The mechanism of sertraline-induced [Ca<sup>2+</sup>]<sub>i</sub> rise in human OC2 oral cancer cells

Chien, Jau-Min; Chou, Chiang-Ting; Pan, Chih-Chuan; Kuo, Chun-Chi; Tsai, Jeng-Yu; Liao, Wei-Chuan; Kuo, Daih‐Huang; Shieh, Pochuen; Ho, Chin-Man; Chu, Sau-Tung; Su, Hsing‐Hao; Chi, Cao-Chuan; Jan, Chung‐Ren

doi:10.1177/0960327110396523

Cited by 15 publications

(12 citation statements)

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“…Previous studies showed that SSRI antidepressants increase [Ca 2+ ] i in a variety of cells such as oral cells, prostatic cells, and prefrontal cortex astrocytes and that a sustained increase in [Ca 2+ ] i induces cell damage and may even cause cell death [16-18]. However, little is known about the role of Ca 2+ signaling in fluoxetine-induced death of glioma cells.…”

Section: Resultsmentioning

confidence: 99%

“…Although the pathways underlying cell death are complicated, mechanisms associated with changes in the mitochondrial membrane permeability were shown to play important roles in cell death triggered by a mitochondrial matrix Ca 2+ overload [14, 15]. Interestingly, it was shown that an SSRI increased [Ca 2+ ] i in different cancer cells such as oral cancer cells, prostate cancer cells, and bladder cancer cells, and the elevation of [Ca 2+ ] i was mediated by either transmembrane Ca 2+ influx or Ca 2+ release from the internal stores, or both [16-18]. Therefore, we hypothesized that fluoxetine, one of the most prescribed SSRI, will increase the [Ca 2+ ] i , thereby triggering apoptosis in gliomas.…”

Section: Introductionmentioning

confidence: 99%

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Fluoxetine, an antidepressant, suppresses glioblastoma by evoking AMPAR-mediated calcium-dependent apoptosis

et al. 2014

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The efficacy of glioblastoma chemotherapy is not satisfactory; therefore, a new medication is expected to improve outcomes. As much evidence shows that antidepressants decrease cancer incidence and improve patients' quality of life, we therefore attempted to explore the potential for fluoxetine to be used to treat GBM and its possible underlying mechanism. The expression level of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) was determined using immunohistochemical staining and PCR analysis. The mechanism of fluoxetine-induced apoptosis of gliomas was elucidated. Computer modeling and a binding assay were conducted to investigate the interaction of fluoxetine with the AMPAR. The therapeutic effect of fluoxetine was evaluated using an animal model. We found that fluoxetine directly bound to AMPAR, thus inducing transmembrane Ca2+ influx. The rise in the intracellular calcium concentration ([Ca2+]i) causes mitochondrial Ca2+ overload, thereby triggering apoptosis. AMPARs are excessively expressed in glioma tissues, suggesting that fluoxetine specifically executes glioma cells. Our in vivo study revealed that fluoxetine suppressed the growth of glioblastomas in brains of Nu/Nu mice, an effect similar to that produced by temozolomide. Our preclinical studies suggest fluoxetine, a commonly used antidepressant, might be selectively toxic to gliomas and could provide a new approach for managing this disease.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Fluoxetine, an antidepressant, suppresses glioblastoma by evoking AMPAR-mediated calcium-dependent apoptosis

et al. 2014

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“…An inhibition of Ca 2+ channels mediated by sertraline has also been reported in excitable cells [6], but its effect on these channels seems to be different in other cell types [12]. Several studies [9, 11, 12] found that it can induce an influx of Ca 2+ via store-operated Ca 2+ channels in nonexcitable cells. An additional effect of sertraline was recently described in human platelets, where it caused a reduction in glutamate uptake [10].…”

Section: Discussionmentioning

confidence: 99%

“…Among these additional biological effects, sertraline was recently reported to inhibit Na + and K + voltage-dependent channels [3–9] as well as to reduce glutamate uptake [10]. Regarding an effect of sertraline on Ca 2+ channels, it was recently reported that it can induce a rise in the levels of cytosolic free Ca 2+ partly through these channels and also through endoplasmic reticulum release in cancer cells [11, 12], where it also induced apoptosis [12, 13]. Although sertraline is considered a safe drug, several reports have associated it with toxic effects on the liver [14–16] and hepatic cells [2, 13, 17].…”

