The Mechanism of Sertraline-induced [Ca2+]i Rise in Human PC3 Prostate Cancer Cells

Abstract

-free medium, pre-treatment with the endoplasmic reticulum Ca 2+ pump inhibitor thapsigargin or 2,5-di-(t-butyl)-1,4-hydroquinone nearly abolished sertraline-induced Ca ] i rises by causing phospholipase C-dependent Ca 2+ release from the endoplasmic reticulum and via multiple Ca 2+ influx pathways that involve store-operated Ca 2+ channels. Sertraline also induced apoptosis that was not triggered by [Ca 2+ ] i rise.

Sertraline Induces Toxicity and Behavioral Alterations in Planarians

“…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].…”

“…For instance, considering a sertraline incubation of 24 h, cytotoxicity was observed from 20  µ M in human prostate-cancer cells (PC3) [12] as well as in osteosarcoma cells (MG63) (Lin et al, 2013), from 25  µ M in a human hepatoma cell line (HepG2) [13], from 30  µ M in human platelets [10], and from 37.5  µ M in rat primary hepatocytes [2]. Additional evidence regarding sertraline toxicity has been reported in some organisms, such as the parasite Leishmania donovani [33], fish, and aquatic invertebrates [34].…”

“…It has been recently shown that it may cause inhibition of different types of Na + and K + channels [3–8]. 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.…”

“…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].…”

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

“…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].…”