECPs of P-gp substrates derived 2 distinct ECP groups (ECPGs). Interestingly, HCA of the P-gp substrates based on ECP similarities also showed 2 distinct classes, which happened to be dominated by the 2 ECPGs, respectively. In the light of available experimental proofs and molecular docking results, the 2 distinct ECPGs were proved to be closely related to the binding profiles of R- and H-site substrates, respectively. The present study demonstrates, for the first time, a successful ECP model, which can not only accurately predict P-gp substrates, but also identify their potential substrate-binding sites. PMID:26899974

  18. Inhibition of adherence of multi-drug resistant E. coli by proanthocyanidin.

    Science.gov (United States)

    Gupta, Ashish; Dwivedi, Mayank; Mahdi, Abbas Ali; Nagana Gowda, G A; Khetrapal, Chunni Lal; Bhandari, Mahendra

    2012-04-01

    Proanthocyanidin is commonly used for inhibiting urinary tract infection (UTI) of sensitive strains of Escherichia coli. The aim of this study was to investigate the effect of proanthocyanidin on adherence of uropathogenic multi-drug resistant E. coli to uroepithelial cells, which has not yet been investigated so far. Extracts of the purified proanthocyanidin were prepared from dried cranberry juice. Purity and structural assignment of proanthocyanidin was assessed using high performance liquid chromatography and (13)C nuclear magnetic resonance spectroscopy, respectively. Subsequently, its affect on multi-drug resistant bacteria as well as quantification of anti-adherence bioactivity on human vaginal and bladder epithelial cells was appraised. Inhibition of adherence to an extent of about 70% with multi-drug resistant E. coli strains was observed on uroepithelial cell. The anti-adherence bioactivity of the proanthocyanidin was detected at concentrations of 10-50 g/ml with significant bacteriuria. Probable proanthocyanidin through A-type linkages either combines to P-fimbriae of bacterial cells or modifies the structural entity of P-fimbriae and inhibits bacterial adherence to uroepithelial cells. The proanthocyanidin exhibited anti-adherence property with multi-drug resistant strains of uropathogenic P-fimbriated E. coli with in vitro study. Hence proanthocyanidin may be considered as an inhibitory agent for multi-drug resistant strains of E. coli adherence to uroepithelial cells. PMID:21688109

  19. Activating PKC-β1 at the blood–brain barrier reverses induction of P-glycoprotein activity by dioxin and restores drug delivery to the CNS

    OpenAIRE

    WANG, XUEQIAN; Hawkins, Brian T.; Miller, David S.

    2011-01-01

    Upregulation of blood–brain barrier (BBB) P-glycoprotein expression causes central nervous system (CNS) pharmacoresistance. However, activation of BBB protein kinase C-β1 (PKC-β1) rapidly reduces basal P-glycoprotein transport activity. We tested whether PKC-β1 activation would reverse CNS drug resistance caused by dioxin acting through aryl hydrocarbon receptor. A selective PKC-β1 agonist abolished the increase in P-glycoprotein activity induced by dioxin in isolated rat brain capillaries an...

  20. Draft Genome Sequences of Multidrug-Resistant Acinetobacter sp. Strains from Colombian Hospitals

    OpenAIRE

    Barreto-Hernández, Emiliano; Falquet2, Laurent; Reguero, María T.; Mantilla, José R.; Valenzuela, Emilia M.; González, Elsa; Cepeda, Alexandra; Escalante, Andrea

    2013-01-01

    The draft genome sequences of the strains Acinetobacter baumannii 107m, Acinetobacter nosocomialis 28F, and Acinetobacter pittii 42F, isolated from Colombian hospitals, are reported here. These isolates are causative of nosocomial infections and are classified as multidrug resistant, as they showed resistance to four different antibiotic groups.

  1. Comparative genomics of the IncA/C multidrug resistance plasmid family

    Science.gov (United States)

    Multidrug resistance (MDR) plasmids belonging to the IncA/C plasmid family are widely distributed among Salmonella and other enterobacterial isolates from agricultural sources and have, at least once, also been identified in a drug resistant Yersinia pestis isolate (IP275) from Madagascar. Here, we...

  2. Genome Sequence of Riemerella anatipestifer Strain RCAD0122, a Multidrug-Resistant Isolate from Ducks

    Science.gov (United States)

    Song, Xiao-Heng; Zhou, Wang-Shu; Wang, Jiang-Bo; Liu, Ma-Feng; Wang, Ming-Shu; Cheng, An-Chun; Jia, Ren-Yong; Chen, Shun; Sun, Kun-Feng; Yang, Qiao; Wu, Ying; Chen, Xiao-Yue

    2016-01-01

    Riemerella anatipestifer is an important pathogenic bacterium in waterfowl and other avian species. We present here the genome sequence of R. anatipestifer RCAD0122, a multidrug-resistant strain isolated from infected ducks. The isolate contains at least nine types of antibiotic resistance-associated genes. PMID:27151800

  3. Rapid detection of multidrug-resistant Mycobacterium tuberculosis using the malachite green decolourisation assay

    OpenAIRE

    Ahmet Yilmaz Coban; Meltem Uzun

    2013-01-01

    Early detection of drug resistance in Mycobacterium tuberculosis isolates allows for earlier and more effective treatment of patients. The aim of this study was to investigate the performance of the malachite green decolourisation assay (MGDA) in detecting isoniazid (INH) and rifampicin (RIF) resistance in M. tuberculosis clinical isolates. Fifty M. tuberculosis isolates, including 19 multidrug-resistant, eight INH-resistant and 23 INH and RIF-susceptible samples, were tested. The sensitivity...

  4. Chemosensitization of multidrug resistant Candida albicans by the oxathiolone fused chalcone derivatives

    OpenAIRE

    ?a?cka, Izabela; Konieczny, Marek T.; Bu?akowska, Anita; Kodedov, Marie; Gakov, Dana; Maurya, Indresh K.; Prasad, Rajendra; Milewski, S?awomir

    2015-01-01

    Three structurally related oxathiolone fused chalcone derivatives appeared effective chemosensitizers, able to restore in part sensitivity to fluconazole of multidrug-resistant C. albicans strains. Compound 21 effectively chemosensitized cells resistant due to the overexpression of the MDR1 gene, compound 6 reduced resistance of cells overexpressing the ABC-type drug transporters CDR1/CDR2 and derivative 18 partially reversed fluconazole resistance mediated by both types of yeast drug efflux ...

  5. Multidrug Resistant Salmonella typhi in Asymptomatic Typhoid Carriers among Food Handlers in Namakkal District, Tamil Nadu

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    Senthilkumar B

    2005-01-01

    Full Text Available Purpose: to screen Salmonella typhi in asymptomatic typhoid carriers and to find out drug resistance and ability of the strains to transmit drug resistance to other bacteria. Methods: Cultural characters, biochemical tests, antibiotic sensitivity test (disc diffusion, agarose gel electrophoresis, and conjugation protocols were done. Thirty five stool samples were collected from the suspected food handlers for the study. Results: Among 35 samples, (17.14% yielded a positive result. Out of these 4 (20.0% were women and 2 (13.33% were men. The isolates were tested with a number of conventional antibiotics viz, amikacin, amoxicillin, ampicillin, chloramphenicol, ciprofloxacin, co-trimaxazole, rifampicin, gentamicin, nalidixic acid, ofloxacin and tetracycline. Five isolates were having the multidrug resistant character. Four (66.66% multidrug resistant isolates were found to have plasmids, while one (16.66% multidrug resistant isolate had no plasmid and the chromosome encoded the resistance. Only one strain (16.66% showed single antibiotic resistance in the study and had no plasmid DNA. The molecular weights of the plasmids were determined and found to be 120 kb.The mechanism of spreading of drug resistance through conjugation process was analyzed. In the conjugation studies, the isolates having R+ factor showed the transfer of drug resistance through conjugation, which was determined by the development of antibiotic resistance in the recipients. Conclusion: This study shows that drug resistant strains are able to transfer genes encoding drug resistance.

  6. Pumping of drugs by P-glycoprotein

    DEFF Research Database (Denmark)

    Litman, Thomas; Skovsgaard, Torben; Stein, Wilfred D

    2003-01-01

    levels of drug resistance and P-gp content. For daunorubicin as a transport substrate, Kapp was independent of [P-gp] for verapamil but increased strictly linearly with [P-gp] for vinblastine, cyclosporin A, and XR9576. A theoretical analysis of the kinetics of drug pumping and its reversal shows that...... Kapp for inhibition should increase linearly with the amount of pumps present in the membrane for a reverser that inhibits pumping from the cytoplasmic face. In contrast, if the reverser acts by blocking transport from the outer face, i.e., preemptively, Kapp should be independent of the number of...... pumps present. The experimental data suggest that verapamil blocks pumping at the extracellular face of the membrane, whereas the other three blockers act on pumping from the cytoplasmic phase. The maximum degree of inhibition was the same for all four blockers; thus, they do not act in parallel but...

  7. Multidrug resistance factor - glycoprotein P in rheumatoid arthritis

    Directory of Open Access Journals (Sweden)

    I P Kolosova

    2003-02-01

    Full Text Available Objective. To assess expression of P-glycoprotein (Pgp on peripheral blood (PB lymphocytes and its changes during therapy in pts with rheumatoid arthritis (RA. Methods. 51 RA pts and 11 healthy donors (control group were examined. 35 pts were followed up. 20 of them were treated with methotrexate (MT and 15 with glucocorticosteroid (GCS pulse therapy (PT. Pgp expression was examined with flow cytofluorometry with monoclonal antibodies (UIC2 PE, Immunotech. Results. Pgp expression on PB lymphocytes in RA was significantly more prominent (29,3 29,9 % than in control group (2,5 2,0 %, P<0,01. Pgp expression did not depend on pts age and sex, duration and stage of the disease, presence or absence history of disease modifying drugs therapy. PT with GCS but not MT significantly decreased Pgp expression (from 57,2±27,0 % to 28,8135,2 %, r<0,05. Conclusion. RA patients have increased Pgp expression, which is probably biologically sensible but clinically unfavourable response of immunocompetent cells to durable application of such foreign substances as medications. PT with GCS decrease Pgp expression on lymphocytes while treatment with MT does not change it.

  8. Expression of the human multidrug transporter in insect cells by a recombinant baculovirus

    International Nuclear Information System (INIS)

    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 obtain large quantities and further investigate its structure and mechanism of action. MDR1 cDNA was inserted into the genome of the Autographa californica nuclear polyhedrosis virus under the control of the polyhedrin promoter. Spodoptera frugiperda insect cells synthesized high levels of recombinant multidrug transporter 2-3 days after infection. The transporter was localized by immunocytochemical methods on the external surface of the plasma membranes, in the Golgi apparatus, and within the nuclear envelope. The human multidrug transporter expressed in insect cells is not susceptible to endoglycosidase F treatment and has a lower apparent molecular weight of 140,000, corresponding to the nonglycosylated precursor of its authentic counterpart expressed in multidrug-resistant cells. Labeling experiments showed that the recombinant multidrug transporter is phosphorylated and can be photoaffinity labeled by [3H]azidopine, presumably at the same two sites as the native protein. Various drugs and reversing agents compete with the [3H]azidopine binding reaction when added in excess, indicating that the recombinant human multidrug transporter expressed in insect cells is functionally similar to its authentic counterpart

  9. Expression of the human multidrug transporter in insect cells by a recombinant baculovirus

    Energy Technology Data Exchange (ETDEWEB)

    Germann, U.A.; Willingham, M.C.; Pastan, I.; Gottesman, M.M. (National Institutes of Health, Bethesda, MD (USA))

    1990-03-06

    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 obtain large quantities and further investigate its structure and mechanism of action. MDR1 cDNA was inserted into the genome of the Autographa californica nuclear polyhedrosis virus under the control of the polyhedrin promoter. Spodoptera frugiperda insect cells synthesized high levels of recombinant multidrug transporter 2-3 days after infection. The transporter was localized by immunocytochemical methods on the external surface of the plasma membranes, in the Golgi apparatus, and within the nuclear envelope. The human multidrug transporter expressed in insect cells is not susceptible to endoglycosidase F treatment and has a lower apparent molecular weight of 140,000, corresponding to the nonglycosylated precursor of its authentic counterpart expressed in multidrug-resistant cells. Labeling experiments showed that the recombinant multidrug transporter is phosphorylated and can be photoaffinity labeled by ({sup 3}H)azidopine, presumably at the same two sites as the native protein. Various drugs and reversing agents compete with the ({sup 3}H)azidopine binding reaction when added in excess, indicating that the recombinant human multidrug transporter expressed in insect cells is functionally similar to its authentic counterpart.

  10. Cyclooxygenase-2, multidrug resistance 1, and breast cancer resistance protein gene polymorphisms and inflammatory bowel disease in the Danish population

    DEFF Research Database (Denmark)

    Østergaard, Mette; Ernst, Anja; Labouriau, Rodrigo S.; Dagiliené, Enrika; Krarup, H.B.; Christensen, Marian; Thorsgaard, Niels; Jacobsen, Bent A; Tage-Jensen, Ulrik; Overvad, Kim; Autrup, Herman; Andersen, Vibeke

    2009-01-01

    involved in these processes were associated with CD and UC. MATERIAL AND METHODS: Allele frequencies of the cyclooxygenase 2 (COX-2/PTGS2/PGHS2) G-765C and breast cancer resistance protein (BCRP/ABCG2) C421A as well as allele and haplotype frequencies of multidrug resistance 1 (MDR1, ABCB1) SNPs G2677T...

  11. Does a multi-drug resistant Escherichia coli facilitate dissemination of resistance to Salmonella in dairy calves?

    Science.gov (United States)

    Previous research conducted by our laboratory investigated the incidence of multi-drug resistant (MDR) Salmonella in dairy cattle and reported that individual cattle, and most often calves, can shed multiple Salmonella serotypes that vary in the degree of antibiotic resistance. More recently, we di...

  12. [Prevalence of multidrug-resistant Proteus spp. strains in clinical specimens and their susceptibility to antibiotics].

    Science.gov (United States)

    Reśliński, Adrian; Gospodarek, Eugenia; Mikucka, Agnieszka

    2005-01-01

    Proteus sp. are opportunistic microorganisms which cause urinary tract and wounds infections, bacteriaemia and sepsis. The aim of this study was analysis of prevalence of multidrug-resistant Proteus sp. strains in clinical specimens and evaluation of their susceptibility to selected antibiotics. The study was carried out of 1499 Proteus sp. strains were isolated in 2000-2003 from patients of departments and dispensaries of the University Hospital CM in Bydgoszcz UMK in Torun. The strains were identified on the basis of appearance of bacterial colonies on bloody and McConkey's agars, movement ability, indole and urease production and in questionable cases biochemical profile in ID GN or ID E (bio-Mérieux) tests was also included. Antibiotic susceptibility was tested by disk diffusion method. Isolated strains were regarded as multidrug-resistant when they were resistant to three kinds of antibiotics at least. Received Proteus sp. the most frequently belonged to P. mirabilis species (92.3%). Most of these bacteria were isolated from urine from patients of Rehabilitation Clinic. All of multidrug-resistant strains were resistant to penicillins and cephalosporins, 98.9% to co-trimoxazole, 77.7% to quinolones, 63.8% to tetracyclines, 38.5% to aminoglycosides, 19.3% to monobactams and 3.4% to carbapenems. Almost 25% multidrug-resistant Proteus sp. produced ESBL. PMID:16134389

  13. Multidrug resistant Acinetobacter baumannii: a descriptive study in a city hospital

    Directory of Open Access Journals (Sweden)

    Pratap Siddharth

    2010-07-01

    Full Text Available Abstract Background Multidrug resistant Acinetobacter baumannii, (MRAB is an important cause of hospital acquired infection. The purpose of this study is to determine the risk factors for MRAB in a city hospital patient population. Methods This study is a retrospective review of a city hospital epidemiology data base and includes 247 isolates of Acinetobacter baumannii (AB from 164 patients. Multidrug resistant Acinetobacter baumannii was defined as resistance to more than three classes of antibiotics. Using the non-MRAB isolates as the control group, the risk factors for the acquisition of MRAB were determined. Results Of the 247 AB isolates 72% (177 were multidrug resistant. Fifty-eight percent (143/247 of isolates were highly resistant (resistant to imipenem, amikacin, and ampicillin-sulbactam. Of the 37 patients who died with Acinetobacter colonization/infection, 32 (86% patients had the organism recovered from the respiratory tract. The factors which were found to be significantly associated (p ≤ 0.05 with multidrug resistance include the recovery of AB from multiple sites, mechanical ventilation, previous antibiotic exposure, and the presence of neurologic impairment. Multidrug resistant Acinetobacter was associated with significant mortality when compared with sensitive strains (p ≤ 0.01. When surgical patients (N = 75 were considered separately, mechanical ventilation and multiple isolates remained the factors significantly associated with the development of multidrug resistant Acinetobacter. Among surgical patients 46/75 (61% grew a multidrug resistant strain of AB and 37/75 (40% were resistant to all commonly used antibiotics including aminoglycosides, cephalosporins, carbepenems, extended spectrum penicillins, and quinolones. Thirty-five percent of the surgical patients had AB cultured from multiple sites and 57% of the Acinetobacter isolates were associated with a co-infecting organism, usually a Staphylococcus or Pseudomonas. As in medical patients, the isolation of Acinetobacter from multiple sites and the need for mechanical ventilation were significantly associated with the development of MRAB. Conclusions The factors significantly associated with MRAB in both the general patient population and surgical patients were mechanical ventilation and the recovery of Acinetobacter from multiple anatomic sites. Previous antibiotic use and neurologic impairment were significant factors in medical patients. Colonization or infection with MRAB is associated with increased mortality.

  14. Antimicrobial potential of Pakistani medicinal plants against multi-drug resistance Staphylococcus aureus

    OpenAIRE

    Rahat Ejaz; Ashfaq, Usman A.; Sobia Idrees

    2014-01-01

    Objective: To determine resistance patterns of Staphylococcus aureus (S. aureus) isolated from different areas of Pakistan and to identify antimicrobial agents against multi-drug resistant S. aureus strains. Methods: A total of 67 samples (sewerage, nasal and milk) were collected from different farm areas of Pakistan to identify local strains of S. aureus. Sixteen out of 67 samples were positive for S. aureus. Only 6 out of 16 S. aureus strains showed resistance to antibiot...

  15. Priorities in the prevention and control of multidrug-resistant Enterobacteriaceae in hospitals.

    LENUS (Irish Health Repository)

    Khan, A S

    2012-10-01

    Multidrug-resistant Enterobacteriaceae (MDE) are a major public health threat due to international spread and few options for treatment. Furthermore, unlike meticillin-resistant Staphylococcus aureus (MRSA), MDE encompass several genera and multiple resistance mechanisms, including extended-spectrum beta-lactamases and carbapenemases, which complicate detection in the routine diagnostic laboratory. Current measures to contain spread in many hospitals are somewhat ad hoc as there are no formal national or international guidelines.

  16. Low-level quinolone-resistance in multi-drug resistant typhoid

    International Nuclear Information System (INIS)

    To find out the frequency of low-level quinolone-resistance in Multi-Drug Resistant (MDR) typhoid using nalidixic acid screening disc. Blood was obtained from suspected cases of typhoid fever and cultured in to BacT/ALERT. The positive blood cultures bottles were subcultured. The isolates were identified by colony morphology and biochemical tests using API-20E galleries. Susceptibility testing of isolates was done by modified Kirby-Bauer disc diffusion method on Muellar Hinton Agar. For the isolates, which were resistant to nalidixic acid by disc diffusion method, Minimal Inhibitory Concentrations (MICs) of ciprofloxacin and nalidixic acid were determined by using the E-test strips. Disc diffusion susceptibility tests and MICs were interpreted according to the guidelines provided by National Committee for Control Laboratory Standard (NCCLS). A total of 21(65.5%) out of 32 isolates of Salmonellae were nalidixic acid-resistant by disk diffusion method. All the nalidixic acid-resistant isolates by disc diffusion method were confirmed by MICs for both ciprofloxacin and nalidixic acid. All the nalidixic acid-resistant isolates had a ciprofloxacin MIC of 0.25-1 microg/ml (reduced susceptibility) and nalidixic acid MICs > 32 microg (resistant). Out of all Salmonella isolates, 24 (75%) were found to be MDR, and all were S. typbi. Low-level quinolone-resistance in typhoid was high in this small series. Screening for nalidixic acid resistance with a 30 microg nalidixic acid disk is a reliable and cost-effective method to detect low-level fluoroquinolone resistance, especially in the developing countries. (author)

  17. Prevalence of multidrug resistant pathogens in children with urinary tract infection: a retrospective analysis

    Directory of Open Access Journals (Sweden)

    Srinivasan S, Madhusudhan NS

    2014-11-01

    Full Text Available Urinary tract infection (UTI is one of the commonest medical problems in children. It can distress the child and may cause kidney damage. Prompt diagnosis and effective treatment can prevent complications in the child. But treatment of UTI in children has now become a challenge due to the emergence of multidrug resistant bacteria. Aims & Objectives: To know the bacteriological profile and susceptibility pattern of urinary tract infections in children and to know the prevalence of multidrug resistant uropathogens. Materials & Methods: A retrospective analysis was done on all paediatric urine samples for a period of one year. A total of 1581 samples were included in the study. Antimicrobial susceptibility testing was done on samples showing significant growth by Kirby-Bauer disc diffusion method. Statistical analysis: Prevalence and pattern were analyzed using proportions and percentages. Results: E.coli was the most predominant organism (56% causing UTI in children followed by Klebsiella sp (17%. Fifty three percent of gram negative organisms isolated from children were found to be multidrug resistant. Majority of E. coli isolates were found to be highly resistant to Ampicillin (91% and Cotrimoxazole (82% and highly sensitive to Imipenem (99% and Amikacin (93%. Conclusion: Paediatric UTI was common in children less than 5 years of age. Gram negative bacteria (E. coli and Klebsiella sp were more common than gram positive bacteria. Our study revealed that multidrug resistance was higher in E.coli.

  18. Epstein-Barr virus-negative aggressive natural killer-cell leukaemia with high P-glycoprotein activity and phosphorylated extracellular signal-regulated protein kinases 1 and 2

    Directory of Open Access Journals (Sweden)

    Sanja Perkovic

    2012-09-01

    Full Text Available Aggressive natural killer-cell leukaemia (ANKL is a rare type of disease with fulminant course and poor outcome. The disease is more prevalent among Asians than in other ethnic groups and shows strong association with Epstein-Barr virus (EBV and P-glycoprotein (P-gp expression associated with multidrug resistance. Here we present a case of a 47 year old Caucasian female with a prior medical history of azathioprine treated ulcerative colitis who developed EBV-negative form of ANKL. The patient presented with hepatosplenomegaly, fever and nausea with peripheral blood and bone marrow infiltration with up to 70% of atypical lymphoid cells positive for cCD3, CD2, CD7, CD56, CD38, CD45, TIA1 and granzyme B, and negative for sCD3, CD4, CD5, CD8, CD34 and CD123 indicative of ANKL. Neoplastic CD56+ NK-cells showed high level of P-glycoprotein expression and activity, but also strong expression of phosphorylated extracellular signal-regulated protein kinases 1 and 2 (ERK1/2 MAP kinase. The patient was treated with an intensive polychemotherapy regimen designed for treatment of acute lymphoblastic leukaemia, but one month after admission developed sepsis, coma and died of cardiorespiratory arrest. We present additional evidence that, except for the immunophenotype, leukaemic NK-cells resemble normal NK-cells in terms of P-gp functional capacity and expression of phosphorylated ERK1/2 signalling molecule. In that sense drugs that block P-glycoprotein activity and activated signalling pathways might represent new means for targeted therapy.

  19. Discovery of a new series of jatrophane and lathyrane diterpenes as potent and specific P-glycoprotein modulators.

    Science.gov (United States)

    Barile, Elisa; Borriello, Marianna; Di Pietro, Attilio; Doreau, Agnès; Fattorusso, Caterina; Fattorusso, Ernesto; Lanzotti, Virginia

    2008-05-21

    A new series of diterpenes, the jatrophanes euphoscopin M (1), euphoscopin N (2) and euphornin L (3), and the lathyrane euphohelioscopin C (7) were isolated from plants of Euphorbia helioscopia L., together with four other known analogues, euphoscopin C (4), euphornin (5), epieuphoscopin B (6) and euphohelioscopin A (8). The new compound stereostructures were elucidated by NMR analysis and computational data. The resulting isolated diterpenes were found to be potent inhibitors of P-glycoprotein (ABCB1), while showing an absence of significant activity against BCRP (ABCG2), despite the high substrate overlapping of these transporters, thus including them in the third-generation class of specific multidrug transporter modulators. PMID:18452010

  20. Antimycobacterial Assessment of Salicylanilide Benzoates including Multidrug-Resistant Tuberculosis Strains

    Directory of Open Access Journals (Sweden)

    Ji?ina Stola?kov

    2012-10-01

    Full Text Available The increasing emergence especially of drug-resistant tuberculosis has led to a strong demand for new anti-tuberculosis drugs. Eighteen salicylanilide benzoates were evaluated for their inhibition potential against Mycobacterium tuberculosis, Mycobacterium avium and two strains of Mycobacterium kansasii; minimum inhibitory concentration values ranged from 0.5 to 16 ?mol/L. The most active esters underwent additional biological assays. Four benzoates inhibited effectively the growth of five multidrug-resistant strains and one extensively drug-resistant strain of M. tuberculosis at low concentrations (0.252 ?mol/L regardless of the resistance patterns. The highest rate of multidrug-resistant mycobacteria inhibition expressed 4-chloro-2-[4-(trifluoromethyl-phenylcarbamoyl]phenyl benzoate (0.251 ?mol/L. Unfortunately, the most potent esters were still considerably cytotoxic, although mostly less than their parent salicylanilides.

