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Strategies for overcoming ABC-transporters-mediated multidrug resistance (MDR) of tumor cells

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Borowski E., Bontemps-Gracz M. M., Piwkowska A.
Acta Biochimica Polonica
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2005
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vol. 52
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issue 3
609-627
EN
The development of multidrug resistance (MDR) of tumors is a major cause of failure in antitumor chemotherapy. This type of crossresistance is due to the expression of ABC transporter glycoproteins actively effluxing the drug from the cells against the concentration gradient at the expense of metabolic energy, thus preventing the accumulation in cells of therapeutic concentration of active agents. In this review strategies for overcoming this adverse phenomenon are discussed. They comprise the control of expression of MDR glycoprotein transporters and control of the functioning of the expressed transporter proteins. The latter approach is discussed in more detail, comprising the following general strategies: (i) development of compounds that are not substrates of efflux pump(s), (ii) use of agents that inactivate (inhibit) MDR proteins, (iii) design of cytostatics characterized by fast cellular uptake, surpassing their mediated efflux, (iv) use of compounds competing with the drug for the MDR protein-mediated efflux. Positive and negative aspects of these strategies are analysed, with special attention put on strategy based on the use of MDR modulators in combination therapy, allowing the restoration of cytotoxic activity of clinical cytostatics towards resistant tumor cells.
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Multidrug resistance-associated protein - reduction of expression in human leukaemia cells by antisense phosphorothioate olignucleotides.

100%
Niewiarowski W., Gendaszewska E., Rębowski G., Wójcik M., Mikołajczyk B., Soszyński M., Bartosz G.
Acta Biochimica Polonica
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2000
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vol. 47
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issue 4
1183-1188
EN
Multidrug resistance-associated protein (MRP1) causes cellular drug resistance in several cancer cell lines. In this paper we show that antisense oligonucleotides decrease MRP1 expression in human leukaemia cells. We investigated biological activity of a series of 12 linear phosphorothioate oligonucleotides, complementary to several regions of MRP1 mRNA. The oligonucleotides were administered to leukaemia HL60/ADR cells overexpressing MRP1 protein. Then, the level of MRP1 mRNA was determined by means of semiquantitative RT-PCR and the protein level by reaction with specific monoclonal antibodies. Some of the investigated antisense oligonucleotides decrease the expression level of the MRP1 protein by 46% and its mRNA level by 76%.
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Effects and time-kill assessment of amoxicillin used in combination with chloramphenicol against bacteria of clinical importance

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Olajuyigbe O., Coopoosamy R., Afolayan A.
Acta Biochimica Polonica
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2017
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vol. 64
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issue 4
609-613
EN
With the emergence of multidrug-resistant organisms in an era when drug development faces challenges causing pharmaceutical companies to curtail or abandon research on anti-infective agents, the use of combined existing antimicrobial agents may be an alternative. This study evaluated the effects of combining amoxicillin and chloramphenicol, to which many bacteria have become resistant, in vitro against Gram positive and Gram negative bacteria by agar diffusion, checkerboard and time-kill assays. The test isolates were susceptible to amoxicillin with minimum inhibitory concentrations (MICs) ranging between 0.448 and 500 µg/ml and between 1.953 and 31.25 µg/ml for chloramphenicol. Upon combining these agents, there was a drastic reduction in their MICs indicating an increased antibacterial activity that showed synergistic interaction against all the bacteria. At the highest concentrations, the inhibition zones ranges were 20.33-38.33±0.58 µg/ml for amoxicillin, 27.67-37.67±0.58 µg/ml for chloramphenicol and 31.67-39.33±0.58 µg/ml for the combined agents. The fractional inhibitory concentration indices (FICIs) showed synergy ranging from 0.129 to 0.312 while FICIs for additive interaction were between 0.688 and 1.0. There was no antagonistic interaction. At the 1/2MICs of the combined antibiotics, all the tested bacteria, except for Klebsiella pneumoniae ATCC 4352, Proteus vulgaris CSIR 0030 and Enterococcus cloacae ATCC 13047 were eliminated before 24 h. At the MICs, all the tested bacteria were eliminated except Enterococcus cloacae ATCC 13047 which was almost totally eliminated. Post-antibiotic assessment after 48 h showed that all the cultures were sterile except for that of Enterococcus cloacae ATCC 13047. The lack of antagonism between these antibacterial agents in checkerboard and time-kill assays suggested that combining amoxicillin with chloramphenicol can provide an improved therapy in comparison to the use of each antibiotic individually. The study indicates the potential beneficial value of combining amoxicillin and chloramphenicol in the treatment of microbial infections in clinical settings.
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Inhibitors of N-glycosylation as a potential tool for analysis of the mechanism of action and cellular localisation of glycoprotein P

