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
{"title":"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。","authors":"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","doi":"10.54817/ic.v63n3a04","DOIUrl":null,"url":null,"abstract":"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.","PeriodicalId":14514,"journal":{"name":"Investigacion clinica","volume":" ","pages":""},"PeriodicalIF":0.1000,"publicationDate":"2022-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"1","resultStr":"{\"title\":\"Effect of tetrahydroquinoline derivatives on the intracellular Ca2+ homeostasis in breast cancer cells (MCF-7) and its relationship with apoptosis.\",\"authors\":\"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\",\"doi\":\"10.54817/ic.v63n3a04\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"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.\",\"PeriodicalId\":14514,\"journal\":{\"name\":\"Investigacion clinica\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":0.1000,\"publicationDate\":\"2022-08-28\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"1\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Investigacion clinica\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.54817/ic.v63n3a04\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q4\",\"JCRName\":\"MEDICINE, RESEARCH & EXPERIMENTAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Investigacion clinica","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.54817/ic.v63n3a04","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
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.