  1. [Antimicrobial therapy in severe infections with multidrug-resistant Gram-negative bacterias].

    Science.gov (United States)

    Duszyńska, Wiesława

    2010-01-01

    Multidrug-resistant Gram-negative bacteria pose a serious and rapidly emerging threat to patients in healthcare settings, and are especially prevalent and problematic in intensive therapy units. Recently, the emergence of pandrug-resistance in Gram-negative bacteria poses additional concerns. This review examines the clinical impact and epidemiology of multidrug-resistant Gram-negative bacteria as a cause of increased morbidity and mortality among ITU patients. Beta-lactamases, cephalosporinases and carbapenemases play the most important role in resistance to antibiotics. Despite the tendency to increased resistance, carbapenems administered by continuous infusion remain the most effective drugs in severe sepsis. Drug concentration monitoring, albeit rarely used in practice, is necessary to ensure an effective therapeutic effect. PMID:21413423

  2. Molecular characterization of multidrug-resistant Shigella spp. of food origin.

    Science.gov (United States)

    Ahmed, Ashraf M; Shimamoto, Tadashi

    2015-02-01

    Shigella spp. are the causative agents of food-borne shigellosis, an acute enteric infection. The emergence of multidrug-resistant clinical isolates of Shigella presents an increasing challenge for clinicians in the treatment of shigellosis. Several studies worldwide have characterized the molecular basis of antibiotic resistance in clinical Shigella isolates of human origin, however, to date, no such characterization has been reported for Shigella spp. of food origin. In this study, we characterized the genetic basis of multidrug resistance in Shigella spp. isolated from 1600 food samples (800 meat products and 800 dairy products) collected from different street venders, butchers, retail markets, and slaughterhouses in Egypt. Twenty-four out of 27 Shigella isolates (88.9%) showed multidrug resistance phenotypes to at least three classes of antimicrobials. The multidrug-resistant Shigella spp. were as follows: Shigella flexneri (66.7%), Shigella sonnei (18.5%), and Shigella dysenteriae (3.7%). The highest resistance was to streptomycin (100.0%), then to kanamycin (95.8%), nalidixic acid (95.8%), tetracycline (95.8%), spectinomycin (93.6%), ampicillin (87.5%), and sulfamethoxazole/trimethoprim (87.5%). PCR and DNA sequencing were used to screen and characterize integrons and antibiotic resistance genes. Our results indicated that 11.1% and 74.1% of isolates were positive for class 1 and class 2 integrons, respectively. Beta-lactamase-encoding genes were identified in 77.8% of isolates, and plasmid-mediated quinolone resistance genes were identified in 44.4% of isolates. These data provide useful information to better understand the molecular basis of antimicrobial resistance in Shigella spp. To the best of our knowledge, this is the first report of the molecular characterization of antibiotic resistance in Shigella spp. isolated from food. PMID:25485847

  3. Multidrug Resistant CTX-M-Producing Escherichia coli: A Growing Threat among HIV Patients in India.

    Science.gov (United States)

    Padmavathy, Kesavaram; Padma, Krishnan; Rajasekaran, Sikhamani

    2016-01-01

    Extended Spectrum β-Lactamases (ESBLs) confer resistance to third-generation cephalosporins and CTX-M types have emerged as the most prominent ESBLs worldwide. This study was designed to determine the prevalence of CTX-M positive ESBL-producing urinary E. coli isolates from HIV patients and to establish the association of multidrug resistance, phylogeny, and virulence profile with CTX-M production. A total of 57 ESBL producers identified among 76 E. coli strains isolated from HIV patients from South India were screened for bla CTX-M, AmpC production, multidrug resistance, and nine virulence associated genes (VAGs), fimH, pap, afa/dra, sfa/foc, iutA, fyuA, iroN, usp, and kpsMII. The majority (70.2%) of the ESBL producers harbored bla CTX-M and were AmpC coproducers. Among the CTX-M producers, 47.5% were found to be UPEC, 10% harbored as many as 7 VAGs, and 45% possessed kpsMII. Multidrug resistance (CIP(R)SXT(R)GEN(R)) was significantly more common among the CTX-M producers compared to the nonproducers (70% versus 41.2%). However, 71.4% of the multidrug resistant CTX-M producers exhibited susceptibility to nitrofurantoin thereby making it an effective alternative to cephalosporins/fluoroquinolones. The emergence of CTX-M-producing highly virulent, multidrug resistant uropathogenic E. coli is of significant public health concern in countries like India with a high burden of HIV/AIDS. PMID:27123344

  4. Hospital acquired urinary tract infection by multidrug-resistant Brevundimonas vesicularis

    OpenAIRE

    Puneet K Gupta; Suma B Appannanavar; Harsimran Kaur; Mr. Vikas Gupta; Balvinder Mohan; Neelam Taneja

    2014-01-01

    Infections caused by Brevundimonas vesicularis, a nonfermenting Gram-negative bacterium, are very rare. Here, we report the first case of multidrug-resistant hospital acquired urinary tract infection by B. vesicularis. Patient was successfully treated with antimicrobial therapy with piperacillin-tazobactam and amikacin.

  5. Study on tumor cells' multidrug resistance and its reversion by Chinese herbs

    Directory of Open Access Journals (Sweden)

    CHEN Xin-Yi

    2003-09-01

    Full Text Available ABSTRACT: Multidrug resistance (MDR is an important biological behavior of tumor cells in chemotherapy. And it is also one of the major causes of clinical chemotherapy failure. According to the literature at home and abroad, and combining with the results of anthors' investigations, this paper mainly discusses the mechanism of tumor cells' MDR and its reversion by Chinese herbs.

  6. Nitrate reductase assay using sodium nitrate for rapid detection of multidrug resistant tuberculosis

    OpenAIRE

    Macedo, Mara Bidart; Groll, Andrea Von; Fissette, Krista; Palomino, Juan Carlos; DA SILVA, Pedro Eduardo Almeida; Martin, Anandi

    2012-01-01

    We validated the nitrate reductase assay (NRA) for the detection of multidrug-resistant Mycobacterium tuberculosis (MDR-TB) using sodium nitrate (NaNO3) in replacement of potassium nitrate (KNO3) as nitrate source. NaNO3 is cheaper than KNO3 and has no restriction on use which facilitates the implementation of NRA to detect MDR-TB.

  7. First Genome Sequence of a Mexican Multidrug-Resistant Acinetobacter baumannii Isolate.

    Science.gov (United States)

    Graña-Miraglia, Lucía; Lozano, Luis; Castro-Jaimes, Semiramis; Cevallos, Miguel A; Volkow, Patricia; Castillo-Ramírez, Santiago

    2016-01-01

    Acinetobacter baumanniihas emerged as an important nosocomial pathogen worldwide. Here, we present the draft genome of the first multidrug-resistantA. baumanniiisolate, sampled from a tertiary hospital in Mexico City. This genome will provide a starting point for studying the genomic diversity of this species in Mexico. PMID:27013043

  8. The Growing Problem of Multidrug-Resistant Tuberculosis in North Korea

    OpenAIRE

    Seung, Kwonjune J.; Linton, Stephen W.

    2013-01-01

    Kwonjune Seung and Stephen Linton from the non-governmental organization EugeneBell discuss the worryingly high levels of multidrug-resistant tuberculosis they have observed in North Korea's tuberculosis sanatoria. Please see later in the article for the Editors' Summary

  9. Colistin Methanesulfonate against Multidrug-Resistant Acinetobacter baumannii in an In Vitro Pharmacodynamic Model▿

    OpenAIRE

    Kroeger, Lisa A.; Hovde, Laurie B.; Mitropoulos, Isaac F.; Schafer, Jeremy; John C. Rotschafer

    2007-01-01

    Using an in vitro pharmacodynamic model, a multidrug-resistant strain of Acinetobacter baumannii was exposed to colistin methanesulfonate alone and in combination with ceftazidime. Pre- and postexposure colistin sulfate MICs were determined. A single daily dose of colistin methanesulfonate combined with continuous-infusion ceftazidime prevented regrowth and postexposure MIC increases.

  10. Multidrug resistance and retroviral transduction potential in human small cell lung cancer cell lines

    DEFF Research Database (Denmark)

    Theilade, M D; Gram, G J; Jensen, P B; Cianfriglia, M; Rørth, M; Hansen, J E

    1999-01-01

    Multidrug resistance (MDR) remains a major problem in the successful treatment of small cell lung cancer (SCLC). New treatment strategies are needed, such as gene therapy specifically targeting the MDR cells in the tumor. Retroviral LacZ gene-containing vectors that were either pseudotyped for the...

  11. Multidrug-resistant tuberculosis: treatment outcome in Denmark, 1992-2007

    DEFF Research Database (Denmark)

    Bang, Didi; Lillebaek, Troels; Thomsen, Vibeke Østergaard; Andersen, Ase Bengård

    2010-01-01

    A retrospective nationwide study including all culture-verified multidrug-resistant (MDR) tuberculosis (TB) cases was performed in Denmark. The aim was to examine the long-term treatment outcome of MDR-TB, to assess if MDR-TB transmission occurs, and to evaluate a rapid mutation analysis detecting...

  12. Fecal Microbiota Transplantation Inhibits Multidrug-Resistant Gut Pathogens: Preliminary Report Performed in an Immunocompromised Host.

    Science.gov (United States)

    Biliński, Jarosław; Grzesiowski, Paweł; Muszyński, Jacek; Wróblewska, Marta; Mądry, Krzysztof; Robak, Katarzyna; Dzieciątkowski, Tomasz; Wiktor-Jedrzejczak, Wiesław; Basak, Grzegorz W

    2016-06-01

    Colonization of the gastrointestinal tract with multidrug-resistant (MDR) bacteria is a consequence of gut dysbiosis. We describe the successful utilization of fecal microbiota transplantation to inhibit Klebsiella pneumoniae MBL(+) and Escherichia coli ESBL(+) gut colonization in the immunocompromised host as a novel tool in the battle against MDR microorganisms. ClinicalTrials.gov identifier NCT02461199. PMID:26960790

  13. Antibiotic exposure can induce various bacterial virulence phenotypes in multidrug-resistant Salmonella enterica serovar Typhimurium

    Science.gov (United States)

    Salmonella is one of the most prevalent bacterial foodborne diseases in the United States and causes an estimated 1 million human cases every year. Multidrug-resistant (MDR) Salmonella has emerged as a public health issue as it has been associated with increased morbidity in humans and mortality in...

  14. Recycling antibiotics into GUMBOS: A new combination strategy to combat multi-drug resistant bacteria

    Science.gov (United States)

    The emergence of multi-drug resistant bacteria, coupled with the lack of new antibiotics in development, is fast evolving into a global crisis. New strategies utilizing existing antibacterial agents are urgently needed. We propose one such strategy in which four outmoded ß-lactam antibiotics (amp...

  15. Activity of Host Antimicrobials against Multidrug-Resistant Acinetobacter baumannii Acquiring Colistin Resistance through Loss of Lipopolysaccharide

    OpenAIRE

    García-Quintanilla, Meritxell; Pulido, Marina R.; Moreno-Martínez, Patricia; Martín-Peña, Reyes; López-Rojas, Rafael; Pachón, Jerónimo; McConnell, Michael J

    2014-01-01

    Acinetobacter baumannii can acquire resistance to the cationic peptide antibiotic colistin through complete loss of lipopolysaccharide (LPS) expression. The activities of the host cationic antimicrobials LL-37 and human lysozyme against multidrug-resistant clinical isolates of A. baumannii that acquired colistin resistance through lipopolysaccharide loss were characterized. We demonstrate that LL-37 has activity against strains lacking lipopolysaccharide that is similar to that of their colis...

  16. Multidrug-Resistant Hepatitis B Virus Strain in a Chronic Turkish Patient

    Directory of Open Access Journals (Sweden)

    Murat Sayan

    2010-04-01

    Full Text Available Hepatitis B virus (HBV strains, resistant to at least two anti-HBV agents from different subclasses of nucleos(tide analogues (NUCs without a cross-resistance profile, are defined as multidrug-resistant. However, there are limited in vivo data for resistance to multiple NUCs. In this study, we report the case of the emergence of a multidrug-resistant HBV strain in a Turkish patient receiving sequential therapy. Polymerase gene mutations of HBV were detected using direct sequencing, line probe assay and clonal analysis. Twelve months after the start of lamivudine (LAM therapy, virological breakthrough occurred (4.2E+07 IU/ml and the rtM204V variant was detected in the patients sera: adefovir (ADV was added to the therapy. ADV therapy was continued as monotherapy for 11 months, until the occurrence of clinical breakthrough i.e. alanine aminotransferase (ALT 60 IU/L, and emergence of drug resistance to ADV (rtN236T. At that time, switch therapy was resumed with ADV + entecavir (ETV in combination for 5 months. In the 18th month of the ETV monotherapy, direct sequencing showed reduced susceptibility to ETV (rtL180M+rtM204V. Currently, ETV + tenofovir (TDF are being used as antiviral treatment and the HBV DNA load has decreased substantially (<1.0E+02 IU/ml. In conclusion, we have detected an HBV strain with multidrug-resistance, which had a very fast course of development. Patients with a multidrug-resistant profile should be more frequently followed up both by direct sequencing and line probe assay, for the detection of possible novel HBV variants and low level mutants present in the viral population, in case of the sudden emergence of drug resistance.

  17. Evaluation of [11C]laniquidar as a tracer of P-glycoprotein: radiosynthesis and biodistribution in rats

    International Nuclear Information System (INIS)

    At present, P-glycoprotein (P-gp) function can be studied using positron emission tomography (PET) together with a labelled P-gp substrate such as (R)-[11C]verapamil. Such a tracer is, however, less suitable for investigating P-gp (over)expression. Laniquidar is a third-generation P-gp inhibitor, which has been used in clinic trials for modulating multidrug resistance transporters. The purpose of the present study was to develop the radiosynthesis of [11C]laniquidar and to assess its suitability as a tracer of P-gp expression. The radiosynthesis of [11C]laniquidar was performed by methylation of the carboxylic acid precursor with [11C]CH3I. The product was purified by HPLC and reformulated over a tC18 Seppak, yielding a sterile solution of [11C]laniquidar in saline. For evaluating [11C]laniquidar, rats were injected with 20 MBq [11C]laniquidar via a tail vein and sacrificed at 5, 15, 30 and 60 min after injection. Several tissues and distinct brain regions were dissected and counted for radioactivity. In addition, uptake of [11C]laniquidar in rats pretreated with cyclosporine A and valspodar (PSC 833) was determined at 30 min after injection. Finally, the metabolic profile of [11C]laniquidar in plasma was determined. [11C]Laniquidar could be synthesized in moderate yields with high specific activity. Uptake in brain was low, but significantly increased after administration of cyclosporine A. Valspodar did not have any effect on cerebral uptake of [11C]laniquidar. In vivo rate of metabolism was relatively low. Further kinetic studies are needed to investigate the antagonistic behaviour of [11C]laniquidar at tracer level.

  18. Technetium-99m sestamibi imaging in paediatric neuroblastoma and ganglioneuroma and its relation to P-glycoprotein

    International Nuclear Information System (INIS)

    Imaging with technetium-99m sestamibi offers a non-invasive approach to detect the presence of functional P-glycoprotein (Pgp), one of the major causes of multidrug resistance, in human malignancies. A clinical role for Pgp has been suggested in the subpopulation of primary neuroblastoma without amplification of the proto-oncogene MYCN. We wanted to evaluate the usefulness of 99mTc-sestamibi scintigraphy in the screening of neural crest tumours for the presence of Pgp. In ten children suffering from MYCN-negative neuroblastoma, ganglioneuroblastoma or ganglioneuroma, 99mTc-sestamibi imaging was performed at initial diagnosis. All patients underwent planar imaging 20-30 min and 3.5-4 h after intravenous injection of 740 MBq/1.73 m299mTc-sestamibi. Tumour to normal tissue ratios, as well as washout rates, were determined and compared with in vitro flow cytometric analysis of Pgp expression and function. Pgp expression was analysed flow cytometrically with the monoclonal antibodies 4E3 and MRK16, and Pgp function was evaluated by means of rhodamine 123 uptake and efflux either in the absence or in the presence of the Pgp inhibitor verapamil. In nine of ten patients, we found that the intratumoral 99mTc-sestamibi activity was comparable to the background activity, which might be suggestive of Pgp presence. This was confirmed flow cytometrically in all but one patient. 99mTc-sestamibi enhancement was seen in the primary tumour and the bone marrow metastases of one of the ten patients, and this result was concordant with a negative Pgp status. The findings presented suggest that 99mTc-sestamibi imaging results might correlate with the presence of functional Pgp in neural crest tumours without MYCN amplification. (orig.)

  19. Technetium-99m sestamibi imaging in paediatric neuroblastoma and ganglioneuroma and its relation to P-glycoprotein

    Energy Technology Data Exchange (ETDEWEB)

    Moerloose, B. de; Dhooge, C.; Benoit, Y.; Laureys, G. [Department of Pediatrics, University Hospital Gent (Belgium); Wiele, C. van de; Dierckx, R.A. [Department of Nuclear Medicine, University Hospital Gent (Belgium); Philippe, J. [Department of Clinical Chemistry, Microbiology and Immunology, University Hospital Gent (Belgium); Speleman, F. [Department of Medical Genetics, University Hospital Gent (Belgium)

    1999-04-29

    Imaging with technetium-99m sestamibi offers a non-invasive approach to detect the presence of functional P-glycoprotein (Pgp), one of the major causes of multidrug resistance, in human malignancies. A clinical role for Pgp has been suggested in the subpopulation of primary neuroblastoma without amplification of the proto-oncogene MYCN. We wanted to evaluate the usefulness of {sup 99m}Tc-sestamibi scintigraphy in the screening of neural crest tumours for the presence of Pgp. In ten children suffering from MYCN-negative neuroblastoma, ganglioneuroblastoma or ganglioneuroma, {sup 99m}Tc-sestamibi imaging was performed at initial diagnosis. All patients underwent planar imaging 20-30 min and 3.5-4 h after intravenous injection of 740 MBq/1.73 m{sup 2} {sup 99m}Tc-sestamibi. Tumour to normal tissue ratios, as well as washout rates, were determined and compared with in vitro flow cytometric analysis of Pgp expression and function. Pgp expression was analysed flow cytometrically with the monoclonal antibodies 4E3 and MRK16, and Pgp function was evaluated by means of rhodamine 123 uptake and efflux either in the absence or in the presence of the Pgp inhibitor verapamil. In nine of ten patients, we found that the intratumoral {sup 99m}Tc-sestamibi activity was comparable to the background activity, which might be suggestive of Pgp presence. This was confirmed flow cytometrically in all but one patient. {sup 99m}Tc-sestamibi enhancement was seen in the primary tumour and the bone marrow metastases of one of the ten patients, and this result was concordant with a negative Pgp status. The findings presented suggest that {sup 99m}Tc-sestamibi imaging results might correlate with the presence of functional Pgp in neural crest tumours without MYCN amplification. (orig.) With 4 figs., 2 tabs., 44 refs.

  20. Management of multidrug-resistant TB: novel treatments and their expansion to low resource settings

    OpenAIRE

    Sloan, Derek J.; Lewis, Joseph M

    2016-01-01

    Despite overall progress in global TB control, the rising burden of multidrug-resistant TB (MDR-TB) threatens to undermine efforts to end the worldwide epidemic. Of the 27 countries classified as high burden for MDR-TB, 17 are in ‘low’ or ‘low–middle’ income countries. Shorter, all oral and less toxic multidrug combinations are required to improve treatment outcomes in these settings. Suitability for safe co-administration with HIV drugs is also desirable. A range of strategies and several ne...

  1. Multidrug resistance (MDR) in brain tumors; its clinical importance

    International Nuclear Information System (INIS)

    MDR is one of the important factors affecting chemotherapy in high grade brain malignancies. Especially it affects commonly used agents such as vincristine, VP16, VM26, and cisplatin. MDR1 gene encoded P-glycoprotein (Pgp) prevents intratumoral retention of such drugs by expelling them at the plasma membrance of brain tumor cells. Therefore, the objective of this study was to evaluate MDR in various brain tumors including metastatic tumors including metastatic tumors by dual isotope SPECT, Northern blotting or immunohistochemical staining (IHCS) using JSB-1 monoclonal antibody against MDR1 gene encoded Pgp. Twenty one patients with various brain tumors of primary, secondary, and recurrent tumors were included from 2 institutions. Whenever possible, surgical specimen from these patients were obtained to study MDR. SPET was performed with a tripple head system (Trionix, Twinsburg, Ohio or MultiSPECT 3, Siemens). Three millicuries of 201Tl chloride and 20 mCi of 99mTc-sestamibi were adminstered and SPET was performed in about 15 min. Nineteen percent of patients had MIBI (-) and Tl (+) suggesting MDR (+). MIBI tumor uptake was higher in recurrence (6.67 +/- 1.3) than the stable original tumors (3.12 +/-0.77) (For 201Tl, 3.65 +/-2.2 Vs 1.5 +/-0.41). Three recurrent gliomas biopsied showed positive blotting and these patients failed several courses of chemotherapy. Six patients with various tumors such as oligodendroglioma, meningioma, recurrent G-M (2), and astrocytoma (2) were studied by IHCS, Weakly positive MDR was seen in one recurrent G-M and an astrocytoma case. Positive MDR was seen in the other recurrent G-M and a meningioma. In conclusion, MDR in brain tumors is detected successfully by dual isotope SPECT studies in a limited number of patients. MDR in benign brain tumors has no clinical significance since they are cured by surgical removal. However, we believe its presence in metastatic and high grade especially recurrent tumors is an essential information prior to the innitiation of chemotherapy

  2. Acquired and Transmitted Multidrug Resistant Tuberculosis: The Role of Social Determinants.

    Science.gov (United States)

    Odone, Anna; Calderon, Roger; Becerra, Mercedes C; Zhang, Zibiao; Contreras, Carmen C; Yataco, Rosa; Galea, Jerome; Lecca, Leonid; Bonds, Matthew H; Mitnick, Carole D; Murray, Megan B

    2016-01-01

    Although risk factors for multi-drug resistant tuberculosis are known, few studies have differentiated between acquired and transmitted resistance. It is important to identify factors associated with these different mechanisms to optimize control measures. We conducted a prospective cohort study of index TB patients and their household contacts in Lima, Peru to identify risk factors associated with acquired and transmitted resistance, respectively. Patients with higher socioeconomic status (SES) had a 3-fold increased risk of transmitted resistance compared to those with lower SES when acquired resistance served as the baseline. Quality of housing mediated most of the impact of SES. PMID:26765328

  3. Multidrug resistance among different serotypes of clinical Salmonella isolates in Taiwan

    DEFF Research Database (Denmark)

    Lauderdale, T. L.; Aarestrup, Frank Møller; Chen, P. C.; Lai, J. F.; Wang, H. Y.; Shiau, Y. R.; Huang, I. W.; Hung, C. L.

    2006-01-01

    multiresistant to other antimicrobials. Studies are needed to determine the sources of different multidrug-resistant serotypes. Continued national surveillance is underway to monitor changes in resistance trends and to detect further emergence of resistant Salmonella serotypes in Taiwan. (c) 2006 Elsevier Inc......Of the 798 clinical Salmonella isolates collected from multiple hospitals in Taiwan, resistance to ampicillin (48.5%), chloramphenicol (55.3%), streptomycin (59.0%), sulfamethoxazole (68.0%), and tetracycline (67.8%) was high, whereas resistance to all 5 antimicrobials (ACSSuT R-type) comprised 327...

  4. Effect Of Withania somnifera Leaf Extracts As Antibacterial Agent Against Multidrug Resistant Bacteria

    Directory of Open Access Journals (Sweden)

    Rinku Kumar Chandoria

    2012-12-01

    Full Text Available This study was designed to examine the phytochemical composition and to evaluate antibacterial potential of Withania Somnifera leaf against multidrug resistant bacteria & FT-IR Spectra of different bioactive compounds. Toluene, ethanol, and aqueous extracts of W. Somnifera (leaves were subjected for in vitro antibacterial activity using agar well diffusion against different bacteria of clinical relevance including multi-drug resistant methicillin resistant Staphylococcus aureus (MRSA and vancomycin resistant Enterococcus (VRE sps.The toluene extract resulted maximal active as antibacterial agent and found significantly higher active than aqueous extract (P<0.05. The difference between antibacterial activities of toluene and ethanol or ethanol and aqueous extract was statistically non significant (P>0.05. The maximum activity was observed against Staphylococcus aureus. The extracts (at least one also showed antibacterial activity against Bacillus cereus, coagulase negative staphylococcus, Streptococcus pneumoinae, Shigella dysenteriae, Methicillin resistant Staphylococcus aureus (MRSA and vancomycin resistant Enterococcus (VRE sps. Minimum inhibitory concentrations of plant extract were found in the ranges of 0.156mg/ml to 0.625mg/ml for test strains. Phytochemical analyses revealed the presence of various metabolites like phlobtannins, tannins, steroids and alkaloids which may contribute for the antimicrobial action of leaves extract of W. Somnifera. The partial characterization of the crude extracts by IR spectral analysis revealed the possible presence of different bioactive compounds in the extracts. The leaves of W. Somnifera showed promising antibacterial activity against various clinically important bacteria and multidrug resistant MRSA and VRE.  

