四氢喹啉衍生物对癌症细胞内Ca2+稳态的影响及其与细胞凋亡的关系。

IF 0.1 4区 医学 Q4 MEDICINE, RESEARCH & EXPERIMENTAL
S. Maksoud, A. Mayora, Laura Colma, F. Sojo, Adriana Pimentel, V. Kouznetsov, Diego Merchán-Arena, Angel H. Romero, F. Arvelo, J. D. de Sanctis, G. Benaim
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引用次数: 1

摘要

四氢喹啉衍生物是一种有趣的结构,具有广泛的生物活性,包括抗肿瘤作用。本研究测定了合成的四氢喹啉类药物JS-56和js -92对MCF-7乳腺癌细胞凋亡、细胞内Ca2+浓度([Ca2+]i)和sarco(endo)质网Ca2+- atp酶(SERCA)活性的影响。采用比色法评估MCF-7细胞活力和SERCA活性。Fura-2和罗丹明123分别测定细胞内Ca2+浓度和线粒体电化学电位。TUNEL法检测DNA片段,荧光法检测caspase活性和NF-κ b依赖性基因表达。硅模型用于分子对接分析。这些化合物增加细胞内Ca2+浓度;主要的贡献是来自细胞外环境的Ca2+的进入。JS-56和JS-92都通过依赖和独立于该细胞器Ca2+摄取的过程抑制SERCA的活性并消散线粒体电化学电位。此外,JS-56和JS-92在MCF-7细胞中产生细胞毒性。JS-92的效果高于JS-56。这两种化合物都能激活半胱天冬酶7和9,导致DNA断裂,并增强了12-肉豆蔻酸酯-13-醋酸酯对NF-κ b依赖性基因表达的影响。分子对接分析表明,这两种化合物对SERCA具有较高的相互作用,类似于thapsigargin。这两种四氢喹啉衍生物通过凋亡事件的组合诱导细胞死亡,增加[Ca2+]i,并通过直接相互作用抑制SERCA活性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Effect of tetrahydroquinoline derivatives on the intracellular Ca2+ homeostasis in breast cancer cells (MCF-7) and its relationship with apoptosis.
Tetrahydroquinoline derivatives are interesting structures exhib-iting a wide range of biological activities, including antitumor effects. In this investigation, the effect of the synthesized tetrahydroquinolines JS-56 and JS-92on apoptosis, intracellular Ca2+ concentration ([Ca2+]i),and the sarco(endo)plas-mic reticulum Ca2+-ATPase (SERCA) activity was determined on MCF-7 breast cancer cells.Colorimetric assays were used to assess MCF-7 cells viability and SERCA activity. Fura-2 and rhodamine 123 were used to measure the intracellu-lar Ca2+ concentration and the mitochondrial electrochemical potential, respectively. TUNEL assay was used to analyze DNA fragmentation, while caspase activi-ty and NF-κB-dependent gene expression were assessed by luminescence. In silicomodels were used for molecular docking analysis. These compounds increase intracellular Ca2+ concentration; the main contribution is the Ca2+ entry from the extracellular milieu. Both JS-56 and JS-92 inhibit the activity of SERCA and dissipate the mitochondrial electrochemical potentialthrough processes depen-dent and independent of the Ca2+ uptake by this organelle. Furthermore, JS-56 and JS-92 generate cytotoxicity in MCF-7 cells. The effect of JS-92 is higher than JS-56. Both compounds activate caspases 7 and 9, cause DNA fragmentation, and potentiate the effect of phorbol 12-myristate-13-acetate on NF-κB-dependent gene expression. Molecular docking analysis suggests that both compounds have a high interaction for SERCA, similar to thapsigargin. Both tetrahydroquinoline derivatives induced cell death through a combination of apoptotic events, in-crease [Ca2+]i, and inhibit SERCA activity by direct interaction.
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来源期刊
Investigacion clinica
Investigacion clinica MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
0.20
自引率
50.00%
发文量
2
审稿时长
>12 weeks
期刊介绍: Estudios humanos, animales y de laboratorio relacionados con la investigación clínica y asuntos conexos.
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