Section: Introductionmentioning

confidence: 99%

Sertraline Induces Toxicity and Behavioral Alterations in Planarians

Thumé

Frizzo

2017

BioMed Research International

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Toxicity attributed to sertraline has been demonstrated recently in different cell types and also in some organisms. We investigated the effect of sertraline on planarians, which are considered suitable for investigations in neurotoxicology and currently are widely used as an animal model in neuropharmacological studies. Planarians treated with 10 µM sertraline showed a rapid reduction in their spontaneous movement until they became completely motionless and then showed a series of asynchronous paroxysms (seizures) followed by progressive tissue damage, beginning 48 h after the sertraline treatment, and died approximately 72 h later. Our data showed that sertraline does not cause planarian death within the range of therapeutic concentrations; however, behavioral alterations were observed with concentrations that can be considered compatible with therapeutic ones, such as a significant reduction in planarian locomotory activity at 0.4 µM. Treatment with 4 µM sertraline had a significant effect, reducing planarian locomotory activity and increasing the number of asynchronous paroxysms; both effects were significantly maintained even 24 h after the sertraline was withdrawn. These behavioral changes observed at low micromolar concentrations suggest that sertraline might have residual biological consequences for planarians, even after it is withdrawn.

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“…Sertraline was shown to induce cytotoxicity in a human osteosarcoma cell line [238], a human prostate cancer cell line [239] and a squamous oral cancer cell line [240] by mediating phospholipase C -dependent Ca++ release from the endoplasmic reticulum, ER, and Ca++ cell entry by L-type Ca++ channels. Inhibition of proliferation by sertraline of colon cancer cell lines, both in vitro and when xenografted, was traced to Bcl-2 inhibition [241].…”

Section: Introductionmentioning

confidence: 99%

CUSP9* treatment protocol for recurrent glioblastoma: aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, ritonavir, sertraline augmenting continuous low dose temozolomide

Kast¹,

2014

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CUSP9 treatment protocol for recurrent glioblastoma was published one year ago. We now present a slight modification, designated CUSP9*. CUSP9* drugs- aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, sertraline, ritonavir, are all widely approved by regulatory authorities, marketed for non-cancer indications. Each drug inhibits one or more important growth-enhancing pathways used by glioblastoma. By blocking survival paths, the aim is to render temozolomide, the current standard cytotoxic drug used in primary glioblastoma treatment, more effective. Although esthetically unpleasing to use so many drugs at once, the closely similar drugs of the original CUSP9 used together have been well-tolerated when given on a compassionate-use basis in the cases that have come to our attention so far. We expect similarly good tolerability for CUSP9*. The combined action of this suite of drugs blocks signaling at, or the activity of, AKT phosphorylation, aldehyde dehydrogenase, angiotensin converting enzyme, carbonic anhydrase -2,- 9, -12, cyclooxygenase-1 and -2, cathepsin B, Hedgehog, interleukin-6, 5-lipoxygenase, matrix metalloproteinase -2 and -9, mammalian target of rapamycin, neurokinin-1, p-gp efflux pump, thioredoxin reductase, tissue factor, 20 kDa translationally controlled tumor protein, and vascular endothelial growth factor. We believe that given the current prognosis after a glioblastoma has recurred, a trial of CUSP9* is warranted.

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The mechanism of sertraline-induced [Ca²⁺]_i rise in human OC2 oral cancer cells

Cited by 15 publications

References 41 publications

Fluoxetine, an antidepressant, suppresses glioblastoma by evoking AMPAR-mediated calcium-dependent apoptosis

Fluoxetine, an antidepressant, suppresses glioblastoma by evoking AMPAR-mediated calcium-dependent apoptosis

Sertraline Induces Toxicity and Behavioral Alterations in Planarians

CUSP9* treatment protocol for recurrent glioblastoma: aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, ritonavir, sertraline augmenting continuous low dose temozolomide

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The mechanism of sertraline-induced [Ca2+]i rise in human OC2 oral cancer cells

Cited by 15 publications

References 41 publications

Fluoxetine, an antidepressant, suppresses glioblastoma by evoking AMPAR-mediated calcium-dependent apoptosis

Fluoxetine, an antidepressant, suppresses glioblastoma by evoking AMPAR-mediated calcium-dependent apoptosis

Sertraline Induces Toxicity and Behavioral Alterations in Planarians

CUSP9* treatment protocol for recurrent glioblastoma: aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, ritonavir, sertraline augmenting continuous low dose temozolomide

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The mechanism of sertraline-induced [Ca²⁺]_i rise in human OC2 oral cancer cells