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Oncotarget. 2017 Aug 24;8(44):77436-77452. doi: 10.18632/oncotarget.20497. eCollection 2017 Sep 29.

Oxidative stress-induced JNK/AP-1 signaling is a major pathway involved in selective apoptosis of myelodysplastic syndrome cells by Withaferin-A.

Author information

1
Markey Cancer Center and Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, KY 40536, USA.
2
Department of Internal Medicine, University of Kentucky, Lexington, KY 40536, USA.
3
Comprehensive Cancer Center and Department of Internal Medicine, Ohio State University, Columbus, OH 43210, USA.
4
Biostatistics Core, Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA.
5
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, OH 45229, USA.
6
Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY 40536, USA.
7
Department of Natural Products, National Institute of Pharmaceutical Research, S.A.S Nagar, Punjab 160062, India.
8
Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, KY 40536, USA.
9
Department of Laboratory Medicine, Kawasaki Medical School, Kurashiki, Okayama 701-0192, Japan.
10
Department of Pharmacology and Toxicology, and James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA.

Abstract

Myelodysplastic syndromes (MDS) are a diverse group of malignant clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, dysplastic cell morphology in one or more hematopoietic lineages, and a risk of progression to acute myeloid leukemia (AML). Approximately 50% of MDS patients respond to current FDA-approved drug therapies but a majority of responders relapse within 2-3 years. There is therefore a compelling need to identify potential new therapies for MDS treatment. We utilized the MDS-L cell line to investigate the anticancer potential and mechanisms of action of a plant-derived compound, Withaferin A (WFA), in MDS. WFA was potently cytotoxic to MDS-L cells but had no significant effect on the viability of normal human primary bone marrow cells. WFA also significantly reduced engraftment of MDS-L cells in a xenotransplantation model. Through transcriptome analysis, we identified reactive oxygen species (ROS)-activated JNK/AP-1 signaling as a major pathway mediating apoptosis of MDS-L cells by WFA. We conclude that the molecular mechanism mediating selective cytotoxicity of WFA on MDS-L cells is strongly associated with induction of ROS. Therefore, pharmacologic manipulation of redox biology could be exploited as a selective therapeutic target in MDS.

KEYWORDS:

JNK/AP-1 signaling; Withaferin A (WFA); apoptosis; myelodysplastic syndrome (MDS); reactive oxygen species (ROS)

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