  5. Colonization of pressure ulcers by multidrug-resistant microorganisms in patients receiving home care.

    Science.gov (United States)

    Cataldo, Maria Concetta; Bonura, Celestino; Caputo, Giuseppe; Aleo, Aurora; Rizzo, Giovanna; Geraci, Daniela Maria; Cal, Cinzia; Fasciana, Teresa; Mattaliano, Anna Rita; Mammina, Caterina

    2011-12-01

    Colonization and/or infection with multidrug-resistant microorganisms (MDRO) of pressure ulcers in patients receiving care at home have seldom been investigated. The objective of this study was to assess the prevalence of MDRO colonization in pressure ulcers of patients receiving home care in Palermo, Italy. Vancomycin-resistant Enterococcus (VRE), methicillin-resistant Staphylococcus aureus (MRSA), and multidrug-resistant Gram-negative bacilli (MDRGN) were isolated, identified, and characterized from pressure ulcers and selected home environment surfaces. Thirty-two patients were enrolled, of whom 12 were under antimicrobial therapy. Five patients had been admitted to hospital in the preceding year. Nineteen patients tested positive for 1 or more MDROs. In particular, 1 patient was colonized by a vanA-containing strain of VRE, 5 by MRSA, and 17 by MDRGN of different species. Our findings suggest that pressure ulcers in home care patients could play a role in bringing MDROs into the community setting. PMID:21728745

  6. Development of Classification Models for Identifying “True” P-glycoprotein (P-gp Inhibitors Through Inhibition, ATPase Activation and Monolayer Efflux Assays

    Directory of Open Access Journals (Sweden)

    Anna Maria Bianucci

    2012-06-01

    Full Text Available P-glycoprotein (P-gp is an efflux pump involved in the protection of tissues of several organs by influencing xenobiotic disposition. P-gp plays a key role in multidrug resistance and in the progression of many neurodegenerative diseases. The development of new and more effective therapeutics targeting P-gp thus represents an intriguing challenge in drug discovery. P-gp inhibition may be considered as a valid approach to improve drug bioavailability as well as to overcome drug resistance to many kinds of tumours characterized by the over-expression of this protein. This study aims to develop classification models from a unique dataset of 59 compounds for which there were homogeneous experimental data on P-gp inhibition, ATPase activation and monolayer efflux. For each experiment, the dataset was split into a training and a test set comprising 39 and 20 molecules, respectively. Rational splitting was accomplished using a sphere-exclusion type algorithm. After a two-step (internal/external validation, the best-performing classification models were used in a consensus predicting task for the identification of compounds named as “true” P-gp inhibitors, i.e., molecules able to inhibit P-gp without being effluxed by P-gp itself and simultaneously unable to activate the ATPase function.

  7. Chemotherapeutic Activities of Carthami Flos and Its Reversal Effect on Multidrug Resistance in Cancer Cells

    OpenAIRE

    Wu, Jimmy Yiu-Cheong; Yu, Zhi-Ling; Fong, Wang-Fun; Shi, Yi-Qian

    2013-01-01

    Multidrug-resistance (MDR) represents a major cause of failure in cancer chemotherapy. The need for a reduction in MDR by natural-product-based drugs of low toxicity led to the current investigation of applying medicinal herbs in future cancer adjuvant therapy. Carthami Flos (CF), the dried flower of safflower (Carthamus tinctorius L.), is one of the most popular traditional Chinese medicinal herbs used to alleviate pain, increase circulation, and reduce blood-stasis syndrome. The drug resist...

  8. Multidrug-resistant Acinetobacter Infection Mortality Rate and Length of Hospitalization

    OpenAIRE

    Sunenshine, Rebecca H.; Wright, Marc-Oliver; Maragakis, Lisa L.; Harris, Anthony D.; Song, Xiaoyan; Hebden, Joan; Cosgrove, Sara E; Anderson, Ashley; Carnell, Jennifer; Jernigan, Daniel B.; Kleinbaum, David G.; Perl, Trish M.; Standiford, Harold C.; Srinivasan, Arjun

    2007-01-01

    Acinetobacter infections have increased and gained attention because of the organism’s prolonged environmental survival and propensity to develop antimicrobial drug resistance. The effect of multidrug-resistant (MDR) Acinetobacter infection on clinical outcomes has not been reported. A retrospective, matched cohort investigation was performed at 2 Baltimore hospitals to examine outcomes of patients with MDR Acinetobacter infection compared with patients with susceptible Acinetobacter infectio...

  9. Plasmid profiling of multidrug resistant Escherichia coli strains isolated from urinary tract infection patients

    OpenAIRE

    Sabin Khadgi; Uddhav Timilsina; Basudha Shrestha

    2013-01-01

    Introduction- Urinary tract infection is a common community-acquired bacterial disease. Escherichia coli is reported to be the major cause of urinary tract infection. Aim & Objective- The study was conducted with the aim of determining the antibiotic resistance pattern and plasmid profile of multidrug resistant Escherichia coli isolated from Urinary Tract Infection patients. Materials and Method- Antibiotic susceptibility tests were performed against E. coli following the protocol for the Kir...

  10. Safety and effectiveness of colistin compared with tobramycin for multi-drug resistant Acinetobacter baumannii infections

    OpenAIRE

    Cohen Karen; van Zyl-Smit Richard; Bamford Colleen; Gounden Ronald; Maartens Gary

    2009-01-01

    Abstract Background Nosocomial infections due to multi-drug resistant Acinetobacter baumannii are often treated with colistin, but there are few data comparing its safety and efficacy with other antimicrobials. Methods A retrospective cohort study of patients treated with colistin or tobramycin for A. baumannii infections in intensive care units (ICUs) at Groote Schuur hospital. Colistin was used for A. baumannii isolates which were resistant to all other available antimicrobials. In the tobr...

  11. Multi-Drug Resistant Bacteria Isolated from Fish and Fish Handlers in Maiduguri, Nigeria

    OpenAIRE

    Hafsat Ali Grema; Yaqub Ahmed Geidam; Abubakar Suleiman; Isa Adamu Gulani; Roy Bitrus Birma

    2015-01-01

    Multi-drug resistant bacteria were isolated from fresh fish and fish handlers using conventional methods of bacterial isolation such as colonial morphology, gram staining and biochemical tests. The bacteria isolated include Staphylococcus aureus, Streptococcus sp, E. coli, Klebsiella sp, Proteus sp. and Brucella sp. bacterial isolates were subjected to antibiotic susceptibility testing using disc diffusion technique against ten antimicrobial agents. S. aureus isolates showed resistance to gen...

  12. Bactericidal activities of peptide antibiotics against multidrug-resistant Enterococcus faecium.

    OpenAIRE

    Mobarakai, N; Quale, J M; Landman, D.

    1994-01-01

    Multidrug-resistant Enterococcus faecium has emerged as a serious pathogen for which no effective therapy has been established. In this report, we describe the activities of two peptide antibiotics, ramoplanin and daptomycin, against 15 isolates of E. faecium resistant to vancomycin, ampicillin, and aminoglycosides using time-kill experiments. Both antibiotics were rapidly bactericidal when tested in broth; however, the addition of 50% serum resulted in significant regrowth. The combination o...

  13. Fallopia japonica, a Natural Modulator, Can Overcome Multidrug Resistance in Cancer Cells

    OpenAIRE

    Safaa Yehia Eid; Mahmoud Zaki El-Readi; Mohamed Lotfy Ashour; Michael Wink

    2015-01-01

    Resistance of cancer cells to chemotherapy is controlled by the decrease of intracellular drug accumulation, increase of detoxification, and diminished propensity of cancer cells to undergo apoptosis. ATP-binding cassette (ABC) membrane transporters with intracellular metabolic enzymes contribute to the complex and unresolved phenomenon of multidrug resistance (MDR). Natural products as alternative medicine have great potential to discover new MDR inhibitors with diverse modes of action. In t...

  14. Molecular Characterization of the Multidrug Resistant Escherichia coli ST131 Clone

    OpenAIRE

    Schembri, Mark A.; Ben Zakour, Nouri L; Phan, Minh-Duy; Forde, Brian M.; Stanton-Cook, Mitchell; Scott A. Beatson

    2015-01-01

    Escherichia coli ST131 is a recently emerged and globally disseminated multidrug resistant clone associated with urinary tract and bloodstream infections in both community and clinical settings. The most common group of ST131 strains are defined by resistance to fluoroquinolones and possession of the type 1 fimbriae fimH30 allele. Here we provide an update on our recent work describing the globally epidemiology of ST131. We review the phylogeny of ST131 based on whole genome sequence data and...

  15. Molecular Characterization of the Multidrug Resistant Escherichia coli ST131 Clone

    OpenAIRE

    Schembri, Mark A.; Ben Zakour, Nouri L; Minh-Duy Phan; Forde, Brian M.; Mitchell Stanton-Cook; Scott A. Beatson

    2015-01-01

    Escherichia coli ST131 is a recently emerged and globally disseminated multidrug resistant clone associated with urinary tract and bloodstream infections in both community and clinical settings. The most common group of ST131 strains are defined by resistance to fluoroquinolones and possession of the type 1 fimbriae fimH30 allele. Here we provide an update on our recent work describing the globally epidemiology of ST131. We review the phylogeny of ST131 based on whole genome sequence data an...

  16. Eradication of multidrug-resistant A. baumannii in burn wounds by antiseptic pulsed electric field

    OpenAIRE

    Golberg, Alexander; Broelsch, G. Felix; Vecchio, Daniela; Khan, Saiqa; Hamblin, Michael R.; Austen, William G.; Sheridan, Robert L.; Yarmush, Martin L.

    2014-01-01

    Emerging bacterial resistance to multiple drugs is an increasing problem in burn wound management. New non-pharmacologic interventions are needed for burn wound disinfection. Here we report on a novel physical method for disinfection: antiseptic pulsed electric field (PEF) applied externally to the infected burns. In a mice model, we show that PEF can reduce the load of multidrug resistant Acinetobacter baumannii present in a full thickness burn wound by more than four orders of magnitude, as...

  17. Multidrug Resistant CTX-M-Producing Escherichia coli: A Growing Threat among HIV Patients in India

    OpenAIRE

    Padmavathy, Kesavaram; Padma, Krishnan; Rajasekaran, Sikhamani

    2016-01-01

    Extended Spectrum β-Lactamases (ESBLs) confer resistance to third-generation cephalosporins and CTX-M types have emerged as the most prominent ESBLs worldwide. This study was designed to determine the prevalence of CTX-M positive ESBL-producing urinary E. coli isolates from HIV patients and to establish the association of multidrug resistance, phylogeny, and virulence profile with CTX-M production. A total of 57 ESBL producers identified among 76 E. coli strains isolated from HIV patients fro...

  18. High isolation rates of multidrug-resistant bacteria from water and carpets of mosques

    Directory of Open Access Journals (Sweden)

    Mostafa Mohamed Mohamed Ali

    2014-08-01

    Full Text Available Objective: There is little information regarding the isolation of antimicrobial-resistant potentially pathogenic bacteria from water and carpets of mosques worldwide. The objective of the present investigation is to determine the bacteriological quality of water and carpets of mosques in Elkhomes city in Libya. Methods: Potentially pathogenic bacteria were isolated from water samples (n=44 and dust samples from carpets (n=50 of 50 mosques in Elkhomes city, Libya, using standard bacteriological procedures. Susceptibility of isolated bacteria to antimicrobial agents was determined by the disc-diffusion method. Results: Of the water samples examined, 12 (27.3% were positive for Escherichia coli, 10 (22.7% for Klebsiella spp., and 15 (34.1% for other enteric bacteria. Of the dust samples of carpets examined, 6 (12% were positive for E. coli, 33 (66% for Klebsiella spp., and 30 (60% for Staphylococcus spp. Multidrug resistance (MDR, resistance to three or more antimicrobial groups was found among 48.7% (19/37 and 46.9% (30/64 of the examined enterobacteria from water and carpets, respectively, and among 66.7% (20/30 of Staphylococcus spp. from carpets. In addition, methicillin-resistant Staphylococcus aureus (MRSA was isolated from a carpet of one mosque. Conclusion: Presence of multidrug-resistant potentially pathogenic bacteria in examined water and carpets indicate that mosques as communal environments may play a role in the spread of multidrug-resistant bacteria in the community and pose a serious health risk to worshipers.

  19. Phase IB study of doxorubicin in combination with the multidrug resistance reversing agent S9788 in advanced colorectal and renal cell cancer.

    Science.gov (United States)

    Punt, C J; Voest, E E; Tueni, E; Van Oosterom, A T; Backx, A; De Mulder, P H; Hecquet, B; Lucas, C; Gerard, B; Bleiberg, H

    1997-01-01

    S9788 is a new triazineaminopiperidine derivate capable of reversing multidrug resistance (MDR) in cells resistant to chemotherapeutic agents such as doxorubicin. It does not belong to a known class of MDR revertants, but its action involves the binding of P-glycoprotein. Thirty-eight evaluable patients with advanced colorectal or renal cell cancer were treated with doxorubicin alone (16 patients) followed after disease progression with combination treatment of doxorubicin plus S9788 (12 patients) or upfront with the combination of doxorubicin plus S9788 (22 patients). S9788 was given i.v. as a loading dose of 56 mg m-2 over 30 min followed by doxorubicin given at 50 mg m-2 as a bolus infusion. Thereafter, a 2-h infusion of S9788 was administered at escalating doses ranging from 24 to 120 mg m-2 in subsequent cohorts of 4-10 patients. Pharmacokinetic analysis demonstrated that concentrations of S9788 that are known to reverse MDR in vitro were achieved in patients at non-toxic doses. Compared with treatment with doxorubicin alone, treatment with the combination of doxorubicin and S9788 produced a significant increase in the occurrence of WHO grade 3-4 granulocytopenia. Treatment with S9788 was cardiotoxic as it caused a dose-dependent and reversible increase in corrected QT intervals as well as clinically non-significant arrhythmias on 24- or 48-h Holter recordings. Although clinically relevant cardiac toxicities did not occur, the study was terminated as higher doses of S9788 may increase the risk of severe cardiac arrhythmias. Twenty-nine patients treated with S9788 plus doxorubicin were evaluable for response, and one patient, who progressed after treatment with doxorubicin alone, achieved a partial response. We conclude that S9788 administered at the doses and schedule used in this study results in relevant plasma concentrations in humans and can safely be administered in combination with doxorubicin. PMID:9374386

  20. Intraventricular ciprofloxacin usage in treatment of multidrug-resistant central nervous system infections: report of four cases

    Directory of Open Access Journals (Sweden)

    Ayse Karaaslan

    2014-12-01

    Full Text Available In recent years, multidrug-resistant microorganisms appear as important nosocomial pathogens which treatment is quite difficult. As sufficient drug levels could not be achieved in cerebrospinal fluid during intravenous antibiotic therapy for central nervous system infections and due to multidrug-resistance treatment alternatives are limited. In this study, four cases of central nervous system infections due to multidrug-resistant microorganisms who were successfully treated with removal of the devices and intraventricular ciprofloxacin are presented. In conclusion, intraventricular ciprofloxacin can be used for treatment of central nervous system infections if the causative microorganism is sensitive to the drug and no other alternative therapy is available.

  1. Intraventricular Ciprofloxacin Usage in Treatment of Multidrug-Resistant Central Nervous System Infections: Report of Four Cases

    Science.gov (United States)

    Karaaslan, Ayşe; Kadayifçi, Eda Kepenekli; Turel, Ozden; Toprak, Demet Gedikbaşi; Soysal, Ahmet; Bakir, Mustafa

    2014-01-01

    In recent years, multidrug-resistant microorganisms appear as important nosocomial pathogens which treatment is quite difficult. As sufficient drug levels could not be achieved in cerebrospinal fluid during intravenous antibiotic therapy for central nervous system infections and due to multidrug-resistance treatment alternatives are limited. In this study, four cases of central nervous system infections due to multidrug-resistant microorganisms who were successfully treated with removal of the devices and intraventricular ciprofloxacin are presented. In conclusion, intraventricular ciprofloxacin can be used for treatment of central nervous system infections if the causative microorganism is sensitive to the drug and no other alternative therapy is available. PMID:25635219

  2. Reversal effects of nomegestrol acetate on multidrug resistance in adriamycin-resistant MCF7 breast cancer cell line

    International Nuclear Information System (INIS)

    Chemotherapy is important in the systematic treatment of breast cancer. To enhance the response of tumours to chemotherapy, attention has been focused on agents to reverse multidrug resistance (MDR) and on the sensitivity of tumour cells to chemical drugs. Hundreds of reversal drugs have been found in vitro, but their clinical application has been limited because of their toxicity. The reversal activity of progestogen compounds has been demonstrated. However, classical agents such as progesterone and megestrol (MG) also have high toxicity. Nomegestrol (NOM) belongs to a new derivation of progestogens and shows very low toxicity. We studied the reversal activity of NOM and compared it with that of verapamil (VRP), droloxifene (DRO), tamoxifen (TAM) and MG, and investigated the reversal mechanism, i.e. effects on the expression of the MDR1, glutathione S-transferase Pi (GSTπ), MDR-related protein (MRP) and topoisomerase IIα (TopoIIα) genes, as well as the intracellular drug concentration and the cell cycle. The aim of the study was to examine the reversal effects of NOM on MDR in MCF7/ADR, an MCF7 breast cancer cell line resistant to adriamycin (ADR), and its mechanism of action. MCF7/ADR cells and MCF7/WT, an MCF7 breast cancer cell line sensitive to ADR, were treated with NOM as the acetate ester. With an assay based on a tetrazolium dye [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide; MTT], the effects of various concentrations of NOM on MDR in MCF7/ADR cells were studied. Before and after the treatment with 5 μM NOM, the expression of the MDR-related genes MDR1, GSTπ, TopoIIα and MRP were assayed with a reverse transcriptase polymerase chain reaction (RT-PCR) immunocytochemistry assay. By using flow cytometry (FCM), we observed the intracellular ADR concentration and the effects of combined treatment with NOM and ADR on the cell cycle. Results collected were analysed with Student's t test. NOM significantly reversed MDR in MCF7/ADR cells. After treatment NOM at 20, 10 and 5 μM, chemosensitivity to ADR increased 21-fold, 12-fold and 8-fold, respectively. The reversal activity of NOM was stronger than that of the precursor compound MG, and comparable to that of VRP. After treatment with 5 μM NOM, the expression of both the MDR1 and the GSTπ mRNA genes began to decline on the second day (P <0.05 and P <0.01, respectively), and reached the lowest level on the third day (both P <0.01); however, on the fifth day the expression levels began to increase again (both P <0.05). The expression of MRP and TopoIIα had no significant changes. Changes in the expression of P-glycoprotein (P-gp) and GSTπ were similar to those of their mRNA expressions, showing early declines and late increases. Two hours after treatment with 20, 10 and 5 μM NOM, the intracellular ADR concentration increased 2.7-fold, 2.3-fold and 1.5-fold respectively. However, NOM did not increase ADR accumulation in MCF7/WT cells. FCM data showed that after 48 h of combined administration of NOM (20 μM) and ADR (from low to high concentration), MCF7/ADR cells showed a gradual arrest at the G2M phase with increasing ADR dose. The arrest effect with combined drug treatment was stronger than that with the single ADR treatment. MDR is the major mechanism of drug resistance in malignant tumour cells. To overcome MDR and to increase chemosensitivity, many reversal agents have been found. Most progestogen compounds have been demonstrated to have reversal effects, but we found no data on NOM, a new progestogen compound. Our results show that NOM has strong reversal activity. The reversal effects were stronger than those of the precursor compound, MG, and were comparable to that of VRP. Because NOM has low toxicity, it might have good prospects in clinical application. Using RT-PCR and immunocytochemistry assays, we studied the effects of NOM on MDR-related genes. The results were that NOM could markedly downregulate the mRNA and protein expression levels of MDR1 and GSTπ. TopoIIα and MRP gene expression showed no significant changes. It is known that P-gp induces MDR in tumour cells mainly by decreasing the intracellular drug concentration. After treatment with NOM, the intracellular drug concentration in MCF7/ADR cells increased significantly. Combined treatment with NOM and ADR induced arrest at the G2M phase. It is worth noting that NOM caused an early decrease and a late increase in the expression of some MDR-related genes in a time-dependent manner. The phenomena raise a question for the continued administration of reversal agents in clinics that merits further study. We demonstrate that NOM has strong reversal effects on MDR in MCF7/ADR cells. The reversal is via different routes, namely downregulating the mRNA and protein expression levels of MDR1 and GSTπ, increasing intracellular drug concentration and arresting cells at the G2M phase (NOM in combination with ADR). The reversal mechanism needs further study

  3. The Role of Antimicrobial Peptides in Preventing Multidrug-Resistant Bacterial Infections and Biofilm Formation

    Directory of Open Access Journals (Sweden)

    Kyung-Soo Hahm

    2011-09-01

    Full Text Available Over the last decade, decreasing effectiveness of conventional antimicrobial-drugs has caused serious problems due to the rapid emergence of multidrug-resistant pathogens. Furthermore, biofilms, which are microbial communities that cause serious chronic infections and dental plaque, form environments that enhance antimicrobial resistance. As a result, there is a continuous search to overcome or control such problems, which has resulted in antimicrobial peptides being considered as an alternative to conventional drugs. Antimicrobial peptides are ancient host defense effector molecules in living organisms. These peptides have been identified in diverse organisms and synthetically developed by using peptidomimic techniques. This review was conducted to demonstrate the mode of action by which antimicrobial peptides combat multidrug-resistant bacteria and prevent biofilm formation and to introduce clinical uses of these compounds for chronic disease, medical devices, and oral health. In addition, combinations of antimicrobial peptides and conventional drugs were considered due to their synergetic effects and low cost for therapeutic treatment.

  4. Inducible phenotypic multidrug resistance in the fungus Mucor racemosus.

    OpenAIRE

    Leathers, T. D.; Sypherd, P S

    1985-01-01

    The dimorphic fungus Mucor racemosus exhibited a single-step, inducible resistance to cycloheximide, trichodermin, and amphotericin B. Cells adapted to inhibitory levels of the antibiotics after 12 to 40 h. The adaptation involved all the cells in the population and was not the result of the selection of resistant mutants. Adaptation to one drug provided cross resistance to other, dissimilar drugs. Resistance was lost within several generations of growth in the absence of the inhibitors.

  5. Low Fitness Cost of the Multidrug Resistance Gene cfr▿

    OpenAIRE

    LaMarre, Jacqueline M.; Locke, Jeffrey B.; Shaw, Karen J.; Mankin, Alexander S.

    2011-01-01

    The recently described rRNA methyltransferase Cfr that methylates the conserved 23S rRNA residue A2503, located in a functionally critical region of the ribosome, confers resistance to an array of ribosomal antibiotics, including linezolid. A number of reports of linezolid-resistant cfr-positive clinical strains indicate the possible rapid spread of this resistance mechanism. Since the rate of dissemination and the efficiency of maintenance of a resistance gene depend on the fitness cost asso...

  6. Vitamin E derivative-based multifunctional nanoemulsions for overcoming multidrug resistance in cancer.

    Science.gov (United States)

    Zheng, Nannan; Gao, Yanan; Ji, Hongyu; Wu, Linhua; Qi, Xuejing; Liu, Xiaona; Tang, Jingling

    2016-08-01

    The multidrug resistance (MDR), including intrinsic and acquired multidrug resistance, is a major problem in tumor chemotherapy. Here, we proposed a strategy for modulating intrinsic and/or acquired multidrug resistance by altering the levels of Bax and Bcl-2 expression and inhibiting the transport function of P-gp, increasing the intracellular concentration of its substrate anticancer drugs. Vitamin E derivative-based nanoemulsions containing paclitaxel (MNEs-PTX) were fabricated in this study, and in vitro anticancer efficacy of the nanoemulsion system was evaluated in the paclitaxel-resistant human ovarian carcinoma cell line A2780/Taxol. The MNEs-PTX exhibited a remarkably enhanced antiproliferation effect on A2780/Taxol cells than free paclitaxel (PTX) (p Vitamin E derivative-based multifunctional nanoemulsion (MNEs) obviously increased intracellular accumulation of rhodamine 123 (P-gp substrate). Overexpression of Bcl-2 is generally associated with tumor drug resistance, we found that MNEs could reduce Bcl-2 protein level and increase Bax protein level. Taken together, our findings suggest that anticancer drugs associated with MNEs could play a role in the development of MDR in cancers. PMID:26710274

  7. Multi-Drug Resistant Bacteria Isolated from Fish and Fish Handlers in Maiduguri, Nigeria

    Directory of Open Access Journals (Sweden)

    Hafsat Ali Grema

    2015-07-01

    Full Text Available Multi-drug resistant bacteria were isolated from fresh fish and fish handlers using conventional methods of bacterial isolation such as colonial morphology, gram staining and biochemical tests. The bacteria isolated include Staphylococcus aureus, Streptococcus sp, E. coli, Klebsiella sp, Proteus sp. and Brucella sp. bacterial isolates were subjected to antibiotic susceptibility testing using disc diffusion technique against ten antimicrobial agents. S. aureus isolates showed resistance to gentamycin, tetracycline, oxacillin, ciprofloxacin and cefoxitin while Streptococcus sp were resistant to tetracycline, chloramphenicol and clindamycin. All the bacterial isolates were resistant to tetracycline while susceptible to cefoxitin, cephazolin, erythromycin and clindamycin. The multi drug resistance pattern of Staphylococcus aureus isolates showed resistance to three and more antimicrobial agents while none was resistant to 10 antimicrobial agents. All other isolates were resistant to four and more different antimicrobial agents while no isolates was resistant to one and ten antimicrobial agents. Therefore the continuous monitoring and surveillance of multi-drug resistant bacteria in fish and fish handlers will not only reduce the risk of disease to the fishes but public health hazard to fish handlers and consumers in general.

