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Synergistic suppression of t(8;21)-positive leukemia cell growth by combining oridonin and MAPK1/ERK2 inhibitors
- Source :
- Oncotarget
- Publication Year :
- 2016
-
Abstract
- // Pavel Spirin 1, * , Timofey Lebedev 1, * , Natalia Orlova 1, * , Alexey Morozov 1 , Nadezhda Poymenova 1 , Sergey E. Dmitriev 1, 2 , Anton Buzdin 1, 3, 4 , Carol Stocking 5 , Olga Kovalchuk 6, 7 and Vladimir Prassolov 1 1 Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia 2 Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119992, Russia 3 Dmitry Rogachev Federal Research Center of Pediatric Hematology, Oncology and Immunology, Moscow 117997, Russia 4 National Research Centre “Kurchatov Institute”, Centre for Convergence of Nano-, Bio-, Information and Cognitive Sciences and Technologies, Moscow 123182, Russia 5 Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany 6 OncoFinder Ltd, Lethbridge, AB T1K7X8, Canada 7 Department of Biological Sciences, University of Lethbridge, Lethbridge, AB T1K3M4, Canada * These authors have contributed equally to this work Correspondence to: Pavel Spirin, email: spirin.pvl@gmail.com Keywords: acute myeloid leukemia, signaling pathways, RUNX1-ETO, ERK2-inhibitors Received: September 16, 2016 Accepted: April 18, 2017 Published: June 16, 2017 ABSTRACT 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.
- Subjects :
- 0301 basic medicine
acute myeloid leukemia
03 medical and health sciences
0302 clinical medicine
Intracellular signaling pathways
hemic and lymphatic diseases
Medicine
MAPK1
business.industry
Cell growth
Kinase
Myeloid leukemia
medicine.disease
signaling pathways
Transplantation
Leukemia
030104 developmental biology
Oncology
030220 oncology & carcinogenesis
RUNX1-ETO
Immunology
ERK2-inhibitors
Cancer research
Stem cell
business
Research Paper
Subjects
Details
- ISSN :
- 19492553
- Volume :
- 8
- Issue :
- 34
- Database :
- OpenAIRE
- Journal :
- Oncotarget
- Accession number :
- edsair.doi.dedup.....bf6159582a8c75270568c518ccdd230c