σ Binding site ligands inhibit cell proliferation in mammary and colon carcinoma cell lines and melanoma cells in culture

Brent, Paul J.; Pang, Gerald

doi:10.1016/0014-2999(95)00115-2

Cited by 80 publications

(62 citation statements)

References 21 publications

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“…The present s2/Bcl-XS-mediated apoptotic component consistently accounts for approximately 20% of HAL's cytotoxicity (and, thus, may be overshadowed by the more pronounced Vitamin E-sensitive oxidative stress-associated component already described 4,17,18 ). Although our functional data reveal a rank-order potency reminiscent of s2 receptor activation, 11,38 for example, rimcazole4HAL444DTG ¼ SKF, this does not necessarily reflect the rank-orders obtained by standard radioligand binding studies (see Table 1). Indeed, even pharmacologic profiles for an individual receptor determined by radioligand binding studies often do not concord and may reflect different s1 or s2 receptor subtypes, strain, species and tissue differences, possible allosteric modulation and even non-specific binding to metabolic enzymes.…”

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confidence: 60%

“…20,21,39 Functional studies oftentimes contribute to the confusion as many such studies rely on HAL for its presumed capacity as a s receptor 'antagonist', whereas it has been clearly shown that HAL can act as a s2 receptor agonist in certain cases (present study). 11,38 Any discrepancy between functional and binding data could simply reflect the differential ability of s2 ligands to access intracellular s2 receptors, as suggested by Vilner et al, 12,29 or could reflect blunting of the s2 effect by simultaneous activation of the s1 receptors as demonstrated presently with DTG (and evidenced indirectly by our N2a neuroblastoma cell cultures, which do not respond to s1 receptor activation and are much more sensitive to HAL). The atypical antipsychotics OLA and QUE do not initiate the Bcl-XS-mediated mechanism, which corroborates our demonstrations of greater neuroprotective potential of atypical antipsychotics, versus the more traditional HAL, in several models of cell death/stress (see Wei et al 16 and references therein).…”

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confidence: 61%

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Haloperidol induces apoptosis via the σ2 receptor system and Bcl-XS

Wei

Dai

et al. 2006

Pharmacogenomics J

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Toxicity of the typical antipsychotic haloperidol (HAL) comprises an apoptotic component that we link to pro-apoptotic Bcl-XS in PC12 preneuronal and N2a neuroblastoma cells. The mitochondrial translocation of Bcl-XS and its interaction with the pore-forming voltage-dependent anion channel (VDAC) correlates with the redistribution of cytochrome c and the cleavage of Poly(ADP-ribose) polymerase. Haloperidol-induced apoptosis is mediated by the sigma2 (s2) receptor system and does not involve the expected antagonism of the dopamine D 2 receptor, nor is it influenced by Vitamin E-or p53/Bax-mediated events. Pathological relevance is demonstrated by the cytotoxic synergism between HAL and the Alzheimer diseaserelated peptide b-amyloid(1-40), which correlates with Bcl-XS expression and its interaction with VDAC, and with cytosolic cytochrome c translocation. These data provide for a unique apoptotic mechanism that could underscore the clinical risks associated with HAL, particularly following chronic regimens or in the elderly.

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confidence: 60%

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confidence: 61%

Haloperidol induces apoptosis via the σ2 receptor system and Bcl-XS

Wei

Dai

et al. 2006

Pharmacogenomics J

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“…According to previous studies of sigma1R, we found that sigma1R had two transmembrane segments with the NH 2 and COOH termini on the cytoplasmic side of the membrane (Aydar et al 2002). Sigma1R drugs were observed to combine with the receptor and play an important role in inhibition of proliferation and apoptosis of cancer cells (Brent and Pang 1995;Spruce et al 2004). The effects were achieved by interactions with ion channels.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of Sigma1 Receptor and Its Positive Associations With Pathologic TNM Classification in Esophageal Squamous Cell Carcinoma

Xu¹,

Li²,

Zhang³

et al. 2012

J Histochem Cytochem.