  8. Management of patients with multidrug-resistant/extensively drug-resistant tuberculosis in Europe: a TBNET consensus statement

    OpenAIRE

    Lange, C; Abubakar, I.; Alffenaar, J.-W. C.; BOTHAMLEY, G.; Caminero, J.A.; A. C. C. CARVALHO; Chang, K.-C.; Codecasa, L.; Correia, A.; Crudu, V.; Davies, P.; Dedicoat, M; F. Drobniewski; Duarte, R.; Ehlers, C.

    2014-01-01

    The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) substantially challenges TB control, especially in the European Region of the World Health Organization, where the highest prevalence of MDR/XDR cases is reported. The current management of patients with MDR/XDR-TB is extremely complex for medical, social and public health systems. The treatment with currently available anti-TB therapies to achieve relapse-free cure is long and undermined by a hi...

  9. Multidrug-resistant Gram-negative bacterial infections: the emerging threat and potential novel treatment options.

    Science.gov (United States)

    Vergidis, Paschalis I; Falagas, Matthew E

    2008-02-01

    Gram-negative bacterial infections constitute an emerging threat because of the development of multidrug-resistant organisms. There is a relative shortage of new drugs in the antimicrobial development pipeline that have been tested in vitro and evaluated in clinical studies. Antibiotics that are in the pipeline for the treatment of serious Gram-negative bacterial infections include the cephalosporins, ceftobiprole, ceftarolin and FR-264205. Tigecycline is the first drug approved from a new class of antibiotics called glycylcyclines, and there has been renewed interest in this drug for the treatment of some multidrug-resistant Gram-negative organisms. Carbapenems in the pipeline include tomopenem, with the approved drugs doripenem and faropenem, an oral agent, under evaluation for activity against multidrug-resistant Gram-negative bacterial infections. Polymyxins are old antibiotics traditionally considered to be toxic, but which are being used because of their activity against resistant Gram-negative organisms. New pharmacokinetic and pharmacodynamic data are available regarding the use of these agents. Finally, antimicrobial peptides and efflux pump inhibitors are two new classes of agents under development. This review of investigational antibiotics shows that several new agents will become available in the coming years, even though the pace of antimicrobial research is far from ideal. PMID:18246520

  10. Functionalized Multiwalled Carbon Nanotubes as Carriers of Ruthenium Complexes to Antagonize Cancer Multidrug Resistance and Radioresistance.

    Science.gov (United States)

    Wang, Ni; Feng, Yanxian; Zeng, Lilan; Zhao, Zhennan; Chen, Tianfeng

    2015-07-15

    Multidrug resistance and radioresistance are major obstacles for successful cancer therapy. Due to the unique characteristics of high surface area, improved cellular uptake, and the possibility to be easily bound with therapeutics, carbon nanotubes (CNTs) have attracted increasing attention as potential nanodrug delivery systems. In this study, a CNT-based radiosensitive nanodrug delivery system was rationally designed to antagonize the multidrug resistance in hepatocellular carcinoma. The nanosystem was loaded with a potent anticancer ruthenium polypyridyl complex (RuPOP) via ?-? interaction and formation of a hydrogen bond. The functionalized nanosystem (RuPOP@MWCNTs) enhanced the cellular uptake of RuPOP in liver cancer cells, especially drug-resistant R-HepG2 cells, through endocytosis. Consistently, the selective cellular uptake endowed the nanosystem amplified anticancer efficacy against R-HepG2 cells but not in normal cells. Interestingly, RuPOP@MWCNTs significantly enhanced the anticancer efficacy of clinically used X-ray against R-HepG2 cells through induction of apoptosis and G0/G1 cell cycle arrest, with the involvement of ROS overproduction, which activated several downstream signaling pathways, including DNA damage-mediated p53 phosphorylation, activation of p38, and inactivation of AKT and ERK. Moreover, the nanosystem also effectively reduces the toxic side effects of loaded drugs and prolongs the blood circulation in vivo. Taken together, the results demonstrate the rational design of functionalized carbon nanotubes and their application as effective nanomedicine to overcome cancer multidrug resistance. PMID:26107995

  11. Characterization of putative multidrug resistance transporters of the major facilitator-superfamily expressed in Salmonella Typhi.

    Science.gov (United States)

    Shaheen, Aqsa; Ismat, Fouzia; Iqbal, Mazhar; Haque, Abdul; De Zorzi, Rita; Mirza, Osman; Walz, Thomas; Rahman, Moazur

    2015-05-01

    Multidrug resistance mediated by efflux pumps is a well-known phenomenon in infectious bacteria. Although much work has been carried out to characterize multidrug efflux pumps in Gram-negative and Gram-positive bacteria, such information is still lacking for many deadly pathogens. The aim of this study was to gain insight into the substrate specificity of previously uncharacterized transporters of Salmonella Typhi to identify their role in the development of multidrug resistance. S. Typhi genes encoding putative members of the major facilitator superfamily were cloned and expressed in the drug-hypersensitive Escherichia coli strain KAM42, and tested for transport of 25 antibacterial compounds, including representative antibiotics of various classes, antiseptics, dyes and detergents. Of the 15 tested putative transporters, STY0901, STY2458 and STY4874 exhibited a drug-resistance phenotype. Among these, STY4874 conferred resistance to at least ten of the tested antimicrobials: ciprofloxacin, norfloxacin, levofloxacin, kanamycin, streptomycin, gentamycin, nalidixic acid, chloramphenicol, ethidium bromide, and acriflavine, including fluoroquinolone antibiotics, which were drugs of choice to treat S. Typhi infections. Cell-based functional studies using ethidium bromide and acriflavine showed that STY4874 functions as a H(+)-dependent exporter. These results suggest that STY4874 may be an important drug target, which can now be tested by studying the susceptibility of a STY4874-deficient S. Typhi strain to antimicrobials. PMID:25724589

  12. In vitro Antibacterial Activity of Aqueous and Ethanol Extracts of Aristolochia indica and Toddalia asiatica Against Multidrug-Resistant Bacteria.

    Science.gov (United States)

    Venkatadri, B; Arunagirinathan, N; Rameshkumar, M R; Ramesh, Latha; Dhanasezhian, A; Agastian, P

    2015-01-01

    Bacteria have developed multidrug resistance against available antimicrobial agents. Infectious diseases caused by these multidrug-resistant bacteria are major causes of morbidity and mortality in human beings. Synthetic drugs are expensive and inadequate for the treatment of diseases, causing side effects and ineffective against multidrug-resistant bacteria. The medicinal plants are promising to have effective antimicrobial property due to presence of phytochemical compounds like alkaloids, flavanoids, tannins and phenolic compounds. The present study aimed to find the antimicrobial activity of medicinal plants against multidrug-resistant bacteria. Multidrug-resistant bacteria were identified by Kirby-Bauer disc diffusion method. Production of β-lactamases (extended spectrum β-lactamases, metallo β-lactamase and AmpC β-lactamase) were identified by combination disc method. Antibacterial activity of aqueous and ethanol extract of Aristolochia indica and Toddalia asiatica were detected by agar well diffusion assay and minimum inhibitory concentration. All bacteria used in this study showed antibiotic resistance to ≥3 antibiotics. Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Proteus mirabilis and Vibrio cholerae were found to be positive for β-lactamase production. Ethanol extract of Aristolochia indica showed more significant antibacterial activity against multidrug-resistant bacteria than Toddalia asiatica. Ethanol extracts of Aristolochia indica and Toddalia asiatica showed minimum inhibitory concentration values of 50-100 μg/ml and 100-200 μg/ml, respectively against multidrug-resistant bacteria. From this study, it was concluded that Aristolochia indica has more potential to treat multidrug-resistant bacteria than Toddalia asiatica. PMID:26997710

  13. The Taccalonolides: Microtubule Stabilizers that Circumvent Clinically Relevant Taxane Resistance Mechanisms

    OpenAIRE

    April L. Risinger; Jackson, Evelyn M.; Polin, Lisa A; Helms, Gregory L.; LeBoeuf, Desiree A.; Joe, Patrick A.; Hopper-Borge, Elizabeth; Ludueña, Richard F; Kruh, Gary D.; Mooberry, Susan L.

    2008-01-01

    The taccalonolides are a class of structurally and mechanistically distinct microtubule-stabilizing agents isolated from Tacca chantrieri. A crucial feature of the taxane family of microtubule stabilizers is their susceptibility to cellular resistance mechanisms including overexpression of P-glycoprotein, MRP7 and the βIII isotype of tubulin. The ability of four taccalonolides, A, E, B and N, to circumvent these multidrug resistance mechanisms was studied. Taccalonolides A, E, B and N were ef...

  14. ABCB1 gene polymorphisms is not associated with drug-resistant epilepsy in Romanian children

    Directory of Open Access Journals (Sweden)

    Butila Anamaria Todoran

    2015-12-01

    Full Text Available Background: P-glycoprotein (P-gp, a drug efflux transporter, encoded by the gene MDR1 ABCB1 multidrug resistant, reduces the penetration through the brain by the AEDs. Overexpression of Pgp in blood-brain barrier in epileptic patients play an important rol in pharmacoresistance. The aim of this study was to evaluate a possible association between C1236T and G2677T ABCB1 gene polymorphisms and drug-resistant epilepsy in Romanian children.

  15. Multidrug-resistant and extensively drug-resistant tuberculosis: a review of current concepts and future challenges.

    Science.gov (United States)

    Günther, Gunar

    2014-06-01

    Multidrug-resistant and extensively drug-resistant tuberculosis are recent global health issues, which makes tuberculosis - after the success of short course treatment during the second half of the last century - a major health challenge. Globalisation, health inequalities, competing economic interests and political instability contribute substantially to the spread of drug-resistant strains, which are associated with high rates of morbidity and mortality. Issues such as increasing transmission of drug-resistant strains, poor diagnostic coverage and a lengthy, toxic treatment need to be overcome by innovative approaches to tuberculosis control, prevention, diagnostics and treatment. This review addresses recent developments and future concepts. PMID:24889573

  16. Complete Genome Sequence of Streptococcus pneumoniae Strain A026, a Clinical Multidrug-Resistant Isolate Carrying Tn2010

    OpenAIRE

    Sui, Zhihai; Zhou, Wenqing; Yao, Kaihu; Liu, Li; ZHANG, GANG; YANG, Yonghong; Feng, Jie

    2013-01-01

    Streptococcus pneumoniae is a primary cause of bacterial infection in humans. Here, we present the complete genome sequence of S.pneumoniae strain A026, which is a multidrug-resistant strain isolated from cerebrospinal fluid.

  17. The role of half-transporters in multidrug resistance

    DEFF Research Database (Denmark)

    Bates, S E; Robey, R; Miyake, K; Rao, K; Ross, D D; Litman, Thomas

    2001-01-01

    role of drug transporters in clinical drug resistance. These newly identified transporters include additional members of the MRP family, ABC2, and a new half-transporter, MXR/BCRP/ABCP1. This half-transporter confers high levels of resistance to mitoxantrone, anthracyclines, and the camptothecins SN-38...

  18. Cooperative Antibiotic Resistance in a Multi-Drug Environment

    Science.gov (United States)

    Yurtsev, Eugene; Dai, Lei; Gore, Jeff

    2013-03-01

    The emergence of antibiotic resistance in bacteria is a significant health concern. A frequent mechanism of antibiotic resistance involves the production of an enzyme which inactivates the antibiotic. By inactivating the antibiotic, resistant cells can ``share'' their resistance with other cells in the bacterial population, suggesting that it may be possible to observe cooperation between strains that inactivate different antibiotics. Here, we experimentally track the population dynamics of two E. coli strains in the presence of two different antibiotics. We find that together the strains are able to grow in antibiotic concentrations that inhibit growth of either of the strains individually. We observe that even when there is stable coexistence between the two strains, the population size of each strain can undergo large oscillations. We expect that our results will provide insight into the evolution of antibiotic resistance and the evolutionary origin of phenotypic diversity and cooperative behaviors.

  19. Advantage and limitations of nitrofurantoin in multi-drug resistant Indian scenario.

    Science.gov (United States)

    Shakti, Laishram; Veeraraghavan, Balaji

    2015-01-01

    Infections caused by antibiotic resistant pathogens are of significant concern and are associated with higher mortality and morbidity. Nitrofurantoin is a broad-spectrum bactericidal antibiotic and is effectively used to treat urinary tract infections (UTIs) caused by E. coli, Klebsiella sp., Enterobacter sp., Enterococcus sp. and Staphylococcus aureus. It interfere with the synthesis of cell wall, bacterial proteins and DNA of both Gram positive and Gram negative pathogens. Nitrofurantoin has been used successfully for treatment and prophylaxis of acute lower urinary tract infections. With the emergence of antibiotic resistance, nitrofurantoin has become the choice of agent for treating UTIs caused by multi-drug resistant pathogens. PMID:26470951

  20. Overexpression of CDX2 in gastric cancer cells promotes the development of multidrug resistance

    OpenAIRE

    Yan, Lin-Hai; Wei, Wei-Yuan; Cao, Wen-Long; Zhang, Xiao-Shi; Xie, Yu-Bo; XIAO Qiang

    2014-01-01

    Modulator of multidrug resistance (MDR) gene is a direct transcriptional target of CDX2. However, we still speculate whether CDX2 affects MDR through other ways. In this study, a cisplatin-resistant (SGC7901/DDP) and a 5-fluoro-2, 4(1h,3h)pyrimidinedione-resistant (BGC823/5-FU) gastric cancer cell line with stable overexpression of CDX2 were established. The influence of overexpression of CDX2 on MDR was assessed by measuring IC50 of SGC7901/DDP and BGC823/5-FU cells to cisplatin, doxorubicin...

  1. Multidrug-resistant tuberculosis in Ethiopia: efforts to expand diagnostic services, treatment and care

    OpenAIRE

    Biadglegne, Fantahun; Sack, Ulrich; Rodloff, Arne C

    2014-01-01

    The emergence of drug-resistant tuberculosis (TB), particularly multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB, is a major public health problem. The purpose of this review is to describe the current status of MDR-TB and factors that increase the risk of this infection. We conducted a systematic review of the literature on MDR-TB in Ethiopia. Out of 766 articles, 23 were found to meet eligibility criteria and included in this review. Among the 23 papers, six of them reporte...

  2. Multidrug-resistant Streptococcus pneumoniae isolates from healthy Ghanaian preschool children

    DEFF Research Database (Denmark)

    Dayie, Nicholas Tete Kwaku Dzifa; Arhin, Reuben E.; Newman, Mercy J.; Dalsgaard, Anders; Bisgaard, Magne; Frimodt-Møller, Niels; Slotved, Hans-Christian

    2015-01-01

    Streptococcus pneumoniae is the cause of high mortality among children worldwide. Antimicrobial treatment and vaccination are used to control pneumococcal infections. In Ghana, data on antimicrobial resistance and the prevalence of multidrug-resistant pneumococcal clones are scarce; hence, the aim...... of this study was to determine the antibiogram of S. pneumoniae recovered from Ghanaian children younger than six years of age and to what extent resistances were due to the spread of certain sero- and multilocus sequence typing (MLST) types. The susceptibility of 115 pneumococcal isolates, recovered...

  3. Molecular modeling of the human multidrug resistance protein 1 (MRP1/ABCC1)

    International Nuclear Information System (INIS)

    Multidrug resistance protein 1 (MRP1/ABCC1) is a 190 kDa member of the ATP-binding cassette (ABC) superfamily of transmembrane transporters that is clinically relevant for its ability to confer multidrug resistance by actively effluxing anticancer drugs. Knowledge of the atomic structure of MRP1 is needed to elucidate its transport mechanism, but only low resolution structural data are currently available. Consequently, comparative modeling has been used to generate models of human MRP1 based on the crystal structure of the ABC transporter Sav1866 from Staphylococcus aureus. In these Sav1866-based models, the arrangement of transmembrane helices differs strikingly from earlier models of MRP1 based on the structure of the bacterial lipid transporter MsbA, both with respect to packing of the twelve helices and their interactions with the nucleotide binding domains. The functional importance of Tyr324 in transmembrane helix 6 predicted to project into the substrate translocation pathway was investigated

  4. Multidrug resistant Kluyvera ascorbata septicemia in an adult patient: a case report

    Directory of Open Access Journals (Sweden)

    Freeman Clyde

    2010-06-01

    Full Text Available Abstract Introduction Kluyvera ascorbata has become increasingly significant due to its potential to cause a wide range of infections, as well as its ability to transfer gene encoding for CTX-M- type extended spectrum B-lactamases (ESBLs to other Enterobacteriaceae. Case presentation We report the case of a 64-year-old African-American male diagnosed with severe sepsis due to a multidrug resistant Kluyvera ascorbata, which was isolated from his blood. He was treated with meropenem and had a favorable outcome. Conclusion To the best of our knowledge, this is the first case report of a multidrug resistant Kluyvera ascorbata isolated from the blood in an adult patient with sepsis.

  5. Nuclear texture and chromatin structure in OV1/VCR human multidrug-resistant cell line.

    Science.gov (United States)

    Yatouji, Sonia; Trussardi-Regnier, Aurelie; Trentesaux, Chantal; Liautaud-Roger, Françoise; Dufer, Jean

    2003-10-01

    Previous studies have demonstrated that multidrug-resistant leukemic cells displayed nuclear texture changes. In this work, the human ovarian carcinoma cell line IGROV1 and its multidrug-resistant variant OV1/VCR were studied. Cell smears of these cell populations were analysed by image cytometry. As compared to sensitive cells, OV1/VCR display a chromatin global decondensation as assessed by textural features analysis. In order to correlate this decondensation with alterations in chromatin structure, DNase I was used. OV1/VCR DNA displayed an increased DNase I sensitivity, suggesting an increased chromatin accessibility. Furthermore, OV1/VCR cells displayed an increased level in acetylated histone H4, a mechanism known to be associated with transcriptionally active chromatin and relaxed chromatin conformation. PMID:12964008

  6. Daunorubicin-loaded magnetic nanoparticles of Fe3O4 overcome multidrug resistance and induce apoptosis of K562-n/VCR cells in vivo

    Directory of Open Access Journals (Sweden)

    Bao-an Chen

    2009-09-01

    Full Text Available Bao-an Chen1, Bin-bin Lai1, Jian Cheng1, Guo-hua Xia1, Feng Gao1, Wen-lin Xu2, Jia-hua Ding1, Chong Gao1, Xin-chen Sun3, Cui-rong Xu1, Wen-ji Chen1, Ning-na Chen1, Li-jie Liu4, Xiao-mao Li5, Xue-mei Wang61Department of Hematology, 3Department of Oncology, the Affiliated Zhongda Hospital, Clinical Medical School, Southeast University, Nanjing, People’s Republic of China; 2Department of Hematology, the Affiliated People’s Hospital, Jiangsu University, Zhenjiang, People’s Republic of China; 4Institution of Physiology, 6State Key Lab of Bioelectronics (Chien-shiung Wu Laboratory, Southeast University, Nanjing, People’s Republic of China; 5Department of Physics, University of Saarland, Saarbruechen, GermanyAbstract: Multidrug resistance (MDR is a major obstacle to cancer chemotherapy. We evaluated the effect of daunorubicin (DNR-loaded magnetic nanoparticles of Fe3O4 (MNPs-Fe3O4 on K562-n/VCR cells in vivo. K562-n and its MDR counterpart K562-n/VCR cell were inoculated into nude mice subcutaneously. The mice were randomly divided into four groups: group A received normal saline, group B received DNR, group C received MNPs-Fe3O4, and group D received DNR-loaded MNPs-Fe3O4. For K562-n/VCR tumor, the weight was markedly lower in group D than that in groups A, B, and C. The transcriptions of Mdr-1 and Bcl-2 gene were significantly lower in group D than those in groups A, B, and C. The expression of Bcl-2 was lower in group D than those in groups A, B, and C, but there was no difference in the expression of P-glycoprotein. The transcriptions and expressions of Bax and caspase-3 in group D were increased significantly when compared with groups A, B, and C. In conclusion, DNR-loaded MNPs-Fe3O4 can overcome MDR in vivo.Keywords: multidrug-resistance reversal, leukemia, magnetic nanoparticles of Fe3O4, in vivo

  7. Colistin Therapy in a 23-Week Gestational-Age Neonate with Multidrug-Resistant Acinetobacter baumannii Pneumonia

    Directory of Open Access Journals (Sweden)

    Mirjana Lulic-Botica

    2011-01-01

    Full Text Available Multidrug-resistant pathogens are becoming more difficult to treat with significantly increasing infection rates. The lack of new antibiotics to combat these strains has led to the resurgence of older antibiotics. This case highlights the first reported use of colistimethate sodium treatment in a 23-week gestational-age neonate with multidrug-resistant Acinetobacter baumannii pneumonia who developed acute renal failure and seizures shortly after initiation of treatment.

  8. Comparison of the multi-drug resistant human hepatocellular carcinoma cell line Bel-7402/ADM model established by three methods

    OpenAIRE

    Zhong Xingguo; Xiong Maoming; Meng Xiangling; Gong Renhua

    2010-01-01

    Abstract Background To compare the biological characteristics of three types of human hepatocellular carcinoma multi-drug resistant cell sub-lines Bel-7402/ADM models established by three methods. Methods Established human hepatocellular carcinoma adriamycin (ADM) multi-drug resistant cell sub-lines models Bel-7402/ADMV, Bel-7402/ADML and Bel-7402/ADMS by three methods of in vitro concentration gradient increased induction, nude mice liver-implanted induction and subcutaneous-implanted induct...

  9. Insights into a Multidrug Resistant Escherichia coli Pathogen of the Globally Disseminated ST131 Lineage: Genome Analysis and Virulence Mechanisms

    OpenAIRE

    Totsika, Makrina; Scott A. Beatson; Sarkar, Sohinee; Phan, Minh-Duy; Petty, Nicola K; Bachmann, Nathan; Szubert, Marek; Sidjabat, Hanna E.; Paterson, David L; Upton, Mathew; Schembri, Mark A.

    2011-01-01

    Escherichia coli strains causing urinary tract infection (UTI) are increasingly recognized as belonging to specific clones. E. coli clone O25b:H4-ST131 has recently emerged globally as a leading multi-drug resistant pathogen causing urinary tract and bloodstream infections in hospitals and the community. While most molecular studies to date examine the mechanisms conferring multi-drug resistance in E. coli ST131, relatively little is known about their virulence potential. Here we examined E. ...

  10. Reversal of multidrug resistance by co-delivery of paclitaxel and lonidamine using a TPGS and hyaluronic acid dual-functionalized liposome for cancer treatment.

    Science.gov (United States)

    Assanhou, Assogba G; Li, Wenyuan; Zhang, Lei; Xue, Lingjing; Kong, Lingyi; Sun, Hongbin; Mo, Ran; Zhang, Can

    2015-12-01

    Multidrug resistance (MDR) remains the primary issue in cancer therapy, which is characterized by the overexpressed P-glycoprotein (P-gp)-included efflux pump or the upregulated anti-apoptotic proteins. In this study, a D-alpha-tocopheryl poly (ethylene glycol 1000) succinate (TPGS) and hyaluronic acid (HA) dual-functionalized cationic liposome containing a synthetic cationic lipid, 1,5-dioctadecyl-N-histidyl-L-glutamate (HG2C18) was developed for co-delivery of a small-molecule chemotherapeutic drug, paclitaxel (PTX) with a chemosensitizing agent, lonidamine (LND) to treat the MDR cancer. It was demonstrated that the HG2C18 lipid contributes to the endo-lysosomal escape of the liposome following internalization for efficient intracellular delivery. The TPGS component was confirmed able to elevate the intracellular accumulation of PTX by inhibiting the P-gp efflux, and to facilitate the mitochondrial-targeting of the liposome. The intracellularly released LND suppressed the intracellular ATP production by interfering with the mitochondrial function for enhanced P-gp inhibition, and additionally, sensitized the MDR breast cancer (MCF-7/MDR) cells to PTX for promoted induction of apoptosis through a synergistic effect. Functionalized with the outer HA shell, the liposome preferentially accumulated at the tumor site and showed a superior antitumor efficacy in the xenograft MCF-7/MDR tumor mice models. These findings suggest that this dual-functional liposome for co-delivery of a cytotoxic drug and an MDR modulator provides a promising strategy for reversal of MDR in cancer treatment. PMID:26426537

  11. Genetic relatedness and molecular characterization of multidrug resistant Acinetobacter baumannii isolated in central Ohio, USA

    Directory of Open Access Journals (Sweden)

    Tadesse Daniel

    2009-06-01

    Full Text Available Abstract Background Over the last decade, nosocomial infections due to Acinetobacter baumannii have been described with an increasing trend towards multidrug resistance, mostly in intensive care units. The aim of the present study was to determine the clonal relatedness of clinical isolates and to elucidate the genetic basis of imipenem resistance. Methods A. baumannii isolates (n = 83 originated from two hospital settings in central Ohio were used in this study. Pulsed-field gel electrophoresis genotyping and antimicrobial susceptibility testing for clinically relevant antimicrobials were performed. Resistance determinants were characterized by using different phenotypic (accumulation assay for efflux and genotypic (PCR, DNA sequencing, plasmid analysis and electroporation approaches. Results The isolates were predominantly multidrug resistant (>79.5% and comprised of thirteen unique pulsotypes, with genotype VII circulating in both hospitals. The presence of blaOXA-23 in 13% (11/83 and ISAba1 linked blaOXA-66 in 79.5% (66/83 of clinical isolates was associated with high level imipenem resistance. In this set of OXA producing isolates, multidrug resistance was bestowed by blaADC-25, class 1 integron-borne aminoglycoside modifying enzymes, presence of sense mutations in gyrA/parC and involvement of active efflux (with evidence for the presence of adeB efflux gene. Conclusion This study underscores the major role of carbapenem-hydrolyzing class D β-lactamases, and in particular the acquired OXA-23, in the dissemination of imipenem-resistant A. baumannii. The co-occurrence of additional resistance determinant could also be a significant threat.

