Z-Ligustilide Selectively Targets AML by Restoring Nuclear Receptors Nur77 and NOR-1-mediated Apoptosis and Differentiation.

Acute myeloid leukemia (AML) is a devastating hematologic malignancy with a high mortality. The nuclear receptors Nur77 and NOR-1 are commonly downregulated in human AML blasts and have emerged as key therapeutic targets for AML. This study aimed to identify Z-ligustilide (Z-LIG), the main phthalide of Rhizoma Chuanxiong, as a potential agent that can selectively target AML. The anti-AML activity of Z-LIG was evaluated in vitro and in vivo, and the effect and underlying mechanisms of Z-LIG on the restoration of Nur77 and NOR-1 was determined. Moreover, the role of Nur77 and NOR-1 in the regulation of Z-LIG-induced apoptosis and differentiation of AML cells was explored. Z-LIG preferentially inhibited the viability of human AML cells, as well as suppressed the proliferation and colony formation ability. Notably, a concentration-dependent dual effect of Z-LIG was observed in AML cells: inducing apoptosis at relatively high concentrations (25 μM to 100 μM) and promoting differentiation at relatively low concentrations (10 μM and 25 μM). Importantly, Z-LIG restored Nur77 and NOR-1 expression in AML cells by increasing Ace-H3 (lys9/14) enrichment in their promoters. Meanwhile, Z-LIG enhanced the recruitment of p300 and reduced the recruitment of HDAC1, HDAC4/5/7, and MTA1 in the Nur77 promoter and enhanced the recruitment of p-CREB and reduced HDAC1 and HDAC3 in the NOR-1 promoter. Furthermore, Z-LIG-induced apoptosis was shown to be correlated with the mitochondria localization of Nur77/NOR-1 and subsequent Bcl-2 conformational change, converting Bcl-2 from a cyto-protective phenotype into a cyto-destructive phenotype. Z-LIG-promoted differentiation was found to be related to Nur77/NOR-1-mediated myeloid differentiation-associated transcription factors Jun B, c-Jun, and C/EBPβ. Finally, silencing of Nur77 and NOR-1 attenuated anti-AML activity of Z-LIG in NOD/SCID mice. Our study suggests that Z-LIG may serve as a novel bifunctional agent for AML by restoring Nur77/NOR-1-mediated apoptosis and differentiation. Copyright © 2020. Published by Elsevier GmbH.

Citation

Chengqiang Wang, Gen Liu, Guojun Dou, Yi Yang, Lu Chen, Hui Ma, Zhuyun Jiang, Haoyue Ma, Chenglong Li, Li Li, Mingdong Jiang, Qianwei Lu, Pan Li, Hongyi Qi. Z-Ligustilide Selectively Targets AML by Restoring Nuclear Receptors Nur77 and NOR-1-mediated Apoptosis and Differentiation. Phytomedicine : international journal of phytotherapy and phytopharmacology. 2021 Feb;82:153448

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PMID: 33421904

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