Ca2+-dependent mechanisms of cytotoxicity and programmed cell death

Orrenius, Sten; McCabe, Michael J.; Nicotera, Pierluigi

doi:10.1016/0378-4274(92)90208-2

Cited by 202 publications

(114 citation statements)

References 15 publications

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“…In the present study, we used the much more practical externally applied electrodes. Furthermore, as the available data suggests that treatment may need to be prolonged, the use of conducting electrodes may result in serious problems: local damage to the skin because of electrolysis and the generation of free radicals at the electrode-tissue interface, skin permeabilization by the transdermal currents (18,19), and calcium accumulation within cells (20) that can result in cell death (21). Clearly, the first 2 adverse effects do not occur at the surface of insulated electrodes.…”

Section: Discussionmentioning

confidence: 99%

Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors

Kirson

Dbalý

Tovaryś

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

743

921

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We have recently shown that low intensity, intermediate frequency, electric fields inhibit by an anti-microtubule mechanism of action, cancerous cell growth in vitro. Using implanted electrodes, these fields were also shown to inhibit the growth of dermal tumors in mice. The present study extends these findings to additional cell lines [human breast carcinoma; MDA-MB-231, and human non-small-cell lung carcinoma (H1299)] and to animal tumor models (intradermal B16F1 melanoma and intracranial F-98 glioma) using external insulated electrodes. These findings led to the initiation of a pilot clinical trial of the effects of TTFields in 10 patients with recurrent glioblastoma (GBM). Median time to disease progression in these patients was 26.1 weeks and median overall survival was 62.2 weeks. These time to disease progression and OS values are more than double the reported medians of historical control patients. No device-related serious adverse events were seen after >70 months of cumulative treatment in all of the patients. The only device-related side effect seen was a mild to moderate contact dermatitis beneath the field delivering electrodes. We conclude that TTFields are a safe and effective new treatment modality which effectively slows down tumor growth in vitro, in vivo and, as demonstrated here, in human cancer patients.cancer ͉ glioblastoma ͉ tumor treating fields B Because living cells consist of ions, polar or charged molecules, membranes, and organelles, they are responsive to and often generate electric fields and currents. The electric activity of cells plays a key roll in many essential biological processes. The electric fields associated with all of the above phenomena are in the range of 0-10

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Section: Discussionmentioning

confidence: 99%

Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors

Kirson

Dbalý

Tovaryś

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

743

921

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“…The reaction of particles with cell membranes results in the generation of ROS, and the generated oxidative stress may cause a breakdown of membrane lipids, imbalance of intracellular calcium homeostasis, and alterations in metabolic pathways (32)(33)(34). The imbalance of calcium homeostasis finally results in calcium-dependent endonuclease activation, which is believed to initiate chromatin fragmentation, another key feature of apoptotic cells (35,36).…”

Section: Discussionmentioning

confidence: 99%

Evidence that ultrafine titanium dioxide induces micronuclei and apoptosis in Syrian hamster embryo fibroblasts.

Rahman

Lohani

Dopp

et al. 2002

Environ Health Perspect

355

218

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Inhaled ultrafine titanium dioxide (UF-TiO2) particles cause pronounced pulmonary inflammation, in contrast to fine TiO2. Previous studies provide evidence for the production of reactive oxygen species by alveolar macrophages, after overloading with UF-TiO2 particles and cytotoxicity of UF-TiO2 in rat lung alveolar macrophages. UF-TiO2 also causes pulmonary fibrosis and lung tumors in rats. UF-TiO2 particles are photogenotoxic, but in general, information on the genotoxicity of UF-TiO2 is still limited. We studied the potential of UF-TiO2 (particle size less than or equal to 20 nm) and fine TiO2 (particle size > 200 nm) to induce chromosomal changes, which can be monitored by the formation of micronuclei (MN) in Syrian hamster embryo (SHE) cells. We also analyzed UF-TiO2-treated cells for apoptosis induction. The MN assay revealed a significant increase in MN induction (p less than or equal to 0.05) in SHE cells after treatment with UF-TiO2 (1.0 micro g/cm2) for 12 hr (mean, 24.5 MN/1,000 cells), 24 hr (mean, 31.13 MN/1,000 cells), 48 hr (mean, 30.8 MN/1,000 cells), 66 hr (mean, 31.2 MN/1,000 cells), and 72 hr (mean, 31.3 MN/1,000 cells). Bisbenzimide staining of the fixed cells revealed typical apoptotic structures (apoptotic bodies), and the apoptosis-specific "DNA ladder pattern" resulting from internucleosomal cleavage was identified by gel electrophoresis. Furthermore, transmission electron microscopy of the exposed cells revealed the typical chromatin compaction of apoptosis.

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“…With transient increases in cytosolic Ca 2ϩ , many intracellular enzymes including phospholipases, proteases, and endonucleases can be activated, while prolonged or unregulated cytosolic Ca 2ϩ elevation can further lead to apoptosis or cell death (41,42). Although the molecular mechanism underlying apoptosis mediated by Ca 2ϩ in vivo remains to be fully defined, accumulation of mitochondrial Ca 2ϩ or activation of caspase-12 or other Ca 2ϩ -dependent intracellular enzymes may be the possible mechanisms (39,43).…”

mentioning

confidence: 99%

Critical Upstream Signals of Cytochrome c Release Induced by a Novel Bcl-2 Inhibitor

Chen²,

Huang³

2004

Journal of Biological Chemistry

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Ca2+-dependent mechanisms of cytotoxicity and programmed cell death

Cited by 202 publications

References 15 publications

Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors

Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors

Evidence that ultrafine titanium dioxide induces micronuclei and apoptosis in Syrian hamster embryo fibroblasts.

Critical Upstream Signals of Cytochrome c Release Induced by a Novel Bcl-2 Inhibitor

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