The apoptotic and anti-proliferative effects of Neosetophomone B in T-cell acute lymphoblastic leukaemia via PI3K/AKT/mTOR pathway inhibition.

IF 5.9 1区 生物学 Q2 CELL BIOLOGY Cell Proliferation Pub Date : 2024-11-14 DOI:10.1111/cpr.13773
Shilpa Kuttikrishnan, Abdul W Ansari, Muhammad Suleman, Fareed Ahmad, Kirti S Prabhu, Tamam El-Elimat, Feras Q Alali, Ammira S Al Shabeeb Akil, Ajaz A Bhat, Maysaloun Merhi, Said Dermime, Martin Steinhoff, Shahab Uddin
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Abstract

The phosphatidylinositol 3-kinase/Protein Kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signalling pathway is pivotal in various cancers, including T-cell acute lymphoblastic leukaemia (T-ALL), a particularly aggressive type of leukaemia. This study investigates the effects of Neosetophomone B (NSP-B), a meroterpenoid fungal metabolite, on T-ALL cell lines, focusing on its anti-cancer mechanisms and therapeutic potential. NSP-B significantly inhibited the proliferation of T-ALL cells by inducing G0/G1 cell cycle arrest and promoting caspase-dependent apoptosis. Additionally, NSP-B led to the dephosphorylation and subsequent inactivation of the PI3K/AKT/mTOR signalling pathway, a critical pathway in cell survival and growth. Molecular docking studies revealed a strong binding affinity of NSP-B to the active site of AKT, primarily involving key residues crucial for its activity. Interestingly, NSP-B treatment also induced apoptosis and significantly reduced proliferation in phytohemagglutinin-activated primary human CD3+ T cells, accompanied by a G0/G1 cell cycle arrest. Importantly, NSP-B did not affect normal primary T cells, indicating a degree of selectivity in its action, targeting only T-ALL cells and activated T cells. In conclusion, our findings highlight the potential of NSP-B as a novel therapeutic agent for T-ALL, specifically targeting the aberrantly activated PI3K/AKT/mTOR pathway and being selective in action. These results provide a strong basis for further investigation into NSP-B's anti-cancer properties and potential application in T-ALL clinical therapies.

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Neosetophomone B 通过抑制 PI3K/AKT/mTOR 通路对 T 细胞急性淋巴细胞白血病具有凋亡和抗增殖作用。
磷脂酰肌醇 3- 激酶/蛋白激酶 B/雷帕霉素哺乳动物靶标(PI3K/AKT/mTOR)信号通路在多种癌症中起着关键作用,包括 T 细胞急性淋巴细胞白血病(T-ALL),这是一种侵袭性特别强的白血病类型。本研究调查了一种经萜类真菌代谢物 Neosetophomone B(NSP-B)对 T-ALL 细胞系的影响,重点研究其抗癌机制和治疗潜力。NSP-B通过诱导G0/G1细胞周期停滞和促进卡巴酶依赖性凋亡,明显抑制了T-ALL细胞的增殖。此外,NSP-B 还能导致 PI3K/AKT/mTOR 信号通路的去磷酸化和随后的失活,而 PI3K/AKT/mTOR 信号通路是细胞存活和生长的关键通路。分子对接研究显示,NSP-B 与 AKT 的活性位点有很强的结合亲和力,主要涉及对其活性至关重要的关键残基。有趣的是,NSP-B 还能诱导植物血凝素激活的原代人类 CD3+ T 细胞凋亡,并显著减少其增殖,同时使细胞周期停滞在 G0/G1。重要的是,NSP-B 不影响正常的原代 T 细胞,这表明其作用具有一定程度的选择性,只针对 T-ALL 细胞和活化的 T 细胞。总之,我们的研究结果凸显了 NSP-B 作为 T-ALL 新型治疗药物的潜力,它专门针对异常激活的 PI3K/AKT/mTOR 通路,并具有选择性作用。这些结果为进一步研究 NSP-B 的抗癌特性和在 T-ALL 临床疗法中的潜在应用奠定了坚实的基础。
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来源期刊
Cell Proliferation
Cell Proliferation 生物-细胞生物学
CiteScore
14.80
自引率
2.40%
发文量
198
审稿时长
1 months
期刊介绍: Cell Proliferation Focus: Devoted to studies into all aspects of cell proliferation and differentiation. Covers normal and abnormal states. Explores control systems and mechanisms at various levels: inter- and intracellular, molecular, and genetic. Investigates modification by and interactions with chemical and physical agents. Includes mathematical modeling and the development of new techniques. Publication Content: Original research papers Invited review articles Book reviews Letters commenting on previously published papers and/or topics of general interest By organizing the information in this manner, readers can quickly grasp the scope, focus, and publication content of Cell Proliferation.
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