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Abstract

The effects of extracellular Mg2+ on both dynamic changes of [Ca2+]i and apoptosis rate were analysed. The consequences of spatial and temporal dynamic changes of intracellular Ca2+ on apoptosis, in thapsigargin- and the calcium-ionophore 4BrA23187-treated MCF7 cells were first determined. Both 4BrA23187 and thapsigargin induced an instant increase of intracellular Ca2+ concentrations ([Ca2+]i) which remained quite elevated (> 150 nM) and lasted for several hours. [Ca2+]i increases were equivalent in the cytosol and the nucleus. The treatments that induced apoptosis in MCF7 cells were systematically associated with high and sustained [Ca2+]i (150 nM) for several hours. The initial [Ca2+]i increase was not determinant in the events triggering apoptosis. Thapsigargin-mediated apoptosis and [Ca2+]i rise were abrogated when cells were pretreated with the calcium chelator BAPTA. The role of the extracellular Mg2+ concentration has been studied in thapsigargin treated cells. High (10 mM) extracellular Mg2+, caused an increase in basal [Mg2+]i from 0.8+/-0.3 to 1.6+/-0.5 mM. As compared to 1.4 mM extracellular Mg2+, 1 microM thapsigargin induces, in 10 mM Mg2+, a reduced percentage from 22 to 11% of fragmented nuclei, a lower sustained [Ca2+]i and a lower Ca2+ influx through the plasma membrane. In conclusion, the cell death induced by thapsigargin was dependent on high and sustained [Ca2+]i which was inhibited by high extracellular and intracellular Mg2+.

Optimizing an Osteosarcoma-Fibroblast Coculture Model to Study Antitumoral Activity of Magnesium-Based Biomaterials

“…Consequently, shifting the ratio towards the magnesium would inhibit Ca influx and tumor cell proliferation. These findings were also supported by the work from Pereira et al The authors observed an inhibited chemically triggered Ca influx through the plasma membrane of MCF-7 cells in the presence of high extracellular Mg levels [ 63 ]. Normally, Ca influxes the cells following absorption to mitochondria and the endoplasmic reticulum.…”

Functional Module Connectivity Map (FMCM): A Framework for Searching Repurposed Drug Compounds for Systems Treatment of Cancer and an Application to Colorectal Adenocarcinoma

“…We identified thapsigargin to be beneficial to the apoptosis FM but broadly harmful to the signal transduction, transcription, cell proliferation, and RNA metabolic process FMs. This drug has been reported to have the ability to promote apoptosis on prostate and breast cancer cells but also to stimulate cell growth in mouse keratinocyte models (Table 1) [42]–[47].…”

The anti-apoptotic effect of regucalcin is mediated through multisignaling pathways

“…Experiments on the nucleus isolated from cells clearly demonstrate the induction of Ca 2+ -dependent endonuclease activity during triggering apoptosis events [47]. Rises in intracellular Ca 2+ concentration activates endonuclease that mediates DNA cleavages into oligonucleosome fragments [48]. Regucalcin has been shown to have an inhibitory effect on Ca 2+ -activated DNA fragmentation in isolated rat liver nucleus [41].…”

“…Thapsigargin-induced DNA fragmentation in the hepatoma cells is not altered after culture with caspase inhibitor, suggesting that thapsigargin-mediated apoptosis is independent on activation of caspases [48]. Overexpression of regucalcin in hepatoma cells suppresses thapsigargin-induced DNA fragmentation [36].…”