F281, synthetic agonist of the sigma-2 receptor, induces Ca2+ efflux from the endoplasmic reticulum and mitochondria in SK-N-SH cells

Cassano, Giuseppe; Gasparre, Giuseppe; Niso, Mauro; Contino, Marialessandra; Scalera, Vito; Colabufo, Nicola Antonio

doi:10.1016/j.ceca.2008.12.005

Cited by 48 publications

(48 citation statements)

References 31 publications

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“…A variety of pathways have been described in response to sigma-2 receptor activation, indicating that there exists more than one mechanism of sigma-2 receptor-induced cell death (Zeng et al, 2012). Furthermore, discrete ligands induce independent apoptotic pathways even within a cell type, again suggesting the ability of the sigma-2 receptor to activate multiple signaling pathways (Crawford and Bowen 2002;Cassano et al, 2009;Zeng et al, 2012;Cesen et al, 2013). The sigma-2 receptor has received attention for its potential use as a chemotherapeutic target.…”

Section: Introductionmentioning

confidence: 99%

“…For example, one criterion for classification of a sigma-2 receptor agonist is stimulated transient release of calcium from thapsigargin-sensitive pools in the endoplasmic reticulum (Vilner and Bowen 2000;Cassano et al, 2009). However, this calcium signal is not a trigger for apoptosis, since cells appear normal if the ligand is removed after the transient returns to baseline (unpublished observation).…”

Section: Introductionmentioning

confidence: 99%

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Sigma-2 Receptors Play a Role in Cellular Metabolism: Stimulation of Glycolytic Hallmarks by CM764 in Human SK-N-SH Neuroblastoma

Nicholson

Mésangeau

McCurdy

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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Sigma-2 receptors are attractive antineoplastic targets due to their ability to induce apoptosis and their upregulation in rapidly proliferating cancer cells compared with healthy tissue. However, this role is inconsistent with overexpression in cancer, which is typically associated with upregulation of prosurvival factors. Here, we report a novel metabolic regulatory function for sigma-2 receptors. CM764 [6-acetyl-3-(4-(4-(2-amino-4-fluorophenyl)piperazin-1-yl)butyl)benzo[d ]oxazol-2 (3H)-one] binds with K i values of 86.6 6 2.8 and 3.5 6 0.9 nM at the sigma-1 and sigma-2 receptors, respectively. CM764 increased reduction of MTT [3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide] in human SK-N-SH neuroblastoma compared with untreated cells, an effect not due to proliferation. This effect was attenuated by five different sigma antagonists, including CM572 [3-(4-(4-(4-fluorophenyl)piperazin-1-yl)butyl)-6-isothiocyanatobenzo[d]oxazol-2(3H)-one], which has no significant affinity for sigma-1 receptors. This effect was also observed in MG-63 osteosarcoma and HEK293T cells, indicating that this function is not exclusive to neuroblastoma or to cancer cells. CM764 produced an immediate, robust, and transient increase in cytosolic calcium, consistent with sigma-2 receptor activation. Additionally, we observed an increase in the total NAD 1 /NADH level and the ATP level in CM764-treated SK-N-SH cells compared with untreated cells. After only 4 hours of treatment, basal levels of reactive oxygen species were reduced by 90% in cells treated with CM764 over untreated cells, and HIF1a and VEGF levels were increased after 3-24 hours of treatment. These data indicate that sigma-2 receptors may play a role in induction of glycolysis, representing a possible prosurvival function for the sigma-2 receptor that is consistent with its upregulation in cancer cells compared with healthy tissue.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Sigma-2 Receptors Play a Role in Cellular Metabolism: Stimulation of Glycolytic Hallmarks by CM764 in Human SK-N-SH Neuroblastoma

