Jiyuan Oridonin A Overcomes Differentiation Blockade in Acute Myeloid Leukemia Cells With MLL Rearrangements via Multiple Signaling Pathways

Qu, Mei; Duan, Yu; Zhao, Min; Wang, Zhanju; Zhao, Mengjie; Zhao, Yao; Wang, Haihua; Yu, Ke; Liu, Ying; Liu, Hong‐Min; Wei, Liuya; Hu, Zhenbo

doi:10.3389/fonc.2021.659720

Cited by 10 publications

(11 citation statements)

References 32 publications

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“…THP-1, MOLM-13, SEM and MV4-11 cells were cultured with P6 (0–2.0 µM) in 2.6% methycellulose medium containing 10% FBS in a 24-well flat-bottomed plate for 12 days ( Qu et al, 2021 ). The number of individual colonies consisting of more than approximately 50 cells was counted by a CX43 microscope (Olympus, Shinjuku-ku, Tokyo, Japan) with an Olympus EP50 camera (Olympus, Shinjuku-ku, Tokyo, Japan).…”

Section: Methodsmentioning

confidence: 99%

Discovery of 2-(4-Acrylamidophenyl)-Quinoline-4-Carboxylic Acid Derivatives as Potent SIRT3 Inhibitors

Hui

Wang

et al. 2022

Front. Chem.

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In discovery of novel SIRT3 inhibitors for the treatment of cancer, a series of 2-(4-acrylamidophenyl)-quinoline-4-carboxylic acid derivatives were designed and synthesized. Among the derived compounds, molecule P6 exhibited SIRT3 inhibitory selectivity with IC50 value of 7.2 µM over SIRT1 (32.6 µM) and SIRT2 (33.5 µM). molecular docking analysis revealed a specific binding pattern of P6 in the active site of SIRT3 compared with the bindings in the active site of SIRT1 and SIRT2. In the antiproliferative and colony forming assay, molecule P6 showed potent inhibitory activity against a group of MLLr leukemic cell lines. Further analysis revealed that induction of G0/G1 phase cell cycle arrest and cell differentiation, but not apoptosis, makes contributions to the anticancer effects of P6. Collectively, a potent SIRT3 inhibitor (P6) was discovered as a lead compound for the leukemic differentiation therapy.

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Section: Methodsmentioning

confidence: 99%

Discovery of 2-(4-Acrylamidophenyl)-Quinoline-4-Carboxylic Acid Derivatives as Potent SIRT3 Inhibitors

Hui

Wang

et al. 2022

Front. Chem.

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“…Kasumi-1 was incubated with 0.5 μM of I13 for 48 h, and the cells were collected for RNA extraction and mRNA sequencing analysis. As described in our previous work ( 16 , 17 ), the cDNA library was sequenced by Illumina genome analyzer. Levels of gene expression were estimated using fragments per kilobase of exon per million fragments mapped (FPKM) values.…”

Section: Methodsmentioning

confidence: 99%

The Histone Deacetylase Inhibitor I13 Induces Differentiation of M2, M3 and M5 Subtypes of Acute Myeloid Leukemia Cells and Leukemic Stem-Like Cells

Zhao

et al. 2022

Front. Oncol.

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Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by reduced differentiation of myeloid cells and uncontrolled cell proliferation. AML is prone to drug resistance and has a high recurrence rate during treatment with cytarabine-based chemotherapy. Our study aims to explore the cell differentiation effect of a potent histone deacetylase inhibitor (HDACi), I13, and its possible mechanism on AML cell lines (Kasumi-1, KG-1, MOLM-13 and NB4). It has been shown that I13 can significantly inhibit proliferation and colony formation of these AML cells by inducing cell differentiation coupled with cell-cycle exit at G0/G1. Mechanically, I13 presented the property of HDAC inhibition, as assessed by the acetylation of histone H3, which led to the differentiation of Kasumi-1 cells. In addition, the HDAC inhibition of I13 likely dictated the activation of the antigen processing and presentation pathway, which maybe has the potential to promote immune cells to recognize leukemic cells and respond directly against leukemic cells. These results indicated that I13 could induce differentiation of M3 and M5 subtypes of AML cells, M2 subtype AML cells with t(8;21) translocation and leukemic stem-like cells. Therefore, I13 could be an alternative compound which is able to overcome differentiation blocks in AML.

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“…Since the t (8; 21) translocation occurs in primary cases of AML, mRNA-Sequencing (mRNA-seq) was performed for Kasumi-1 cells. Similar to our previous work [ 18 ], cells treated with I3 for 48 h were collected for RNA extraction. Sequencing libraries were prepared, the mRNAs levels were estimated, and differential expression analysis was performed using DESeq R packages.…”

Section: Methodsmentioning

confidence: 99%

Histone Deacetylase Inhibitor I3 Induces the Differentiation of Acute Myeloid Leukemia Cells with t (8; 21) or MLL Gene Translocation and Leukemic Stem-Like Cells

Zhao

Duan

Wang

et al. 2022

Journal of Oncology

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Acute myeloid leukemia (AML) is a heterogeneous disorder characterized by the clonal expansion and differentiation arrest of leukemic cells in peripheral blood and bone marrow. Though the treatment using cytarabine-based protocol for AML patients with t (8; 21) translocation has improved the 5-year overall survival rate, drug resistance continues to be the principal limiting factor for the cure of the disease. In addition, very few AML patients with mixed lineage leukemia gene rearrangements (MLLr) have a desirable outcome. This study evaluated the cell differentiation effect of a potent HDAC (histone deacetylase) inhibitor, I3, and its possible mechanism on the AML cells with t (8; 21) translocation or MLLr and leukemic stem-like cells (Kasumi-1, KG-1, MOLM-13, and THP-1). I3 exhibited efficient anti-proliferative activity on these cells via promoting cell differentiation, accompanied by the cell cycle exit at G0/G1. Importantly, I3 showed the properties of HDAC inhibition, as assessed by the acetylation of histones H3 and H4, which resulted in blocking the activation of the VEGF (vascular endothelial growth factor)-MAPK (mitogen-activated protein kinase) signaling pathway in the Kasumi-1 cell line. These data demonstrate that I3 could be a potent chromatin-remodeling agent to surmount the differentiation block in AML patients, including those with t (8; 21) translocation or MLLr, and could be a potent and selective agent for AML treatment.

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Jiyuan Oridonin A Overcomes Differentiation Blockade in Acute Myeloid Leukemia Cells With MLL Rearrangements via Multiple Signaling Pathways

Cited by 10 publications

References 32 publications

Discovery of 2-(4-Acrylamidophenyl)-Quinoline-4-Carboxylic Acid Derivatives as Potent SIRT3 Inhibitors

Discovery of 2-(4-Acrylamidophenyl)-Quinoline-4-Carboxylic Acid Derivatives as Potent SIRT3 Inhibitors

The Histone Deacetylase Inhibitor I13 Induces Differentiation of M2, M3 and M5 Subtypes of Acute Myeloid Leukemia Cells and Leukemic Stem-Like Cells

Histone Deacetylase Inhibitor I3 Induces the Differentiation of Acute Myeloid Leukemia Cells with t (8; 21) or MLL Gene Translocation and Leukemic Stem-Like Cells

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