.sigma. Ligands with Subnanomolar Affinity and Preference for the .sigma.2 Binding Site. 1. 3-(.omega.-Aminoalkyl)-1H-indoles

Perregaard, Jens; Moltzen, Ejner K.; Meier, Eddi; Sanchéz, Connie

doi:10.1021/jm00011a019

Cited by 109 publications

(100 citation statements)

References 13 publications

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“…22 Siramesine and 3 H-siramesine (reviewed in ref. 23) were kindly provided by Christian Thomsen (Lundbeck A/S, Valby, Denmark). Rimcazole, haloperidol, (+)-pentazocine, α-tocopherol, 3-MA, rapamycin, NH 4 Cl, bafilomycin A and concanamycin A were from SIGMA-Aldrich (St Louis, MO, USA).…”

Section: Methodsmentioning

confidence: 99%

Anti-cancer agent siramesine is a lysosomotropic detergent that induces cytoprotective autophagosome accumulation

Ostenfeld¹,

Høyer-Hansen²,

Bastholm³

et al. 2008

Autophagy

140

120

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A σ-2 receptor ligand siramesine induces lysosomal leakage and cathepsin-dependent death of cancer cells in vitro and displays potent anti-cancer activity in vivo. The mechanism by which siramesine destabilizes lysosomes is, however, unknown. Here, we show that siramesine induces a rapid rise in the lysosomal pH that is followed by lysosomal leakage and dysfunction. The rapid accumulation of siramesine into cancer cell lysosomes, its ability to destabilize isolated lysosomes, and its chemical structure as an amphiphilic amine indicate that it is a lysosomotropic detergent. Notably, siramesine triggers also a substantial Atg6-and Atg7-dependent accumulation of autophagosomes that is associated with a rapid and sustained inhibition of mammalian target of rapamycin complex 1 (mTORC1; an inhibitor of autophagy). Siramesine fails, however, to increase the degradation rate of long-lived proteins. Thus, the massive accumulation of autophagosomes is likely to be due to a combined effect of activation of autophagy signaling and decreased autophagosome turnover. Importantly, pharmacological and RNA interference-based inhibition of autophagosome formation further sensitizes cancer cells to siramesine-induced cytotoxicity. These data identify siramesine as a lysosomotropic detergent that triggers cell death via a direct destabilization of lysosomes and cytoprotection by inducing the accumulation of autophagosomes. Threrefore, the combination of siramesine with inhibitors of autophagosome formation appears as a promising approach for future cancer therapy.

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Section: Methodsmentioning

confidence: 99%

Anti-cancer agent siramesine is a lysosomotropic detergent that induces cytoprotective autophagosome accumulation

Ostenfeld¹,

Høyer-Hansen²,

Bastholm³

et al. 2008

Autophagy

140

120

View full text Add to dashboard Cite

show abstract

“…23). The recombinant human TNF was kindly provided by A. Cerami (Kenneth Warren Laboratories, Tarrytown) and the cathepsin B inhibitor R-2525 by B. Rydzewski (Celera Applied Biosystems, Foster City, CA).…”

Section: Methodsmentioning

confidence: 99%

“…23,24), was originally developed for the treatment of anxiety and depression (25). Although the clinical trials failed to show the requested efficacy in the treatment of psychiatric disorders, they presented siramesine as a nontoxic and well-tolerated compound in humans.…”

Section: Introductionmentioning

confidence: 99%

Effective Tumor Cell Death by σ-2 Receptor Ligand Siramesine Involves Lysosomal Leakage and Oxidative Stress

