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Amy Hauck Newman - One of the best experts on this subject based on the ideXlab platform.
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Decreases in cocaine self-administration with dual inhibition of the dopamine transporter and σ receptors.
The Journal of pharmacology and experimental therapeutics, 2011Co-Authors: Takato Hiranita, Theresa Kopajtic, Amy Hauck Newman, Paul L. Soto, Stephen J Kohut, Jianjin Cao, Gianluigi Tanda, Jonathan L. KatzAbstract:Sigma receptor (σR) antagonists attenuate many behavioral effects of cocaine but typically not its reinforcing effects in self-administration procedures. However, the σR antagonist Rimcazole and its N-propylphenyl analogs, [3-(cis-3,5-dimethyl-4-[3-phenylpropyl]-1-piperazinyl)-propyl]diphenylamine hydrochloride (SH 3-24) and 9-[3-(cis-3,5-dimethyl-4-[3-phenylpropyl]-1-piperazinyl)-propyl]carbazole hydrobromide (SH 3-28), dose-dependently decreased the maximal rates of cocaine self-administration without affecting comparable responding maintained by food reinforcement. In contrast, a variety of σR antagonists [N-phenethylpiperidine oxalate (AC927), N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine dihydrobromide (BD 1008), N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino) ethylamine dihydrobromide (BD 1047), N-[2-(3,4-dichlorophenyl) ethyl]-4-methylpiperazine dihydrochloride (BD 1063), and N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine monohydrochloride (NE-100)] had no effect on cocaine self-administration across the range of doses that decreased rates of food-maintained responding. Rimcazole analogs differed from selective σR antagonists in their dual affinities for σRs and the dopamine transporter (DAT) assessed with radioligand binding. Selective DAT inhibitors and σR antagonists were studied alone and in combination on cocaine self-administration to determine whether actions at both σRs and the DAT were sufficient to reproduce the effects of Rimcazole analogs. Typical DAT inhibitors [2β-carbomethoxy-3β-(4-fluorophenyl)tropane (WIN 35,428), methylphenidate, and nomifensine] dose-dependently shifted the cocaine dose-effect curve leftward. Combinations of DAT inhibitor and σR antagonist doses that were behaviorally inactive alone decreased cocaine self-administration without effects on food-maintained responding. In addition, whereas the DAT inhibitors were self-administered at rates similar to those of cocaine, neither Rimcazole analogs nor typical σR antagonists (NE-100 and AC927) maintained responding above control levels across a wide range of doses. These findings suggest that the unique effects of Rimcazole analogs are due to dual actions at the DAT and σRs and that a combined target approach may have utility in development of medical treatments for cocaine abuse.
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Relationship between Conformational Changes in the Dopamine Transporter and Cocaine-Like Subjective Effects of Uptake Inhibitors
Molecular pharmacology, 2007Co-Authors: Claus J. Loland, Jonathan L. Katz, Amy Hauck Newman, Jianjing Cao, Rajeev I. Desai, Mu-fa Zou, Peter Grundt, Klaus Gerstbrein, Harald H. Sitte, Ulrik GetherAbstract:Cocaine exerts its stimulatory effect by inhibiting the dopamine transporter (DAT). However, novel benztropine- and Rimcazole-based inhibitors show reduced stimulant effects compared with cocaine, despite higher affinity and selectivity for DAT. To investigate possible mechanisms, we compared the subjective effects of different inhibitors with their molecular mode of interaction at the DAT. We determined how different inhibitors affected accessibility of the sulfhydryl-reactive reagent [2-(trimethylammonium)ethyl]-methanethiosulfonate to an inserted cysteine (I159C), which is accessible when the extracellular transporter gate is open but inaccessible when it is closed. The data indicated that cocaine analogs bind an open conformation, whereas benztropine and Rimcazole analogs bind a closed conformation. Next, we investigated the changes in inhibition potency of [(3)H]dopamine uptake of the compounds at a mutant DAT (Y335A) characterized by a global change in the conformational equilibrium. We observed a close relationship between the decrease in potencies of inhibitors at this mutant and cocaine-like responding in rats trained to discriminate cocaine from saline injections. Our data suggest that chemically different DAT inhibitors stabilize distinct transporter conformations and that this in turn affects the cocaine-like subjective effects of these compounds in vivo.
