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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.

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


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.


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

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