期刊
INVESTIGACION CLINICA
卷 63, 期 3, 页码 243-261出版社
INST INVESTIGACION CLINICA
DOI: 10.54817/IC.v63n3a04
关键词
Ca2+; apoptosis; tetrahydroquinolines; mitocondria; SERCA; NF-kappa B
资金
- Fondo Nacional de Ciencia, Tecnologia e Investigacion, Venezuela (FONACIT) [2017000274, 2018000010]
- Consejo de Desarrollo Cientifico y Humanistico-Universidad Central de Venezuela (CDCH-UCV) [PG-03-8728-2013/2]
Tetrahydroquinoline derivatives JS-56 and JS-92 exhibit antitumor effects on MCF-7 breast cancer cells by increasing intracellular Ca2+ concentration, inhibiting SERCA activity, and inducing cell death.
Tetrahydroquinoline derivatives are interesting structures exhibiting a wide range of biological activities, including antitumor effects. In this investigation, the effect of the synthesized tetrahydroquinolines JS-56 and JS-92 on apoptosis, intracellular Ca2+ concentration ([Ca2+](i)), and the sarco(endo)plasmic 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 intracellular Ca2+ concentration and the mitochondrial electrochemical potential, respectively. TUNEL assay was used to analyze DNA fragmentation, while caspase activity and NF-kappa B-dependent gene expression were assessed by luminescence. In silico models 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 potential through processes dependent 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-kappa B-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, increase [Ca2+](i), and inhibit SERCA activity by direct interaction.
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