et al. 2005

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Acquired resistance to classic caspase-mediated apoptosis is a common problem for the treatment of human cancer. Here, we show that siramesine, a novel S-2 receptor ligand, effectively induces caspase-independent programmed cell death in immortalized and transformed cells of various origins. Siramesine-treated tumor cells displayed increased levels of reactive oxygen species, lysosomal membrane permeabilization, chromatin condensation, and shrinkage and detachment of cells. Lipid antioxidants (A-tocopherol and ;-tocopherol), but not other tested antioxidants (butylated hydroxyanisol or N-acetyl cysteine), effectively inhibited siramesine-induced morphologic changes and cell death. Cathepsin B inhibitors (CA-074-Me and R-2525) conferred similar, but less pronounced protection, whereas ectopic expression of antiapoptotic protein Bcl-2, lack of wild-type p53 as well as pharmacologic inhibitors of caspases (zVADfmk, DEVD-CHO, and LEHD-CHO), calpains (PD150606), and serine proteases (N-tosyl-L-phenylalanine chloromethyl ketone and pefabloc) failed to protect cells against siramesineinduced death. Importantly, transformation of murine embryonic fibroblasts with activated c-src or v-Ha-ras oncogenes greatly sensitized them to siramesine-induced cytotoxicity. Furthermore, p.o. administration of well-tolerated doses of siramesine had a significant antitumorigenic effect in orthotopic breast cancer and s.c. fibrosarcoma models in mice. These results present siramesine as a promising new drug for the treatment of tumors resistant to traditional therapies. (Cancer Res 2005; 65(19): 8975-83)

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“…Although reports of σ 2 ligands abound in the literature (Bertha et al, 1995;Bowen et al, 1995a,b;Kassiou et al, 2005;Mach et al, 1995;Maeda et al, 2002;Maier and Wunsch, 2002;Perregaard et al, 1995;Vangveravong et al, 2006), the primary criterion for these claims appears to be reasonable affinity for this receptor subtype relative to σ 1 , with little consideration for selectivity as compared to non-σ binding sites. In addition, the few σ 2 compounds that have been tested in functional studies appear to act as agonists (Bowen et al, 1995a,b;Crawford et al, 2002;Vilner and Bowen, 2000).…”

Section: Introductionmentioning

confidence: 99%

Effects of UMB24 and (±)-SM 21, putative σ2-preferring antagonists, on behavioral toxic and stimulant effects of cocaine in mice

Matsumoto

Pouw

Mack

et al. 2007

Pharmacology Biochemistry and Behavior

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Earlier studies have demonstrated that antagonism of σ 1 receptors attenuates the convulsive, lethal, locomotor stimulatory and rewarding actions of cocaine in mice. In contrast, the contribution of σ 2 receptors is unclear because experimental tools to selectively target this subtype are unavailable. To begin addressing this need, we characterized UMB24 (1-(2-phenethyl)-4-(2-pyridyl)-piperazine) and (±)-SM 21 (3α-tropanyl-2-(4-chorophenoxy)butyrate) in receptor binding and behavioral studies. Receptor binding studies confirmed that UMB24 and (±)-SM 21 display preferential affinity for σ 2 over σ 1 receptors. In behavioral studies, pretreatment of Swiss Webster mice with UMB24 or (±)-SM 21 significantly attenuated cocaine-induced convulsions and locomotor activity, but not lethality. When administered alone, (±)-SM 21 produced no significant effects compared to control injections of saline, but UMB24 had locomotor depressant actions. Together, the data suggest that σ 2 receptor antagonists have the potential to attenuate some of the behavioral effects of cocaine, and further development of more selective, high affinity ligands are warranted.

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.sigma. Ligands with Subnanomolar Affinity and Preference for the .sigma.2 Binding Site. 1. 3-(.omega.-Aminoalkyl)-1H-indoles

Cited by 109 publications

References 13 publications

Anti-cancer agent siramesine is a lysosomotropic detergent that induces cytoprotective autophagosome accumulation

Anti-cancer agent siramesine is a lysosomotropic detergent that induces cytoprotective autophagosome accumulation

Effective Tumor Cell Death by σ-2 Receptor Ligand Siramesine Involves Lysosomal Leakage and Oxidative Stress

Effects of UMB24 and (±)-SM 21, putative σ2-preferring antagonists, on behavioral toxic and stimulant effects of cocaine in mice

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