100%
Wojtowicz K., Szaflarski W., Januchowski R., Zawierucha P., Nowicki M., Zabel M.
Acta Biochimica Polonica
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2012
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vol. 59
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issue 4
445-450
EN
Multidrug resistance has for many years attracted attention of numerous investigators. Attempts have also been made to increase efficiency of anti-neoplastic therapy. For this reason, most of efforts have been devoted to analysing proteins engaged in the mechanism of multidrug resistance such as the N-glycosylated membrane protein glycoprotein P. Interestingly, glycosylation probably plays a significant role in the intracellular location and activity of modified proteins. Inhibitors of glycosylation have been demonstrated to alter the activity of glycoprotein P in various ways, depending on the cell line examined. These inhibitors markedly reduce multidrug resistance of cancer cells, thus promoting success of anti-neoplastic therapy. Here, we review the basic knowledge on N-glycosylation inhibitors, their effect on glycoprotein P and their therapeutic potential.
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The ability to overcome multidrug resistance of tumor cell lines by novel acridine cytostatics with condensed heterocyclic rings.

100%
Bontemps-Gracz M. M., Kupiec A., Antonini I., Borowski E.
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EN
Two recently synthesized groups of acridine cytostatics containing fused heterocyclic ring(s): pyrazoloacridines (PAC) and pyrazolopyrimidoacridines (PPAC) were tested in regard to their in vitro cytotoxic activity towards a panel of sensitive and resistant human tumor cell lines. The obtained results corroborate our earlier hypothesis on the essential role of heterocyclic ring fused to the acridine moiety in the ability of acridine cytostatics to overcome multidrug resistance of tumor cells. The presence, location and kind of substituents considerably influenced both the cytotoxic activity of the derivatives and their ability to overcome multidrug resistance. The same factors also affected the cytostatics ability to differentiate between tumor cell lines with various types of drug exporting pumps.
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Comparative studies on cell stimulatory, permeabilizing and toxic effects induced in sensitive and multidrug resistant fungal strains by amphotericin B (AMB) and N-methyl-N-D-fructosyl amphotericin B methyl ester (MFAME).

100%
Szlinder-Richert J., Cybulska B., Grzybowska J., Borowski E., Prasad R.
Acta Biochimica Polonica
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2000
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vol. 47
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issue 1
133-140
EN
N-Methyl-N-D-fructosyl-amphotericin B methyl ester (MFAME) is a new derivative of amphotericin B, which is characterised by low toxicity to mammalian cells and good solubility in water of its salts. The antifungal activity and effects of MFAME towards Candida albicans and Saccharomyces cerevisiae multidrug resistant MDR(+) and sensitive MDR(-) strains was compared with those of parent compound. The results obtained indicate that MDR(+) S. cerevisiae was sensitive to MFAME as well as to AMB. MFAME exhibited the same effects on fungal cells studied as parent antibiotic. The two antibiotics, depending on the dose applied induced cell stimulation, K+ efflux, and/or had a toxic effect.
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Transport of glutathione-conjugates in human erythrocytes.

100%
Sharma R., Awasthi S., Zimniak P., Awasthi Y. C.
Acta Biochimica Polonica
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2000
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vol. 47
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issue 3
751-762
EN
The last step of detoxification of both endogenous and environmental toxicants is typically a conjugation that produces a bulky hydrophilic molecule. The excretion of such conjugates out of cells is of sufficient biological importance to have led to the evolution of ATP-driven export pumps for this purpose. The substrate specificity of such transporters is broad, and in some cases it has been shown to include not only anionic conjugates but also neutral or weakly cationic drugs. In the present article, we review the molecular identity, functional and structural characteristics of these pumps, mainly on the example of human erythrocytes, and discuss their physiological role in detoxification and in the multidrug resistance phenotype of cancer cells.
8
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Transport functions and physiological significance of 76 kDa Ral-binding GTPase activating protein (RLIP76).

