Arsenic disulfide-triggered apoptosis and erythroid differentiation in myelodysplastic syndrome and acute myeloid leukemia cell lines

摘要

Objectives Effects of arsenic disulfide (Assub2/subSsub2/sub) were investigated by focusing on growth inhibition, apoptosis induction, and erythroid differentiation in MDS-L, F-36p and HL-60 cells, derived from myelodysplastic syndrome (MDS), MDS/acute myeloid leukemia (AML), and de novo AML, respectively. Methods Cell viability was determined by MTT assay. Apoptosis induction was analyzed using Annexin V/propidium iodide staining. Erythroid differentiation was assessed by the expression level of CD235a, a marker for detection of the erythroid cell lineage. The activation of p38 MAPK and the expression profile of apoptosis-related proteins Bcl-2 and Bid were analyzed using western blot. Results Assub2/subSsub2/sub inhibited cell growth of these cell lines. Of note, the ICsub50/sub value of Assub2/subSsub2/sub in MDS-L cells was comparable to that in F-36p cells, and was half of that in HL-60 cells. A dose-dependent decrease in cell viability and concomitant increase in the percentage of apoptotic cells were observed in F-36p cells treated with 8 and 16 μM Assub2/subSsub2/sub for 72 hours. However, similar phenomena were only observed in HL-60 cells when treated with as high as 16 μM Assub2/subSsub2/sub. Furthermore, Assub2/subSsub2/sub exerted more potent erythroid differentiation-inducing activity on F-36p cells than HL-60 cells. Interestingly, negative correlation between p38 MAPK signaling pathway and Assub2/subSsub2/sub-induced erythroid differentiation was observed in HL-60 cells. Treatment with relatively high concentration of Assub2/subSsub2/sub resulted in the downregulation of Bcl-2 and Bid proteins in HL-60 cells. Discussion These results suggest that compared to AML cell line, MDS and MDS/AML cell lines are more sensitive to not only the erythroid differentiation-inducing activity of Assub2/subSsub2/sub, but also its cytotoxicity associated with apoptosis induction. These findings further provide novel insight into Assub2/subSsub2/sub action toward its use for clinical application in patients with hematological disorders.