将雷帕霉素与新型 PI3K/Akt/mTOR 抑制剂 microRNAs 结合应用于 NOTCH1 驱动的 T 细胞急性淋巴细胞白血病(T-ALL)。

IF 2.2 4区 工程技术 Q3 PHARMACOLOGY & PHARMACY Bioimpacts Pub Date : 2024-01-01 Epub Date: 2023-11-28 DOI:10.34172/bi.2023.28870
Fateme Arjmand, Samaneh Shojaei, Mitra Khalili, Hossein Dinmohammadi, Behzad Poopak, Samira Mohammadi-Yeganeh, Yousef Mortazavi
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引用次数: 0

摘要

导言PI3K/AKT/mTOR信号通路在T细胞急性淋巴细胞白血病(T-ALL)的发病过程中起着重要作用。雷帕霉素能抑制 mTOR 的活性,因此是血液恶性肿瘤的潜在治疗策略。此外,微RNA(miRNA)已成为T-ALL病理生理学和治疗中的关键调控因子。本研究旨在探讨雷帕霉素和miRNAs在T-ALL细胞中抑制PI3K/AKT/mTOR通路的联合作用:方法:利用生物信息学算法寻找抑制PI3K/AKT/mTOR通路的miRNA。研究人员收集了 25 份 T-ALL 患者的骨髓样本和 5 份非白血病患者的对照骨髓样本。选择 Jurkat 细胞系作为 T-ALL 的代表模型。采用定量实时 PCR(qRT-PCR)技术评估基因和 miRNA 的表达水平。将两种在临床样本和 Jurkat 细胞中均表现出下调的 miRNA 转染到 Jurkat 细胞系中,以研究它们对靶基因表达的影响。此外,为了评估 miRNA 与雷帕霉素联合疗法的潜力,还进行了细胞凋亡和细胞周期测定:结果:六个 miRNA(miR-3143、miR-3182、miR-99a/100、miR-155、miR-576-5p 和 miR-501-3p)被预测为 PI3K/AKT/mTOR 通路的抑制剂。对临床样本和 Jurkat 细胞系的表达分析表明,miR-3143 和 miR-3182 同时下调。转染研究表明,外源过表达 miR-3143 和 miR-3182 能有效抑制 Jurkat 细胞系中的 PI3K/AKT/mTOR 信号传导。此外,当 miR-3143 和 miR-3182 与雷帕霉素一起作为双重抑制剂使用时,可显著增加 Jurkat 细胞系的细胞凋亡并导致细胞周期停滞:这些初步结果凸显了通过雷帕霉素和 miR-3143/miR-3182 的多靶点治疗策略改善 T-ALL 治疗的潜力。
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Integrating rapamycin with novel PI3K/Akt/mTOR inhibitor microRNAs on NOTCH1-driven T-cell acute lymphoblastic leukemia (T-ALL).

Introduction: The PI3K/AKT/mTOR signaling pathway plays a significant role in the development of T-cell acute lymphoblastic leukemia (T-ALL). Rapamycin is a potential therapeutic strategy for hematological malignancies due to its ability to suppress mTOR activity. Additionally, microRNAs (miRNAs) have emerged as key regulators in T-ALL pathophysiology and treatment. This study aimed to investigate the combined effects of rapamycin and miRNAs in inhibiting the PI3K/AKT/mTOR pathway in T-ALL cells.

Methods: Bioinformatic algorithms were used to find miRNAs that inhibit the PI3K/AKT/mTOR pathway. Twenty-five bone marrow samples were collected from T-ALL patients, alongside five control bone marrow samples from non-leukemia patients. The Jurkat cell line was chosen as a representative model for T-ALL. Gene and miRNA expression levels were assessed using quantitative real-time PCR (qRT-PCR). Two miRNAs exhibiting down-regulation in both clinical samples and Jurkat cells were transfected to the Jurkat cell line to investigate their impact on target gene expression. Furthermore, in order to evaluate the potential of combination therapy involving miRNAs and rapamycin, apoptosis and cell cycle assays were carried out.

Results: Six miRNAs (miR-3143, miR-3182, miR-99a/100, miR-155, miR-576-5p, and miR-501- 3p) were predicted as inhibitors of PI3K/AKT/mTOR pathway. The expression analysis of both clinical samples and the Jurkat cell line revealed a simultaneous downregulation of miR-3143 and miR-3182. Transfection investigation demonstrated that the exogenous overexpression of miR-3143 and miR-3182 can effectively inhibit PI3K/AKT/mTOR signaling in the Jurkat cell line. Moreover, when used as a dual inhibitor along with rapamycin, miR-3143 and miR-3182 significantly increased apoptosis and caused cell cycle arrest in the Jurkat cell line.

Conclusion: These preliminary results highlight the potential for improving T-ALL treatment through multi-targeted therapeutic strategies involving rapamycin and miR-3143/miR-3182.

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来源期刊
Bioimpacts
Bioimpacts Pharmacology, Toxicology and Pharmaceutics-Pharmaceutical Science
CiteScore
4.80
自引率
7.70%
发文量
36
审稿时长
5 weeks
期刊介绍: BioImpacts (BI) is a peer-reviewed multidisciplinary international journal, covering original research articles, reviews, commentaries, hypotheses, methodologies, and visions/reflections dealing with all aspects of biological and biomedical researches at molecular, cellular, functional and translational dimensions.
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