  12. Assessment of Carbapenem Susceptibility and Multidrug-Resistance in Pseudomonas aeruginosa Burn Isolates in Tehran

    Directory of Open Access Journals (Sweden)

    Fereshteh Eftekhar

    2013-04-01

    Full Text Available Background: Pseudomonas aeruginosais an opportunistic pathogen which causes severe, acute and chronic nosocomial infections. These infections are difficult to eradicate since the organisms are usually multidrug-resistant. Carbapenems are considered as the most effective drugs against these isolates. However, recent emergence of carbapenem-resistant P. aeruginosa has become a major healthcare problem..Objectives: The present study was conducted to determine the antibiotic susceptibility of P. aeruginosa burn isolates to 13 antibiotics including imipemen and meropenem..Materials and Methods: One hundred and thirty three P. aeruginosa burn isolates were collected from Shahid Motahari Burn Hospital between July and December 2011. The majority of the isolates were from wounds (88.7%, followed by 5.26% from blood, 4.15% from subclavian catheters and 1.5% from urine. The antibiotic susceptibility profiles were studied by the agar disc diffusion..Results: The results showed 99.2% resistance to carbenicillin, 98.4% to ticarcillin, 96.2% to ciprofloxacin, 95.4% to co-trimoxazole, 94.7% to imipenem and meropenem, 93.9% to piperacillin, 93.2% to azetronam, 92.4% to tobramycin, 91.7% to cefepime, 89.4% to amikacin and ceftazidime, and finally 87.2% to piperacillin-tazobactam. Overall, 100% of the isolates showed multidrug-resistance (resistance to ≥ 3 classes of antibiotics including theimipenem- resistant isolates..Conclusions: The high rate of multidrug-resistance is alarming and it is crucial to screen for carbapenem resistance prior to - antibiotic therapy.

  13. Human ABCG2: structure, function, and its role in multidrug resistance

    OpenAIRE

    Mo, Wei; Zhang, Jian-Ting

    2011-01-01

    Human ABCG2 is a member of the ATP-binding cassette (ABC) transporter superfamily and is known to contribute to multidrug resistance (MDR) in cancer chemotherapy. Among ABC transporters that are known to cause MDR, ABCG2 is particularly interesting for its potential role in protecting cancer stem cells and its complex oligomeric structure. Recent studies have also revealed that the biogenesis of ABCG2 could be modulated by small molecule compounds. These modulators, upon binding to ABCG2, acc...

  14. Design real-time reversal of tumor multidrug resistance cleverly with shortened carbon nanotubes

    OpenAIRE

    Wu, Pingping; Li, Shang; Zhang, HaiJun

    2014-01-01

    Multidrug resistance (MDR) in tumors renders many currently available chemotherapeutic drugs ineffective. Research in nanobiotechnology-based therapeutic alternatives has provided innovative and promising strategies to overcome MDR. The aim of this study was to investigate whether the new strategy of a co-loaded reversal agent and chemotherapeutic drug with shortened carbon nanotubes (CNTs) would show useful effects on the real-time reversal of tumor MDR. CNTs were cut and purified via ultras...

  15. Generation and characterisation of antibodies specific for the multidrug resistance-associated protein, MRP

    OpenAIRE

    Connolly, Lisa

    1999-01-01

    Multidrug resistance associated protein 1 (MRP1) is a 190kD integral membrane glycoprotein which belongs to the ATP-binding cassette (ABC) superfamily of transport proteins. The MRP1 specific MAbs, MRPrl, MRPm6 and QCRL-1 have facilitated both clinical and experimental investigations of this protein to date. In this thesis we have used various types of MRP 1-related immunogens in various species and utilising different immunisation protocols with the objective of producing additional MRP1 spe...

  16. Redox Control of Multidrug Resistance and Its Possible Modulation by Antioxidants

    OpenAIRE

    Aysegul Cort; Tomris Ozben; Luciano Saso; Chiara De Luca; Liudmila Korkina

    2016-01-01

    Clinical efficacy of anticancer chemotherapies is dramatically hampered by multidrug resistance (MDR) dependent on inherited traits, acquired defence against toxins, and adaptive mechanisms mounting in tumours. There is overwhelming evidence that molecular events leading to MDR are regulated by redox mechanisms. For example, chemotherapeutics which overrun the first obstacle of redox-regulated cellular uptake channels (MDR1, MDR2, and MDR3) induce a concerted action of phase I/II metabolic en...

  17. Nitrate reductase assay using sodium nitrate for rapid detection of multidrug resistant tuberculosis

    Directory of Open Access Journals (Sweden)

    Maíra Bidart Macedo

    2012-09-01

    Full Text Available We validated the nitrate reductase assay (NRA for the detection of multidrug-resistant Mycobacterium tuberculosis (MDR-TB using sodium nitrate (NaNO3 in replacement of potassium nitrate (KNO3 as nitrate source. NaNO3 is cheaper than KNO3 and has no restriction on use which facilitates the implementation of NRA to detect MDR-TB.

  18. Multidrug-resistant Bacteroides fragilis group on the rise in Europe?

    DEFF Research Database (Denmark)

    Hartmeyer, G N; Sóki, J; Nagy, E; Justesen, U S

    We report a case of multidrug-resistance (MDR) in a strain of Bacteroides fragilis from a blood culture and abdominal fluid in a Danish patient. The patient had not been travelling for several years and had not received antibiotics prior to the present case. We also summarize the cases that have...... been reported to date of MDR B. fragilis group in Europe. As far as we know, a case like this with MDR B. fragilis has not been described in Scandinavia before....

  19. The Outcomes of Using Colistin for Treating Multidrug Resistant Acinetobacter Species Bloodstream Infections

    OpenAIRE

    Lim, Seung-Kwan; Lee, Sang-Oh; Choi, Seong-Ho; Choi, Jae-Phil; Kim, Sung-Han; Jeong, Jin-Yong; Choi, Sang-Ho; Woo, Jun Hee; Kim, Yang Soo

    2011-01-01

    Despite the identification of Acinetobacter baumannii isolates that demonstrate susceptibility to only colistin, this antimicrobial agent was not available in Korea until 2006. The present study examined the outcomes of patients with multidrug resistant (MDR) Acinetobacter species bloodstream infection and who were treated with or without colistin as part of their regimen. The colistin group was given colistin as part of therapy once colistin became available in 2006. The non-colistin group w...

  20. Utilization of colistin for treatment of multidrug-resistant Pseudomonas aeruginosa

    OpenAIRE

    Sabuda, Deana M.; Laupland, Kevin; Pitout, Johann; Dalton, Bruce; Rabin, Harvey; Louie, Thomas; Conly, John

    2008-01-01

    BACKGROUND: Colistin is uncommonly used in clinical practice; however, the emergence of multidrug-resistant organisms has rekindled interest in this potentially toxic therapeutic option. The present study describes the authors’ experience with colistin in the management of patients who were infected with metallo-beta-lactamase (MBL)-producing Pseudomonas aeruginosa within the Calgary Health Region (Calgary, Alberta).METHOD: Adult patients who received colistimethate sodium (colistin) between ...

  1. Predictors of Multidrug Resistant Acinetobacter Baumannii Infections in Surgical Intensive Care Patients: A Retrospective Analysis

    OpenAIRE

    Aynur Camkıran; Aycan Kundakcı; Coşkun Araz; Arash Pirat; Pınar Zeyneloğlu; Hande Arslan; Gülnaz Arslan

    2011-01-01

    Objective: Multidrug resistant Acinetobacter baumannii (MRAB) is an important cause of hospital acquired infection and leads to an increasing morbidity and mortality in intensive care units (ICU). The aim of this study was to investigate the predictors of MRAB infection in surgical ICU patients. Material and Method: The charts of the patients who were admitted to the ICU between January 2008 and August 2010 were reviewed to identify patients with MRAB infection. Recorded data were as fo...

  2. Genome of Multidrug-Resistant Uropathogenic Escherichia coli Strain NA114 from India ▿

    OpenAIRE

    Avasthi, Tiruvayipati Suma; Kumar, Narender; Baddam, Ramani; Hussain, Arif; Nandanwar, Nishant; Jadhav, Savita; Ahmed, Niyaz

    2011-01-01

    Uropathogenic Escherichia coli (UPEC) causes serious infections in people at risk and has a significant environmental prevalence due to contamination by human and animal excreta. In developing countries, UPEC assumes importance in certain dwellings because of poor community/personal hygiene and exposure to contaminated water or soil. We report the complete genome sequence of E. coli strain NA114 from India, a UPEC strain with a multidrug resistance phenotype and the capacity to produce extend...

  3. Short-course treatment for multidrug-resistant tuberculosis: the STREAM trials

    OpenAIRE

    Riya Moodley; Thomas R. Godec

    2016-01-01

    Multidrug-resistant (MDR) tuberculosis (TB) is a threat to global TB control, as suboptimal and poorly tolerated treatment options have resulted in largely unfavourable outcomes for these patients. The last of six cohort studies conducted in Bangladesh which assessed a new shorter regimen using currently available TB drugs showed promising results and offered the possibility of a more acceptable and more effective regimen than the one recommended by the World Health Organization (WHO). The ai...

  4. Multidrug-resistant Salmonella enterica serotype Typhi, Gulf of Guinea Region, Africa.

    Science.gov (United States)

    Baltazar, Murielle; Ngandjio, Antoinette; Holt, Kathryn Elizabeth; Lepillet, Elodie; Pardos de la Gandara, Maria; Collard, Jean-Marc; Bercion, Raymond; Nzouankeu, Ariane; Le Hello, Simon; Dougan, Gordon; Fonkoua, Marie-Christine; Weill, Franois-Xavier

    2015-04-01

    We identified 3 lineages among multidrug-resistant (MDR) Salmonella enterica serotype Typhi isolates in the Gulf of Guinea region in Africa during the 2000s. However, the MDR H58 haplotype, which predominates in southern Asia and Kenya, was not identified. MDR quinolone-susceptible isolates contained a 190-kb incHI1 pST2 plasmid or a 50-kb incN pST3 plasmid. PMID:25811307

  5. Overcoming multidrug resistance by polymer inhibitors of ABC transporter MDR1

    Czech Academy of Sciences Publication Activity Database

    Cuchalová, Lucie; Šubr, Vladimír; Koziolová, Eva; Janoušková, Olga; Hvězdová, Zuzana; Eckschlager, T.; Etrych, Tomáš; Ulbrich, Karel

    Vancouver : Keystone Symposia, 2015. 78 /J1-1035/. [Integrating Metabolism and Tumor Biology , PI 3-Kinase Signaling Pathways in Disease. 13.01.2015-18.01.2015, Vancouver] R&D Projects: GA MŠk(CZ) EE2.3.30.0029; GA ČR(CZ) GAP301/12/1254 Institutional support: RVO:61389013 Keywords : multidrug resistance * drug delivery Subject RIV: CD - Macromolecular Chemistry

  6. Plasma Drug Activity in Patients on Treatment for Multidrug-Resistant Tuberculosis

    OpenAIRE

    Mpagama, Stellah G.; Ndusilo, Norah; Stroup, Suzanne; Kumburu, Happiness; Peloquin, Charles A; Gratz, Jean; Houpt, Eric R.; Kibiki, Gibson S; Scott K. Heysell

    2014-01-01

    Little is known about plasma drug concentrations relative to quantitative susceptibility in patients with multidrug-resistant tuberculosis (MDR-TB). We previously described a TB drug activity (TDA) assay that determines the ratio of the time to detection of plasma-cocultured Mycobacterium tuberculosis versus control growth in a Bactec MGIT system. Here, we assess the activity of individual drugs in a typical MDR-TB regimen using the TDA assay. We also examined the relationship of the TDA to t...

  7. HIV, multidrug-resistant TB and depressive symptoms: when three conditions collide

    OpenAIRE

    Das, Mrinalini; Isaakidis, Petros; Van den Bergh, Rafael; Kumar, Ajay MV; Nagaraja, Sharath Burugina; Valikayath, Asmaa; Jha, Santosh; Jadhav, Bindoo; Ladomirska, Joanna

    2014-01-01

    Background: Management of multidrug-resistant TB (MDR-TB) patients co-infected with human immunodeficiency virus (HIV) is highly challenging. Such patients are subject to long and potentially toxic treatments and may develop a number of different psychiatric illnesses such as anxiety and depressive disorders. A mental health assessment before MDR-TB treatment initiation may assist in early diagnosis and better management of psychiatric illnesses in patients already having two stigmatising and...

  8. Characterization of Antimicrobial Susceptibility Profile of Biofield Treated Multidrug-resistant Klebsiella oxytoca

    OpenAIRE

    Mahendra Kumar Trivedi

    2015-01-01

    Klebsiella are opportunistic pathogens that cause a wide spectrum of severe diseases. The aim of the present study was to investigate the impact of biofield treatment on multidrug resistant strain of K. oxytoca with respect to antibiogram pattern along with biochemical study and biotype number. Clinical lab isolate of K. oxytoca was divided into two groups i.e. control and treated. Control group remain untreated and treated group was subjected to Mr. Trivedi’s biofield. The analysis was...

  9. Biofield Treatment: An Alternative Approach to Combat Multidrug-Resistant Susceptibility Pattern of Raoultella ornithinolytica

    OpenAIRE

    Trivedi, Mahendra Kumar

    2015-01-01

    Raoultella ornithinolytica is belongs to the family of Enterobacteriaceae, a Gram-negative encapsulated aerobic bacillus associated with bacteremia and urinary tract infections. As biofield therapy is increasingly popular in biomedical heath care, so present study aimed to evaluate the impact of Mr. Trivedi’s biofield treatment on antimicrobial sensitivity, minimum inhibitory concentration (MIC), biochemical study, and biotype number of multidrug resistant strain of R. ornithinolytica. ...

  10. Evaluation of Aromatic Plants and Compounds Used to Fight Multidrug Resistant Infections

    OpenAIRE

    Ramar Perumal Samy; Jayapal Manikandan; Mohammed Al Qahtani

    2013-01-01

    Traditional medicine plays a vital role for primary health care in India, where it is widely practiced to treat various ailments. Among those obtained from the healers, 78 medicinal plants were scientifically evaluated for antibacterial activity. Methanol extract of plants (100  μ g of residue) was tested against the multidrug resistant (MDR) Gram-negative and Gram-positive bacteria. Forty-seven plants showed strong activity against Burkholderia pseudomallei (strain TES and KHW) and Staphyloc...

  11. Left-Sided Endocarditis Associated with Multi-Drug Resistance Acinetobacter Lwoffii

    Directory of Open Access Journals (Sweden)

    Naghmeh Moshtaghi

    2009-09-01

    Full Text Available Acinetobacter lwoffii, an important nosocomial pathogen, is a gram-negative aerobic bacillus that is a component of the normal flora on the skin, oropharynx, and perineum of about 20-25% of healthy individuals. We herein present a case of a 66-year-old man with combined mitral and aortic valve endocarditis associated with multi-drug resistance acinetobacter lowffii bacteremia.

  12. Two or three days of ofloxacin treatment for uncomplicated multidrug-resistant typhoid fever in children.

    OpenAIRE

    Vinh, H; Wain, J; Vo, T N; Cao, N N; Mai, T C; Bethell, D; Nguyen, Van T. T.; Tu, S D; Nguyen, M.D.; White, N. J.

    1996-01-01

    An open randomized comparison of 2 days (Ofx2) versus 3 days (Ofx3) of oral ofloxacin treatment (15 mg/kg/day) was conducted with Vietnamese children between 1 and 15 years of age with suspected typhoid fever. Of 108 children enrolled, 100 were blood culture positive for Salmonella typhi, and 86% of the isolates were multidrug resistant. There were no significant adverse effects. The therapeutic responses were similar in both groups, with mean (+/- standard deviation) fever clearances of 107 ...

  13. A case of acute postoperative keratitis after deep anterior lamellar keratoplasty by multidrug resistant Klebsiella

    Directory of Open Access Journals (Sweden)

    Leena Bajracharya

    2015-01-01

    Full Text Available A healthy lady of 42 years underwent deep anterior lamellar keratoplasty for granular dystrophy. The very next day, it was complicated by development of infectious keratitis. The organism was identified as multidrug resistant Klebsiella pneumoniae. Donor corneal button may be implicated in the transmission of infection in an otherwise uneventful surgery and follow-up. Nosocomial infections are usually severe, rapidly progressive and difficult to treat. Finally, the lady had to undergo therapeutic penetrating keratoplasty for complete resolution of infection.

  14. Multidrug resistance and retroviral transduction potential in human small cell lung cancer cell lines

    DEFF Research Database (Denmark)

    Theilade, M D; Gram, G J; Jensen, P B; Cianfriglia, M; Rørth, M; Hansen, J E

    1999-01-01

    Multidrug resistance (MDR) remains a major problem in the successful treatment of small cell lung cancer (SCLC). New treatment strategies are needed, such as gene therapy specifically targeting the MDR cells in the tumor. Retroviral LacZ gene-containing vectors that were either pseudotyped for the...... cells, and that MLV-A as well as GALV-1 retroviral vectors are suitable for further development of gene therapy in SCLC....

  15. Retrospective Comparison of Levofloxacin and Moxifloxacin on Multidrug-Resistant Tuberculosis Treatment Outcomes

    OpenAIRE

    Lee, Jinwoo; Lee, Chang-Hoon; Kim, Deog Kyeom; Yoon, Ho Il; Kim, Jae Yeol; Lee, Sang-Min; Yang, Seok-Chul; Lee, Jae Ho; Yoo, Chul-Gyu; Lee, Choon-Taek; Chung, Hee Soon; Kim, Young Whan; Han, Sung Koo; Yim, Jae-Joon

    2011-01-01

    Background/Aims To compare the effect of levofloxacin and moxifloxacin on treatment outcomes among patients with multidrug-resistant tuberculosis (MDR-TB). Methods A retrospective analysis of 171 patients with MDR-TB receiving either levofloxacin or moxifloxacin was performed. Treatment responses were categorized into treatment success (cured and treatment completed) or adverse treatment outcome (death, failure, and relapsed). Results The median age of the patients was 42.0 years. Approximate...

  16. Role of wild birds as carriers of multi-drug resistant Escherichia coli and Escherichia vulneris

    OpenAIRE

    Shobrak, Mohammed Y.; Abo-Amer, Aly E.

    2015-01-01

    Emergence and distribution of multi-drug resistant (MDR) bacteria in environments pose a risk to human and animal health. A total of 82 isolates of Escherichia spp. were recovered from cloacal swabs of migrating and non-migrating wild birds. All bacterial isolates were identified and characterized morphologically and biochemically. 72% and 50% of isolates recovered from non-migrating and migrating birds, respectively, showed positive congo red dye binding (a virulence factor). Also, hemolysin...

  17. Starvation, detoxification, and multidrug resistance in cancer therapy

    OpenAIRE

    Lee, Changhan; Raffaghello, Lizzia; LONGO, VALTER D.

    2012-01-01

    The selection of chemotherapy drugs is based on the cytotoxicity to specific tumor cell types and the relatively low toxicity to normal cells and tissues. However, the toxicity to normal cells poses a major clinical challenge, particularly when malignant cells have acquired resistance to chemotherapy. This drug resistance of cancer cells results from multiple factors including individual variation, genetic heterogeneity within a tumor, and cellular evolution. Much progress in the understandin...

  18. Antiviral Drug- and Multidrug Resistance in Cytomegalovirus Infected SCT Patients

    OpenAIRE

    Katharina Ghring; Klaus Hamprecht; Gerhard Jahn

    2015-01-01

    In pediatric and adult patients after stem cell transplantation (SCT) disseminated infections caused by human cytomegalovirus (HCMV) can cause life threatening diseases. For treatment, the three antivirals ganciclovir (GCV), foscarnet (PFA) and cidofovir (CDV) are approved and most frequently used. Resistance to all of these antiviral drugs may induce a severe problem in this patient cohort. Responsible for resistance phenomena are mutations in the HCMV phosphotransferase-gene (UL97) and the ...

  19. Reducing the price of treatment for multidrug-resistant tuberculosis through the Global Drug Facility

    Directory of Open Access Journals (Sweden)

    Kaspars Lunte

    2015-04-01

    Full Text Available Problem Many countries have limited experience of securing the best prices for drugs and have little negotiating power. This is particularly true for the complex, lengthy and expensive regimens used to treat multidrug-resistant tuberculosis. Approach The Stop TB Partnerships Global Drug Facility is dedicated to improving worldwide access to antituberculosis medicines and diagnostic techniques that meet international quality standards. Local setting The Global Drug Facility is able to secure price reductions through competitive tendering among prequalified drug manufacturers and by consolidating orders to achieve large purchase volumes. Consolidating the market in this way increases the incentives for suppliers of quality-assured medicines. Relevant changes In 2013 the Global Drug Facility reduced the price of the second-line drugs it supplies for multidrug-resistant tuberculosis: the overall cost of the longest and most expensive treatment regimen for a patient decreased by 26% from 7890 United States dollars (US$ in 2011 to US$5822 in 2013. Lessons learnt The price of treatment for multidrug-resistant tuberculosis supplied by the Global Drug Facility was reduced by consolidating orders to achieve large purchase volumes, by international, competitive bidding and by the existence of donor-funded medicine stockpiles. The rise in the number of suppliers of internationally quality-assured drugs was also important. The savings achieved from lower drug costs could be used to increase the number of patients on high-quality treatment.

  20. Genomic structure, gene expression, and promoter analysis of human multidrug resistance-associated protein 7

    Energy Technology Data Exchange (ETDEWEB)

    Kao, Hsin-Hsin; Chang, Ming-Shi; Cheng, Jan-Fang; Huang, Jin-Ding

    2002-03-15

    The multidrug resistance-associated protein (MRP) subfamily transporters associated with anticancer drug efflux are attributed to the multidrug-resistance of cancer cells. The genomic organization of human multidrug resistance-associated protein 7 (MRP7) was identified. The human MRP7 gene, consisting of 22 exons and 21 introns, greatly differs from other members of the human MRP subfamily. A splicing variant of human MRP7, MRP7A, expressed in most human tissues, was also characterized. The 1.93-kb promoter region of MRP7 was isolated and shown to support luciferase activity at a level 4- to 5-fold greater than that of the SV40 promoter. Basal MRP7 gene expression was regulated by 2 regions in the 5-flanking region at 1,780 1,287 bp, and at 611 to 208 bp. In Madin-Darby canine kidney (MDCK) cells, MRP7 promoter activity was increased by 226 percent by genotoxic 2-acetylaminofluorene and 347 percent by the histone deacetylase inhibitor, trichostatin A. The protein was expressed in the membrane fraction of transfected MDCK cells.

