Dataset Information

Shikonin Exerts an Antileukemia Effect against FLT3-ITD Mutated Acute Myeloid Leukemia Cells via Targeting FLT3 and Its Downstream Pathways.

ABSTRACT:

Introduction

Acute myeloid leukemia (AML) with internal tandem duplication (ITD) mutations in Fms-like tyrosine kinase 3 (FLT3) has an unfavorable prognosis. Recently, using newly emerging inhibitors of FLT3 has led to improved outcomes of patients with FLT3-ITD mutations. However, drug resistance and relapse continue to be significant challenges in the treatment of patients with FLT3-ITD mutations. This study aimed to evaluate the antileukemic effects of shikonin (SHK) and its mechanisms of action against AML cells with FLT3-ITD mutations in vitro and in vivo.

Methods

The CCK-8 assay was used to analyze cell viability, and flow cytometry was used to detect cell apoptosis and differentiation. Western blotting and real-time polymerase chain reaction were used to examine the expression of certain proteins and genes. Leukemia mouse model was created to evaluate the antileukemia effect of SHK against FLT3-ITD mutated leukemia in vivo.

Results

After screening a series of leukemia cell lines, those with FLT3-ITD mutations were found to be more sensitive to SHK in terms of proliferation inhibition and apoptosis induction than those without FLT3-ITD mutation. SHK suppresses the expression and phosphorylation of FLT3 receptors and their downstream molecules. Inhibition of the NF-κB/miR-155 pathway is an important mechanism through which SHK kills FLT3-AML cells. Moreover, a low concentration of SHK promotes the differentiation of AML cells with FLT3-ITD mutations. Finally, SHK could significantly inhibit the growth of MV4-11 cells in leukemia bearing mice.

Conclusion

The findings of this study indicate that SHK may be a promising drug for the treatment of FLT3-ITD mutated AML.

SUBMITTER: Zhao MN

PROVIDER: S-EPMC11251672 | biostudies-literature | 2024

REPOSITORIES: biostudies-literature

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Publications

Shikonin Exerts an Antileukemia Effect against FLT3-ITD Mutated Acute Myeloid Leukemia Cells via Targeting FLT3 and Its Downstream Pathways.

Zhao Mu-Nan MN Su Long L Song Fei F Wei Zhi-Feng ZF Qin Tian-Xue TX Zhang Yun-Wei YW Li Wei W Gao Su-Jun SJ

Acta haematologica 20231103 3

<h4>Introduction</h4>Acute myeloid leukemia (AML) with internal tandem duplication (ITD) mutations in Fms-like tyrosine kinase 3 (FLT3) has an unfavorable prognosis. Recently, using newly emerging inhibitors of FLT3 has led to improved outcomes of patients with FLT3-ITD mutations. However, drug resistance and relapse continue to be significant challenges in the treatment of patients with FLT3-ITD mutations. This study aimed to evaluate the antileukemic effects of shikonin (SHK) and its mechanism ...[more]

PMID: 37926079

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Project description:Acute myeloid leukemia (AML) is an aggressive hematologic malignancy which is cured in a minority of patients. A FLT3-internal tandem duplication (ITD) mutation, found in approximately a quarter of patients with de novo AML, imparts a particularly poor prognosis. Patients with FLT3-ITD AML often present with more aggressive disease and have a significantly higher propensity for relapse after remission. The therapeutic approach for these patients has traditionally included intensive induction chemotherapy, followed by consolidative chemotherapy or hematopoietic cell transplantation (HCT). In recent years, multiple small molecule inhibitors of the FLT3 tyrosine kinase have been studied preclinically and in clinical trials. The earlier generation of these agents, often non-specific and impacting a variety of tyrosine kinases, produced at best transient peripheral blood responses in early clinical trials. Additionally, the combination of FLT3 inhibitors with cytotoxic regimens has not, as of yet, demonstrated an improvement in overall survival. Nevertheless, multiple current trials, including those with sorafenib, lestaurtinib, and midostaurin, continue to study the combination of FLT3 inhibitors with standard chemotherapy. Factors such as sustained FLT3 inhibition, protein binding, pharmacokinetics, and the presence of elevated FLT3-ligand levels appear to significantly impact the potency of these agents in vivo. In recent years, the development of more specific and potent agents has generated hope that FLT3 inhibitors may play a more prominent role in the treatment of FLT3-ITD AML in the near future. Nevertheless, questions remain regarding the optimal timing and schedule for incorporation of FLT3 inhibitors. The suitability, type, and timing of allogeneic HCT in the therapeutic approach for these patients are also issues which require further study and definition. Recent retrospective data appears to support the efficacy of allogeneic HCT in first complete remission, possibly due to a graft versus leukemia effect. However, larger prospective studies are necessary to further elucidate the role of HCT and its potential combination with FLT3 inhibitor therapy. We are hopeful that current clinical investigation will lead to an optimization and improvement of outcomes for these patients.

Project description:Purpose: Wnt/β-catenin signaling is required for leukemic stem cell function. FLT3 mutations are frequently observed in acute myeloid leukemia (AML). Anomalous FLT3 signaling increases β-catenin nuclear localization and transcriptional activity. FLT3 tyrosine kinase inhibitors (TKI) are used clinically to treat FLT3-mutated AML patients, but with limited efficacy. We investigated the antileukemia activity of combined Wnt/β-catenin and FLT3 inhibition in FLT3-mutant AML.Experimental Design: Wnt/β-catenin signaling was inhibited by the β-catenin/CBP antagonist C-82/PRI-724 or siRNAs, and FLT3 signaling by sorafenib or quizartinib. Treatments on apoptosis, cell growth, and cell signaling were assessed in cell lines, patient samples, and in vivo in immunodeficient mice by flow cytometry, Western blot, RT-PCR, and CyTOF.Results: We found significantly higher β-catenin expression in cytogenetically unfavorable and relapsed AML patient samples and in the bone marrow-resident leukemic cells compared with circulating blasts. Disrupting Wnt/β-catenin signaling suppressed AML cell growth, induced apoptosis, abrogated stromal protection, and synergized with TKIs in FLT3-mutated AML cells and stem/progenitor cells in vitro The aforementioned combinatorial treatment improved survival of AML-xenografted mice in two in vivo models and impaired leukemia cell engraftment. Mechanistically, the combined inhibition of Wnt/β-catenin and FLT3 cooperatively decreased nuclear β-catenin and the levels of c-Myc and other Wnt/β-catenin and FLT3 signaling proteins. Importantly, β-catenin inhibition abrogated the microenvironmental protection afforded the leukemic stem/progenitor cells.Conclusions: Disrupting Wnt/β-catenin signaling exerts potent activities against AML stem/progenitor cells and synergizes with FLT3 inhibition in FLT3-mutant AML. These findings provide a rationale for clinical development of this strategy for treating FLT3-mutated AML patients. Clin Cancer Res; 24(10); 2417-29. ©2018 AACR.

Dataset Information

Shikonin Exerts an Antileukemia Effect against FLT3-ITD Mutated Acute Myeloid Leukemia Cells via Targeting FLT3 and Its Downstream Pathways.

Introduction

Methods

Results

Conclusion

Publications

Shikonin Exerts an Antileukemia Effect against FLT3-ITD Mutated Acute Myeloid Leukemia Cells via Targeting FLT3 and Its Downstream Pathways.

Similar Datasets

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