Synergistic suppression of t(8;21)-positive leukemia cell growth by combining oridonin and MAPK1/ERK2 inhibitors
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Pavel Spirin1,*, Timofey Lebedev1,*, Natalia Orlova1,*, Alexey Morozov1, Nadezhda Poymenova1, Sergey E. Dmitriev1,2, Anton Buzdin1,3,4, Carol Stocking5, Olga Kovalchuk6,7 and Vladimir Prassolov1
1Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia
2Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119992, Russia
3Dmitry Rogachev Federal Research Center of Pediatric Hematology, Oncology and Immunology, Moscow 117997, Russia
4National Research Centre “Kurchatov Institute”, Centre for Convergence of Nano-, Bio-, Information and Cognitive Sciences and Technologies, Moscow 123182, Russia
5Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany
6OncoFinder Ltd, Lethbridge, AB T1K7X8, Canada
7Department of Biological Sciences, University of Lethbridge, Lethbridge, AB T1K3M4, Canada
*These authors have contributed equally to this work
Pavel Spirin, email: firstname.lastname@example.org
Keywords: acute myeloid leukemia, signaling pathways, RUNX1-ETO, ERK2-inhibitors
Received: September 16, 2016 Accepted: April 18, 2017 Published: June 16, 2017
One of the most common chromosomal translocations in acute myeloid leukemia is t(8;21)(q22;q22), which results in the appearance of abnormal transcripts encoding for the fusion protein RUNX1-ETO. Therefore, this oncoprotein is considered to be a pertinent and promising target for treating t(8;21) leukemia. Previously, we have shown that downregulation of RUNX1-ETO leads to activation of intracellular signaling pathways enhancing cell survival and determined that the protein ERK2 can mediate activation of most of these pathways. Here we used a combination of oridonin (natural tetracycline diterpenoid), which has been shown to exhibit anti-RUNX1-ETO activity, and ERK2 kinase inhibitors. We found that treatment of leukemic t(8;21)-positive Kasumi-1 cells with oridonin cause decrease of phosphorylated ERK1/2. Treatment of these cells with ERK2 inhibitors makes them more sensitive to RUNX1-ETO inhibition with oridonin. Therefore we postulate that simultaneous inhibition of RUNX1-ETO and ERK2 cause synergistic effect on survival of leukemic cells.
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