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.
Highlights
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) [1, 2]
Since MDS-L cells have a deletion in chromosome 5 [19], we assessed the relative efficacy of Withaferin A (WFA) in comparison to LENA
We demonstrated that the plant-derived steroidal lactone isolated from Withania somnifera, WFA, is selectively cytotoxic to MDS-L cells both in vitro and in vivo
Summary
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) [1, 2]. Ineffective hematopoiesis manifests clinically as cytopenias – anemia being the most common, bleeding and recurrent infections [1, 3]. 30% of MDS patients progress to AML while progressive disease in the other 70% culminates in complete bone marrow failure [4]. MDS are generally thought of as diseases of the elderly, with a median age at diagnosis of 65-70 years [1]. The age of diagnosis for t-MDS correlates with the age of cytotoxic therapy treatment [5]
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