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Berlin Brandenburg

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  • 1
    Language: English
    In: Journal of Inorganic Biochemistry, Nov, 2012, Vol.116, p.1(10)
    Description: To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.jinorgbio.2012.07.010 Byline: Ganna V. Kalayda, Christina H. Wagner, Ulrich Jaehde Keywords: Cisplatin resistance; Cisplatin uptake; Copper transporter 1; Fluorescent cisplatin analogue Abstract: Defects in intracellular accumulation of the antitumour drug cisplatin are a commonly observed feature in the cells selected for cisplatin resistance. Copper transporter 1 (CTR1) has been suggested to play an important role in drug uptake and resistance. Here, we describe a detailed investigation of the involvement of CTR1 in cisplatin uptake and its relevance for cisplatin resistance using a well characterised sensitive/cisplatin-resistant cell line pair: A2780 human ovarian carcinoma cell line and its cisplatin-resistant variant A2780cis. A2780cis cells showed decreased cisplatin accumulation and lower CTR1 expression compared to A2780 cells. Co-incubation with copper sulphate affected neither cisplatin accumulation (determined by flameless atomic absorption spectrometry) nor its cytotoxicity (determined using an MTT-assay, MTT=3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide). In both cell lines, CTR1 was localised near the nucleus as found using confocal fluorescence microscopy. The steady-state localisation of the protein in perinuclear region appears to involve its continuous endocytosis from cell surface. In contrast to copper, cisplatin exposure had no influence on the sub cellular localisation of CTR1. Co-localisation between CTR1 and a fluorescent cisplatin analogue labelled with carboxyfluorescein-diacetate could be observed in vesicular structures when continuous retrieval of the protein from cell membrane was inhibited. Our results strongly suggest that CTR1 mediates cisplatin uptake in the cell lines studied. Upon its transport across the plasma membrane by CTR1 the platinum drug is likely to be internalised along with the protein. Our findings imply that reduced CTR1 expression accounts for decreased cisplatin accumulation and represents one of the determinants of cisplatin resistance in A2780cis cell line. Article History: Received 24 October 2011; Revised 9 July 2012; Accepted 9 July 2012
    Keywords: Cells (Biology) ; Cisplatin ; Carcinoma
    ISSN: 0162-0134
    Source: Cengage Learning, Inc.
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  • 2
    In: ELECTROPHORESIS, February 2015, Vol.36(4), pp.509-517
    Description: Pt‐based anticancer drugs, such as cisplatin, are known to undergo several (bio‐)chemical transformation steps after administration. Hydrolysis and adduct formation with small nucleophiles and larger proteins are their most relevant reactions on the way to the final reaction site (DNA), but there are still many open questions regarding the identity and pharmacological relevance of various proposed adducts and intermediates. Furthermore, the role of buffer components or additives, which are inevitably added to samples during any type of analytical measurement, has been frequently neglected in previous studies. Here, we report on adduct formation reactions of the fluorescent cisplatin analogue carboxyfluorescein diacetate platinum (CFDA‐Pt) in commonly used buffers and cell culture medium. Our results indicate that chelation reactions with noninnocent buffers (e.g., Tris) and components of the cell culture/cell lysis medium must be taken into account when interpreting results. Adduct formation kinetics was followed up to 60 h at nanomolar concentrations of CFDA‐Pt by using CE‐LIF. CE‐MS enabled the online identification of such unexpected adducts down to the nanomolar concentration range. By using an optimized sample preparation strategy, unwanted adducts can be avoided and several fluorescent adducts of CFDA‐Pt are detectable in sensitive and cisplatin‐resistant cancer cell lines. By processing samples rapidly after incubation, we could even identify the initial, but transient, Pt species in the cells as deacetylated CFDA‐Pt with unaltered complexing environment at Pt. Overall, the proposed procedure enables a very sensitive and accurate analysis of low molecular mass Pt species in cancer cells, involving a fast CE‐LIF detection within 5 min.
    Keywords: Cancer Cell Lines ; Ce‐Lif ; Fluorescent Cisplatin Analogue ; Platinum Adducts
    ISSN: 0173-0835
    E-ISSN: 1522-2683
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  • 3
    Language: English
    In: Electrophoresis, 2018, Vol.39(12)
    Description: Byline: Sandra Kotz, Maximilian Kullmann, Ganna V. Kalayda, Nadine Dyballa-Rukes, Ulrich Jaehde, Sabine Metzger ***** No abstract is available for this article. *****
    Keywords: Ovarian Cancer ; Antineoplastic Agents
    ISSN: 0173-0835
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  • 4
    Language: English
    In: Electrophoresis, 2015, Vol.36(21), pp.2811-2819
    Description: Cisplatin is one of the most widely used anticancer agents, but a major problem for successful chemotherapy is the development of drug resistance of tumor cells against cisplatin. Resistance to cisplatin is a multifactorial problem. A method to detect and identify intracellular cisplatin–protein adducts was developed using a fluorescent carboxyfluorescein‐diacetate‐labeled cisplatin analogue (CFDA–cisplatin), 2DE, and ESI‐MS/MS. We identified several CFDA–cisplatin–protein adducts including members of the protein disulfide isomerase family (PDI). These are the first results of the detection of intracellular CFDA–cisplatin–protein adducts, which may help to understand the resistance mechanism of cisplatin. ; p. 2811-2819.
