diptoindonesin-g and Leukemia--Myeloid--Acute

Exploration of a new differentiation therapy that extends the range of differentiation for treating acute myeloid leukemia (AML) is attractive to researchers and clinicians. Here we report that diptoindonesin G (Dip G), a natural resveratrol aneuploid, exerts antiproliferative activity by inducing G2/M phase arrest and cell differentiation in AML cell lines and primary AML cells. Gene-profiling experiments showed that treating human leukemia HL-60 cells with Dip G was associated with a remarkable upregulation of STAT1 target gene expression, including IFIT3 and CXCL10. Mechanistically, Dip G activated ERK, which caused phosphorylation of STAT1 at Ser727 and selectively enhanced the interaction of p-STAT1 (Ser727) and p-ERK, further promoting their nuclear translocation. The nuclear translocation of p-STAT1 and p-ERK enhanced the transactivation of STAT1-targeted genes in AML cells. Furthermore, in vivo treatment of HL-60 xenografts demonstrated that Dip G significantly inhibited tumor growth and reduced tumor weight by inducing cell differentiation. Taken together, these results shed light on an essential role for ERK-mediated nuclear translocation of p-STAT1 (Ser727) and its full transcriptional activity in Dip G-induced differentiation of AML cells. Furthermore, these results demonstrate that Dip G could be used as a differentiation-inducing agent for AML therapy, particularly for non-acute promyelocytic leukemia therapy.

Topics: Animals; Antineoplastic Agents; Benzofurans; Caspase 3; Caspase Inhibitors; Cell Differentiation; Cell Line, Tumor; Cell Nucleus; Cell Proliferation; Chemokine CXCL10; Extracellular Signal-Regulated MAP Kinases; HL-60 Cells; Humans; Intracellular Signaling Peptides and Proteins; Leukemia, Myeloid, Acute; Mice; Mice, Inbred NOD; Mice, SCID; Phosphorylation; STAT1 Transcription Factor; Up-Regulation