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Relationship between Conformational Changes in the Dopamine Transporter and Cocaine-Like Subjective Effects of Uptake Inhibitors
2007Co-Authors: Claus J. Lol, Amy Hauck Newman, Jianjing Cao, Rajeev I. Desai, Mu-fa Zou, Peter Grundt, Klaus Gerstbrein, Harald H. Sitte, Jonathan L. KatzAbstract:Cocaine exerts its stimulatory effect by inhibiting the dopamine transporter (DAT). However, novel benztropine- and Rimcazole-based inhibitors show reduced stimulant effects compared with cocaine, despite higher affinity and selectivity for DAT. To in-vestigate possible mechanisms, we compared the subjective effects of different inhibitors with their molecular mode of in-teraction at the DAT. We determined how different inhibitors affected accessibility of the sulfhydryl-reactive reagent [2-(tri-methylammonium)ethyl]-methanethiosulfonate to an inserted cysteine (I159C), which is accessible when the extracellular transporter gate is open but inaccessible when it is closed. The data indicated that cocaine analogs bind an open conforma-tion, whereas benztropine and Rimcazole analogs bind a closed conformation. Next, we investigated the changes in inhibitio
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Dual probes for the dopamine transporter and sigma1 receptors: novel piperazinyl alkyl-bis(4'-fluorophenyl)amine analogues as potential cocaine-abuse therapeutic agents.
Journal of medicinal chemistry, 2003Co-Authors: Jianjing Cao, Jonathan L. Katz, Theresa Kopajtic, Stephen M. Husbands, Wayne D. Bowen, Santosh S. Kulkarni, Wanda Williams, Clifford George, Amy Hauck NewmanAbstract:Both dopamine uptake inhibitors and σ1 receptor antagonists have been implicated as potential pharmacotherapeutics for the treatment of cocaine abuse. While the dopamine uptake inhibitors may share with cocaine neurochemical mechanisms underlying reinforcing properties, σ1 antagonists have been shown to attenuate some behavioral actions and toxic side effects associated with cocaine overdose. Rimcazole, a σ1 receptor antagonist that binds to the DAT (Ki = 224 nM), is not behaviorally cocaine-like and attenuates some of the behavioral actions of cocaine. To determine the roles of both DAT and σ1 receptors in the behavioral actions of Rimcazole, a series of analogues was synthesized. Initial studies identified two analogues (1 and 4) that showed high to moderate affinities for both DAT and σ1 receptors and failed to show cocaine-like discriminative stimulus (DS) effects. A second series of bis(4‘-fluorophenyl)amine analogues have now been prepared in which the most potent DAT compound, 19 (Ki = 8.5 nM), was...
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Behavioral effects of Rimcazole analogues alone and in combination with cocaine
European journal of pharmacology, 2003Co-Authors: Jonathan L. Katz, Therissa A. Libby, Theresa Kopajtic, Stephen M. Husbands, Amy Hauck NewmanAbstract:Abstract Several σ receptor ligands have been reported to also have affinity for the dopamine transporter, among them Rimcazole (9-[3-( cis -3,5-dimethyl-1-piperazinyl)propyl]carbazole dihydrochloride). However, Rimcazole lacks behavioral effects like those of other dopamine uptake inhibitors, such as cocaine and GBR 12909 (1-(2-[bis(4-fluorophenyl)methoxy]ethyl)-4-(3-phenylpropyl)piperazine dihydrochloride). Because of this profile, the interactions with cocaine of Rimcazole and several of its novel analogues were assessed. The compounds studied were Rimcazole, its N -methyl analogue, SH 1–73 (9-[3-( cis -3,5-dimethyl-4-methyl-1-piperazinyl)-propyl]carbazole hydrobromide), the dibrominated analogue, SH 1–76 (3,6-dibromo-9-[3-( cis -3,5-dimethyl-1-piperazinyl)-propyl]carbazole hydrochloride), and the N -propylphenyl analogues, SH 3–24 ([3-( cis -3,5-dimethyl-4-[3-phenylpropyl]-1-piperazinyl)-propyl]diphenylamine