88%
Awasthi S., Sharma R., Yang Y., Singhal S. S., Pikula S., Bandorowicz-Pikula J., Singh S. V., Zimniak P., Awasthi Y. C.
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vol. 49
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issue 4
855-867
EN
We have recently demonstrated that a previously known Ral-binding GTPase activating protein, RLIP76, can also catalyze ATP-dependent transport of various structurally unrelated xeno- and endobiotics irrespective of their net charge (Awasthi et al., 2000, Biochemistry, 39: 9327). RLIP76 is a non-ATP binding cassette (ABC) protein but it has two ATP-binding sites and shows basal ATPase activity which is stimulated in the presence of its transport substrates (allocrites) such as doxorubicin (DOX) and S-(2,4-dinitrophenyl) glutathione (DNP-SG). Proteoliposomes reconstituted with purified RLIP76 catalyze ATP-dependent, saturable transport of DOX, as well as of glutathione-conjugates including leukotrienes (LTC4) and the GSH-conjugate of 4-hydroxynonenal (GS-HNE). In erythrocytes the majority of transport activity for DOX, GS-HNE, and LTC4 is accounted for by RLIP76. Cells exposed to mild oxidative stress show a rapid and transient induction of RLIP76 resulting in an increased efflux of GS-HNE and acquire resistance to oxidative stress mediated toxicity and apoptosis. Cells transfected with RLIP76 acquire resistance to DOX through increased efflux of the drug suggesting its possible role in the mechanisms of drug-resistance. In this article, we discuss the significance of transport functions of RLIP76 highlighting its role in the defense mechanisms against oxidative injury, and modulation of signaling mechanisms.
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Anti-staphylococcal potential of Callistemon rigidus

88%
Gomber C., Saxena S.
Open Medicine
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2007
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vol. 2
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issue 1
79-88
EN
The last decade witnessed the emergence of Staphylococcus aureus- a versatile human pathogen, as a deadly superbug. The enormous genetic plasticity of the organism assists it to endlessly evolve resistance mechanisms against existing anti-infectives thus necessitating the need to control the spread of resistant staphylococcal isolates in hospitals and health care settings. This in turn demands the incessant exploration of newer biological matrices in search of diverse chemical entities with novel drug targets. Since time immemorial higher plants continue to be the best source of newer compounds with high therapeutic potential. Lead fractions from same or different plants can be developed into effective antibacterial polyherbal formulations. A lead fraction from methanolic extract of leaves of Callistemon rigidus exhibited a dose dependent antistaphylococcal activity during in vitro agar well assay against a panel of twenty seven clinical multidrug resistant S. aureus isolates. Further, minimal inhibitory concentration (MIC) evaluation by in vitro 96-well microplate based assay established a MIC range of 1.25–80 μg/ml as compared to 5–320 μg/ml of positive control, Cefuroxime sodium. The MIC50 and MIC90 of the methanolic lead fraction were 5 μg/ml and 40 μg/ml respectively. The present study thus signifies the vast potential of the lead fraction from Callistemon rigidus for future development into a herbal drug/ formulation and to impede global health crisis due to multidrug resistant Staphylococcus aureus.
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The effect of new non-cross resistant antitumour agents on the energy state of human erythrocytes

88%
Nowak R., Baranowska-Bosiacka I., Stefańska B., Machaliński B., Hłyńczak A. J., Tarasiuk J.
Acta Biochimica Polonica
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2005
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vol. 52
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issue 4
953-957
EN
Multidrug resistance (MDR) of tumour cells is related to the overexpression of ATP-dependent pumps responsible for the active efflux of antitumour agents out of resistant cells. Benzoperimidine and anthrapyridone compounds exhibit comparable cytotoxic activity against sensitive and MDR tumour cells. They diffuse extremely rapidly across the plasma membrane and render the ATP-dependent efflux inefficient. Such uptake could disturb an energy metabolism of normal cells possessing an elevated level of ATP-dependent proteins, especially erythrocytes having a high level of the MRP1, MRP4 and MRP5 proteins. In this study the effect of five antitumour agents: benzoperimidine (BP1), anthrapyridones (CO1, CO7) and reference drugs used in the clinic: doxorubicin (DOX) and pirarubicin (PIRA), on the energetic state in human erythrocytes has been examined. These compounds have various types of structure and kinetics of cellular uptake (slow - DOX, CO7, moderate - PIRA, fast - BP1, CO1) resulting in their different ability to saturate ATP-dependent transporters. The energetic state of erythrocytes was examined by determination of purine nucleotide contents (ATP, ADP, AMP), NAD+ and values of adenylate energy charge (AEC) using an HPLC method. It was found that the level of nucleotides as well as the AEC value of erythrocytes were not changed during 24 h of incubation with these agents independently of their structure and ability to saturate ATP-dependent pumps. This is a very promising result in view of their potential use in the clinic as antitumour drugs against multidrug resistant cancers.
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Role of NAD(P)H:quinone oxidoreductase (NQO1) in apoptosis induction by aziridinylbenzoquinones RH1 and MeDZQ

