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

// Karine Z. Oben 1 , Sara S. Alhakeem 1 , Mary K. McKenna 1 , Jason A. Brandon 2 , Rajeswaran Mani 3 , Sunil K. Noothi 1 , Liu Jinpeng 4 , Shailaja Akunuru 5 , Sanjit K. Dhar 6 , Inder P. Singh 7 , Ying Liang 6 , Chi Wang 4 , Ahmed Abdel-Latif 2 , Harold F. Stills Jr 8 , Daret K. St. Clair 6 , Hartmut Geiger 5 , Natarajan Muthusamy 3 , Kaoru Tohyama 9 , Ramesh C. Gupta 10 and Subbarao Bondada 1 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 Correspondence to: Subbarao Bondada, email: bondada@email.uky.edu Keywords: myelodysplastic syndrome (MDS), Withaferin A (WFA), apoptosis, JNK/AP-1 signaling, reactive oxygen species (ROS) Received: June 20, 2017 Accepted: July 16, 2017 Published: August 24, 2017 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.