hydrochloride) and SH 3–28 (9-[3-( cis -3,5-dimethyl-4-[3-phenylpropyl]-1-piperazinyl)-propyl]carbazole hydrobromide). The former has a diphenyl-amine group in place of the carbazole moiety of Rimcazole, giving the compound additional structural similarity to GBR 12909. The Rimcazole analogues produced dose-related decreases in locomotor activity, and also decreased cocaine-stimulated activity in mice. In rats trained to discriminate 10 mg/kg cocaine (i.p.) from saline injections, cocaine and GBR 12909 each produced a dose-related increase in cocaine-appropriate responding. Cocaine also increased rates of responding. SH 3–28 decreased cocaine-appropriate responding at the cocaine training dose to about 58% (SH 3–28) with two of five subjects selecting the cocaine response key. Neither Rimcazole nor SH 3–24 produced a significant attenuation of the discriminative effects of cocaine. Rimcazole and its analogs all attenuated the increases in rates of responding produced by cocaine. In contrast to effects obtained with Rimcazole analogs, GBR 12909 potentiated the cocaine-induced increases in locomotor activity and operant behavior, as well as the discriminative-stimulus effects of cocaine. The present results indicate that analogues of Rimcazole can attenuate the behavioral effects of cocaine, and though the mechanism for these effects is not presently clear, it is possible that this attenuation maybe mediated by actions of the Rimcazole analogues at the dopamine transporter and/or σ receptors.
Jonathan L. Katz - One of the best experts on this subject based on the ideXlab platform.
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A behavioral economic analysis of the effects of Rimcazole on reinforcing effects of cocaine injection and food presentation in rats
Psychopharmacology, 2019Co-Authors: Martin O. Job, Jonathan L. KatzAbstract:Rationale and objectives Rimcazole, a σ-receptor antagonist with affinity for the dopamine transporter (DAT), decreases rates of cocaine self-administration at doses lower than those that affect food-reinforced responding. As response rates are multiply determined, behavioral-economic analyses were used to provide measures of the reinforcing effectiveness of cocaine and food after Rimcazole treatment. Further, effects of combinations of the DAT inhibitor, methylphenidate, and σ-receptor antagonists (BD1008, BD1063) were compared to those of Rimcazole to assess mechanism of Rimcazole effects. Methods Male Sprague-Dawley rats were trained to lever press with food reinforcement (one or three 20-mg sucrose pellets) or cocaine injection (0.1 or 0.32 mg/kg) under fixed-ratio (FR) 5-response schedules. Drugs or vehicle were administered (i.p.) 5-min before sessions in which FR value was increased from 5 to 80. Economic demand functions were generated from effects of FR value (price) on intake (consumption), with the parameters of demand, consumption at no cost (Q_0) and sensitivity to price (essential value, EV), derived. Results Rimcazole dose-dependently decreased Q_0 and EV at both cocaine doses/injection. In contrast, Rimcazole had no effect on these parameters at either food amount. Combinations of methylphenidate and the σ-receptor antagonists decreased Q_0 at the lower cocaine dose/injection but had no effect on EV; these treatments were ineffective on both economic parameters at the higher cocaine dose/injection and at either food amount. Conclusions Though the drug combinations only replicated Rimcazole’s effects incompletely, the present results suggest a specific decrease in the reinforcing effects of cocaine due to dual DAT σ-receptor blockade.
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A behavioral economic analysis of the effects of Rimcazole on reinforcing effects of cocaine injection and food presentation in rats.
