Author ORCID Identifier

http://orcid.org/0000-0003-0195-7253

Year of Publication

2017

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Medicine

Department

Microbiology, Immunology, and Molecular Genetics

First Advisor

Dr. Subbarao Bondada

Abstract

Myelodysplastic syndromes (MDS) are a diverse group of clonal hematologic disorders characterized by ineffective blood cell production (hematopoiesis), dysplastic (abnormal) cell morphology in one or more hematopoietic lineages, and progression to acute myeloid leukemia (AML). The response rate to current FDA approved therapies is low and not durable. Just about 50% of MDS patients respond to these drug therapies and a majority of responders relapse within 2-3 years. Hence there is a compelling need to investigate new therapy options.

We investigated the anticancer potential and possible underlying molecular mechanisms of action of a plant-derived compound, Withaferin A (WFA) in MDS. We utilized the MDS-L cell line model to test the efficacy of WFA both in vitro and in vivo. WFA exhibited potent but selective cytotoxicity to MDS-L cells as seen by a dose-dependent decrease in cell viability of these cells when treated with WFA whereas WFA had no apparent significant effect on the viability of normal primary human bone marrow cells. In addition, WFA significantly reduced engraftment of MDS-L cells in a xenotransplantation model. Through the use of microarray gene expression analysis, we identified that reactive oxygen species (ROS)-activated JNK/AP-1 signaling is a major pathway mediating apoptosis of MDS-L cells by WFA. Increase in ROS plays a central role in the cytotoxicity of WFA in MDS-L cells. Consistent with the finding that increase in ROS plays a central role in mediating WFA cytotoxicity in MDS-L cells, WFA did not increase ROS levels in normal bone marrow cells.

Taken together, these results suggest that pharmacologic manipulation of redox biology could be exploited to selectively target malignant cells while sparing normal cells in MDS.

Digital Object Identifier (DOI)

https://doi.org/10.13023/ETD.2017.011

Available for download on Tuesday, January 30, 2018

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