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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This work was supported by grants from the Edward P. Evan's Foundation; National Institutes of Health [#RO1 CA165469]; University of Kentucky COBRE Early Career Program (P20 GM103527); the flow cytometry and cell sorting, and the biostatistics and bioinformatics shared resources of the University Kentucky Markey Cancer Center (P30CA177558).
Oben, Karine Z.; Alhakeem, Sara S.; McKenna, Mary Kathryn; Brandon, Jason A.; Mani, Rajeswaran; Noothi, Sunil K.; Liu, Jinpeng; Akunuru, Shailaja; Dhar, Sanjit Kumar; Singh, Inder P.; Liang, Ying; Wang, Chi; Abdel-Latif, Ahmed; Stills, Harold F. Jr.; St Clair, Daret K.; Geiger, Hartmut; Muthusamy, Natarajan; Tohyama, Kaoru; Gupta, Ramesh C.; and Bondada, Subbarao, "Oxidative Stress-Induced JNK/AP-1 Signaling is a Major Pathway Involved in Selective Apoptosis of Myelodysplastic Syndrome Cells by Withaferin-A" (2017). Markey Cancer Center Faculty Publications. 86.