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.
|Number of pages||17|
|State||Published - 2017|
Bibliographical noteFunding Information:
We thank Beth W. Gachuki, the light microscopy core and the research communications office for their support and suggestions. We thank Jennifer Strange and Dr. Greg Baumann for flow cytometry experiments. 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 et al.
- JNK/AP-1 signaling
- Myelodysplastic syndrome (MDS)
- Withaferin A (WFA)
- reactive oxygen species (ROS)
ASJC Scopus subject areas