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Drug screen in patient cells suggests quinacrine to be repositioned for treatment of acute myeloid leukemia
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
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2015 (English)In: Blood Cancer Journal, ISSN 2044-5385, E-ISSN 2044-5385, Vol. 5, e307Article in journal (Refereed) Published
Abstract [en]

To find drugs suitable for repositioning for use against leukemia, samples from patients with chronic lymphocytic, acute myeloid and lymphocytic leukemias as well as peripheral blood mononuclear cells (PBMC) were tested in response to 1266 compounds from the LOPAC1280 library (Sigma). Twenty-five compounds were defined as hits with activity in all leukemia subgroups (<50% cell survival compared with control) at 10 mu M drug concentration. Only one of these compounds, quinacrine, showed low activity in normal PBMCs and was therefore selected for further preclinical evaluation. Mining the NCI-60 and the NextBio databases demonstrated leukemia sensitivity and the ability of quinacrine to reverse myeloid leukemia gene expression. Mechanistic exploration was performed using the NextBio bioinformatic software using gene expression analysis of drug exposed acute myeloid leukemia cultures (HL-60) in the database. Analysis of gene enrichment and drug correlations revealed strong connections to ribosomal biogenesis nucleoli and translation initiation. The highest drug-drug correlation was to ellipticine, a known RNA polymerase I inhibitor. These results were validated by additional gene expression analysis performed in-house. Quinacrine induced early inhibition of protein synthesis supporting these predictions. The results suggest that quinacrine have repositioning potential for treatment of acute myeloid leukemia by targeting of ribosomal biogenesis.

Place, publisher, year, edition, pages
2015. Vol. 5, e307
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Cancer and Oncology
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URN: urn:nbn:se:uu:diva-255299DOI: 10.1038/bcj.2015.31ISI: 000354102400008PubMedID: 25885427OAI: oai:DiVA.org:uu-255299DiVA: diva2:824347
Available from: 2015-06-22 Created: 2015-06-15 Last updated: 2017-12-04Bibliographically approved

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Eriksson, AnnaHassan, Sadia BashirGullbo, JoachimJarvius, MalinNygren, PeterFryknäs, MårtenHöglund, MartinLarsson, Rolf

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Eriksson, AnnaHassan, Sadia BashirGullbo, JoachimJarvius, MalinNygren, PeterFryknäs, MårtenHöglund, MartinLarsson, Rolf
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HaematologyDepartment of Medical SciencesCancer Pharmacology and Computational MedicineExperimental and Clinical Oncology
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