Knowledge of the pathogenesis of AML has seen great progress due to recent advances in genetic studies. However, the long-term survival of AML patients is still unsatisfactory. A block in differentiation is one of the characteristics of leukemia. C/EBPα is an essential transcription factor for the differentiation of cells in the liver, lung, adipose tissues, and bone marrow. In the hematopoietic system, C/EBPα is expressed in myeloid cells and is required for granulocytic and monocytic differentiation. C/EBPα also plays an important role in myeloid cell differentiation and in the enhancement of C/EBPα expression/activity. This can lead to granulocytic differentiation in AML cells. In this study, ICCB280 is a potent inducer of C/EBPα. It exhibits anti-leukemic properties including terminal differentiation, proliferation arrest, and apoptosis through activation of C/EBPα and affecting its downstream targets.
ICCB280 suppresses the HL-60 cell growth, with an IC50 of 8.6 μM. ICCB280 increases C/EBPα expression (mRNA and protein). It also modulates its target genes in HL-60 cells. Moreover, ICCB280 induces granulocytic differentiation and subsequent apoptosis in HL-60 cells. ICCB280 also induces myeloid differentiation of leukemia cell lines by increasing the expression of C/EBPα and C/EBPε. It also decreases the expression of c-Myc. In addition, it induces an increase in surface CD11b expression. That is one of the characteristics of neutrophilic differentiation. CCB280 also leads to an increase in C/EBPα expression and modulates its target genes. Furthermore, ICCB280 and G-CSF cooperatively induce granulocytic differentiation.
In summary, ICCB280 is a lead compound. It exhibits anti-leukemic properties including terminal differentiation, proliferation arrest, and apoptosis.