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Ginsenoside Rd Induces Differentiation of Myeloid Leukemia Cells via Regulating ERK/GSK-3β Signaling Pathway

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Abstract

Objective

To investigate the role of ginsenoside Rd (GRd) in acute myeloid leukemia (AML) cell differentiation.

Methods

AML cells were treated with GRd (25, 50, 100 and 200 µg/mL), retinoic acid (RA, 0.1g/L) and PD98059 (20 mg/mL) for 72 h, cell survival was detected by methylthiazolyldiphenyl-tetrazolium bromide and colony formation assays, and cell cycle was detected by flow cytometry. Cell morphology and differentiation were observed by Wright-Giemsa staining, peroxidase chemical staining and cellular immunochemistry assay, respectively. The protein expression levels of GATA binding protein 1 (GATA-1), purine rich Box-1 (PU.1), phosphorylated-extracellular signal-related kinase (p-ERK), ERK, phosphorylated-glycogen synthase kinase-3β (p-GSK3β), GSK3β and signal transducer and activator of transcription 1 (STAT1) were detected by Western blot. Thirty-six mice were randomly divided into 3 groups using a random number table: model control group (non-treated), GRd group [treated with 200 mg/(kg·d) GRd] and homoharringtonine (HTT) group [treated with 1 mg/(kg·d) HTT]. A tumor-bearing nude mouse model was established, and tumor weight and volume were recorded. Changes of subcutaneous tumor tissue were observed after hematoxylin and eosin staining. WT1 and GATA-1 expressions were detected by immunohistochemical staining.

Results

The cell survival was inhibited by GRd in a dose-dependent manner and GRd caused G0/G1 cell arrest (p<0.05). GRd treatment induced leukemia cell differentiation, showing increased expressions of peroxidase and specific proteins concerning erythrogenic or granulocytic differentiation (p<0.05). GRd treatment elicited upregulation of p-ERK, p-GSK-3β and STAT1 expressions in cells, and reversed the effects of PD98059 on inhibiting the expressions of peroxidase, GATA-1 and PU.1 (P<0.05). After GRd treatment, tumor weight and volume of mice were decreased, and tumor cells underwent massive apoptosis and necrosis (P<0.05). WT1 level was decreased, and GATA-1 level was significantly increased in subcutaneous tumor tissues (P<0.05 or P<0.01).

Conclusion

GRd might induce the differentiation of AML cells via regulating the ERK/GSK-3β signaling pathway.

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Authors and Affiliations

  1. Department of Hematology, Tongde Hospital of Zhejiang Province, Hangzhou, 310012, China

    Yu-xia Jiang

  2. Institute of Hematology Research, the First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, 310006, China

    Yan-na Zhao, Xiao-ling Yu &  Li-ming Yin

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  1. Yu-xia Jiang
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  2. Yan-na Zhao
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Contributions

Yin LM made substantial contributions to conception and design. Jiang YX and Yin LM drafted the article and critically revised it for important intellectual content. Jiang YX, Zhao YN, Yu XL and Yin LM were responsible for data acquisition, data analysis and interpretation. All authors read and approved the final version for publication and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of the work are appropriately investigated and resolved.

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Correspondence to Li-ming Yin.

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The authors declare no conflict of interest.

Additional information

Supported by the General Program of National Natural Science Foundation of China under Grant (No. 81873113), the Natural Science Foundation of Zhejiang Province (No. LY18H290004)

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Jiang, Yx., Zhao, Yn., Yu, Xl. et al. Ginsenoside Rd Induces Differentiation of Myeloid Leukemia Cells via Regulating ERK/GSK-3β Signaling Pathway. Chin. J. Integr. Med. (2023). https://doi.org/10.1007/s11655-023-3561-z

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