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Combination screening in vitro identifies synergistically acting KP372-1 and cytarabine against 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, Cancer Pharmacology and Computational Medicine.
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 Medical Sciences, Biochemial structure and function.
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2016 (English)In: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 118, 40-49 p.Article in journal (Refereed) Published
Abstract [en]

Cytogenetic lesions often alter kinase signaling in acute myeloid leukemia (AML) and the addition of kinase inhibitors to the treatment arsenal is of interest. We have screened a kinase inhibitor library and performed combination testing to find promising drug-combinations for synergistic killing of AML cells. Cytotoxicity of 160 compounds in the library InhibitorSelect (TM) 384-Well Protein Kinase Inhibitor I was measured using the fluorometric microculture cytotoxicity assay (FMCA) in three AML cell lines. The 15 most potent substances were evaluated for dose-response. The 6 most cytotoxic compounds underwent combination synergy analysis based on the FMCA readouts after either simultaneous or sequential drug addition in AML cell lines. The 4 combinations showing the highest level of synergy were evaluated in 5 primary AML samples. Synergistic calculations were performed using the combination interaction analysis package COMBIA, written in R, using the Bliss independence model. Based on obtained results, an iterative combination search was performed using the therapeutic algorithmic combinatorial screen (TACS) algorithm. Of 160 substances, cell survival was <= 50% at <0.5 mu M for Cdk/Crk inhibitor, KP372-1, synthetic fascaplysin, herbimycin A, PDGF receptor tyrosine kinase inhibitor IV and reference-drug cytarabine. KP372-1, synthetic fascaplysin or herbimycin A obtained synergy when combined with cytarabine in AML cell lines MV4-11 and HL-60. KP372-1 added 24 h before cytarabine gave similar results in patient cells. The iterative search gave further improved synergy between cytarabine and KP372-1. In conclusion, our in vitro studies suggest that combining KP372-1 and cytarabine is a potent and synergistic drug combination in AML.

Place, publisher, year, edition, pages
2016. Vol. 118, 40-49 p.
Keyword [en]
Acute myeloid leukemia, Drug development, Tyrosine kinase inhibitor, Synergy, KP372-1
National Category
Pharmaceutical Sciences Cancer and Oncology Hematology
Identifiers
URN: urn:nbn:se:uu:diva-308649DOI: 10.1016/j.bcp.2016.08.020ISI: 000386105300005PubMedID: 27565890OAI: oai:DiVA.org:uu-308649DiVA: diva2:1050598
Available from: 2016-11-29 Created: 2016-11-29 Last updated: 2017-01-03Bibliographically approved

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Österroos, AlbinKashif, MuhammadHaglund, CarolineBlom, KristinHöglund, MartinAndersson, ClaesGustafsson, Mats G.Eriksson, Anna
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