The Sigma Receptor Ligand, Reduced Haloperidol, Induces Apoptosis and Increases Intracellular-Free Calcium Levels [Ca2+]iin Colon and Mammary Adenocarinoma Cells

Brent, Paul J.; Pang, Gerald; Little, Gillian H.; Dosen, Peter J.; Helden, Dirk F. van

doi:10.1006/bbrc.1996.0208

Cited by 52 publications

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“…Studies examining the actions of -2 agonists in neuroblastoma cells and colon and mammary carcinoma cells demonstrated that ligands that interacted with -2 receptors could release Ca 2ϩ stores, which triggered subsequent extracellular Ca 2ϩ influx after the depletion of the stores. Prolonged exposure to ligands resulted in cell death via apoptosis (Brent et al, 1996;Vilner and Bowen, 2000). In C6 glioma cells, the dosedependent cytotoxic effect of ligands was reported to result in receptor-mediated alterations in cellular morphology, cessation of cell division, and inhibition of calmodulin activity (Lee and Hait, 1985;Vilner et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

The Ca²⁺Channel Antagonists Mibefradil and Pimozide Inhibit Cell Growth via Different Cytotoxic Mechanisms

et al. 2002

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We show that mitogenic cells expressing T-type Ca 2ϩ channels (T-channels) are more sensitive to the antiproliferative effects of the drugs pimozide and mibefradil than cells without significant T-channel expression. The growth of Y79 and WERI-Rb1 retinoblastoma cells, as well as MCF7 breast cancer epithelial cells, all of which express T-channel current and mRNA for T-channel subunits, is inhibited by pimozide and mibefradil with IC 50 values between 0.6 and 1.5 M. Proliferation of glioma C6 cells, which show little T-channel expression, is less sensitive to these drugs (IC 50 ϭ 8 and 5 M for pimozide and mibefradil, respectively). Neither drug seems to alter cell cycle or the expression of cyclins. Although this strong correlation between T-channel expression and growth inhibition exists, the following results suggest that the drugs inhibit cell growth via different cytotoxic pathways: 1) pimozide and mibefradil have additive effects on T-channel current inhibition, whereas the antiproliferative activity of the drugs together is synergistic; 2) an increase in the number of apoptotic Y79 and MCF7 cells and a decrease in the mRNA for the antiapoptotic gene Bcl-2 is detected only in pimozide-treated cells, whereas in mibefradiltreated cells, the toxicity is primarily necrotic; and 3) growth inhibition by mibefradil is reduced in Y79 cells transfected with T-channel antisense and in differentiated Y79 cells (which have decreased T-channel expression), but growth inhibition by pimozide is affected to a lesser extent. These results suggest that pimozide and mibefradil inhibit cell proliferation via different cytotoxic pathways and that in the case of pimozide, it is unlikely that this effect is mediated solely by T-channel inhibition.

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Section: Discussionmentioning

confidence: 99%

The Ca²⁺Channel Antagonists Mibefradil and Pimozide Inhibit Cell Growth via Different Cytotoxic Mechanisms

et al. 2002

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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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“…10,16,29,30 These studies are underscored by the pervasive and questionable use of HAL in the treatment of diverse mental health issues worldwide. The lack of effect of the s1-selective ligand, SKF, on HAL-induced cytotoxicity indicates a functionally compromised s1 receptor system in these cells (('): HAL alone; (J): HAL þ 50 mM SKF).…”

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“…Furthermore, s1 receptor agonists may mitigate clinically relevant depression associated with, and a possible risk factor for, Alzheimer disease. 47 In addition, neuronal apoptosis induced by the Ab (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) fragment was recently shown to downregulate the expression of two anti-apoptotic Bcl-2 homologues, namely Bcl-w and Bcl-XL. 48 The synergism we demonstrate between HAL and the Ab(1-40) peptide, which correlates with increased detection of Bcl-XS and of a Bcl-XS-VDAC complex that coincides with an increase in cytosolic cytochrome c, could have serious impact in the clinical setting.…”

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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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The Sigma Receptor Ligand, Reduced Haloperidol, Induces Apoptosis and Increases Intracellular-Free Calcium Levels [Ca2+]iin Colon and Mammary Adenocarinoma Cells

Cited by 52 publications

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The Ca²⁺Channel Antagonists Mibefradil and Pimozide Inhibit Cell Growth via Different Cytotoxic Mechanisms

The Ca²⁺Channel Antagonists Mibefradil and Pimozide Inhibit Cell Growth via Different Cytotoxic Mechanisms

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

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

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The Sigma Receptor Ligand, Reduced Haloperidol, Induces Apoptosis and Increases Intracellular-Free Calcium Levels [Ca2+]iin Colon and Mammary Adenocarinoma Cells

Cited by 52 publications

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The Ca2+Channel Antagonists Mibefradil and Pimozide Inhibit Cell Growth via Different Cytotoxic Mechanisms

The Ca2+Channel Antagonists Mibefradil and Pimozide Inhibit Cell Growth via Different Cytotoxic Mechanisms

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

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

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The Ca²⁺Channel Antagonists Mibefradil and Pimozide Inhibit Cell Growth via Different Cytotoxic Mechanisms

The Ca²⁺Channel Antagonists Mibefradil and Pimozide Inhibit Cell Growth via Different Cytotoxic Mechanisms