探索马拉巴里酮 A 在三阴性乳腺癌细胞中的凋亡诱导作用:一种分离自肉豆蔻(Myristica malabarica Lam)果皮的酰基酚植物实体。

IF 4.1 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Pothiyil S. Vimalkumar, Neethu Sivadas, Vishnu Priya Murali, Daisy R. Sherin, Madhukrishnan Murali, Anuja Gracy Joseph, Kokkuvayil Vasu Radhakrishnan and Kaustabh Kumar Maiti
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引用次数: 0

摘要

肉豆蔻(Myristica malabarica Lam.)俗称马拉巴尔肉豆蔻或假肉豆蔻,被用作传统药物和香料。我们的研究重点是马拉巴尔肉豆蔻酮,这是一组从马拉巴尔肉豆蔻果皮中分离出来的独特的次级代谢产物。我们研究了马拉巴里酮对三阴性乳腺癌(TNBC)细胞系的选择性细胞毒性。其中,恶霉灵 A(Mal-A)对 TNBC 细胞(MDA-MB-231)显示出更强的毒性,IC50 为 8.81 ± 0.03 μM。体外荧光测定证实了 Mal-A 的凋亡能力及其诱导核破碎的能力。此外,超灵敏表面增强拉曼光谱证实了细胞凋亡过程中的 DNA 断裂。细胞周期分析表明,Mal-A 通过下调参与细胞周期进展的关键调控蛋白,使细胞停滞在亚 G0 期。Caspase 3、9 和 8 表达水平的升高表明,外源性和内源性凋亡途径都参与其中。最后,对凋亡途径中蛋白质表达模式的评估显示,Fas/FasL、TNF/TNFR1 和 p53 等关键凋亡蛋白上调,而 XIAP、cIAP-2 和 Livin 等几种凋亡抑制蛋白下调。这些发现在硅学分子对接中得到了进一步验证。Mal-A 与 TNF、Fas、HTRA、Smac 和 XIAP 等凋亡蛋白有很强的亲和力,对接得分在 -5.1 至 -7.2 kcal mol-1 之间。随后,分子动力学模拟证实了其结合稳定性。这一确凿的体外评估验证了 Mal-A 是一种有效的抗 TNBC 植物实体。据我们所知,这项研究是首次对 Mal-A 在 TNBC 细胞中的抗癌作用进行全面评估。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Exploring apoptotic induction of malabaricone A in triple-negative breast cancer cells: an acylphenol phyto-entity isolated from the fruit rind of Myristica malabarica Lam.†

Exploring apoptotic induction of malabaricone A in triple-negative breast cancer cells: an acylphenol phyto-entity isolated from the fruit rind of Myristica malabarica Lam.†

Exploring apoptotic induction of malabaricone A in triple-negative breast cancer cells: an acylphenol phyto-entity isolated from the fruit rind of Myristica malabarica Lam.†

Myristica malabarica Lam., commonly known as Malabar nutmeg or false nutmeg, is used in traditional medicine and as a spice. Our exploration focuses on malabaricones, a distinct group of secondary metabolites isolated from the fruit rind of M. malabarica. We investigated the selective cytotoxicity of malabaricones against the triple-negative breast cancer (TNBC) cell line. In particular, malabaricone A (Mal-A) displays heightened toxicity towards TNBC cells (MDA-MB-231), with an IC50 of 8.81 ± 0.03 μM. In vitro fluorimetric assays confirmed the apoptotic capability of Mal-A and its capacity to induce nuclear fragmentation. Additionally, ultrasensitive surface-enhanced Raman spectroscopy confirms DNA fragmentation during cellular apoptosis. Cell cycle analysis indicates arrest during the sub-G0 phase by downregulating key regulatory proteins involved in cell cycle progression. Increased expression levels of caspase 3, 9, and 8 suggest involvement of both extrinsic and intrinsic apoptotic pathways. Finally, assessment of protein expression patterns within apoptotic pathways reveals upregulation of key apoptotic proteins like Fas/FasL, TNF/TNFR1, and p53, coupled with downregulation of several inhibitors of apoptosis proteins such as XIAP, cIAP-2, and Livin. These findings are further verified with in silico molecular docking. Mal-A reveals a strong affinity towards apoptotic proteins, including TNF, Fas, HTRA, Smac, and XIAP, with docking scores ranging from −5.1 to −7.2 kcal mol−1. Subsequently, molecular dynamics simulation confirms the binding stability. This conclusive in vitro evaluation validates Mal-A as a potent phyto-entity against TNBC. To the best of our knowledge, this study represents the first comprehensive anticancer evaluation of Mal-A in TNBC cells.

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CiteScore
5.80
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