HIF-1α contributes to tumour-selective killing by the sigma receptor antagonist rimcazole

Achison, Marcus; Boylan, M.; Hupp, Ted R.; Spruce, Barbara A.

doi:10.1038/sj.onc.1209890

Cited by 22 publications

(16 citation statements)

References 32 publications

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“…Interestingly, sigma-1 receptors have also been linked to HIF1a. The blockade of sigma-1 receptors by the putative antagonist rimcazole in normoxic colorectal and mammary carcinoma cells increases HIF1a, but with a cytotoxic effect in this case (Achison et al, 2007). Thus, regulation of HIF1a by sigma-1 and sigma-2 receptor subtypes may be complex, with different viability outcomes depending on cell type and sigma ligand.…”

Section: Activation Of Sigma-2 Receptor Induces Metabolic Stimulationmentioning

confidence: 90%

“…A hallmark of cells undergoing glycolysis under normoxic conditions (aerobic glycolysis) is the expression of HIF1a. A link between treatment of tumor cells with the sigma modulator rimcazole and increased expression of HIF1a has been established previously (Achison et al, 2007). Therefore, we decided to investigate whether this transiently expressed protein might be stabilized or increasingly translated upon treatment with CM764.…”

Section: Cm764-induced Production Of Rosmentioning

confidence: 93%

See 1 more Smart Citation

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: Activation Of Sigma-2 Receptor Induces Metabolic Stimulationmentioning

confidence: 90%

Section: Cm764-induced Production Of Rosmentioning

confidence: 93%

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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“…Mutations in the TP53 gene, which are strong determinants of chemoresistance, do not affect the sensitivity of cancer cells to sigma-2-induced apoptosis [63,[79][80][81]. Moreover, sigma-2 induced apoptosis can be caspase-independent [80,81] and may therefore also occur in cells with caspase dysfunction.…”

Section: Mechanisms Underlying Cytotoxicitymentioning

confidence: 99%

Sigma Receptors in Oncology: Therapeutic and Diagnostic Applications of Sigma Ligands

Waarde¹,

Rybczynska²,

Ramakrishnan³

et al. 2010

CPD

100

105

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Sigma receptors (subtypes sigma-1 and sigma-2) are a unique class of binding sites expressed throughout the mammalian body. The endogenous ligand for these sites has not been identified, but steroid hormones (particularly progesterone), sphingolipid-derived amines and N,N-dimethyltryptamine can bind with fairly high affinity. Sigma receptors are overexpressed in rapidly proliferating cells, like cancer cells. Particularly the sigma-2 subtype is upregulate when cells divide and down regulated when they become quiescent. Sigma ligands, especially sigma-2 agonists, can inhibit proliferation and induce apoptosis by a mechanism involving changes in cytosolic Ca(2+), ceramide and sphingolipid levels. Tumor cells are much more sensitive to such treatment than cells from their tissue of origin. Sigma ligands induce apoptosis not only in drug-sensitive but also in drug-resistant cancer cells (e.g., cells with p53 mutations, or caspase dysfunction). Moreover, sigma ligands may abrogate P-glycoprotein-mediated drug resistance and at subtoxic doses, they can potentiate the effect of conventional cytostatics. Thus, sigma-2 agonists may be developed as antineoplastic agents for the treatment of drug-resistant tumors. A large number of radiolabeled sigma ligands has been prepared for SPECT (single-photon emission computed tomography) and PET (positron emission tomography) imaging. Such radiopharmaceuticals can be used for tumor detection, tumor staging, and evaluation of anti-tumor therapy. There is still a need for the development of ligands with (1) high selectivity for the sigma-2 subtype, (2) defined action (agonist or antagonist) and (3) optimal pharmacokinetics (low affinity for P-glycoprotein, high and specific tumor uptake, and rapid washout from non-target tissues).

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“…Previous reports have suggested that following insult, sigma 1 receptor agonists promote cell survival, while sigma 1 receptor antagonism tends to promote cell death (Achison et al, 2007; Antonini et al, 2009; Maurice and Su, 2009; Ruscher et al, 2011; Spruce et al, 2004; Tchedre and Yorio 2008; Yang et al, 2007). The present study, which uses a novel set of D2-like dopamine and sigma receptor selective compounds, suggests that under certain conditions sigma 1 antagonists may also act as potent neuroprotectants.…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective effects of high affinity sigma 1 receptor selective compounds

et al. 2012

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We previously reported that the antipsychotic drug haloperidol, a multifunctional D2-like dopamine and sigma receptor subtype antagonist, has neuroprotective properties. In this study we further examined the association between neuroprotection and receptor antagonism by evaluating a panel of novel compounds with varying affinity at sigma and D2-like dopamine receptors. These compounds were evaluated using an in vitro cytotoxicity assay that utilizes a hippocampal-derived cell line, HT-22, in the presence or absence of varying concentrations (5 to 20 mM) of glutamate. While haloperidol was found to be a potent neuroprotective agent in this in vitro cell assay, the prototypic sigma 1 receptor agonist (+)-pentazocine was found not to be neuroprotective. Subsequently, the potency for the neuroprotection of HT-22 cells was evaluated for a) three SV series indoles which have nMolar affinity at D2-like receptors but varying affinity at sigma 1 receptor and b) two benzyl phenylacetamides sigma 1 receptor selective compounds which bind with low affinity at D2-like receptors but have nMolar affinity for the sigma 1 receptor. We observed that cytoprotection correlated with the affinity of the compounds for sigma 1 receptors. Based upon results from the HT-22 cell-based in vitro assay, two phenylacetamides, LS-127 and LS-137, were further evaluated in vivo using a transient middle cerebral artery occlusion (t-MCAO) model of stroke. At a dose of 100 µg/kg, both LS-127 and LS-137 attenuated infarct volume by approximately 50%. These studies provide further evidence that sigma 1 receptor selective compounds can provide neuroprotection in cytotoxic situations. These results also demonstrate that sigma 1 receptor selective benzyl phenylacetamides are candidate pharmacotherapeutic agents that could be used to minimize neuronal death after a stroke or head trauma.

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HIF-1α contributes to tumour-selective killing by the sigma receptor antagonist rimcazole

Cited by 22 publications

References 32 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

Sigma Receptors in Oncology: Therapeutic and Diagnostic Applications of Sigma Ligands

Neuroprotective effects of high affinity sigma 1 receptor selective compounds

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