    Keywords: Fluorescence ; Drug Resistance ; Cisplatin ; Drug Therapy ; Two-Dimensional Gel Electrophoresis ; Neoplasm Cells ; Protein Disulfide-Isomerase
    ISSN: 0173-0835
    Source: AGRIS (Food and Agriculture Organization of the United Nations)
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  • 5
    In: ELECTROPHORESIS, November 2015, Vol.36(21-22), pp.2811-2819
    Description: Cisplatin is one of the most widely used anticancer agents, but a major problem for successful chemotherapy is the development of drug resistance of tumor cells against cisplatin. Resistance to cisplatin is a multifactorial problem. A method to detect and identify intracellular cisplatin–protein adducts was developed using a fluorescent carboxyfluorescein‐diacetate‐labeled cisplatin analogue (CFDA–cisplatin), 2DE, and ESI‐MS/MS. We identified several CFDA–cisplatin–protein adducts including members of the protein disulfide isomerase family (PDI). These are the first results of the detection of intracellular CFDA–cisplatin–protein adducts, which may help to understand the resistance mechanism of cisplatin.
    Keywords: Carboxyfluorescein‐Diacetate‐Labeled Cisplatin Analogue ; Cisplatin ; Cisplatin–Protein Adducts ; Protein Marker Grid ; Two‐Dimensional Gel Electrophoresis
    ISSN: 0173-0835
    ISSN: ELECTROPHORESIS
    E-ISSN: 1522-2683
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  • 6
    Language: English
    In: Electrophoresis, November 2015, Vol.36(21-22), pp.2811-2819
    Description: Cisplatin is one of the most widely used anticancer agents, but a major problem for successful chemotherapy is the development of drug resistance of tumor cells against cisplatin. Resistance to cisplatin is a multifactorial problem. A method to detect and identify intracellular cisplatin-protein adducts was developed using a fluorescent carboxyfluorescein-diacetate-labeled cisplatin analogue (CFDA-cisplatin), 2DE, and ESI-MS/MS. We identified several CFDA-cisplatin-protein adducts including members of the protein disulfide isomerase family (PDI). These are the first results of the detection of intracellular CFDA-cisplatin-protein adducts, which may help to understand the resistance mechanism of cisplatin.
    Keywords: Carboxyfluorescein-Diacetate-Labeled Cisplatin Analogue ; Cisplatin ; Cisplatin-Protein Adducts ; Protein Marker Grid ; Two-Dimensional Gel Electrophoresis
    ISSN: 01730835
    E-ISSN: 1522-2683
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  • 7
    In: ELECTROPHORESIS, June 2018, Vol.39(12), pp.1488-1496
    Description: Intracellular binding of cisplatin to proteins has been associated with acquired resistance to chemotherapy. In our previous study we established an analytical method for the identification of intracellular cisplatin‐binding proteins. The method used a fluorescent carboxyfluorescein‐diacetate‐labeled cisplatin analogue (CFDA‐cisplatin), two‐dimensional gel electrophoresis (2DE) and mass spectrometry, which allows detecting and identifying intracellular CFDA‐cisplatin‐containing protein adducts in the acidic pH range (pH 4–7). Based on this analytical method we extended the identification of intracellular cisplatin‐protein adducts to the alkaline pH range (pH 6–10) giving chance to discover new important binding partners. 2DE analysis of alkaline proteins is challenging due to the difficult separation of basic proteins during the isoelectric focusing (IEF). The establishment of an optimized IEF protocol for basic proteins enabled us to identify several intracellular CFDA‐cisplatin‐binding proteins including enzymes of the glucose and serine metabolism like alpha enolase and D‐3‐phosphoglycerate 1‐dehydrogenase.