Nicholson

Mésangeau

McCurdy

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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“…For example, Mach and colleagues have used the criteria of caspase-3 activation and loss of cell viability in EMT-6 mouse breast cancer and MDA-MB-435 human melanoma cells to define putative sigma-2 agonists and antagonists that correlated with comparisons to siramesine (19-{4-[1-(4-fluorophenyl)-1H-indol-3-yl]butyl}-3H-spiro[2-benzofuran-1,49-piperidine]), a presumed sigma-2 full agonist (Ostenfeld et al, 2005;Zeng et al, 2012Zeng et al, , 2014. The sigma-2 receptors mediate a rapid and transient calcium release from the endoplasmic reticulum of SK-N-SH neuroblastoma cells (Vilner and Bowen, 2000;Cassano et al, 2009). We have characterized CB-64D [(1)-1R,5R-(E)-8-benzylidene-5-(3-hydroxyphenyl)-2-methylmorphan-7-one] and CB-184 [(1)-1R,5R-(E)-8-(3,4-dichlorobenzylidene)-5-(3-hydroxyphenyl)-2-methylmorphan-7-one] as sigma-2 agonists based on their ability to induce a calcium transient and apoptotic cell death in SK-N-SH neuroblastoma and breast tumor cell lines (Bowen et al, 1995;Crawford and Bowen, 2002).…”

Section: Introductionmentioning

confidence: 99%

Characterization of CM572, a Selective Irreversible Partial Agonist of the Sigma-2 Receptor with Antitumor Activity

Nicholson

Comeau

Mésangeau

et al. 2015

J Pharmacol Exp Ther

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The sigma-2 receptors are promising therapeutic targets because of their significant upregulation in tumor cells compared with normal tissue. Here, we characterize CM572 [3-(4-(4-(4-14.6 6 6.9 nM), a novel isothiocyanate derivative of the putative sigma-2 antagonist, SN79 [6-acetyl-3-(4-(4-(4-CM572 bound irreversibly to sigma-2 receptors by virtue of the isothiocyanate moiety but not to sigma-1. Studies in human SK-N-SH neuroblastoma cells revealed that CM572 induced an immediate dose-dependent increase in cytosolic calcium concentration. A 24-hour treatment of SK-N-SH cells with CM572 induced dose-dependent cell death, with an EC 50 5 7.6 6 1.7 mM. This effect was sustained over 24 hours even after a 60-minute pretreatment with CM572, followed by extensive washing to remove ligand, indicating an irreversible effect consistent with the irreversible binding data. Western blot analysis revealed that CM572 also induced cleavage activation of proapoptotic BH3-interacting domain death agonist. These data suggest irreversible agonist-like activity. Low concentrations of CM572 that were minimally effective were able to attenuate significantly the calcium signal and cell death induced by the sigma-2 agonist CB-64D [(1)-1R,5R-(E)-8-benzylidene-5-(3-hydroxyphenyl)-2-methylmorphan-7-one]. CM572 was also cytotoxic against PANC-1 pancreatic and MCF-7 breast cancer cell lines. The cytotoxic activity of CM572 was selective for cancer cells over normal cells, being much less potent against primary human melanocytes and human mammary epithelial cells. Taken together, these data show that CM572 is a selective, irreversible sigma-2 receptor partial agonist. This novel irreversible ligand may further our understanding of the endogenous role of this receptor, in addition to having potential use in targeted cancer diagnosis and therapy.

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“…Several studies have shown that σ 2 ligands induced cell death. The proposed mechanisms of cell death include caspase-independent apoptosis [40], lysosomal leakage [41], Ca 2+ release [42,43], oxidative stress [41], ceramide production [44] and autophagy [45]. However, the subcellular localizations where the σ 2 ligands bind and function were not known.…”

Section: Confocal and Two Photon Microscopy Studies Of σ 2 Receptors mentioning

confidence: 99%

Imaging the Sigma-2 Receptor for Diagnosis and Prediction of Therapeutic Response

Zeng¹,

Xu²,

Mach³

2011

Breast Cancer - Recent Advances in Biology, Imaging and Therapeutics

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F281, synthetic agonist of the sigma-2 receptor, induces Ca2+ efflux from the endoplasmic reticulum and mitochondria in SK-N-SH cells

Cited by 48 publications

References 31 publications

Sigma-2 Receptors Play a Role in Cellular Metabolism: Stimulation of Glycolytic Hallmarks by CM764 in Human SK-N-SH Neuroblastoma

Sigma-2 Receptors Play a Role in Cellular Metabolism: Stimulation of Glycolytic Hallmarks by CM764 in Human SK-N-SH Neuroblastoma

Characterization of CM572, a Selective Irreversible Partial Agonist of the Sigma-2 Receptor with Antitumor Activity

Imaging the Sigma-2 Receptor for Diagnosis and Prediction of Therapeutic Response

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