  1. Resin glycosides from Ipomoea wolcottiana as modulators of the multidrug resistance phenotype in vitro.

    Science.gov (United States)

    Corona-Castañeda, Berenice; Rosas-Ramírez, Daniel; Castañeda-Gómez, Jhon; Aparicio-Cuevas, Manuel Alejandro; Fragoso-Serrano, Mabel; Figueroa-González, Gabriela; Pereda-Miranda, Rogelio

    2016-03-01

    Recycling liquid chromatography was used for the isolation and purification of resin glycosides from the CHCl3-soluble extracts prepared using flowers of Ipomoea wolcottiana Rose var. wolcottiana. Bioassay-guided fractionation, using modulation of both antibiotic activity against multidrug-resistant strains of Gram-negative bacteria and vinblastine susceptibility in breast carcinoma cells, was used to isolate the active glycolipids as modulators of the multidrug resistance phenotype. An ester-type dimer, wolcottine I, one tetra- and three pentasaccharides, wolcottinosides I-IV, in addition to the known intrapilosin VII, were characterized by NMR spectroscopy and mass spectrometry. In vitro assays established that none of these metabolites displayed antibacterial activity (MIC>512μg/mL) against multidrug-resistant strains of Escherichia coli, and two nosocomial pathogens: Salmonella enterica serovar Typhi and Shigella flexneri; however, when tested (25μg/mL) in combination with tetracycline, kanamycin or chloramphenicol, they exerted a potentiation effect of the antibiotic susceptibility up to eightfold (64μg/mL from 512μg/mL). It was also determined that these non-cytotoxic (CI50>8.68μM) agents modulated vinblastine susceptibility at 25μg/mL in MFC-7/Vin(+) cells with a reversal factor (RFMCF-7/Vin(+)) of 2-130 fold. PMID:26774597

  2. Microbiological evaluation of the efficacy of two new biodetergents on multidrug-resistant nosocomial pathogens

    Directory of Open Access Journals (Sweden)

    Negrone Mario

    2009-12-01

    Full Text Available Abstract Background In the last few years, several outbreaks of nosocomial infections caused by multidrug-resistant pathogenic agents have been observed, and various biocides products were developed in order to control this phenomenon. We investigated the efficacy of two natural biodetergents composed of plants and kelps extracts, BATT1 and BATT2, against multidrug-resistant strains. Methods In-vitro antibacterial efficacy of BATT1 and BATT2 against nosocomial multidrug-resistant isolates was assessed using a suspension-inhibition test, with and without bovine serum albumin (BSA. The test was also carried out on glass surfaces with and without BSA. Results In vitro tests with both biocidal disinfectants at 25% concentration demonstrated an overall drop in bacterial, mould and yeast counts after 10 min of contact with or without organic substances. For Pseudomonas aeruginosa, it was necessary to use undiluted disinfectants with and without an organic substance. The same results were obtained in tests carried out on glass surfaces for all strains. Conclusions The natural products BATT1 and BATT2 behave like good biocides even in presence of organic substances. The use of both disinfectants may be beneficial for reducing hospital-acquired pathogens that are not susceptible to disinfectants. However, it has to be stressed that all these experiments were carried out in vitro and they still require validation from use in clinical practice.

  3. In Vitro Antibacterial Properties of Aqueous Garlic Extract (AEG Against Multidrug-Resistant Enterococci

    Directory of Open Access Journals (Sweden)

    Mohammad Bokaeian

    2013-06-01

    Full Text Available Background: As relatively avirulent enteric bacteria, enterococci usually cause infections in immune-compromised patients. The antimicrobial treatment, however, is quite challenging, since enterococci are intrinsically resistant to many antibiotics. Objective of the present study was to examine the antibacterial activity of aqueous garlic extract on isolates of enterococci.Materials and Methods: In this descriptive research, a total of 120 enterococcus isolates including 70 multidrug-resistant isolates causing different infections were collected from three hospitals in Zahedan. The susceptibility of isolates to different antibiotics was measured by agar diffusion test and antibacterial activity of garlic extract was measured using disc-diffusion and microbroth dilution methods.Results: Among 120 enterococcus samples, 95 (79.2% and 25 (20.8% isolates were E. faecalis and E. faecium respectively. The highest resistance was observed in erythromycin (95.8% and the lowest resistance (6.7% in chloramphenicol, while 88.3% and 65.8% of the isolates were resistant to tetracycline and ampicillin respectively. Moreover, 58% of the isolates were Multi-Drug Resistant (MDR and showed resistance to at least three antibiotics. Antibacterial activity of AGE was characterized by inhibition zones of 16.81.8 mm and Minimum Inhibitory Concentration (MIC ranged from 4 to 32 mg/ml. Conclusion: The present study suggests that AGE has a significant anti-enterococcal effect and therefore, supports the use of garlic as an herbal remedy in Zahedan.

  4. Multidrug resistance and integrons in Escherichia coli isolated from chicken in Greece

    Directory of Open Access Journals (Sweden)

    Dakić Ivana

    2011-01-01

    Full Text Available Enteric faecal flora of food-producing animals such as poultry is a potential reservoir for antimicrobial resistance genes which can be transferred to human pathogens via the food chain. The present study investigated 47 strains of Enterobacteriaceae recovered from a variety of chicken specimens for their resistance to 18 antimicrobial agents and the presence of integrons, and analyzed the association between integrons and antimicrobial susceptibility. Multidrug resistance was found in 82.9% of the isolates. The presence of integrons was shown in 68.1% of the strains tested: 42.5% carried a class 1 integron, 10.6% carried a class 2 integron, and 14.9% had both class 1 and 2 integrons. An unusual cassette aacA4-catB3-dfrA1 was revealed in two class 1 integron-positive isolates. The association between the presence of an integron and multidrug resistance was significant (p<0.05. The mercury resistance gene, merA, was found in 44.4% of strains with class 1 integron, indicating the role of Tn21 transposon in dissemination of integrons within the samples studied. The study gives baseline information on the resistance problem and its genetic background in contemporary poultry Enterobacteriaceae in Greece, and suggest the need for the introduction of surveillance programs to monitor antimicrobial resistance that can be potentially transmitted to humans.

  5. Genotyping and serotyping of macrolide and multidrug resistant Streptococcus pneumoniae isolated from carrier children

    Directory of Open Access Journals (Sweden)

    S F Swedan

    2016-01-01

    Full Text Available Aims: Streptococcus pneumoniae, an opportunistic pathogen commonly carried asymptomatically in the nasopharynx of children, is associated with increasing rates of treatment failures due to a worldwide increase in drug resistance. We investigated the carriage of S. pneumoniae in children 5 years or younger, the identity of prevalent serotypes, the rates of resistance to macrolides and other antimicrobial agents and the genotypes responsible for macrolide resistance. Materials and Methods: Nasopharyngeal swabs were collected from 157 children under 5 years for cultural isolation of S. pneumoniae. Antibiogram of isolates  was determined using the disk diffusion test, and the minimal inhibitory concentration to macrolides was determined using the E-test. Isolate serotypes and macrolide resistance genes, erm(B and mef(E, were identified using multiplex polymerase chain reactions. Results: S. pneumoniae was recovered from 33.8% of children; 41.9% among males and 21.9% among females (P = 0.009. The highest carriage rate occurred among age groups 7-12 months and 49-60 months. Most frequent serotypes were 19F, 6A/B, 11A, 19A, 14 and 15B/C.  Resistance to macrolides was 60.4%. Resistance to oxacillin, trimethoprim/sulfamethoxazole and clindamycin was present among 90.6%, 54.7% and 32.1% of isolates, respectively. All isolates were susceptible to chloramphenicol, levofloxacin and vancomycin. Isolates resistant to one or more macrolide drugs were more likely to be multidrug resistant. Resistance to clindamycin or oxacillin coexisted with macrolide resistance. Among the erythromycin-resistant isolates, erm(B, mef(E and erm(B and mef(E genes were present at rates of 43.8%, 37.5% and 6.3%, respectively. Erm(B and mef(E were associated with very high level and moderate-to-high level resistance to macrolides, respectively. Conclusion: A significant proportion of children harboured macrolide and multidrug-resistant S. pneumoniae.

  6. P-glycoprotein inhibition as a strategy to increase drug delivery across the blood-brain barrier: focus on antidepressants

    OpenAIRE

    O'Brien, Fionn E

    2013-01-01

    Depression is among the leading causes of disability worldwide. Currently available antidepressant drugs have unsatisfactory efficacy, with up to 60% of depressed patients failing to respond adequately to treatment. Emerging evidence has highlighted a potential role for the efflux transporter P-glycoprotein (P-gp), expressed at the blood-brain barrier (BBB), in the aetiology of treatment-resistant depression. In this thesis, the potential of P-gp inhibition as a strategy to enhance the brain ...

  7. Hypoxia-inducible factor-1α induces multidrug resistance protein in colon cancer

    Directory of Open Access Journals (Sweden)

    Lv Y

    2015-07-01

    Full Text Available Yingqian Lv, Shan Zhao, Jinzhu Han, Likang Zheng, Zixin Yang, Li Zhao Department of Oncology, The Second Hospital, Hebei Medical University, Shijiazhuang, Hebei Province, People’s Republic of China Abstract: Multidrug resistance is the major cause of chemotherapy failure in many solid tumors, including colon cancer. Hypoxic environment is a feature for all solid tumors and is important for the development of tumor resistance to chemotherapy. Hypoxia-inducible factor (HIF-1α is the key transcription factor that mediates cellular response to hypoxia. HIF-1α has been shown to play an important role in tumor resistance; however, the mechanism is still not fully understood. Here, we found that HIF-1α and the drug resistance-associated gene multidrug resistance associated protein 1 (MRP1 were induced by treatment of colon cancer cells with the hypoxia-mimetic agent cobalt chloride. Inhibition of HIF-1α by RNA interference and dominant-negative protein can significantly reduce the induction of MRP1 by hypoxia. Bioinformatics analysis showed that a hypoxia response element is located at -378 to -373 bp upstream of the transcription start site of MRP1 gene. Luciferase reporter assay combined with mutation analysis confirmed that this element is essential for hypoxia-mediated activation of MRP gene. Furthermore, RNA interference revealed that HIF-1α is necessary for this hypoxia-driven activation of MRP1 promoter. Importantly, chromatin immunoprecipitation analysis demonstrated that HIF-1α could directly bind to this HRE site in vivo. Together, these data suggest that MRP1 is a downstream target gene of HIF-1α, which provides a potential novel mechanism for HIF-1α-mediated drug resistance in colon cancer and maybe other solid tumors as well. Keywords: hypoxia, hypoxia-inducible factor-1α, multidrug resistance associated protein, transcriptional regulation, chemotherapy tolerance

  8. Transgenic Mice that Express the Human Multidrug-Resistance Gene in Bone Marrow Enable a Rapid Identification of Agents that Reverse Drug Resistance

    Science.gov (United States)

    Mickisch, Gerald H.; Merlino, Glenn T.; Galski, Hanan; Gottesman, Michael M.; Pastan, Ira

    1991-01-01

    The development of preclinical models for the rapid testing of agents that circumvent multidrug resistance in cancer is a high priority of research on drug resistance. A common form of multidrug resistance in human cancer results from expression of the MDR1 gene, which encodes a M_r 170,000 glycoprotein that functions as a plasma membrane energy-dependent multidrug efflux pump. We have engineered transgenic mice that express this multidrug transporter in their bone marrow and demonstrated that these animals are resistant to leukopenia by a panel of anticancer drugs including anthracyclines, vinca alkaloids, etoposide, taxol, and actinomycin D. Differential leukocyte counts indicate that both neutrophils and lymphocytes are protected. Drugs such as cisplatin, methotrexate, and 5-fluorouracil, which are not handled by the multidrug transporter, produce bone marrow suppression in both normal and transgenic mice. The resistance conferred by the MDR1 gene can be circumvented in a dose-dependent manner by simultaneous administration of agents previously shown to be inhibitors of the multidrug transporter in vitro, including verapamil isomers, quinidine, and quinine. Verapamil and quinine, both at levels suitable for human trials that produced only partial sensitization of the MDR1-transgenic mice, were fully sensitizing when used in combination. We conclude that MDR1-transgenic mice provide a rapid and reliable system to determine the bioactivity of agents that reverse multidrug resistance in animals.

  9. Occurrence of Multidrug Resistant Staphylococcus aureus in horses in Malaysia

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    Z. Zunita

    2008-12-01

    Full Text Available A total of 22 Staphylococcus aureus were isolated from 50 samples from 8 stable horses. They are positive in the catalase and coagulase tests. Upon testing the cultures with SLIDEX test kit all formed agglutination within a few seconds, confirming they are of S. aureus. When cultured onto MSA, all isolates formed yellow colonies. However, none of the isolates produced blue colonies on ORSAB indicating that there were no MRSA among the S. aureus. There were 13 isolates which were multiresistant. Eleven are resistant to eight out of ten antibiotics tested. All these isolates were found to originate from stable G. One isolate is resistant to 5 antibiotics while another one isolate is resistant to 3 antibiotics. The rest of the isolates are not multiresistant to the antibiotics tested. [Veterinary World 2008; 1(6.000: 165-167

  10. Utility of lytic bacteriophage in the treatment of multidrug-resistant Pseudomonas aeruginosa septicemia in mice

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    Vinodkumar C

    2008-07-01

    Full Text Available Drug resistance is the major cause of increase in morbidity and mortality in neonates. One thousand six hundred forty-seven suspected septicemic neonates were subjected for microbiological analysis over a period of 5 years. Forty-two P. aeruginosa were isolated and the antibiogram revealed that 28 P. aeruginosa were resistant to almost all the common drugs used (multidrug-resistant. The emergence of antibiotic-resistant bacterial strains is one of the most critical problems of modern medicine. As a result, a novel and most effective approaches for treating infection caused by multidrug-resistant bacteria are urgently required. In this context, one intriguing approach is to use bacteriophages (viruses that kill bacteria in the treatment of infection caused by drug-resistant bacteria. In the present study, the utility of lytic bacteriophages to rescue septicemic mice with multidrug-resistant (MDR P. aeruginosa infection was evaluated. MDR P. aeruginosa was used to induce septicemia in mice by intraperitoneal (i.p. injection of 10 7 CFU. The resulting bacteremia was fatal within 48 hrs. The phage strain used in this study had lytic activity against a wide range of clinical isolates of MDR P. aeruginosa. A single i.p. injection of 3 x 10 9 PFU of the phage strain, administered 45 min after the bacterial challenge, was sufficient to rescue 100% of the animals. Even when treatment was delayed to the point where all animals were moribund, approximately 50% of them were rescued by a single injection of this phage preparation. The ability of this phage to rescue septicemic mice was demonstrated to be due to the functional capabilities of the phage and not to a nonspecific immune effect. The rescue of septicemic mice could be affected only by phage strains able to grow in vitro on the bacterial host used to infect the animals and when such strains are heat-inactivated, they lose their ability to rescue the infected mice. Multidrug-resistant bacteria have opened a second window for phage therapy. It would seem timely to begin to look afresh at this approach. A scientific methodology can make phage therapy as a stand-alone therapy for infections that are fully resistant to antibiotics.

  11. What is Multidrug and Extensively Drug Resistant TB?

    Science.gov (United States)

    ... more potent types used to treat MDR TB. Treatment for XDR TB is much more difficult, expensive, and lasts longer. ... of treatment; When healthcare providers prescribe the wrong treatment, the ... poor quality. Drug-resistant TB is more common in people who: Do not ...

  12. Threat of multidrug resistant Staphylococcus aureus in Western Nepal

    DEFF Research Database (Denmark)

    Bhatta, Dharm R.; Cavaco, Lina; Nath, Gopal; Gaur, Abhishek; Gokhale, Shishir; Bhatta, Dwij Raj

    2015-01-01

    ObjectiveTo determine the prevalence of methicillin resistant Staphylococcus aureus (MRSA) and antimicrobial susceptibility patterns of the isolates from Manipal Teaching Hospital, Pokhara, Nepal. MethodsThis study was conducted over a period of 11 months (September 2012August 2013) at the Manip...

  13. Isolation and molecular characterization of multidrug-resistant Gram-negative bacteria from imported flamingos in Japan

    Directory of Open Access Journals (Sweden)

    Fukumoto Yukio

    2009-11-01

    Full Text Available Abstract Imported animals, especially those from developing countries, may constitute a potential hazard to native animals and to public health. In this study, a new flock of lesser flamingos imported from Tanzania to Hiroshima Zoological Park were screened for multidrug-resistant Gram-negative bacteria, integrons and antimicrobial resistance genes. Thirty-seven Gram-negative bacterial isolates were obtained from the flamingos. Seven isolates (18.9% showed multidrug resistance phenotypes, the most common being against: ampicillin, streptomycin, tetracycline, trimethoprim/sulfamethoxazole and nalidixic acid. Molecular analyses identified class 1 and class 2 integrons, β-lactamase-encoding genes, blaTEM-1 and blaCTX-M-2 and the plasmid-mediated quinolone resistance genes, qnrS and qnrB. This study highlights the role of animal importation in the dissemination of multidrug-resistant bacteria, integrons and antimicrobial resistance genes from one country to another.

  14. Hypoxia-inducible factor-1? induces multidrug resistance protein in colon cancer.

    Science.gov (United States)

    Lv, Yingqian; Zhao, Shan; Han, Jinzhu; Zheng, Likang; Yang, Zixin; Zhao, Li

    2015-01-01

    Multidrug resistance is the major cause of chemotherapy failure in many solid tumors, including colon cancer. Hypoxic environment is a feature for all solid tumors and is important for the development of tumor resistance to chemotherapy. Hypoxia-inducible factor (HIF)-1? is the key transcription factor that mediates cellular response to hypoxia. HIF-1? has been shown to play an important role in tumor resistance; however, the mechanism is still not fully understood. Here, we found that HIF-1? and the drug resistance-associated gene multidrug resistance associated protein 1 (MRP1) were induced by treatment of colon cancer cells with the hypoxia-mimetic agent cobalt chloride. Inhibition of HIF-1? by RNA interference and dominant-negative protein can significantly reduce the induction of MRP1 by hypoxia. Bioinformatics analysis showed that a hypoxia response element is located at -378 to -373 bp upstream of the transcription start site of MRP1 gene. Luciferase reporter assay combined with mutation analysis confirmed that this element is essential for hypoxia-mediated activation of MRP gene. Furthermore, RNA interference revealed that HIF-1? is necessary for this hypoxia-driven activation of MRP1 promoter. Importantly, chromatin immunoprecipitation analysis demonstrated that HIF-1? could directly bind to this HRE site in vivo. Together, these data suggest that MRP1 is a downstream target gene of HIF-1?, which provides a potential novel mechanism for HIF-1?-mediated drug resistance in colon cancer and maybe other solid tumors as well. PMID:26251616

  15. Long-term mortality assessment of multidrug-resistant tuberculosis patients treated with delamanid

    OpenAIRE

    Charles D. Wells; Gupta, Rajesh; Hittel, Norbert; Geiter, Lawrence J.

    2015-01-01

    Multidrug-resistant tuberculosis (MDR-TB) is a serious obstacle to TB control [1]. The disproportionately negative outcomes among patients with drug resistance reflect a strong global need to develop new anti-TB drugs [2, 3]. Delamanid is a novel anti-TB agent that has recently been approved for the management of MDR-TB patients [4]. Treatment of MDR-TB patients with delamanid in combination with an optimised background regimen for 2 months significantly improved 2-month sputum culture conver...

  16. Transgenically expressed Parascaris P-glycoprotein-11 can modulate ivermectin susceptibility in Caenorhabditis elegans

    Directory of Open Access Journals (Sweden)

    I. Jana I. Janssen

    2015-08-01

    Full Text Available P-glycoproteins (Pgps are suspected to mediate drug extrusion in nematodes contributing to macrocyclic lactone resistance. This association was recently shown for Parascaris Pgp-11. Ivermectin resistance was correlated with the presence of three pgp-11 single nucleotide polymorphisms and/or increased pgp-11 mRNA levels. In the present study, the ability of Pgp-11 to modulate ivermectin susceptibility was investigated by its expression in a pgp-11-deficient Caenorhabditis elegans strain. Expression of Parascaris pgp-11 in two transgenic lines significantly decreased ivermectin susceptibility in a motility (thrashing assay conducted in liquid medium. The EC50 values increased by 3.2- and 4.6-fold in the two lines relative to a transgenic control strain. This is the first report on the successful functional analysis of a parasitic nematode Pgp in the model organism C. elegans.

  17. Low Fitness Cost of the Multidrug Resistance Gene cfr▿

    Science.gov (United States)

    LaMarre, Jacqueline M.; Locke, Jeffrey B.; Shaw, Karen J.; Mankin, Alexander S.

    2011-01-01

    The recently described rRNA methyltransferase Cfr that methylates the conserved 23S rRNA residue A2503, located in a functionally critical region of the ribosome, confers resistance to an array of ribosomal antibiotics, including linezolid. A number of reports of linezolid-resistant cfr-positive clinical strains indicate the possible rapid spread of this resistance mechanism. Since the rate of dissemination and the efficiency of maintenance of a resistance gene depend on the fitness cost associated with its acquisition, we investigated the fitness cost of cfr expression in a laboratory Staphylococcus aureus strain. We found that acquisition of the cfr gene does not produce any appreciable reduction in the cell growth rate. Only in a cogrowth competition experiment was some loss of fitness observed because Cfr-expressing cells slowly lose to the cfr-negative control strain. Interestingly, cells expressing wild-type and catalytically inactive Cfr had very similar growth characteristics, indicating that the slight fitness cost associated with cfr acquisition stems from expression of the Cfr polypeptide rather than from the modification of the conserved rRNA residue. In some clinical isolates, cfr is coexpressed with the erm gene, which encodes a methyltransferase targeting another 23S rRNA residue, A2058. Dimethylation of A2058 by Erm notably increases the fitness cost associated with the Cfr-mediated methylation of A2503. The generally low fitness cost of cfr acquisition observed in our experiments with the laboratory S. aureus strain offers a microbiological explanation for the apparent spread of the cfr gene among pathogens. PMID:21646483

  18. Management of multidrug-resistant TB: novel treatments and their expansion to low resource settings.

    Science.gov (United States)

    Sloan, Derek J; Lewis, Joseph M

    2016-03-01

    Despite overall progress in global TB control, the rising burden of multidrug-resistant TB (MDR-TB) threatens to undermine efforts to end the worldwide epidemic. Of the 27 countries classified as high burden for MDR-TB, 17 are in 'low' or 'low-middle' income countries. Shorter, all oral and less toxic multidrug combinations are required to improve treatment outcomes in these settings. Suitability for safe co-administration with HIV drugs is also desirable. A range of strategies and several new drugs (including bedaquiline, delamanid and linezolid) are currently undergoing advanced clinical evaluations to define their roles in achieving these aims. However, several clinical questions and logistical challenges need to be overcome before these new MDR-TB treatments fulfil their potential. PMID:26884496

  19. Transmembrane transporters ABCC – structure, function and role in multidrug resistance of cancer cells

    Directory of Open Access Journals (Sweden)

    Sylwia Dębska

    2011-08-01

    Full Text Available Resistance to cytotoxic drugs is a significant problem of systemic treatment of cancers. Apart from drug inactivation, changes in target enzymes and proteins, increased DNA repair and suppression of apoptosis, an important mechanism of resistance is an active drug efflux from cancer cells. Drug efflux across the cell membrane is caused by transport proteins such as ABC proteins (ATP-binding cassette. This review focuses on the ABCC protein subfamily, whose members are responsible for multidrug cross-resistance of cancer cells to cytotoxic agents. The authors discuss the structure of ABCC proteins, their physiological function and diseases provoked by mutations of respective genes, their expression in many different malignancies and its connection with resistance to anticancer drugs, as well as methods of reversion of such resistance.