Psychopharmacology, 2019Co-Authors: Martin O. Job, Jonathan L. KatzAbstract:Rimcazole, a σ-receptor antagonist with affinity for the dopamine transporter (DAT), decreases rates of cocaine self-administration at doses lower than those that affect food-reinforced responding. As response rates are multiply determined, behavioral-economic analyses were used to provide measures of the reinforcing effectiveness of cocaine and food after Rimcazole treatment. Further, effects of combinations of the DAT inhibitor, methylphenidate, and σ-receptor antagonists (BD1008, BD1063) were compared to those of Rimcazole to assess mechanism of Rimcazole effects. Male Sprague-Dawley rats were trained to lever press with food reinforcement (one or three 20-mg sucrose pellets) or cocaine injection (0.1 or 0.32 mg/kg) under fixed-ratio (FR) 5-response schedules. Drugs or vehicle were administered (i.p.) 5-min before sessions in which FR value was increased from 5 to 80. Economic demand functions were generated from effects of FR value (price) on intake (consumption), with the parameters of demand, consumption at no cost (Q0) and sensitivity to price (essential value, EV), derived. Rimcazole dose-dependently decreased Q0 and EV at both cocaine doses/injection. In contrast, Rimcazole had no effect on these parameters at either food amount. Combinations of methylphenidate and the σ-receptor antagonists decreased Q0 at the lower cocaine dose/injection but had no effect on EV; these treatments were ineffective on both economic parameters at the higher cocaine dose/injection and at either food amount. Though the drug combinations only replicated Rimcazole’s effects incompletely, the present results suggest a specific decrease in the reinforcing effects of cocaine due to dual DAT σ-receptor blockade.
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Decreases in cocaine self-administration with dual inhibition of the dopamine transporter and σ receptors.
The Journal of pharmacology and experimental therapeutics, 2011Co-Authors: Takato Hiranita, Theresa Kopajtic, Amy Hauck Newman, Paul L. Soto, Stephen J Kohut, Jianjin Cao, Gianluigi Tanda, Jonathan L. KatzAbstract:Sigma receptor (σR) antagonists attenuate many behavioral effects of cocaine but typically not its reinforcing effects in self-administration procedures. However, the σR antagonist Rimcazole and its N-propylphenyl analogs, [3-(cis-3,5-dimethyl-4-[3-phenylpropyl]-1-piperazinyl)-propyl]diphenylamine hydrochloride (SH 3-24) and 9-[3-(cis-3,5-dimethyl-4-[3-phenylpropyl]-1-piperazinyl)-propyl]carbazole hydrobromide (SH 3-28), dose-dependently decreased the maximal rates of cocaine self-administration without affecting comparable responding maintained by food reinforcement. In contrast, a variety of σR antagonists [N-phenethylpiperidine oxalate (AC927), N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine dihydrobromide (BD 1008), N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino) ethylamine dihydrobromide (BD 1047), N-[2-(3,4-dichlorophenyl) ethyl]-4-methylpiperazine dihydrochloride (BD 1063), and N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine monohydrochloride (NE-100)] had no effect on cocaine self-administration across the range of doses that decreased rates of food-maintained responding. Rimcazole analogs differed from selective σR antagonists in their dual affinities for σRs and the dopamine transporter (DAT) assessed with radioligand binding. Selective DAT inhibitors and σR antagonists were studied alone and in combination on cocaine self-administration to determine whether actions at both σRs and the DAT were sufficient to reproduce the effects of Rimcazole analogs. Typical DAT inhibitors [2β-carbomethoxy-3β-(4-fluorophenyl)tropane (WIN 35,428), methylphenidate, and nomifensine] dose-dependently shifted the cocaine dose-effect curve leftward. Combinations of DAT inhibitor and σR antagonist doses that were behaviorally inactive alone decreased cocaine self-administration without effects on food-maintained responding. In addition, whereas the DAT inhibitors were self-administered at rates similar to those of cocaine, neither Rimcazole analogs nor typical σR antagonists (NE-100 and AC927) maintained responding above control levels across a wide range of doses. These findings suggest that the unique effects of Rimcazole analogs are due to dual actions at the DAT and σRs and that a combined target approach may have utility in development of medical treatments for cocaine abuse.