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SummarySigma1 receptor (sigma1R), a significant protein, has been found to be frequently upregulated in human tumor cells and tissues. It has been demonstrated that sigma1R is involved in proliferation and adhesion of cancer cells. However, the significance of sigma1R expression in esophageal squamous cell carcinoma (ESCC) remains unclear. In this article, by a series of methods, the authors examined the expression of sigma1R protein in ESCC cell lines and tissues. Flow cytometry indicated intense staining of sigma1R in ESCC cells. Immunocytochemistry staining demonstrated that sigma1R was mainly distributed in cytoplasm and nucleus in ESCC cell lines. Western blotting was performed to characterize the relative expression of sigma1R in different ESCC cell lines. Moreover, different levels of sigma1R were presented from normal epithelium to carcinoma by immunohistochemistry analysis, which demonstrated that sigma1R was highly expressed in tumors. Association analysis showed significant correlations between total sigma1R protein levels and pathologic TNM (pTNM) classification of tumors (r=0.216, p=0.011). Furthermore, the sigma1R in the nucleus was significantly correlated with pTNM classification and lymph node metastasis (r=0. 263, p=0.002, and r=0.269, p=0.002, respectively). These data indicated that sigma1R may serve as a potential predictive factor for pTNM classification and tumor development in ESCC. (J Histochem Cytochem 60:457-466, 2012)

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“…Small molecules that bind to the receptor ( ligands) are cytotoxic to neural and nonneural cell lines (8), inhibit proliferation in mammary and colon carcinoma and melanoma cell lines (9), and induce apoptosis in colon and mammary adenocarcinoma cell lines (10,11). There is good evidence that so-called -2 agonists induce apoptosis that is caspase independent in mammary carcinoma cell lines (11,12).…”

Section: Introductionmentioning

confidence: 99%

Small Molecule Antagonists of the σ-1 Receptor Cause Selective Release of the Death Program in Tumor and Self-Reliant Cells and Inhibit Tumor Growth in Vitro and in Vivo

et al. 2004

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The acquisition of resistance to apoptosis, the cell's intrinsic suicide program, is essential for cancers to arise and progress and is a major reason behind treatment failures. We show in this article that small molecule antagonists of the -1 receptor inhibit tumor cell survival to reveal caspase-dependent apoptosis. antagonist-mediated caspase activation and cell death are substantially attenuated by the prototypic -1 agonists (؉)-SKF10,047 and (؉)-pentazocine. Although several normal cell types such as fibroblasts, epithelial cells, and even receptor-rich neurons are resistant to the apoptotic effects of antagonists, cells that can promote autocrine survival such as lens epithelial and microvascular endothelial cells are as susceptible as tumor cells. Cellular susceptibility appears to correlate with differences in receptor coupling rather than levels of expression. In susceptible cells only, antagonists evoke a rapid rise in cytosolic calcium that is inhibited by -1 agonists. In at least some tumor cells, antagonists cause calcium-dependent activation of phospholipase C and concomitant calcium-independent inhibition of phosphatidylinositol 3-kinase pathway signaling. Systemic administration of antagonists significantly inhibits the growth of evolving and established hormone-sensitive and hormone-insensitive mammary carcinoma xenografts, orthotopic prostate tumors, and p53-null lung carcinoma xenografts in immunocompromised mice in the absence of side effects. Release of a receptor-mediated brake on apoptosis may offer a new approach to cancer treatment.

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σ Binding site ligands inhibit cell proliferation in mammary and colon carcinoma cell lines and melanoma cells in culture

Cited by 80 publications

References 21 publications

Haloperidol induces apoptosis via the σ2 receptor system and Bcl-XS

Haloperidol induces apoptosis via the σ2 receptor system and Bcl-XS

Overexpression of Sigma1 Receptor and Its Positive Associations With Pathologic TNM Classification in Esophageal Squamous Cell Carcinoma

Small Molecule Antagonists of the σ-1 Receptor Cause Selective Release of the Death Program in Tumor and Self-Reliant Cells and Inhibit Tumor Growth in Vitro and in Vivo

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