  20. Increasing incidence of multidrug resistant Pseudomonas aeruginosa in inpatients of a tertiary care hospital

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    Ved Prakash

    2014-08-01

    Full Text Available Background: Pseudomonas aeruginosa is an important pathogen isolated from various clinical infections. The occurrence of multidrug-resistant (MDR Pseudomonas aeruginosa strains is increasing worldwide and limiting our therapeutic options resulting in high mortality. We aim to study the incidence of multidrug resistant Pseudomonas aeruginosa in inpatients from various departments along with rate of nosocomial infections. Methods: A cross sectional study from January 1, 2013 to December 31, 2013. A total of 167 Pseudomonas aeruginosa were isolated from 764 clinical specimens. The isolates were identified by standard microbiological techniques. The antibiotic susceptibility was done by Kirby Bauer method. Results: The highest number of isolates were from pulmonary samples n=90 (53.89% followed by pus n=48 (28.74%. Overall, 39 (23.36% isolates were nosocomial. The nosocomial isolates were mainly isolated from department of surgery, orthopaedics, obstetrics and gynaecology followed by others. Among 167 isolates screened, 53 (31.73% were found to be MDR (resistant to and #8805;3 classes of antipseudomonal agents. The resistance was most against cephalosporins [Cefepime (65.26%, cefotaxime (60.47%], fluoroquinolones [Ciprofloxacin (46.1%, levofloxacin (31.87%] aminoglycosides [Amikacin (37.72%, gentamicin (31.13%] followed by ureidopenicillins and carbepenems. About 56.75% isolates were suspected Metallo beta lactamases producers. Conclusion: The study suggests that the incidence of nosocomial infection by multidrug resistant Pseudomonas aeruginosa is increasing globally especially the Metallo Beta lactamases producing strains. So there is a continuous need of conduction of surveillance programmes to formulate rational treatment strategies to combat this emerging challenge. [Int J Res Med Sci 2014; 2(4.000: 1302-1306

  1. The demise of multidrug-resistant HIV-1: the national time trend in Portugal

    Science.gov (United States)

    Vercauteren, Jurgen; Theys, Kristof; Carvalho, Ana Patricia; Valadas, Emlia; Duque, Luis Miguel; Tefilo, Eugnio; Faria, Telo; Faria, Domitlia; Vera, Jos; guas, Maria Joo; Peres, Susana; Mansinho, Kamal; Vandamme, Anne-Mieke; Camacho, Ricardo Jorge; Mansinho, Kamal; Cludia Miranda, Ana; Aldir, Isabel; Ventura, Fernando; Nina, Jaime; Borges, Fernando; Valadas, Emlia; Doroana, Manuela; Antunes, Francisco; Joo Aleixo, Maria; Joo guas, Maria; Botas, Jlio; Branco, Teresa; Vera, Jos; Vaz Pinto, Ins; Poas, Jos; S, Joana; Duque, Luis; Diniz, Antnio; Mineiro, Ana; Gomes, Flora; Santos, Carlos; Faria, Domitlia; Fonseca, Paula; Proena, Paula; Tavares, Lus; Guerreiro, Cristina; Narciso, Jorge; Faria, Telo; Tefilo, Eugnio; Pinheiro, Sofia; Germano, Isabel; Caixas, Umbelina; Faria, Nancy; Paula Reis, Ana; Bentes Jesus, Margarida; Amaro, Graa; Roxo, Fausto; Abreu, Ricardo; Neves, Isabel

    2013-01-01

    Objectives Despite a decreasing mortality and morbidity in treated HIV-1 patients, highly active antiretroviral treatment (HAART) can still fail due to the development of drug resistance. Especially, multidrug-resistant viruses pose a threat to efficient therapy. We studied the changing prevalence of multidrug resistance (MDR) over time in a cohort of HIV-1-infected patients in Portugal. Patients and methods We used data of 8065 HIV-1-infected patients followed from July 2001 up to April 2012 in 22 hospitals located in Portugal. MDR at a specific date of sampling was defined as no more than one fully active drug (excluding integrase and entry inhibitors) at that time authorized by the Portuguese National Authority of Medicines and Health Products (INFARMED), as interpreted with the Rega algorithm version 8.0.2. A generalized linear mixed model was used to study the time trend of the prevalence of MDR. Results We observed a statistically significant decrease in the prevalence of MDR over the last decade, from 6.9% (95% CI: 5.78.4) in 200103, 6.0% (95% CI: 4.97.2) in 200305, 3.7% (95% CI: 2.84.8) in 200507 and 1.6% (95% CI: 1.12.2) in 200709 down to 0.6% (95% CI: 0.30.9) in 200912 [OR?=?0.80 (95% CI: 0.750.86); P?multidrug-resistant HIV-1 is decreasing over time in Portugal, reflecting the increasing efficiency of HAART and the availability of new drugs. Therefore, in designing a new drug, safety and practical aspects, e.g. less toxicity and ease of use, may need more attention than focusing mainly on efficacy against resistant strains. PMID:23228933

  2. High prevalence of multi-drug resistant Streptococcus pneumoniae among healthy children in Thailand.

    Science.gov (United States)

    Thummeepak, Rapee; Leerach, Nontapat; Kunthalert, Duangkamol; Tangchaisuriya, Udomsak; Thanwisai, Aunchalee; Sitthisak, Sutthirat

    2015-01-01

    Antibiotic resistance in Streptococcus pneumoniae is an emerging health problem worldwide. The incidence of antimicrobial-resistant S. pneumoniae is increasing, and nasal colonization of S. pneumoniae in children increases the risk of pneumococcal infection. In this study, the prevalence of S. pneumoniae nasal colonization was studied in Thai children from three different districts. S. pneumoniae nasal colonization was found in 38 of 237 subjects (16.0%). The carriage rate indicated higher rates in two rural districts (18.2% and 29.8%) than in the urban district (2.8%). The antibiotic susceptibility pattern was determined using the disk diffusion method. Prevalence of multi-drug resistance S. pneumoniae (MDR-SP) was 31.6%. Resistance to commonly prescribed antibiotics was found for ampicillin (5.3%), azithromycin (26.3%), cefepime (2.6%), chloramphenicol (18.4%), clindamycin (18.4%), erythromycin (21.1%), oxacillin (44.7%), trimethoprim/sulfamethoxazole (78.9%) and tetracycline (15.8%). All isolates were sensitive to ceftriaxone. The pulsed-field gel electrophoresis pattern was used to compare genetic diversity of the S. pneumoniae isolates. PFGE demonstrated the variation in genotypes of S. pneumoniae from different areas. High prevalence of multi-drug resistance S. pneumoniae nasal colonization in healthy Thai children was indicated. Effective strategies for appropriate use of antibiotics are therefore needed in the community. PMID:25541228

  3. Mercury induces multidrug resistance-associated protein gene through p38 mitogen-activated protein kinase.

    Science.gov (United States)

    Kim, Sang Hyun; Bark, Hyun; Choi, Cheol Hee

    2005-01-15

    The multidrug resistance-associated protein (MRP1) belongs to a drug efflux membrane pump that confers multidrug resistance to the cells. The MRP1 mediates the cellular efflux of various xenobiotics including heavy metals and mediates cellular resistance to heavy metals. Mercury is a well-known health hazard and an environmental contaminant. Recently, information about the uptake of the heavy metals such as mercury has been suggested. However, little is known regarding molecular mechanisms of exporting mercury. This study was designed to determine if mercury could be extruded by MRP1 in acute myeloid leukemia cells (AML-2). The MRP-1-overexpressing AML-2/DX100 cells showed a higher resistance to mercury than AML-2/WT. Probenecid, which is a specific MRP1 inhibitor, decreased the resistance to mercury. Exposing the AML-2 cells to mercury-induced MRP1 gene expression and production without altering the MRP1 activity. Mercury activated p38 mitogen-activated protein kinase (MAPK) and SB 203580, a specific p38 MAPK inhibitor, blocked the mercury-induced MRP1 production. These results suggest that MRP1 can control mercury and p38 MAPK mediates the mercury-induced MRP1 gene expression. PMID:15585369

  4. Diffusion and Persistence of Multidrug Resistant Salmonella Typhimurium Strains Phage Type DT120 in Southern Italy

    Science.gov (United States)

    De Vito, Danila; Monno, Rosa; Nuccio, Federica; Legretto, Marilisa; Oliva, Marta; Coscia, Maria Franca; Dionisi, Anna Maria; Calia, Carla; Capolongo, Carmen

    2015-01-01

    Sixty-two multidrug resistant Salmonella enterica serovar Typhimurium strains isolated from 255 clinical strains collected in Southern Italy in 20062008 were characterised for antimicrobial resistance genes, pulsotype, and phage type. Most strains (83.9%) were resistant to ampicillin, chloramphenicol, streptomycin, sulfamethoxazole, and tetracycline (ACSSuT) encoded in 88.5% by the Salmonella genomic island (SGI1) and in 11.5% by the InH-like integron (blaOXA-30aadA1) and catA1, sul1, and tet(B) genes. STYMXB.0061 (75%) and DT120 (84.6%) were the prevalent pulsotype and phage type identified in these strains, respectively. Five other resistance patterns were found either in single or in a low number of isolates. The pandemic clone DT104 (ACSSuT encoded by SGI1) has been identified in Italy since 1992, while strains DT120 (ACSSuT encoded by SGI1) have never been previously reported in Italy. In Europe, clinical strains DT120 have been reported from sporadic outbreaks linked to the consumption of pork products. However, none of these strains were STYMXB.0061 and SGI1 positive. The prevalent identification and persistence of DT120 isolates would suggest, in Southern Italy, a phage type shifting of the pandemic DT104 clone pulsotype STYMXB.0061. Additionally, these findings raise epidemiological concern about the potential diffusion of these emerging multidrug resistant (SGI linked) DT120 strains. PMID:26060815

  5. Antimicrobial potential of Pakistani medicinal plants against multi-drug resistance Staphylococcus aureus

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    Rahat Ejaz

    2014-09-01

    Full Text Available Objective: To determine resistance patterns of Staphylococcus aureus (S. aureus isolated from different areas of Pakistan and to identify antimicrobial agents against multi-drug resistant S. aureus strains. Methods: A total of 67 samples (sewerage, nasal and milk were collected from different farm areas of Pakistan to identify local strains of S. aureus. Sixteen out of 67 samples were positive for S. aureus. Only 6 out of 16 S. aureus strains showed resistance to antibiotics. Then the antibacterial effect of 29 medicinal plants was evaluated on these S. aureus isolates and a standard S. aureus strain ATCC 25923. The solvents used for the extraction of plants were acetone, dimethyl sulfoxide and methanol. The in vitro antibacterial activity was performed using agar disc diffusion method. Moreover, minimum inhibitory concentration of effective medicinal plant extracts was identified through micro-dilution method to find out their 50% inhibitory concentration. Results: Plant extracts of 5 medicinal plants (Psidium guajava, Nigella sativa, Piper nigrum, Valeriana jatamansi, and Cucurbita pepo exhibited antibacterial activity against locally isolated multidrug resistant strains of S. aureus. The minimum inhibitory concentration of these extracts was ranged from 0.328 to 5.000 mg/mL. Conclusions: Plant extracts of Psidium guajava, Piper nigrum seed, Valeriana jatamansi, Cucurbita pepo and Nigella sativa showed significant in vitro antibacterial activity and thus, such findings may serve as valuable contribution in the treatment of infection and may contribute to the development of potential antimicrobial agents against multi drug resistant strains of S. aureus

  6. The Transcription Factor Mrr1p Controls Expression of the MDR1 Efflux Pump and Mediates Multidrug Resistance in Candida albicans

    OpenAIRE

    Morschhäuser, Joachim; Barker, Katherine S; Liu, Teresa T; Blaß-Warmuth, Julia; Homayouni, Ramin; Rogers, P. David

    2007-01-01

    Constitutive overexpression of the MDR1 (multidrug resistance) gene, which encodes a multidrug efflux pump of the major facilitator superfamily, is a frequent cause of resistance to fluconazole and other toxic compounds in clinical Candida albicans strains, but the mechanism of MDR1 upregulation has not been resolved. By genome-wide gene expression analysis we have identified a zinc cluster transcription factor, designated as MRR1 (multidrug resistance regulator), that was coordinately upregu...

  7. Phenothiazines as a solution for multidrug resistant tuberculosis

    DEFF Research Database (Denmark)

    Kristiansen, Jette E.; Dastidar, Sujata G.; Palchoudhuri, Shauroseni; Roy, Debalina Sinha; Das, Sukhen; Hendricks, Oliver; Christensen, Jørn Bolstad

    2015-01-01

    Historically, multiplicity of actions in synthetic compounds is a rule rather than exception. The science of non-antibiotics evolved in this background. From the antimalarial and antitrypanosomial dye methylene blue, chemically similar compounds, the phenothiazines, were developed. The...... phenothiazines were first recognised for their antipsychotic properties, but soon after their antimicrobial functions came to be known and then such compounds were designated as non-antibiotics. The emergence of highly drug-resistant bacteria had initiated an urgent need to search for novel affordable compounds...... try to remain and multiply silently. Such a small dose is devoid of its adverse side-effects. Recent studies have shown that the (-) thioridazine is a more active antimicrobial agent and devoid of the toxic side effects normally encountered. This review describes the possibilities of bringing down...

  8. Role of Mitochondrial Translocation of Telomerase in Hepatocellular Carcinoma Cells with Multidrug Resistance

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    Xianlong Ling, Lei Wen, Yuan Zhou

    2012-01-01

    Full Text Available Multidrug resistance (MDR is a major obstacle of cancer chemotherapy. This study aimed to investigate the role of mitochondrial translocation of telomerase (hTERT in MDR of human hepatocellular carcinoma (HCC cells. In this study, three HCC cell lines (SK-Hep1/CDDP1 cells, SK-Hep1/CDDP2 cells and SK-Hep1/CDDP3 cells with differential resistance index (RI to cisplatin (CDDP were induced by pulse treatment of SK-Hep1 (human hepatocellular cell line with CDDP in vitro. The RI of SK-Hep1/CDDP1 cells, SK-Hep1/CDDP2 cells and SK-Hep1/CDDP3 cells was 5.14, 8.66, and 14.25, respectively, and all the cell lines showed cross-resistance to Doxorubicin (DOX and 5-Fuorouracil (5-FU. The apoptosis rates in drug-resistant cells were significantly reduced. Cell cycle analysis revealed the ratio of drug-resistant cells in G2/M and S phases increased, while that in G1 phase decreased. Immunofluorescence staining and Western blot assay demonstrated, with the gradual elevation in RI, increasing hTERT translocated from the nuclei to the mitochondria, while real-time PCR indicated the shortening of telomere length in drug-resistant cells under the chemotherapeutic stress and the reduction of damaged mtDNA with the increase in RI. Furthermore, JC-1 staining also indicated the reduction of mitochondrial membrane potential in drug-resistant cells. The mitochondrial translocation of hTERT increases in multidrug-resistant cells and exerts protective effect on mitochondrial function. Drug-resistant tumor cells escape from apoptosis through hTERT-mediated mitochondrial protection. Mitochondrial translocation of hTERT may serve as an underlying mechanism of MDR.

  9. Two Multidrug-Resistant Clinical Isolates of Bacteroides fragilis Carry a Novel Metronidazole Resistance nim Gene (nimJ)

    OpenAIRE

    Husain, Fasahath; Veeranagouda, Yaligara; Hsi, Justin; Meggersee, Rosemary; Abratt, Valerie; Wexler, Hannah M

    2013-01-01

    Two multidrug-resistant Bacteroides fragilis clinical isolates contain and express a novel nim gene, nimJ, that is not recognized by the universal nim primers and can confer increased resistance to metronidazole when introduced into a susceptible strain on a multicopy plasmid. HMW615, an appendiceal isolate, contains at least two copies of nimJ on its genome, while HMW616, an isolate from a patient with sepsis, contains one genomic copy of nimJ. B. fragilis NimJ is phylogenetically closer t...

  10. Selection of a multidrug resistance plasmid by sublethal levels of antibiotics and heavy metals.

    Science.gov (United States)

    Gullberg, Erik; Albrecht, Lisa M; Karlsson, Christoffer; Sandegren, Linus; Andersson, Dan I

    2014-01-01

    How sublethal levels of antibiotics and heavy metals select for clinically important multidrug resistance plasmids is largely unknown. Carriage of plasmids generally confers substantial fitness costs, implying that for the plasmid-carrying bacteria to be maintained in the population, the plasmid cost needs to be balanced by a selective pressure conferred by, for example, antibiotics or heavy metals. We studied the effects of low levels of antibiotics and heavy metals on the selective maintenance of a 220-kbp extended-spectrum β-lactamase (ESBL) plasmid identified in a hospital outbreak of Klebsiella pneumoniae and Escherichia coli. The concentrations of antibiotics and heavy metals required to maintain plasmid-carrying bacteria, the minimal selective concentrations (MSCs), were in all cases below (almost up to 140-fold) the MIC of the plasmid-free susceptible bacteria. This finding indicates that the very low antibiotic and heavy metal levels found in polluted environments and in treated humans and animals might be sufficiently high to maintain multiresistance plasmids. When resistance genes were moved from the plasmid to the chromosome, the MSC decreased, showing that MSC for a specific resistance conditionally depends on genetic context. This finding suggests that a cost-free resistance could be maintained in a population by an infinitesimally low concentration of antibiotic. By studying the effect of combinations of several compounds, it was observed that for certain combinations of drugs each new compound added lowered the minimal selective concentration of the others. This combination effect could be a significant factor in the selection of multidrug resistance plasmids/bacterial clones in complex multidrug environments. Importance: Antibiotic resistance is in many pathogenic bacteria caused by genes that are carried on large conjugative plasmids. These plasmids typically contain multiple antibiotic resistance genes as well as genes that confer resistance to biocides and heavy metals. In this report, we show that very low concentrations of single antibiotics and heavy metals or combinations of compounds can select for a large plasmid that carries resistance to aminoglycosides, β-lactams, tetracycline, macrolides, trimethoprim, sulfonamide, silver, copper, and arsenic. Our findings suggest that the low levels of antibiotics and heavy metals present in polluted external environments and in treated animals and humans could allow for selection and enrichment of bacteria with multiresistance plasmids and thereby contribute to the emergence, maintenance, and transmission of antibiotic-resistant disease-causing bacteria. PMID:25293762

  11. Molecular Characterization of the Multidrug Resistant Escherichia coli ST131 Clone

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    Mark A. Schembri

    2015-06-01

    Full Text Available Escherichia coli ST131 is a recently emerged and globally disseminated multidrug resistant clone associated with urinary tract and bloodstream infections in both community and clinical settings. The most common group of ST131 strains are defined by resistance to fluoroquinolones and possession of the type 1 fimbriae fimH30 allele. Here we provide an update on our recent work describing the globally epidemiology of ST131. We review the phylogeny of ST131 based on whole genome sequence data and highlight the important role of recombination in the evolution of this clonal lineage. We also summarize our findings on the virulence of the ST131 reference strain EC958, and highlight the use of transposon directed insertion-site sequencing to define genes associated with serum resistance and essential features of its large antibiotic resistance plasmid pEC958.

  12. The Role of Cell Density and Intratumoral Heterogeneity in Multidrug Resistance

    Science.gov (United States)

    Lavi, Orit; Greene, James M.; Levy, Doron; Gottesman, Michael M.

    2016-01-01

    Recent data have demonstrated that cancer drug resistance reflects complex biological factors including tumor heterogeneity, varying growth, differentiation, apoptosis pathways, and cell density. As a result, there is a need to find new ways to incorporate these complexities in the mathematical modeling of multidrug resistance. Here, we derive a novel structured population model that describes the behavior of cancer cells under selection with cytotoxic drugs. Our model is designed to estimate intratumoral heterogeneity as a function of the resistance level and time. This updated model of the multidrug resistance problem integrates both genetic and epigenetic changes, density-dependence, and intratumoral heterogeneity. Our results suggest that treatment acts as a selection process, while genetic/epigenetic alterations rates act as a diffusion process. Application of our model to cancer treatment suggests that reducing alteration rates as a first step in treatment causes a reduction in tumor heterogeneity, and may improve targeted therapy. The new insight provided by this model could help to dramatically change the ability of clinical oncologists to design new treatment protocols and analyze the response of patients to therapy. Major Findings We suggest that chemotherapeutic treatment acts as a selection process in the effective drug concentrations range, while genetic/epigenetic alterations act as a diffusion process that results in trait spread based on different stress signals. Application of our model to cancer treatment suggests that reducing the alteration rate as a first step in treatment causes a reduction in tumor heterogeneity, and may improve targeted therapy. PMID:24163380

  13. In vitro activity of the benzoxazinorifamycin KRM-1648 against drug-susceptible and multidrug-resistant tubercle bacilli.

    OpenAIRE

    Luna-Herrera, J.; Reddy, M. V.; Gangadharam, P R

    1995-01-01

    We investigated the activity of benzoxazinorifamycin (KRM-1648) against several drug-susceptible and multidrug-resistant strains of tubercle bacilli. Since KRM-1648 is a rifamycin derivative, we included some strains of Mycobacterium tuberculosis resistant to rifampin (RIF) among the multidrug-resistant strains. For RIF-susceptible strains, the MIC of KRM-1648 was much lower than that of RIF (MICs of KRM-1648 and RIF at which 90% of strains are inhibited, < or = 0.015 and < or = 0.25 microgra...

  14. Identification of multi-drug resistant Pseudomonas aeruginosa clinical isolates that are highly disruptive to the intestinal epithelial barrier

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    Shevchenko Olga

    2006-06-01

    Full Text Available Abstract Background Multi-drug resistant Pseudomonas aeruginosa nosocomial infections are increasingly recognized worldwide. In this study, we focused on the virulence of multi-drug resistant clinical strains P. aeruginosa against the intestinal epithelial barrier, since P. aeruginosa can cause lethal sepsis from within the intestinal tract of critically ill and immuno-compromised patients via mechanisms involving disruption of epithelial barrier function. Methods We screened consecutively isolated multi-drug resistant P. aeruginosa clinical strains for their ability to disrupt the integrity of human cultured intestinal epithelial cells (Caco-2 and correlated these finding to related virulence phenotypes such as adhesiveness, motility, biofilm formation, and cytotoxicity. Results Results demonstrated that the majority of the multi-drug resistant P. aeruginosa clinical strains were attenuated in their ability to disrupt the barrier function of cultured intestinal epithelial cells. Three distinct genotypes were found that displayed an extreme epithelial barrier-disrupting phenotype. These strains were characterized and found to harbor the exoU gene and to display high swimming motility and adhesiveness. Conclusion These data suggest that detailed phenotypic analysis of the behavior of multi-drug resistant P. aeruginosa against the intestinal epithelium has the potential to identify strains most likely to place patients at risk for lethal gut-derived sepsis. Surveillance of colonizing strains of P. aeruginosa in critically ill patients beyond antibiotic sensitivity is warranted.

  15. Biomarkers to optimize antibiotic therapy for pneumonia due to multidrug-resistant pathogens.

    Science.gov (United States)

    Luyt, Charles-Edouard; Combes, Alain; Trouillet, Jean-Louis; Chastre, Jean

    2011-09-01

    No currently available biomarker can be used as a diagnostic marker for ventilator-associated pneumonia due to multidrug-resistant pathogens. Procalcitonin can be used to customize the duration of antimicrobial treatment without excess morbidity and mortality: when its concentration is less than 0.5 ng/mL or has decreased by 80% or more compared with the peak concentration, antibiotics can be stopped. With this strategy, extreme vigilance must be maintained after terminating antimicrobial therapy to detect a recurrent infection. PMID:21867813

  16. Diterpene Constituents of Euphorbia exigua L. and Multidrug Resistance Reversing Activity of the Isolated Diterpenes.

    Science.gov (United States)

    Rédei, Dóra; Boros, Klára; Forgo, Peter; Molnár, Joseph; Kele, Zoltán; Pálinkó, István; Pinke, Gyula; Hohmann, Judit

    2015-08-01

    Phytochemical investigation of the MeOH extract obtained from the aerial parts of the annual weed Euphorbia exigua L. resulted in the isolation of two novel (1, 2) and one known (3) jatrophane diterpenes. Their structures were established by extensive 1D- and 2D-NMR spectroscopy and HR-ESI-MS. The isolated compounds were evaluated for multidrug resistance (MDR) reversing activity on human MDR gene-transfected L5178 mouse lymphoma cells; and all three compounds were found to modulate the intracellular drug accumulation. PMID:26265573

  17. Genome sequencing and annotation of multidrug resistant Mycobacterium tuberculosis (MDR-TB) PR10 strain

    Science.gov (United States)

    Halim, Mohd Zakihalani A.; Jaafar, Mohammad Maaruf; Teh, Lay Kek; Ismail, Mohamad Izwan; Lee, Lian Shien; Ngeow, Yun Fong; Nor, Norazmi Mohd; Zainuddin, Zainul Fadziruddin; Tang, Thean Hock; Najimudin, Mohd Nazalan Mohd; Salleh, Mohd Zaki

    2016-01-01

    Here, we report the draft genome sequence and annotation of a multidrug resistant Mycobacterium tuberculosis strain PR10 (MDR-TB PR10) isolated from a patient diagnosed with tuberculosis. The size of the draft genome MDR-TB PR10 is 4.34 Mbp with 65.6% of G + C content and consists of 4637 predicted genes. The determinants were categorized by RAST into 400 subsystems with 4286 coding sequences and 50 RNAs. The whole genome shotgun project has been deposited at DDBJ/EMBL/GenBank under the accession number CP010968.

  18. The political and ethical challenge of multi-drug resistant tuberculosis.

    Science.gov (United States)

    Degeling, Chris; Mayes, Christopher; Lipworth, Wendy; Kerridge, Ian; Upshur, Ross

    2015-03-01

    This article critically examines current responses to multi-drug resistant tuberculosis (MDR-TB) and argues that bioethics needs to be willing to engage in a more radical critique of the problem than is currently offered. In particular, we need to focus not simply on market-driven models of innovation and anti-microbial solutions to emergent and re-emergent infections such as TB. The global community also needs to address poverty and the structural factors that entrench inequalities-thus moving beyond the orthodox medical/public health frame of reference. PMID:25630591

  19. Genome sequencing and annotation of multidrug resistant Mycobacterium tuberculosis (MDR-TB PR10 strain

    Directory of Open Access Journals (Sweden)

    Mohd Zakihalani A. Halim

    2016-03-01

    Full Text Available Here, we report the draft genome sequence and annotation of a multidrug resistant Mycobacterium tuberculosis strain PR10 (MDR-TB PR10 isolated from a patient diagnosed with tuberculosis. The size of the draft genome MDR-TB PR10 is 4.34 Mbp with 65.6% of G + C content and consists of 4637 predicted genes. The determinants were categorized by RAST into 400 subsystems with 4286 coding sequences and 50 RNAs. The whole genome shotgun project has been deposited at DDBJ/EMBL/GenBank under the accession number CP010968.

  20. Comparative Sequence Analysis of a Multidrug-Resistant Plasmid from Aeromonas hydrophila

    OpenAIRE

    del Castillo, Carmelo S.; Hikima, Jun-ichi; Jang, Ho-Bin; Nho, Seong-Won; Jung, Tae-Sung; Wongtavatchai, Janenuj; Kondo, Hidehiro; Hirono, Ikuo; Takeyama, Haruko; Takashi AOKI

    2013-01-01

    Aeromonas hydrophila is a pathogenic bacterium that has been implicated in fish, animal, and human disease. Recently, a multidrug resistance (MDR) plasmid, pR148, was isolated from A. hydrophila obtained from a tilapia (Oreochromis niloticus) farm in Thailand. pR148 is a 165,906-bp circular plasmid containing 147 coding regions showing highest similarity to pNDM-1_Dok1, an MDR plasmid isolated from a human pathogen. pR148 was also very similar to other IncA/C plasmids isolated from humans, an...

