ArticleBrain research2010
Dual inhibition of sodium-mediated proton and calcium efflux triggers non-apoptotic cell death in malignant gliomas.
Article in Brain research, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers, 1 of them a synthesis that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
17 citing papers in PubMed, 1 synthesis or guideline pooled it, 35 citations in OpenAlex.
- Brain multi-omic Mendelian randomisation to identify novel drug targets for gliomagenesis.Human molecular genetics · 2025Pooled it
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- Ion Channel Drugs Suppress Cancer Phenotype in NG108-15 and U87 Cells: Toward Novel Electroceuticals for Glioblastoma.Cancers · 2022Article
- Anticancer Effects and Mechanisms of OSW-1 Isolated FromFrontiers in oncology · 2021Review
- Hydrogen Ion Dynamics of Cancer and a New Molecular, Biochemical and Metabolic Approach to the Etiopathogenesis and Treatment of Brain Malignancies.International journal of molecular sciences · 2019Review
- Tumour acidosis: from the passenger to the driver's seat.Nature reviews. Cancer · 2017Review
- Mis-trafficking of endosomal urokinase proteins triggers drug-induced glioma nonapoptotic cell death.Molecular pharmacology · 2015Article
- The Na⁺/H⁺ exchanger (NHE1) as a novel co-adjuvant target in paclitaxel therapy of triple-negative breast cancer cells.Oncotarget · 2015Article
- Microenvironmental acidosis in carcinogenesis and metastases: new strategies in prevention and therapy.Cancer metastasis reviews · 2014Review
- Upregulation of NHE1 protein expression enables glioblastoma cells to escape TMZ-mediated toxicity via increased H⁺ extrusion, cell migration and survival.Carcinogenesis · 2014Article
- Malignancy-associated metabolic profiling of human glioma cell lines using 1H NMR spectroscopy.Molecular cancer · 2014Article
- Disrupting proton dynamics and energy metabolism for cancer therapy.Nature reviews. Cancer · 2013Review
- 5-Benzylglycinyl-amiloride kills proliferating and nonproliferating malignant glioma cells through caspase-independent necroptosis mediated by apoptosis-inducing factor.The Journal of pharmacology and experimental therapeutics · 2013Article
- Effective killing of leukemia cells by the natural product OSW-1 through disruption of cellular calcium homeostasis.The Journal of biological chemistry · 2013Article
- A cell-permeant amiloride derivative induces caspase-independent, AIF-mediated programmed necrotic death of breast cancer cells.PloS one · 2013Article
- 2-Amidino analogs of glycine-amiloride conjugates: inhibitors of urokinase-type plasminogen activator.Bioorganic & medicinal chemistry letters · 2012Article
- Interfering with pH regulation in tumours as a therapeutic strategy.Nature reviews. Drug discovery · 2011Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
12 authors at 5 institutions in 1 country.
Funding
Abstract
Malignant glioma cells maintain an elevated intracellular pH (pH(i)) within hypoxic-ischemic tumor microenvironments through persistent activation of sodium-proton transport (McLean et al., 2000). Amiloride has been reported to selectively kill human malignant glioma cell lines but not primary astrocytes (Hegde et al., 2004). While amiloride reduces pH(i) of malignant gliomas by inhibiting isoform 1 of sodium-proton exchange (NHE1), direct acidification was shown to be cytostatic rather than cytotoxic. At cytotoxic concentrations, amiloride has multiple drug targets including inhibition of NHE1 and sodium-calcium exchange. Amiloride's glioma cytotoxicity can be explained, at least in part, by dual inhibition of NHE1 and of Na(+)-dependent calcium efflux by isoform 1.1 of the sodium-calcium exchanger (NCX1.1), which increases [Ca(2+)](i) and initiates glioma cell demise. As a result of persistent NHE1 activity, cytosolic free levels of sodium ([Na(+)](i)) in U87 and C6 glioma cells are elevated 3-fold, as compared with normal astrocytes. Basal cytosolic free calcium levels ([Ca(2+)](i)) also are increased 5-fold. 2', 4'-dichlorobenzamil (DCB) inhibits the sodium-dependent calcium transporter (NCX1.1) much more potently than NHE1. DCB was employed in a concentration-dependent fashion in glioma cells to selectively inhibit the forward mode of NCX1.1 at ≤1μM, while dually inhibiting both NHE1 and NCX1.1 at ≥20μM. DCB (1μM) was not cytotoxic to glioma cells, while DCB (20μM) further increased basal elevated levels of [Ca(2+)](i) in glioma cells that was followed by cell demise. Cariporide and SEA0400 are more selective inhibitors of NHE1 and NCX1.1 than amiloride or DCB, respectively. Individually, Cariporide and SEA0400 are not cytotoxic, but in combination induced glioma cell death. Like amiloride, the combination of Cariporide and SEA0400 produced glioma cell death in the absence of demonstrable caspase activation.
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Registered trials
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