Effect of tetrahydroquinoline derivatives on the intracellular Ca2+ homeostasis in breast cancer cells (MCF-7) and its relationship with apoptosis.

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.

Chemical Activation and Mechanical Sensitization of Piezo1 Enhance TRAIL-Mediated Apoptosis in Glioblastoma Cells

“…Ca 2+ is a ubiquitous secondary messenger that can cause a host of cellular responses in cancer cells including the regulation of this process . Although this relationship is not well studied in glioblastoma, this mechanism has been established in breast and ovarian cancer. , …”

“… 27 Although this relationship is not well studied in glioblastoma, this mechanism has been established in breast and ovarian cancer. 34 , 35 …”

“…27 Although this relationship is not well studied in glioblastoma, this mechanism has been established in breast and ovarian cancer. 34,35 Yoda1 + TRAIL treatments resulted in a significant decrease in cell viability and increase in apoptosis relative to controls 24 h after treatment of the U87 cells and 4 h after treatment of the LN18 cells. This finding demonstrates that the chemical activation of Piezo1 under static conditions enhances TRAILmediated apoptosis through Ca 2+ influx.…”

Unmasking the Mechanism behind Miltefosine: Revealing the Disruption of Intracellular Ca2+ Homeostasis as a Rational Therapeutic Target in Leishmaniasis and Chagas Disease

“…The specific mechanism of induction of apoptosis by miltefosine is not known, but since apoptosis is a well-known Ca 2+ mediated process and involves Ca 2+ signaling in several fragments of this complex progression [49], it is conceivable that, since miltefosine has a profound effect on Ca 2+ regulation in trypanosomatids (see below), part of its mechanism of action could be mediated by the disruption of Ca 2+ homeostasis in the parasite.…”