    Keywords: Alkaline Ph‐Range ; Cfda‐Cisplatin ; Cisplatin ; Two‐Dimensional Gel Electrophoresis
    ISSN: 0173-0835
    E-ISSN: 1522-2683
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  • 8
    Language: English
    In: Cancer Chemotherapy and Pharmacology, 2016, Vol.77(6), pp.1103-1124
    Description: Platinum-based drugs cisplatin, carboplatin and oxaliplatin are widely used in the therapy of human neoplasms. Their clinical success is, however, limited due to severe side effects and intrinsic or acquired resistance to the treatment. Much effort has been put into the development of new platinum anticancer complexes, but none of them has reached worldwide clinical application so far. Nedaplatin, lobaplatin and heptaplatin received only regional approval. Some new platinum complexes and platinum drug formulations are undergoing clinical trials. Here, we review the main classes of new platinum drug candidates, such as sterically hindered complexes, monofunctional platinum drugs, complexes with biologically active ligands, trans-configured and polynuclear platinum complexes, platinum(IV) prodrugs and platinum-based drug delivery systems. For each class of compounds, a detailed overview of the mechanism of action is given, the cytotoxicity is compared to that of the clinically used platinum drugs, and the clinical perspectives are discussed. A critical analysis of lessons to be learned is presented. Finally, a general outlook regarding future directions in the field of new platinum drugs is given.
    Keywords: Platinum drugs ; Resistance ; Toxicity ; Clinical perspective ; Future directions
    ISSN: 0344-5704
    E-ISSN: 1432-0843
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  • 9
    Language: English
    In: PLoS ONE, 01 January 2017, Vol.12(7), p.e0181081
    Description: The efficacy of cisplatin-based chemotherapy in cancer is limited by the occurrence of innate and acquired drug resistance. In order to better understand the mechanisms underlying acquired cisplatin resistance, we have compared the adenocarcinoma-derived non-small cell lung cancer (NSCLC) cell line A549 and its cisplatin-resistant sub-line A549rCDDP2000 with regard to cisplatin resistance mechanisms including cellular platinum accumulation, DNA-adduct formation, cell cycle alterations, apoptosis induction and activation of key players of DNA damage response. In A549rCDDP2000 cells, a cisplatin-induced G2/M cell cycle arrest was lacking and apoptosis was reduced compared to A549 cells, although equitoxic cisplatin concentrations resulted in comparable platinum-DNA adduct levels. These differences were accompanied by changes in the expression of proteins involved in DNA damage response. In A549 cells, cisplatin exposure led to a significantly higher expression of genes coding for proteins mediating G2/M arrest and apoptosis (mouse double minute 2 homolog (MDM2), xeroderma pigmentosum complementation group C (XPC), stress inducible protein (SIP) and p21) compared to resistant cells. This was underlined by significantly higher protein levels of phosphorylated Ataxia telangiectasia mutated (pAtm) and p53 in A549 cells compared to their respective untreated control. The results were compiled in a preliminary model of resistance-associated signaling alterations. In conclusion, these findings suggest that acquired resistance of NSCLC cells against cisplatin is the consequence of altered signaling leading to reduced G2/M cell cycle arrest and apoptosis.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 10
    Language: English
    In: JBIC Journal of Biological Inorganic Chemistry, 2013, Vol.18(2), pp.165-174
    Description: Decreased cellular accumulation of cisplatin is a frequently observed mechanism of resistance to the drug. Beside passive diffusion, several cellular proteins using ATP hydrolysis as an energy source are assumed to be involved in cisplatin transport in and out of the cell. This investigation aimed at clarifying the contribution of intracellular ATP as an indicator of energy-dependent transport to cisplatin resistance using the A2780 human ovarian adenocarcinoma cell line and its cisplatin-resistant variant A2780cis. Depletion of intracellular ATP with oligomycin significantly decreased cellular platinum accumulation (measured by flameless atomic absorption spectrometry) in sensitive but not in resistant cells, and did not affect cisplatin efflux in both cell lines. Inhibition of Na + ,K + -ATPase with ouabain reduced platinum accumulation in A2780 cells but to a lesser extent compared with oligomycin. Western blot analysis revealed lower expression of Na + ,K + -ATPase α 1 subunit in resistant cells compared with sensitive counterparts. The basal intracellular ATP level (determined using a bioluminescence-based assay) was significantly higher in A2780cis cells than in A2780 cells. Our results highlight the importance of ATP-dependent transport, among other processes mediated by Na + ,K + -ATPase, for cisplatin influx in sensitive cells. Cellular platinum accumulation in resistant cells is reduced and less dependent on energy sources, which may partly result from Na + ,K + -ATPase downregulation. Our data suggest the involvement of other ATP-dependent processes beside those regulated by Na + ,K + -ATPase. Higher basal ATP level in cisplatin-resistant cells, which appears to be a consequence of enhanced mitochondrial ATP production, may represent a survival mechanism established during development of resistance.
    Keywords: Cisplatin resistance ; ATP ; Oligomycin ; Na,K-ATPase
    ISSN: 0949-8257
    E-ISSN: 1432-1327
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