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Decreases in cocaine self-administration with dual inhibition of the dopamine transporter and σ receptors. J Pharmacol Exp Ther 339
2011Co-Authors: Takato Hiranita, Theresa Kopajtic, Jianjing Cao, Paul L. Soto, Stephen J Kohut, Amy H. Newman, Gianluigi T, Jonathan L. KatzAbstract:Sigma receptor (R) antagonists attenuate many behavioral ef-fects of cocaine but typically not its reinforcing effects in self-administration procedures. However, the R antagonist Rimcazole and its N-propylphenyl analogs, [3-(cis-3,5-dimethyl-4-[3-phenylpropyl]-1-piperazinyl)-propyl]diphenylamine hydrochloride (SH 3-24) and 9-[3-(cis-3,5-dimethyl-4-[3-phenylpropyl]-1-piperazinyl)-propyl]carbazole hydrobromide (SH 3-28), dose-dependently decreased the maximal rates of cocaine self-administration without affecting comparable responding maintained by food reinforcement. In contrast, a variety of R antagonists [N-phenethylpiperidine oxalate (AC927), N-[2-(3, 4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine di
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Relationship between Conformational Changes in the Dopamine Transporter and Cocaine-Like Subjective Effects of Uptake Inhibitors
Molecular pharmacology, 2007Co-Authors: Claus J. Loland, Jonathan L. Katz, Amy Hauck Newman, Jianjing Cao, Rajeev I. Desai, Mu-fa Zou, Peter Grundt, Klaus Gerstbrein, Harald H. Sitte, Ulrik GetherAbstract:Cocaine exerts its stimulatory effect by inhibiting the dopamine transporter (DAT). However, novel benztropine- and Rimcazole-based inhibitors show reduced stimulant effects compared with cocaine, despite higher affinity and selectivity for DAT. To investigate possible mechanisms, we compared the subjective effects of different inhibitors with their molecular mode of interaction at the DAT. We determined how different inhibitors affected accessibility of the sulfhydryl-reactive reagent [2-(trimethylammonium)ethyl]-methanethiosulfonate to an inserted cysteine (I159C), which is accessible when the extracellular transporter gate is open but inaccessible when it is closed. The data indicated that cocaine analogs bind an open conformation, whereas benztropine and Rimcazole analogs bind a closed conformation. Next, we investigated the changes in inhibition potency of [(3)H]dopamine uptake of the compounds at a mutant DAT (Y335A) characterized by a global change in the conformational equilibrium. We observed a close relationship between the decrease in potencies of inhibitors at this mutant and cocaine-like responding in rats trained to discriminate cocaine from saline injections. Our data suggest that chemically different DAT inhibitors stabilize distinct transporter conformations and that this in turn affects the cocaine-like subjective effects of these compounds in vivo.
B A Spruce - One of the best experts on this subject based on the ideXlab platform.
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HIF-1α contributes to tumour-selective killing by the sigma receptor antagonist Rimcazole
Oncogene, 2007Co-Authors: M Achison, M T Boylan, T R Hupp, B A SpruceAbstract:We have previously reported tumour-selective killing by the sigma ( σ ) receptor ligand Rimcazole. We now report that Rimcazole elevates hypoxia inducible factor-1 α (HIF-1 α ) protein levels under normoxic conditions in colorectal (HCT-116) and mammary carcinoma (MDA MB 231) cells but fails to induce HIF-1 α in normal fibroblasts or mammary epithelial cells. Combining the σ -1 agonist (+)-pentazocine with Rimcazole substantially reduces the accumulation of HIF-1 α , confirming that the effect is mediated at least partly by antagonism of σ -1 sites. HIF-1 α knockdown by RNA interference attenuates Rimcazole-induced cell death in both cell types. Thus, the induction of HIF-1 α by Rimcazole contributes to tumour cell killing. In a comparison of HCT-116p53^+/+ and HCT-116p53^−/− cells, HIF-1 α levels are consistently higher after Rimcazole treatment in HCT-116p53^+/+ cells. Furthermore, although Rimcazole kills HCT-116p53^−/− cells, it has a more potent apoptosis-inducing effect in HCT-116p53^+/+ cells. This suggests that the presence of functional p53 protein may enhance death induction by Rimcazole in part through greater induction of HIF-1 α . p53 is not required, however, for the Rimcazole-induced engagement of HIF-1 α in proapoptotic mode as HIF-1 α knockdown attenuates Rimcazole-induced death to comparable extents in p53 mutant and wild-type cell systems. Knowledge of HIF-1 α involvement may assist the re-profiling of Rimcazole and other σ ligands as cancer therapeutics.
