Research Papers:

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, Sara S. Alhakeem, Mary K. McKenna, Jason A. Brandon, Rajeswaran Mani, Sunil K. Noothi, Liu Jinpeng, Shailaja Akunuru, Sanjit K. Dhar, Inder P. Singh, Ying Liang, Chi Wang, Ahmed Abdel-Latif, Harold F. Stills Jr, Daret K. St. Clair, Hartmut Geiger, Natarajan Muthusamy, Kaoru Tohyama, Ramesh C. Gupta and Subbarao Bondada _

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Oncotarget. 2017; 8:77436-77452. https://doi.org/10.18632/oncotarget.20497

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Karine Z. Oben1, Sara S. Alhakeem1, Mary K. McKenna1, Jason A. Brandon2, Rajeswaran Mani3, Sunil K. Noothi1, Liu Jinpeng4, Shailaja Akunuru5, Sanjit K. Dhar6, Inder P. Singh7, Ying Liang6, Chi Wang4, Ahmed Abdel-Latif2, Harold F. Stills Jr8, Daret K. St. Clair6, Hartmut Geiger5, Natarajan Muthusamy3, Kaoru Tohyama9, Ramesh C. Gupta10 and Subbarao Bondada1

1Markey Cancer Center and Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, KY 40536, USA

2Department of Internal Medicine, University of Kentucky, Lexington, KY 40536, USA

3Comprehensive Cancer Center and Department of Internal Medicine, Ohio State University, Columbus, OH 43210, USA

4Biostatistics Core, Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA

5Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center and University of Cincinnati, Cincinnati, OH 45229, USA

6Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY 40536, USA

7Department of Natural Products, National Institute of Pharmaceutical Research, S.A.S Nagar, Punjab 160062, India

8Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, KY 40536, USA

9Department of Laboratory Medicine, Kawasaki Medical School, Kurashiki, Okayama 701-0192, Japan

10Department of Pharmacology and Toxicology, and James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA

Correspondence to:

Subbarao Bondada, email: [email protected]

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


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.

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