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      ABCC6 plays a significant role in the transport of nilotinib and dasatinib, and contributes to TKI resistance in vitro, in both cell lines and primary patient mononuclear cells

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          Abstract

          ATP Binding Cassette family efflux proteins ABCB1 and ABCG2 have previously been demonstrated to interact with Tyrosine Kinase Inhibitors (TKIs); however, evidence for the interaction of other potentially relevant drug transporters with TKIs is lacking. Through Taqman transporter array technology we assessed the impact of nilotinib on mRNA expression of ABC transporters, with ABCC6 identified as a transporter of interest. Additionally, increased expression of ABCC6 mRNA was observed during in vitro development of nilotinib resistance in BCR-ABL1-expressing cell lines. K562 cells exposed to gradually increasing concentrations of nilotinib (to 2 μM) expressed up to 57-fold higher levels of ABCC6 mRNA when compared with control cells ( p = 0.002). Analogous results were observed in nilotinib resistant K562-Dox cells (up to 33-fold higher levels of ABCC6, p = 0.002). IC50 experiments were conducted on patient mononuclear cells in the absence and presence of three ABCC6 inhibitors: indomethacin, probenecid and pantoprazole. Results demonstrated that all three inhibitors significantly reduced nilotinib IC50 ( p<0.001) indicating ABCC6 is likely involved in nilotinib transport. Cell line data confirmed these findings. Similar results were obtained for dasatinib, but not imatinib. Combined, these studies suggest that nilotinib and dasatinib are likely substrates of ABCC6 and to our knowledge, this is the first report of ABCC6 involvement in TKI transport. In addition, ABCC6 overexpression may also contribute to nilotinib and dasatinib resistance in vitro. With nilotinib and dasatinib now front line therapy options in the treatment of CML, concomitant administration of ABCC6 inhibitors may present an attractive option to enhance TKI efficacy.

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          Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction.

          A new method of total RNA isolation by a single extraction with an acid guanidinium thiocyanate-phenol-chloroform mixture is described. The method provides a pure preparation of undegraded RNA in high yield and can be completed within 4 h. It is particularly useful for processing large numbers of samples and for isolation of RNA from minute quantities of cells or tissue samples.
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            Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells.

            The bcr-abl oncogene, present in 95% of patients with chronic myelogenous leukemia (CML), has been implicated as the cause of this disease. A compound, designed to inhibit the Abl protein tyrosine kinase, was evaluated for its effects on cells containing the Bcr-Abl fusion protein. Cellular proliferation and tumor formation by Bcr-Abl-expressing cells were specifically inhibited by this compound. In colony-forming assays of peripheral blood or bone marrow from patients with CML, there was a 92-98% decrease in the number of bcr-abl colonies formed but no inhibition of normal colony formation. This compound may be useful in the treatment of bcr-abl-positive leukemias.
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              Discovery of N-(2-chloro-6-methyl- phenyl)-2-(6-(4-(2-hydroxyethyl)- piperazin-1-yl)-2-methylpyrimidin-4- ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays.

              A series of substituted 2-(aminopyridyl)- and 2-(aminopyrimidinyl)thiazole-5-carboxamides was identified as potent Src/Abl kinase inhibitors with excellent antiproliferative activity against hematological and solid tumor cell lines. Compound 13 was orally active in a K562 xenograft model of chronic myelogenous leukemia (CML), demonstrating complete tumor regressions and low toxicity at multiple dose levels. On the basis of its robust in vivo activity and favorable pharmacokinetic profile, 13 was selected for additional characterization for oncology indications.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: Investigation
                Role: ConceptualizationRole: Writing – review & editing
                Role: ConceptualizationRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                31 January 2018
                2018
                : 13
                : 1
                : e0192180
                Affiliations
                [1 ] Cancer Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, South Australia
                [2 ] School of Medicine, Faculty of Health Sciences, University of Adelaide, Adelaide, South Australia
                [3 ] Division of Haematology, SA Pathology, Adelaide, South Australia
                [4 ] School of Paediatrics, Faculty of Health Sciences, University of Adelaide, Adelaide, South Australia
                [5 ] School of Biological Sciences, Faculty of Sciences, University of Adelaide, Adelaide, South Australia
                Istituto di Genetica Molecolare, ITALY
                Author notes

                Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: LNE has no conflict of interest to declare. DLW receives honoraria and research funds from Novartis Pharmaceuticals and is a member of Advisory Boards for Novartis. TPH receives honoraria and research funds from Novartis Pharmaceuticals, BMS and Ariad and is a member of Advisory Boards for Novartis, BMS and Ariad. However, Novartis, BMS and Ariad had no role in the design of the study, collection and analysis of data nor the decision to publish. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

                Author information
                http://orcid.org/0000-0003-1912-7602
                Article
                PONE-D-17-38149
                10.1371/journal.pone.0192180
                5792028
                29385210
                8659932b-43c7-4947-8fb9-9dbcfc515ea0
                © 2018 Eadie et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 25 October 2017
                : 17 January 2018
                Page count
                Figures: 5, Tables: 1, Pages: 18
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100000926, Leukaemia Foundation;
                Award ID: PhD Scholarship
                Award Recipient :
                LNE performed this research during her doctoral studies which were funded by the Leukaemia Foundation of Australia (LFA). However, the LFA had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Biochemistry
                Enzymology
                Enzyme Inhibitors
                Kinase Inhibitors
                Research and Analysis Methods
                Bioassays and Physiological Analysis
                Transport Inhibition Assay
                Biology and Life Sciences
                Genetics
                Gene Expression
                Medicine and Health Sciences
                Health Care
                Patients
                Biology and Life Sciences
                Molecular Biology
                Molecular Biology Techniques
                Molecular Biology Assays and Analysis Techniques
                Gene Expression and Vector Techniques
                Hyperexpression Techniques
                Research and Analysis Methods
                Molecular Biology Techniques
                Molecular Biology Assays and Analysis Techniques
                Gene Expression and Vector Techniques
                Hyperexpression Techniques
                Biology and Life Sciences
                Molecular Biology
                Molecular Biology Techniques
                Artificial Gene Amplification and Extension
                Polymerase Chain Reaction
                Research and Analysis Methods
                Molecular Biology Techniques
                Artificial Gene Amplification and Extension
                Polymerase Chain Reaction
                Biology and Life Sciences
                Biochemistry
                Enzymology
                Enzyme Inhibitors
                Kinase Inhibitors
                Tyrosine Kinase Inhibitors
                Biology and Life Sciences
                Biochemistry
                Proteins
                Protein Interactions
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

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                Uncategorized

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