88%
Nemeikaitė-Čėnienė A., Dringelienė A., Šarlauskas J., Čėnas N.
Acta Biochimica Polonica
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2005
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vol. 52
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issue 4
937-942
EN
We aimed to characterize the role of NAD(P)H:quinone oxidoreductase (NQO1) in apoptosis induction by antitumour quinones RH1 (2,5-diaziridinyl-3-hydroxymethyl-6-methyl-1,4-benzoquinone) and MeDZQ (2,5-dimethyl-3,6-diaziridinyl-1,4-benzoquinone). Digitonin-permeabilized FLK cells catalyzed NADPH-dependent single- and two-electron reduction of RH1 and MeDZQ. At equitoxic concentrations, RH1 and MeDZQ induced apoptosis more efficiently than the nonalkylating duroquinone or H2O2. The antioxidant N,N'-diphenyl-p-phenylene diamine, desferrioxamine, and the inhibitor of NQO1 dicumarol, protected against apoptosis induction by all compounds investigated, but to a different extent. The results of multiparameter regression analysis indicate that RH1 and MeDZQ most likely induce apoptosis via NQO1-linked formation of alkylating species but not via NQO1-linked redox cycling.
12
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Induction of the multixenobiotic/multidrug resistance system in HeLa cells in response to imidazolium ionic liquids

75%
Rusiecka I., Składanowski A.
Acta Biochimica Polonica
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2011
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vol. 58
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issue 2
187-192
EN
The multixenobiotic/multidrug resistance (MXR/MDR) system controls transport of foreign molecules across the plasma membrane as a preventive measure before toxicity becomes apparent. The system consists of an efflux pump, ABCB1, and/or a member of the ABCC family. Ionic liquids are broadly used solvents with several unique properties such as wide liquid range, negligible vapor pressure, good thermal and chemical stability and extraordinary dissolution properties for organic and inorganic compounds. Ionic liquids containing imidazolium ring are frequently used as solvents in drug synthesis. Constitutive and induced amounts of ABCB1 and ABCC1 proteins were estimated here by Western blotting and quantified by flow cytometry in HeLa cells exposed to three homologous 1-alkyl-3-methylimidazolium and one benzyl ring substituted salts. Aliphatic substituents in position 1 of the salts caused a weak toxicity but 1-benzyl ring was strongly toxic. An 8-day long treatment with 10-4 M 1-hexyl-3-methylimidazolium chloride resulted in an about 1.5-fold increase of ABCB1 level and over 2-fold increase of ABCC1 level. The amounts of both investigated ABC-proteins were linearly dependent on the length of the imidazolium ring side chain. Such distinctive changes of the amount of MXR/MDR proteins measured in cultured cells may be a useful marker when screening for potential toxicity of various chemicals.
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Induction of the multixenobiotic/multidrug resistance system in various cell lines in response to perfluorinated carboxylic acids

75%
Rusiecka I., Składanowski A.
Acta Biochimica Polonica
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2008
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vol. 55
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issue 2
329-337
EN
The multixenobiotic resistance (closely related to multidrug resistance) system controls transport across the plasma membrane as a defense against toxic molecules. Multixenobiotic resistance system consists of an efflux pump, ABCB1 (also named P-glycoprotein, P-gp), and/or a molecule of the ABCC family (also named multiple resistance associated protein, MRP). ABCB1 is able to increase efflux of many low-molecular foreign molecules. Measuring system induction may be used as a biomarker of cell/organism exposure to foreign substances. Various established cell lines were tested for constitutive and induced multixenobiotic resistance proteins by Western blotting immunodetection. The pumping function was indirectly assayed with Rhodamine B by visualization of cell fluorescence in the presence of verapamil. Changes in ABC proteins were measured by flow cytometry after exposition to various perfluorinated carboxylic acids. MCF7 and HeLa cells were found to contain the highest constitutive level of both ABCB1 and ABCC1. HEK293 exhibited much less ABCB1 and no activity of pumping out Rhodamine B. The pumping activity was found to be related to the amount of the cell-type specific 170 kDa ABCB1 protein. An 8-day exposure to 10-4 M perfluorononanoic acid resulted in about 2-2.5-fold increase of ABCB1 level. That was confirmed also for short times by flow cytometry of cells exposed to perfluorinated acids and its natural congeners. Both ABCB1- and ABCC1-related fluorescence increased along with the carbon chain in acids from C6 up to C9 and decreased for C10. Measuring of multixenobiotic resistance changes in vitro induced by chemicals may be a convenient test for screening for their potential toxicity.
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