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HIF-1α contributes to tumour-selective killing by the sigma receptor antagonist Rimcazole
Oncogene, 2006Co-Authors: M Achison, M T Boylan, T R Hupp, B A SpruceAbstract:HIF-1 α contributes to tumour-selective killing by the sigma receptor antagonist Rimcazole
Graeme Henderson - One of the best experts on this subject based on the ideXlab platform.
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The ligand Rimcazole antagonises (+)SKF 10,047, but not (+)3-PPP, in the mouse isolated vas deferens
European journal of pharmacology, 1990Co-Authors: Charles Kennedy, Gavin E. Jarvis, Graeme HendersonAbstract:Abstract We have characterized the actions of several σ receptor ligands on the electrically evoked, neurogenic contractions of the mouse isolated vas deferens. (-)SKF 10,047 was significantly more potent than (+)SKF 10,047 in potentiating twitch contractions and was equipotent with (+)3-PPP. Rimcazole (1 and 3 μM) antagonised the potentiation induced by 100 μM (+)SKF 10,047 and, to a lesser extent, that induced by 30 μM (-)SKF 10,047 but increased that elicited by (+)3-PPP (30 μM). This apparent contradiction may arise from σ agonists acting in this tissue at both σ and non-σ sites.
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the ligand Rimcazole antagonises skf 10 047 but not 3 ppp in the mouse isolated vas deferens
European Journal of Pharmacology, 1990Co-Authors: Charles Kennedy, Gavin E. Jarvis, Graeme HendersonAbstract:Abstract We have characterized the actions of several σ receptor ligands on the electrically evoked, neurogenic contractions of the mouse isolated vas deferens. (-)SKF 10,047 was significantly more potent than (+)SKF 10,047 in potentiating twitch contractions and was equipotent with (+)3-PPP. Rimcazole (1 and 3 μM) antagonised the potentiation induced by 100 μM (+)SKF 10,047 and, to a lesser extent, that induced by 30 μM (-)SKF 10,047 but increased that elicited by (+)3-PPP (30 μM). This apparent contradiction may arise from σ agonists acting in this tissue at both σ and non-σ sites.
M Achison - One of the best experts on this subject based on the ideXlab platform.
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HIF-1α contributes to tumour-selective killing by the sigma receptor antagonist Rimcazole
Oncogene, 2007Co-Authors: M Achison, M T Boylan, T R Hupp, B A SpruceAbstract:We have previously reported tumour-selective killing by the sigma ( σ ) receptor ligand Rimcazole. We now report that Rimcazole elevates hypoxia inducible factor-1 α (HIF-1 α ) protein levels under normoxic conditions in colorectal (HCT-116) and mammary carcinoma (MDA MB 231) cells but fails to induce HIF-1 α in normal fibroblasts or mammary epithelial cells. Combining the σ -1 agonist (+)-pentazocine with Rimcazole substantially reduces the accumulation of HIF-1 α , confirming that the effect is mediated at least partly by antagonism of σ -1 sites. HIF-1 α knockdown by RNA interference attenuates Rimcazole-induced cell death in both cell types. Thus, the induction of HIF-1 α by Rimcazole contributes to tumour cell killing. In a comparison of HCT-116p53^+/+ and HCT-116p53^−/− cells, HIF-1 α levels are consistently higher after Rimcazole treatment in HCT-116p53^+/+ cells. Furthermore, although Rimcazole kills HCT-116p53^−/− cells, it has a more potent apoptosis-inducing effect in HCT-116p53^+/+ cells. This suggests that the presence of functional p53 protein may enhance death induction by Rimcazole in part through greater induction of HIF-1 α . p53 is not required, however, for the Rimcazole-induced engagement of HIF-1 α in proapoptotic mode as HIF-1 α knockdown attenuates Rimcazole-induced death to comparable extents in p53 mutant and wild-type cell systems. Knowledge of HIF-1 α involvement may assist the re-profiling of Rimcazole and other σ ligands as cancer therapeutics.
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HIF-1α contributes to tumour-selective killing by the sigma receptor antagonist Rimcazole
Oncogene, 2006Co-Authors: M Achison, M T Boylan, T R Hupp, B A SpruceAbstract:HIF-1 α contributes to tumour-selective killing by the sigma receptor antagonist Rimcazole
