Adenanthin Upregulates c/ebp β Expression with Induction of Differentiation of the ATRA-Sensitive and -Resistant leukemic Cells.

Application of all-trans retinoic acid (ATRA) has significantly improved the outcome of patients with acute promyelocytic leukemia (APL), a unique subtype of acute myeloid leukemia (AML) characterized with the reciprocal translocation t(15;17) that results in the expression of leukemia-promoting promyelocytic leukemia-retinoic acid receptor-α (PML-RARα) protein. However, most patients usually relapsed in a short period and followed by generation of retinoid resistance. Therefore, it is imperative to explore agents to overcome the resistance. In this work, we found that adenanthin, a diterpenoid compound extracted from medicinal herbs, could induce monocytic differentiation of ATRA-sensitive APL-derived NB4 cells. Especially, the differentiation-inducing effect could also be seen in the agent-treated ATRA-resistant NB4-LR1, NB4-LR2 cells, as evidenced by the morphology and the increased expression of cell surface differentiation antigens CD11b and CD14. Based on this discovery, we also found that adenanthin significantly upregulated the expression of CCAAT enhancer–binding protein beta (C/EBPβ), but not the C/EBPα and C/EBPε at its transcription and protein levels, which was accompanied by the activation of c-Jun N-terminal kinases signal pathway. On the other hand, silence of C/EBPβ by specific small-interfering RNA abrogated the adenanthin induced differentiation in NB4 cells. All these data proposed the role of C/EBPβ in adenanthin induced differentiation. Furthermore, we investigated the potential combinational effects of the natural compound with other known differentiation-inducing agents including ATRA and 1, 25-dihydroxy vitamin D3. The results demonstrated that adenanthin strikingly enhanced ATRA (10nM) induced granulocyte differentiation and 1, 25-dihydroxy vitamin D3 (1nM) induced monocytic differentiation. These results suggest that adenanthin may be a potential antileukemia agent for the ATRA-sensitive and -resistant APL and deserves to be further investigated in the future.