  1. Tetracycline improved the efficiency of other antimicrobials against Gram-negative multidrug-resistant bacteria.

    Science.gov (United States)

    Mawabo, Isabelle K; Noumedem, Jaurès A K; Kuiate, Jules R; Kuete, Victor

    2015-01-01

    Treatment of infectious diseases with antimicrobials constituted a great achievement in the history of medicine. Unfortunately, the emergence of resistant strains of bacteria to all classes of antimicrobials limited their efficacy. The present study was aimed at evaluating the effect of combinations of antibiotics on multi-drug resistant Gram-negative (MDRGN) bacteria. A liquid micro-broth dilution method was used to evaluate the antibacterial activity of 10 different classes of antimicrobials on 20 bacterial strains belonging to six different species. The antimicrobials were associated with phenylalanine β-naphthylamide (PAβN), an efflux pump inhibitor, and with other antimicrobials at their sub-inhibitory concentrations. The effectiveness of each combination was monitored using the minimal inhibitory concentration (MIC) and the fractional inhibitory concentration (FIC). Most of the antimicrobials tested showed low antibacterial activity with a MIC value of 128 mg/L on a majority of the bacterial strains, justifying their multidrug-resistant (MDR) profile. Synergistic effects were mostly observed (FIC≤0.5) when ampicillin (AMP), cloxacillin (CLX), erythromycin (ERY), chloramphenicol (CHL), kanamycin (KAN) and streptomycin (STR) were combined with tetracycline (TET) at the sub-inhibitory concentration of MIC/5 or MIC/10. The results of the present work suggest that the association of several antimicrobials with TET could improve the fight against MDRGN bacterial species. PMID:25458915

  2. Multi-drug resistant Acinetobacter infections in critically injured Canadian forces soldiers

    Directory of Open Access Journals (Sweden)

    Brisebois Ronald

    2007-08-01

    Full Text Available Abstract Background Military members, injured in Afghanistan or Iraq, have returned home with multi-drug resistant Acinetobacter baumannii infections. The source of these infections is unknown. Methods Retrospective study of all Canadian soldiers who were injured in Afghanistan and who required mechanical ventilation from January 1 2006 to September 1 2006. Patients who developed A. baumannii ventilator associated pneumonia (VAP were identified. All A. baumannii isolates were retrieved for study patients and compared with A. baumannii isolates from environmental sources from the Kandahar military hospital using pulsed-field gel electrophoresis (PFGE. Results During the study period, six Canadian Forces (CF soldiers were injured in Afghanistan, required mechanical ventilation and were repatriated to Canadian hospitals. Four of these patients developed A. baumannii VAP. A. baumannii was also isolated from one environmental source in Kandahar a ventilator air intake filter. Patient isolates were genetically indistinguishable from each other and from the isolates cultured from the ventilator filter. These isolates were resistant to numerous classes of antimicrobials including the carbapenems. Conclusion These results suggest that the source of A. baumannii infection for these four patients was an environmental source in the military field hospital in Kandahar. A causal linkage, however, was not established with the ventilator. This study suggests that infection control efforts and further research should be focused on the military field hospital environment to prevent further multi-drug resistant A. baumannii infections in injured soldiers.

  3. Multidrug-Resistance Transporter AbcA Secretes Staphylococcus aureus Cytolytic Toxins.

    Science.gov (United States)

    Yoshikai, Hirono; Kizaki, Hayato; Saito, Yuki; Omae, Yosuke; Sekimizu, Kazuhisa; Kaito, Chikara

    2016-01-15

    Phenol-soluble modulins (PSMs) are Staphylococcus aureus cytolytic toxins that lyse erythrocytes and neutrophils and have important functions in the S. aureus infectious process. The molecular mechanisms of PSM secretion, however, are not well understood. Here we report that knockout of the multidrug-resistance ABC transporter AbcA, which contributes to S. aureus resistance against antibiotics and chemicals, diminished the secreted amount of PSM, leading to the accumulation of PSM in the intracellular fraction. The amount of PSM in the culture supernatants of the abcA knockout mutants was restored by introduction of the wild-type abcA gene, whereas it was not completely restored by introduction of mutant abcA genes encoding AbcA mutant proteins carrying amino acid substitutions in the adenosine triphosphate binding motifs. The abcA knockout mutant exhibited attenuated virulence in a mouse systemic infection model. These findings suggest that the multidrug resistance transporter AbcA secretes PSMs and contributes to S. aureus virulence. PMID:26160745

  4. In vitro activity of antimicrobial combinations against multidrug-resistant Pseudomonas aeruginosa

    Scientific Electronic Library Online (English)

    Denissani Aparecida Ferrari dos Santos, Lima; Margarida Maria Passeri do, Nascimento; Lucia Helena, Vitali; Roberto, Martinez.

    2013-06-01

    Full Text Available Introduction Pseudomonas aeruginosa isolates related to nosocomial infections are often resistant to multiple antibacterial agents. In this study, antimicrobial combinations were evaluated to detect in vitro synergy against clinical isolates of P. aeruginosa. Methods Four clinical P. aeruginosa i [...] solates were selected at random among other isolates from inpatients treated at the public University hospital in Ribeiro Preto, SP, Brazil. Two isolates were susceptible to imipenem (IPM-S) and several other antimicrobials, while the other two isolates were imipenem and multidrug resistant (IPM-R). The checkerboard method was used to assess the interactions between antimicrobials. Results Combinations of imipenem or other anti-Pseudomonas drugs with complementary antibiotics, such as aminoglycosides, fosfomycin and rifampin, reached synergy rates of 20.8%, 50%, 62.5% and 50% for the two IPM-S and two IPM-R Pseudomonas isolates, respectively. Imipenem, piperacillin-tazobactam and ceftazidime yielded a greater synergy rate than cefepime or ciprofloxacin. Synergist combinations were more commonly observed when the complementary drug was tobramycin (65%) or fosfomycin (57%). Conclusions Some antibacterial combinations led to significant reductions of the minimum inhibitory concentrations of both drugs, suggesting that they could be clinically applied to control infections caused by multidrug-resistant P. aeruginosa.

  5. Antibacterial activity of Aristolochia brevipes against multidrug-resistant Mycobacterium tuberculosis.

    Science.gov (United States)

    Navarro-Garca, Vctor Manuel; Luna-Herrera, Julieta; Rojas-Bribiesca, Ma Gabriela; lvarez-Fitz, Patricia; Ros, Mara Yolanda

    2011-01-01

    The increased incidence of Multidrug-Resistant Mycobacterium tuberculosis (MDR-MT) requires the search for alternative antimycobacterial drugs. The main aim of this study was to evaluate the dichloromethane extract from Aristolochia brevipes (Rhizoma) and the compounds isolated from this extract against several mycobacterial strains, sensitive, resistant (monoresistant), and clinical isolates (multidrug-resistant), using the alamarBlue microassay. The extract was fractionated by column chromatography, yielding the following eight major compounds: (1) 6?-7-dehydro-N-formylnornantenine; (2) E/Z-N-formylnornantenine; (3) 7,9-dimethoxytariacuripyrone; (4) 9-methoxy-tariacuripyrone; (5) aristololactam I; (6) ?-sitosterol; (7) stigmasterol; and (8) 3-hydroxy-?-terpineol. The structures of these compounds were elucidated by 1H- and 13C- (1D and 2D) Nuclear Magnetic Resonance (NMR) spectroscopy. This study demonstrates that the dichloromethane extract (rhizome) of A. brevipes possesses strong in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv (Minimum Inhibitory Concentration value [MIC], 12.5 g/mL). The most active compound against all mycobacterial strains tested was the compound aristolactam I (5), with MIC values ranging between 12.5 and 25 g/mL. To our knowledge, this the first report of antimycobacterial activity in this plant. PMID:21876482

  6. In vitro activity of antimicrobial combinations against multidrug-resistant Pseudomonas aeruginosa

    Directory of Open Access Journals (Sweden)

    Denissani Aparecida Ferrari dos Santos Lima

    2013-06-01

    Full Text Available Introduction Pseudomonas aeruginosa isolates related to nosocomial infections are often resistant to multiple antibacterial agents. In this study, antimicrobial combinations were evaluated to detect in vitro synergy against clinical isolates of P. aeruginosa. Methods Four clinical P. aeruginosa isolates were selected at random among other isolates from inpatients treated at the public University hospital in Ribeirão Preto, SP, Brazil. Two isolates were susceptible to imipenem (IPM-S and several other antimicrobials, while the other two isolates were imipenem and multidrug resistant (IPM-R. The checkerboard method was used to assess the interactions between antimicrobials. Results Combinations of imipenem or other anti-Pseudomonas drugs with complementary antibiotics, such as aminoglycosides, fosfomycin and rifampin, reached synergy rates of 20.8%, 50%, 62.5% and 50% for the two IPM-S and two IPM-R Pseudomonas isolates, respectively. Imipenem, piperacillin-tazobactam and ceftazidime yielded a greater synergy rate than cefepime or ciprofloxacin. Synergist combinations were more commonly observed when the complementary drug was tobramycin (65% or fosfomycin (57%. Conclusions Some antibacterial combinations led to significant reductions of the minimum inhibitory concentrations of both drugs, suggesting that they could be clinically applied to control infections caused by multidrug-resistant P. aeruginosa.

  7. Antibacterial Activity of Aristolochia brevipes against Multidrug-Resistant Mycobacterium tuberculosis

    Directory of Open Access Journals (Sweden)

    Mara Yolanda Ros

    2011-08-01

    Full Text Available The increased incidence of Multidrug-Resistant Mycobacterium tuberculosis (MDR-MT requires the search for alternative antimycobacterial drugs. The main aim of this study was to evaluate the dichloromethane extract from Aristolochia brevipes (Rhizoma and the compounds isolated from this extract against several mycobacterial strains, sensitive, resistant (monoresistant, and clinical isolates (multidrug-resistant, using the alamarBlue microassay. The extract was fractionated by column chromatography, yielding the following eight major compounds: (1 6?-7-dehydro-N-formylnornantenine; (2 E/Z-N-formylnornantenine; (3 7,9-dimethoxytariacuripyrone; (4 9-methoxy-tariacuripyrone; (5 aristololactam I; (6 ?-sitosterol; (7 stigmasterol; and (8 3-hydroxy-?-terpineol. The structures of these compounds were elucidated by 1H- and 13C- (1D and 2D Nuclear Magnetic Resonance (NMR spectroscopy. This study demonstrates that the dichloromethane extract (rhizome of A. brevipes possesses strong in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv (Minimum Inhibitory Concentration value [MIC], 12.5 g/mL. The most active compound against all mycobacterial strains tested was the compound aristolactam I (5, with MIC values ranging between 12.5 and 25 g/mL. To our knowledge, this the first report of antimycobacterial activity in this plant.

  8. Place of Colistin-Rifampicin Association in the Treatment of Multidrug-Resistant Acinetobacter Baumannii Meningitis: A Case Study

    Science.gov (United States)

    Souhail, Dahraoui; Bouchra, Belefquih; Belarj, Badia; Laila, Rar; Mohammed, Frikh; Nassirou, Oumarou Mamane; Azeddine, Ibrahimi; Haimeur, Charki; Lemnouer, Abdelhay; Elouennass, Mostafa

    2016-01-01

    Treatment of Acinetobacter baumannii meningitis is an important challenge due to the accumulation of resistance of this bacteria and low meningeal diffusion of several antimicrobial requiring use of an antimicrobial effective combination to eradicate these species. We report a case of Acinetobacter baumannii multidrug-resistant nosocomial meningitis which was successfully treated with intravenous and intrathecal colistin associated with rifampicin.

  9. Population genetics of multi-drug resistant (MDR) IncA/C plasmid in Salmonella enterica isolated from animals

    Science.gov (United States)

    Food animals harboring Multi-Drug Resistant (MDR) Salmonella enterica are a potential source for acquisition of zoonotic pathogens. Plasmids (small, self-replicating, extra-chromosomal DNA) are often associated with antimicrobial resistance and plasmids carrying MDR genes have been found to be a maj...

  10. Draft Genome Sequence of an Invasive Multidrug-Resistant Strain, Pseudomonas aeruginosa BK1, Isolated from a Keratitis Patient

    KAUST Repository

    Jeganathan, Lakshmi Priya

    2014-03-27

    Pseudomonas aeruginosa infections are difficult to treat due to the presence of a multitude of virulence factors and antibiotic resistance. Here, we report the draft genome sequence of P. aeruginosa BK1, an invasive and multidrug-resistant strain, isolated from a bacterial keratitis patient in southern India.

  11. Escherichia coli Sequence Type 131 (ST131) Subclone H30 as an Emergent Multidrug-Resistant Pathogen Among US Veterans

    OpenAIRE

    Colpan, Aylin; Johnston, Brian; Porter, Stephen; Clabots, Connie; Anway, Ruth; Thao, Lao; Kuskowski, Michael A.; Tchesnokova, Veronika; Sokurenko, Evgeni V.; Johnson, James R.; Allen, Bradley L.; Baracco, Gio J.; Bedimo, Roger; Bessesen, Mary; Bonomo, Robert A.

    2013-01-01

    Among US veterans in 2011, Escherichia coli ST131, primarily its H30 subclone, accounted for most antimicrobial-resistant E. coli clinical isolates and was the dominant E. coli strain overall. Possible contributors included multidrug resistance, extensive virulence gene content, and ongoing transmission.

  12. Differences in the motility phenotype of multidrug-resistant Salmonella enterica serovar Typhimurium exposed to various antibiotics

    Science.gov (United States)

    Salmonella enterica serovar Typhimurium (S. Typhimurium) is one of the most prevalent foodborne-associated bacteria in humans and livestock, and over 35 per cent of these isolates are resistant to three or more antibiotics. This is a concern as multidrug-resistant (MDR) Salmonella has been associat...

  13. Fatal septicemia by multidrug-resistant Enterococcus faecium in a case of exomphalos minor

    Directory of Open Access Journals (Sweden)

    Mahantesh V Parande

    2012-01-01

    Full Text Available Exomphalos minor is one among uncommon disorders of the umbilical region. Here, we report a fatal case of exomphalos minor with enterococcal septicemia. A male baby, born with exomphalos minor, developed clinical features of septicemia on the fourth postnatal day. Blood samples were collected by venepuncture from two sites for culture. Enterococcus faecium was isolated from both the blood samples. The swabs collected from the site of exomphalos also yielded growth of Enterococcus faecium, confirming the source of infection. The antibiogram with Minimum Inhibitory Concentrations (MIC for various antibiotics was done for isolates from all three sites, which was similar. The isolate was resistant to multiple antibiotics with high level aminoglycoside resistance. The baby was treated with antibiotics and other supportive measures. However, the baby succumbed to the septicemia. As per our knowledge, this is the first reported case of fatal septicemia by multidrug-resistant Enterococcus faecium in a case of exomphalos minor.

  14. Global Introduction of New Multidrug-Resistant Tuberculosis Drugs—Balancing Regulation with Urgent Patient Needs

    Science.gov (United States)

    Sullivan, Timothy

    2016-01-01

    New treatments for multidrug-resistant tuberculosis (MDR TB) are urgently needed. Two new drugs, bedaquiline and delamanid, have recently been released, and several new drugs and treatment regimens are in the pipeline. Misuse of TB drugs is a principal cause of drug resistance. As new drugs and regimens reach the market, the need to make them available to patients must be balanced with regulation of their use so that resistance to the new drugs can be prevented. To foster the rational use of new drugs, we propose 1) expanding/strengthening the capacity for drug susceptibility testing, beginning with countries with a high TB burden; 2) regulating prescribing practices by banning over-the-counter sale of TB drugs and enacting an accreditation system whereby providers must be certified to prescribe new drugs; and 3) decentralizing MDR TB care in rural communities by employing trained community health workers, using promising mobile technologies, and enlisting the aid of civil society organizations. PMID:26889711

  15. [On the importance of multidrug-resistant strains of pathogenic microorganisms in ophthalmic practice].

    Science.gov (United States)

    Galeeva, G Z; Samoylov, A N; Rascheskov, A Yu

    2015-01-01

    This is a review of epidemiological, microbiological and ophthalmological publications on the importance of multidrug-resistant bacterial strains in medical, particularly ophthalmological, care. Current state of pharmaceutical market and wide variety of generics confuses doctor's (including ophthalmologist's) sense of decision-making on the optimum antibiotic for the treatment of purulent inflammation. Indiscriminate use of antibiotics contributes to multiple drug resistance in bacteria. The world returns to the pre-antibiotic era, in which there was no treatment for severe infectious and inflammatory diseases. The most dangerous multiresistant strains known to medical science and their role in etiology of inflammatory eye diseases are listed in the article. Since neonatal conjunctivitis and postoperative endophthalmitis are the most common ocular inflammatory diseases caused by nosocomial multiresistant bacteria, their etiological classification is also described. Emergence of antibiotic resistance to most frequently used ophthalmic agents and prevention strategies are discussed. PMID:26080593

  16. Multidrug-resistant tuberculosis: treatment outcome in Denmark, 1992-2007

    DEFF Research Database (Denmark)

    Bang, Didi; Lillebaek, Troels; Thomsen, Vibeke Østergaard; Andersen, Ase Bengård

    2010-01-01

    A retrospective nationwide study including all culture-verified multidrug-resistant (MDR) tuberculosis (TB) cases was performed in Denmark. The aim was to examine the long-term treatment outcome of MDR-TB, to assess if MDR-TB transmission occurs, and to evaluate a rapid mutation analysis detecting...... was low at 0.5%. Acquired MDR-TB and active transmission was rare. Mutations in rifampin (rpoB) and isoniazid (katG, inhA) genes correctly determined resistance in 100% and 82% of all isolates tested, respectively. Initial treatment success was 89% for 27 MDR-TB patients with available outcome data...... rifampin and isoniazid resistance in this cohort. Clinical data were obtained from patient records. A restriction fragment length polymorphism genotype database of all TB cases was compared for identical strains indicating active transmission. Twenty-nine cases of MDR-TB were identified and the incidence...

  17. Global Introduction of New Multidrug-Resistant Tuberculosis Drugs-Balancing Regulation with Urgent Patient Needs.

    Science.gov (United States)

    Sullivan, Timothy; Ben Amor, Yanis

    2016-03-01

    New treatments for multidrug-resistant tuberculosis (MDR TB) are urgently needed. Two new drugs, bedaquiline and delamanid, have recently been released, and several new drugs and treatment regimens are in the pipeline. Misuse of TB drugs is a principal cause of drug resistance. As new drugs and regimens reach the market, the need to make them available to patients must be balanced with regulation of their use so that resistance to the new drugs can be prevented. To foster the rational use of new drugs, we propose 1) expanding/strengthening the capacity for drug susceptibility testing, beginning with countries with a high TB burden; 2) regulating prescribing practices by banning over-the-counter sale of TB drugs and enacting an accreditation system whereby providers must be certified to prescribe new drugs; and 3) decentralizing MDR TB care in rural communities by employing trained community health workers, using promising mobile technologies, and enlisting the aid of civil society organizations. PMID:26889711

  18. International spread of multidrug-resistant Salmonella Schwarzengrund in food products

    DEFF Research Database (Denmark)

    Aarestrup, Frank Møller; Hendriksen, Rene S.; Lockett, Jana; Gay, Katie; Teates, Kathryn; McDermott, Patrick F.; White, David G.; Hasman, Henrik; Sørensen, Gitte; Bangtrakulnonth, Aroon; Pornreongwong, Srirat; Pulsrikarn, Chaiwat; Angulo, Frederick J.; Gerner-Smidt, Peter

    2007-01-01

    We compared 581 Salmonella enterica serotype Schwarzengrund isolates from persons, food, and food animals in Denmark, Thailand, and the United States by antimicrobial drug susceptibility and pulsed-field gel electrophoresis (PFGE) typing. Resistance, including resistance to nalidixic acid, was...... frequent among isolates from persons and chickens in Thailand, persons in the United States, and food imported from Thailand to Denmark and the United States. A total of 183 PFGE patterns were observed, and 136 (23.4%) isolates had the 3 most common patterns. Seven of 14 isolates from persons in Denmark...... had patterns found in persons and chicken meat in Thailand; 22 of 390 human isolates from the United States had patterns found in Denmark and Thailand. This study suggests spread of multidrug-resistant S. Schwarzengrund from chickens to persons in Thailand, and from imported Thai food products to...

  19. Optimization of irinotecan chronotherapy with P-glycoprotein inhibition

    International Nuclear Information System (INIS)

    The relevance of P-glycoprotein (P-gp) for irinotecan chronopharmacology was investigated in female B6D2F1 mice. A three-fold 24 h change in the mRNA expression of Abcb1b was demonstrated in ileum mucosa, with a maximum at Zeitgeber Time (ZT) 15 (p < 0.001). No rhythm was found for abcb1a in ileum mucosa, or for Abcb1a/b in Glasgow osteosarcoma (GOS), a mouse tumor cell line moderately sensitive to irinotecan. Non-tumor-bearing mice received irinotecan (50 mg/kg/day i.v. × 4 days) as a single agent or combined with P-gp inhibitor PSC833 (6.25 mg/kg/day i.p. × 4 days) at ZT3 or ZT15, respectively corresponding to the worst or the best irinotecan tolerability. Endpoints involved survival, body weight change and hematologic toxicity. Antitumor efficacy was studied in GOS-bearing mice receiving irinotecan (25, 30 or 40 mg/kg/day × 4 days) and +/− PSC833 at ZT3 or ZT15, with survival, body weight change, and tumor growth inhibition as endpoints. Non-tumor bearing mice lost an average of 17% or 9% of their body weight according to irinotecan administration at ZT3 or ZT15 respectively (p < 0.001). Dosing at ZT15 rather than ZT3 reduced mean leucopenia (9% vs 53%; p < 0.001). PSC833 aggravated irinotecan lethal toxicity from 4 to ∼ 60%. In tumor-bearing mice, body weight loss was ∼ halved in the mice on irinotecan or irinotecan–PSC833 combination at ZT15 as compared to ZT3 (p < 0.001). PSC833–irinotecan at ZT15 increased tumor inhibition by ∼ 40% as compared to irinotecan only at ZT15. In conclusion, P-gp was an important determinant of the circadian balance between toxicity and efficacy of irinotecan. - Highlights: • Irinotecan chronotolerance and chronoefficacy change as drug was applied with PSC833. • P-glycoprotein is an important player of the toxicity and efficacy of irinotecan. • Timing should be considered if chemotherapy is performed with a MDR1 inhibitor

  20. Optimization of irinotecan chronotherapy with P-glycoprotein inhibition

    Energy Technology Data Exchange (ETDEWEB)

    Filipski, Elisabeth; Berland, Elodie [INSERM, U776 “Rythmes biologiques et cancers”, CAMPUS CNRS, 7 rue Guy Môquet, F-94801 Villejuif (France); Univ Paris-Sud, UMR-S0776, Orsay F-91405 (France); Ozturk, Narin [INSERM, U776 “Rythmes biologiques et cancers”, CAMPUS CNRS, 7 rue Guy Môquet, F-94801 Villejuif (France); Univ Paris-Sud, UMR-S0776, Orsay F-91405 (France); Istanbul University Faculty of Pharmacy, Department of Pharmacology, Beyazit TR-34116, Istanbul (Turkey); Guettier, Catherine [Assistance Publique-Hôpitaux de Paris, Unité de Chronothérapie, Département de Cancérologie, Hôpital Paul Brousse, Villejuif F-94807 (France); Horst, Gijsbertus T.J. van der [Department of Genetics, Erasmus University Medical Center, 3000 CA Rotterdam (Netherlands); Lévi, Francis [INSERM, U776 “Rythmes biologiques et cancers”, CAMPUS CNRS, 7 rue Guy Môquet, F-94801 Villejuif (France); Univ Paris-Sud, UMR-S0776, Orsay F-91405 (France); Assistance Publique-Hôpitaux de Paris, Unité de Chronothérapie, Département de Cancérologie, Hôpital Paul Brousse, Villejuif F-94807 (France); and others

    2014-02-01

    The relevance of P-glycoprotein (P-gp) for irinotecan chronopharmacology was investigated in female B6D2F{sub 1} mice. A three-fold 24 h change in the mRNA expression of Abcb1b was demonstrated in ileum mucosa, with a maximum at Zeitgeber Time (ZT) 15 (p < 0.001). No rhythm was found for abcb1a in ileum mucosa, or for Abcb1a/b in Glasgow osteosarcoma (GOS), a mouse tumor cell line moderately sensitive to irinotecan. Non-tumor-bearing mice received irinotecan (50 mg/kg/day i.v. × 4 days) as a single agent or combined with P-gp inhibitor PSC833 (6.25 mg/kg/day i.p. × 4 days) at ZT3 or ZT15, respectively corresponding to the worst or the best irinotecan tolerability. Endpoints involved survival, body weight change and hematologic toxicity. Antitumor efficacy was studied in GOS-bearing mice receiving irinotecan (25, 30 or 40 mg/kg/day × 4 days) and +/− PSC833 at ZT3 or ZT15, with survival, body weight change, and tumor growth inhibition as endpoints. Non-tumor bearing mice lost an average of 17% or 9% of their body weight according to irinotecan administration at ZT3 or ZT15 respectively (p < 0.001). Dosing at ZT15 rather than ZT3 reduced mean leucopenia (9% vs 53%; p < 0.001). PSC833 aggravated irinotecan lethal toxicity from 4 to ∼ 60%. In tumor-bearing mice, body weight loss was ∼ halved in the mice on irinotecan or irinotecan–PSC833 combination at ZT15 as compared to ZT3 (p < 0.001). PSC833–irinotecan at ZT15 increased tumor inhibition by ∼ 40% as compared to irinotecan only at ZT15. In conclusion, P-gp was an important determinant of the circadian balance between toxicity and efficacy of irinotecan. - Highlights: • Irinotecan chronotolerance and chronoefficacy change as drug was applied with PSC833. • P-glycoprotein is an important player of the toxicity and efficacy of irinotecan. • Timing should be considered if chemotherapy is performed with a MDR1 inhibitor.